Bottom-up assembly of synthetic extracellular vesicles

The present invention relates to a method for producing synthetic extracellular vesicles comprising a lipid bilayer including at least two lipids, one or more extracellular vesicle associated proteins, and optionally one or more nucleic acid molecules. The inventive synthetic extracellular vesicles are formed by emulsification using a mechanic emulsifier in the form of polymer shell stabilized synthetic extracellular vesicles. The inventive method allows producing synthetic extracellular vesicles miming the composition and function of natural extracellular vesicles. Therefore, synthetic extracellular vesicles with specific protein and nucleic acids compositions are also disclosed herein, as well as their therapeutic uses.

1. 11. A method for producing synthetic extracellular vesicles comprising: a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to the one or more extracellular vesicle associated protein or fragments thereof; b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock; c) combining said water phase and said oil phase; d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of c) using a mechanic or electronic emulsifier; wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle, wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.
2. 22. The method according to claim 1, wherein the water phase further comprises one or more nucleic acid molecules.
3. 33. The method according to claim 1, further comprising d′) and e) after d): d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in d) by adding a surfactant; and e) purifying the synthetic extracellular vesicles by centrifugation.
4. 44. The method according to claim 1, wherein the water phase of a) comprises at least one lipid coupled to a functional ligand selected from biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and wherein the method optionally comprises after e) the following step: f) coupling the synthetic extracellular vesicles with at least one macromolecule comprising at least one moiety reacting with one of said functional ligands, wherein the macromolecule is selected from the group comprising an extracellular vesicle associated protein or a fragment thereof, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe.

The present application is the national phase entry of PCT Application No. PCT/EP2021/052145, filed Jan. 29, 2021, which claims priority to EP Application Serial No. 20155012.6, filed Jan. 31, 2020, both of which are hereby incorporated herein by reference in their entireties.
SPECIFICATION
The present invention relates to a method for producing synthetic extracellular vesicles comprising a lipid bilayer including at least two lipids, optionally one or more extracellular vesicle associated proteins, and optionally one or more nucleic acid molecules. The inventive synthetic extracellular vesicles are formed by emulsification using a mechanic emulsifier in the form of polymer shell stabilized synthetic extracellular vesicles. The inventive method allows producing synthetic extracellular vesicles miming the composition and function of natural extracellular vesicles. Therefore, synthetic extracellular vesicles with specific protein and nucleic acids composition are also disclosed herein, as well as their therapeutic uses.
BACKGROUND OF THE INVENTION
Extracellular vesicles are membrane-contained small vesicles, secreted by all types of pro- and eukaryotic cells, and play a crucial role in intercellular signaling under both physiological and pathological conditions.
In physiological conditions, extracellular vesicles are important mediators for cell-to-cell and inter-tissue communication, thus playing a role in regulating homeostasis as well as other conditions. In pathological conditions, the information transferred by extracellular vesicles, mainly cancer cell extracellular vesicles, may have detrimental effects. Indeed, extracellular vesicles have been demonstrated to contribute to various pathologies such as tumorigenesis and metastasis, inflammation, and immune system activation.
As a result of the above-mentioned functions, extracellular vesicles may serve as novel tools for various therapeutic and diagnostic applications, such as anti-tumour therapy, pathogen vaccination, immune-modulatory and regenerative therapies and drug delivery. Indeed, extracellular vesicles can be used for the target-specific delivery of nucleic acid molecules, proteins or small molecules into the intracellular environment, where they also act on a genetic level.
The three main categories of extracellular vesicles are apoptotic bodies, shedding microvesicles and exosomes. Microvesicles and exosomes are smaller compared to apoptotic bodies. Additionally they differ from apoptotic bodies in their content, since they rarely contain DNA.
The main function of microvesicles and exosomes is the intercellular transfer of lipids, RNA, and cytosolic proteins, thereby affecting cell metabolism and functions, including, but not limited to migration, cell proliferation and differentiation.
A detailed and precise characterization of the intercellular signalling mechanisms mediated by extracellular vesicles is essential to develop extracellular vesicle-based therapeutic applications. However, the methods of the current art to isolate and purify extracellular vesicles are very complex, long and error prone providing extracellular vesicle preparations with low yield and purity and high variability between different batches, which hamper a correct understanding of extracellular vesicle biology and of their interactions with the environment. Moreover, the exosome preparations oft contain also microvesicles.
Therefore, synthetic and cleaner vesicle formulations are not only highly sought for therapeutic and clinical applications but also to study fundamental aspects of extracellular vesicle biology, signalling, as well as the role of their individual components.
Currently, synthetic exosomes are prepared by two types of methodologies: top-down or bottom-up (Garcia-Manrique P. et al., 2017. Fully Artificial Exosomes: Towards New Theranostic Biomaterials. Trends in Biotechnology). In top-down methodologies, the production of artificial exosomes begins with cultured and eventually engineered cells that are then processed to produce membrane fragments to be used to form the vesicles. Even if these methods enable synthesis of exosomes similarly to their natural counterpart, they still have some drawbacks. Indeed cargo loading is not tightly controlled due to the passive encapsulation of the surrounding medium during membrane fragment self-assembly. Moreover, these exosomes cannot have a defined composition and size, and are usually not homogenous in size. The final purification steps used for exosome isolation are time-consuming and characterized by low purity, yield and reproducibility in term of exosome composition.
The patent applications WO 2019 027847 A1, WO 2019 126068 A1, US 2016 0354313 A1, and US 2016 0354313 A1, and the disclosure of Kooijmans et al. (J. controlled release, 2016, 224, 77-85) refer to extracellular vesicles produced by top-down methodologies.
The international patent application WO 2019 027847 A1 describes the synthesis of bispecific nanoparticle vesicles that are able to redirect immune effector cells towards cancer cells for killing. However, the nanoparticle vesicles are prepared by transducing a population of cells comprising vesicles, such as exosomes, with polynucleotides coding the polypeptides of interest, and thus isolating the transduced vesicles or exosomes. The exosomes released into the culture media are purified using traditional approaches as differential centrifugation, density-gradient- or cushion-based ultracentifugation, precipitation with commercial kits, and affinity and size exclusion chromatography. Thus, the extracellular vesicles or exosomes described in WO 2019 027847 A1 do not possess a membrane bilayer with a defined lipid composition. Moreover, the vesicle preparation can still contain impurities due to the isolation procedure.
The international patent application WO 2019 126068 A1 discloses engineered extracellular vesicles (EVs) produced by using a membrane cloaking platform technology, wherein the cloaking imparts to the EVs enhanced delivery to tissues of interest, such as damaged or dysfunctional tissue. The engineered EV compositions can be used to treat diseases. The EVs are obtained from culture media of not-modified cultured cells using standard methods and then tailored with fluorescent molecules or ligand proteins using the membrane cloaking platform technology. This consists in incubating the exosomes with a lipid anchor molecule, such as DMPE-PEG, bound to a member (e.g. streptavidin) of a coupling moiety and then with a biotinylated antibody or protein of interest.
The US Patent Application US 2016 0354313 A1 discloses a hybridosome, i.e. a hybrid biocompatible carrier, which is synthetized from two different vesicles, one is a naturally secreted vesicle (BDM), one is in vitro produced by using standard methods (EDEM) comprising at least one tunable fusogenic moiety. The hybridome are described as able to deliver bioactive agents into leukocytes or glial cells or into cells during ex-vivo expansion.
The scientific article of Kooijmans et al. discloses the engineering of extracellular vesicles derived from Neuro2A cells or platelets by mixing with nanobody-PEG-micelles, where the nanobodies are specific for a cellular target, such as the epidermal growth factor receptor (EGFR). The disclosed EVs are showed to efficiently target EGFR positive tumor cells, and to be stable in plasma for longer than 60 min post-injection.
The US Patent Application US 2019 202892 A1 discloses extracellular vesicles comprising an immune-modulating component, such as a cytokine or a binding partner of a cytokine (for example IL2, IL7, IL10, IL12, IL15 or others), and optionally a second component such as an activator for a positive co-stimulatory molecule or an activator for a binding partner of a positive co-stimulatory molecule (for example a TNF receptor superfamily member). The extracellular vesicles are obtained by isolation from producer cells using standard methods. In particular, the the extracellular vesicles with an immunomodulating component are obtained by modifying a producer cell with the immunomodulating component, and then obtaining the extracellular vesicles from the conditioned culture media of the modified producer cells.
Bottom-up methodologies to prepare synthetic exosomes involves the preparation of a synthetic bilayer that is then functionalized with selected proteins to mimic desired exosome functions. However, most of these methodologies are characterized by low encapsulation efficiency and high costs, as the methods are adapted from conventional liposome production routes. Moreover, methodologies to synthetize exosomes containing a specific composition of both exosome proteins and nucleic acids such as miRNAs are still missing.
The disclosures US 2017 0128367 A1, and US 2019 343767 A1 refer to synthetic extracellular vesicles or exosomes produced by bottom-up methodologies.
The patent application US 2017 0128367 A1 discloses liposomes comprising a cationic lipid and a lipid covalently conjugated to a PEG derivative, which is bound to a glycosaminoglycan coating the liposome. The PEG serves to stabilize the liposome, whereas the glycosaminoglycan, for example hyaluronic acid, is used to target the cells of interest. The produced liposomes are characterized by a narrow dimension range between 20 and 500 nm.
The patent application US 2019 343767 A1 discloses artificial exosomes comprising rab7, desmoplakin, alpha 2-HS glycoprotein (AHSG), and a cardiolipin or a variant thereof. The exosome can also comprise a cargo molecule as a peptide, a polypeptide, a nucleic acid, a virus, a small molecule, a fluorophore, or a combination thereof. The artificial exosomes are produced by mixing the single components DOPC, cholesterol, and a cardiolipin to form a cardiolipin-containing liposome, and incubating the cardiolipin-containing liposome with rab7, desmoplakin, and AHSG to form an artificial exosome. The artificial exosomes can thereafter optionally be loaded with siRNA molecules.
The disclosure of Weiss et al. (Nature Materials, 2017, 17, 89-96) teaches a high-throughput microfluidic method to generate liposomes to be used as synthetic model cell systems, called protocells, to study interactions of these synthetic cells with physiologically relevant environments such as extracellular matrices, cells or signalling proteins. These mechanically and chemically stable cell-like compartments, called droplet-stabilized GUVs (dsGUVs), can be loaded with biomolecules such as transmembrane and cytoskeleton proteins by microfluidic pico-injection technology. However, this method allows to regulating the diameter of the dsGUVs in the range from 28 μm to 120 μm.
Thus, none of the prior art documents discloses a method to produce fully synthetic extracellular vesicles at high efficiency, high stability, high controlled composition, high purity and reproducibility between different batches.
Therefore, there is still an urgent need for efficient procedures to produce fully synthetic exosomes, or extracellular vesicles with a high defined composition, low variability between different batches, high purity and efficiency.
It is the objective of the present invention to provide synthetic extracellular vesicles assembled with a highly controlled composition and produced surrounded by a stabilizing polymer shell, which can be used for therapeutic applications.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a method for high-throughput bottom-up assembly of fully synthetic extracellular vesicles with analogous functionalities to naturally occurring cell-derived extracellular vesicles. The production method is based on charge-mediated assembly of predefined functionalized lipid vesicles and encapsulation of miRNAs within the polymer shell stabilized lipid vesicles. “Charge mediated” assembly refers to the process in which the negative charge of the vesicles and the negative charge on the periphery of the polimer shell stabilized vesicles are complexed by the cations, such as for example Mg2+ cations. Following their release into an aqueous environment, the respective protein-functionalized synthetic extracellular vesicles can interact with target cells thus influencing their functions, such as metabolism, proliferation, or growth.
The synthetic extracellular vesicles obtained by the highly controlled droplet-stabilized assembly provide a robust platform for therapeutic applications and moreover allow getting new insights into fundamental functioning-principles of extracellular vesicles.
In comparison with the prior art methods, a first advantage of the invention is to provide extracellular vesicles with high stability (FIG. 22) and high controlled composition (FIG. 2) due to the assembly in stabilizing polymer shell surrounded vesicles. The composition of the extracellular vesicles can be adjusted in term of lipid type and charge, lipid ratio, protein to lipid ratio (FIG. 23), protein to protein ratio (FIG. 20), nucleic acid content. Protein to protein ratios and protein to lipid lipid ratios were shown to influence the activity of the synthetic extracellular vesicles on target cells (FIG. 20 and FIG. 23c, respectively).
The assembly in polymer shell stabilized vesicles allows also encapsulation of nucleic acids at high efficiency (FIG. 5), which is very hard to obtain with the current methods.
Moreover, the inventive method allows adjusting the vesicle dimensions by regulating the emulsification speed (Example 2), which is an important factor influencing the activity of the vesicles (FIG. 17).
To notice, the emulsification process allows reaching throughput rates much higher than the throughput rates allowed by microfluidic techniques.
Importantly, the use of emulsification to produce synthetic extracellular vesicles has never been suggested in the prior art so far.
The method also allows obtaining extracellular vesicles preparations with high purity (FIG. 3) and reproducibility between different batches (replicates in FIG. 4).
Moreover, the inventive method allows design and assembly of fully synthetic extracellular vesicles by a polymer shell-stabilized approach that hold a higher therapeutic potential as their laboriously isolated natural analogues (Examples 5-12, FIGS. 7-23), so that they can be used in a multitude of clinical settings.
Moreover, the inventive method for bottom-up assembly of extracellular vesicles, allows controlling the quantity of each individual extracellular vesicle components, which is an essential aspect for therapeutic applications, and also to decipher their roles on disease related states, representing an essential advantage in comparison with natural exosomes.
Non-limiting examples of the extracellular vesicle types are from the group of vesicles that include an exosome, a microvesicle, an apoptotic vesicle, and a liposome.
In particular, the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


The present invention is also directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


According to an aspect of the present invention, the method further comprises after step d) the following steps:

    
    
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation.
    
    


According to a more particular aspect of the present invention, the water phase of step a) comprises at least one lipid coupled to a functional ligand selected from biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and

    
    
        wherein the method optionally comprises after step e) the following step:
        f) coupling the synthetic extracellular vesicles with at least one macromolecule comprising at least one moiety reacting with one of said functional ligands, wherein the macromolecule is selected from the group comprising an extracellular vesicle associated protein, or a fragment thereof, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe.
    
    


According to a still more particular aspect of the present invention, the water phase of step a) comprises one or more nucleic acid molecules selected from the group comprising miRNA molecules miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a.
Further miRNA molecules suitable for the method and the synthetic extracellular vesicles disclosed herein are listed in Table 3.
According to a still more particular aspect of the present invention, the extracellular vesicle associated protein, or a fragment thereof, is selected from the group comprising:

    
    
        a transmembrane protein selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha, integrin α-chains, integrin β-chains, transferrin receptor 1, transferrin receptor 2, lysosome associated membrane proteins, heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer, A Disintegrin And Metalloproteinase Domain 10, CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 or intercellular adhesion molecule 1, CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog, major histocompatibility complex I, major histocompatibility complex II, epidermal growth factor receptor 2, epithelial cell adhesion molecule, glycophorin A, Acetylcholinesterase S and E, amyloid beta precursor protein, multidrug resistance-associated protein 1, stem cells antigen-1, or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport I, II and III, tumour susceptibility gene 101, charged multivesicular body protein, Apoptosis-Linked Gene 2-Interacting Protein X, vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein, flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4, ras homolog family member A, annexins, heat shock proteins, ADP-ribosylation factor 6, syntenin, microtubule-associated protein Tau, or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein, adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand, RANK, RANK Ligand, indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof;
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lamin A/C, inner membrane mitochondrial protein, cytochrome C-1, mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta, member 1, heat shock 70 kDa protein 5, Golgin A2, Autophagy Related 9A, actinin1, actinin4, cytokeratin 18, or a fragment thereof.
    
    


Further extracellular vesicle associated proteins suitable for the method and the synthetic extracellular vesicles disclosed herein are listed in Table 4.
According to a still more particular aspect of the present invention, the water phase of step a) comprises at least two lipids selected from the group comprising:

    
    
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N, N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid—nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole.
    
    


According to a further aspect of the present invention, step d) comprises producing polymer shell stabilized synthetic extracellular vesicles by emulsifying the combined phases at step c) using a mechanic or electronic emulsifier for at least 5 seconds at speed higher than 1,000 rpm.
A preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole.
        one or more extracellular vesicle associated selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha, integrin α-chains, integrin β-chains, transferrin receptor 1, transferrin receptor 2, lysosome associated membrane proteins, heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer, A Disintegrin And Metalloproteinase Domain 10, CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 or intercellular adhesion molecule 1, CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog, major histocompatibility complex I, major histocompatibility complex II, epidermal growth factor receptor 2, epithelial cell adhesion molecule, glycophorin A, acetylcholinesterase S and E, amyloid beta precursor protein, multidrug resistance-associated protein 1, stem cells antigen-1, the protein complexes endosomal sorting complexes required for transport I, II and III, tumour susceptibility gene 101, charged multivesicular body protein, Apoptosis-Linked Gene 2-Interacting Protein X, vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein, flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4, ras homolog family member A, annexins, heat shock proteins, ADP-ribosylation factor 6, syntenin, microtubule-associated protein Tau, cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein, adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand, RANK, RANK Ligand, indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin NC, inner membrane mitochondrial protein, cytochrome C-1, mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta, member 1, heat shock 70 kDa protein 5, Golgin A2, Autophagy Related 9A, actinin1, actinin4, cytokeratin 18, or a fragment thereof.
    
    


A further preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids,
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole;
        one or more extracellular vesicle associated selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha, integrin α-chains, integrin β-chains, transferrin receptor 1, transferrin receptor 2, lysosome associated membrane proteins, heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer, A Disintegrin And Metalloproteinase Domain 10, CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 or intercellular adhesion molecule 1, CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog, major histocompatibility complex I, major histocompatibility complex II, epidermal growth factor receptor 2, epithelial cell adhesion molecule, glycophorin A, acetylcholinesterase S and E, amyloid beta precursor protein, multidrug resistance-associated protein 1, stem cells antigen-1, the protein complexes endosomal sorting complexes required for transport I, II and III, tumour susceptibility gene 101, charged multivesicular body protein, Apoptosis-Linked Gene 2-Interacting Protein X, vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein, flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4, ras homolog family member A, annexins, heat shock proteins, ADP-ribosylation factor 6, syntenin, microtubule-associated protein Tau, cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein, adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand, RANK, RANK Ligand, indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin NC, inner membrane mitochondrial protein, cytochrome C-1, mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta, member 1, heat shock 70 kDa protein 5, Golgin A2, Autophagy Related 9A, actinin1, actinin4, cytokeratin 18, or a fragment thereof; and
        one or more nucleic acid molecules selected from the group comprising DNA, cDNA, mRNA, siRNA, antisense nucleotides, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats guide RNA, miRNA, wherein the miRNA is optionally selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a.
    
    


A particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, with the composition described above and specifically comprising:

    
    
        a lipid bilayer comprising cholesterol, N-stearoyl-D-erythro-sphingosylphosphorylcholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine, 1,2-dioleoyl-sn-glycero-3-phospho-ethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol), 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt), diacylglycerol, phosphatidylinositol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt);
        one or more nucleic acid molecules selected from the group comprising miRNA miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132; and
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, with the composition described above and specifically comprising:

    
    
        one or more functional protein nicotinamide phosphoribosyltransferase, or a fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof; and
        one or more cytosolic proteins selected from the group comprising Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), tumour susceptibility gene 101 protein (TSG101);
        wherein the synthetic extracellular vesicle does not comprise transferrin and albumin, or a fragment thereof.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, with the composition described above and specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising MHCII, CD80, and CD86, or a fragment thereof;
        optionally one or more transmembrane proteins selected from the group comprising CD11c, MHCI, integrin α, integrin β-chains, intercellular adhesion molecule-1, and CD71, or a fragment thereof; and
        one or more functional proteins selected from the group comprising cytokines, interleukins, interleukin 4, milk fat globule-EGF factor 8 protein, growth factors, Fas, Fas Ligand, indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, with the composition described above and specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt);
        functional protein Fas Ligand, or a fragment thereof; and
        optionally functional protein intercellular adhesion protein-1, or a fragment thereof.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, with the composition described above and specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising CD29, CD44, CD90, CD73, CD44, Sca-1, or a fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63, and CD81, or a fragment thereof;
        one or more functional proteins selected from the group comprising Wnta and Wntb, or a fragment thereof;
        at least one nucleic acid molecule selected from the group comprising miR-140-5p, miR-92a-3p-e;
        one or more nucleic acid molecules selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a, let-7a, miR-21, miR124, miR126, miR-133b, miR-191, miR-222, miR-494, miR-6087, miR-30d-5p; and
        optionally one or more nucleic acid molecules selected from the group comprising miR-33b, miR-451, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-K12-3.
    
    


A further particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, with the composition described above and specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol), 1,2-dioleoyl-sn-glycero phosphoethanolamine-N-(lissamine rhodamine B sulfonyl), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt); and
        functional protein RANK, or a fragment thereof.
    
    


A more particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle as described above for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.
DESCRIPTION OF THE INVENTION
Definitions
Unless specifically noted, the embodiments describing “cell-derived vesicles” or “extracellular vesicles” shall include “exosomes”, “liposomes”, “microvesicles” and “apoptotic vesicles” alone or in combination. When the term “exosome” is used as an example, it is understood that liposomes and microvesicles can be substituted therein.
As used herein, the term “extracellular vesicle” refers to a cell-derived vesicle comprising a membrane that encloses an internal space. Extracellular vesicles comprise all membrane-bound vesicles that have a smaller diameter (here determined as hydrodynamic radius) than the cell from which they are derived. Generally extracellular vesicles range in diameter (hydrodynamic radius) from 20 nm to 1000 nm, and can comprise various macromolecular cargo either within the internal space, displayed on the external surface of the extracellular vesicle, and/or spanning the membrane. The cargo can comprise nucleic acids, proteins, carbohydrates, lipids, small molecules, and/or combinations thereof. Two types of extracellular vesicles are exosomes and microvesicles.
As used herein the term “exosome” refers to a cell-derived small (between 20-300 nm in diameter or hydrodynamic radius, more preferably 20-1000 nm in diameter or hydrodynamic radius) vesicle comprising a membrane that encloses an internal space, and which is generated from the cell by direct plasma membrane budding or by fusion of the late endosome with the plasma membrane. The exosome is a species of extracellular vesicle. The exosome comprises lipid or fatty acid and proteins and optionally comprises a), a polynucleotide (e.g., a nucleic acid, RNA, or DNA), a sugar (e.g., a simple sugar, polysaccharide, or glycan), a functional agent (e.g., a therapeutic agent) or other molecules. The exosome can be derived from a producer cell using a technique known in the prior art, and isolated from the producer cell based on its size, density, biochemical parameters, or a combination thereof.
Microvesicles, on the other hand, are released from a cell upon direct budding from the plasma membrane (PM). Microvesicles are typically larger than exosomes and range from approximately 100 nm to 1 μm.
Although these two vesicle-types, microvesicles, and exosomes, are separate classes of vesicles, due to the fact that they overlap in size, and since the commonly used non-specific protocols for exosome isolation and purification rely solely on the vesicle size differences, it is a fact that in many of the reports published, the exosome samples used are impure, since they probably also include microvesicles and large protein aggregates. Because of this, it has been proposed that the term “extracellular vesicles” (EVs) be used as a general term for all small vesicles/particles, including both vesicle types, and also apoptotic bodies or vesicles.
As used herein the term “synthetic exosome” refers to a synthetic exosome that is not secreted, released, or otherwise produced by a cell in vitro or in vivo. As used herein the term “synthetic exosome” refers to a synthetic exosome generated synthetically from a starting lipid mixture, into which one or more polypeptides and/or nucleic acids may be incorporated. Similarly, the term “synthetic extracellular vesicle” refers to a synthetic extracellular vesicle that is not secreted, released, or otherwise produced by a cell in vitro or in vivo. As used herein the term “synthetic extracellular vesicle” refers to a synthetic extracellular vesicle generated synthetically from a starting lipid mixture, into which one or more polypeptides and/or nucleic acids may be incorporated.
“Liposomes” are microscopic vesicles consisting of concentric lipid bilayers. Structurally, liposomes range in size and shape from long tubes to spheres, with dimensions from a few hundred Angstroms to fractions of a millimeter. Vesicle-forming lipids are selected to achieve a specified degree of fluidity or rigidity of the final complex providing the lipid composition of the outer layer.
“Apoptotic bodies” or “apoptotic vesicles” are released during cell death (apoptosis) and are heterogeneously shaped vesicles with sizes between 50-5000 nm. They are formed from the plasma membrane, and they contain DNA, RNA, histones, and signalling molecules. They usually have high amounts of phosphatidylserine in their membranes, since the outer membrane of apoptotic cells is enriched in PS.
“Membrane” as used herein comprises a lipid bilayer that separates an interior space from an exterior space and comprises one or more biological compounds, typically lipids, and optionally polypeptides and/or carbohydrates such as glycan and/or nucleic acids, and/or other macromolecules. In some embodiments, the membrane comprises lipids and fatty acids. In some embodiments, the membrane comprises phospholipids, glycolipids, fatty acids, sphingolipids, phosphoglycerides, sterols, cholesterols, and phosphatidylserines. The extracellular vesicle comprises a membrane as defined herein.
In some embodiments, the extracellular vesicle or exosome further comprises one or more macromolecule in their lumen.
The term “macromolecule” as used herein is selected from the group comprising an extracellular vesicle associated protein, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe.
As used herein, the term “homogeneous” in reference to a population of extracellular vesicles refers to population of vesicles that have the same or a similar amount of one or more proteins, or one or more nucleic acid molecules, or one or more macromolecule. A homogenous population is one wherein about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or 100% of the vesicles share the one or more proteins, or one or more nucleic acid molecules, or one or more macromolecule.
As used herein, the term “heterogeneous” in reference to a population of engineered vesicles refers to population of vesicles that have differing identity or differing amount of one or more proteins, or one or more nucleic acid molecules, or one or more macromolecule.
Moreover, as used herein, the term “homogeneous” in reference to a population of extracellular vesicles also refers to population of vesicles that have the same or a similar size. A homogenous population in size is one wherein the coefficient of variation calculated as [(standard deviation/average size)*100] is lower than 15%, preferably lower than 13%, preferably lower than 10%, preferably lower than 8%, preferably lower than 7%, most preferably lower than 5%.
The extracellular vesicle or exosome can interact with the target cell via membrane fusion and deliver nucleic acid molecules or intracellular proteins or functional proteins to the surface or cytoplasm of a target cell. In some embodiments, membrane fusion occurs between the extracellular vesicle or exosome and the plasma membrane of a target cell. In other embodiments, membrane fusion occurs between the extracellular vesicle or exosome and an endosomal membrane of a target cell.
As used herein, the term “modulate”, “modulating”, “modify”, and/or “modulator” generally refers to the ability to alter, by increase or decrease, e.g., directly or indirectly promoting, stimulating, up-regulating or interfering with/inhibiting/down-regulating a specific concentration, level, expression, function or behaviour, such as, e.g., to act as an antagonist or agonist. In some instances, a modulator can increase and/or decrease a certain concentration, level, activity or function relative to a control, or relative to the average level of activity that would generally be expected or relative to a control level of activity.
In some embodiments, the extracellular vesicle has a hydrodynamic radius between 20-5000 nm, such as between about 20-150 nm, 20-500 nm, 20-1000 nm, 20-2000, nm, 20-3000 nm, 20-4000 nm, 20-5000 nm, 30-150 nm, 30-500 nm, 30-1000 nm, 30-2000, nm, 30-3000 nm, 30-4000 nm, 30-5000 nm, 40-150 nm, 40-500 nm, 40-1000 nm, 40-2000, nm, 40-3000 nm, 40-4000 nm, 40-5000 nm, 70-2000, nm, 70-3000 nm, 70-4000 nm, 70-5000 nm, 50-150 nm, 50-500 nm, 50-1000 nm, 50-2000, nm, 50-3000 nm, 50-4000 nm, 50-5000 nm, 100-150 nm, 100-500 nm, 100-1000 nm, 100-2000, nm, 100-3000 nm, 100-4000 nm, 100-5000 nm, 500-1000 nm, 500-2000, nm, 500-3000 nm, 500-4000 nm, 500-5000 nm.
In other embodiments, the extracellular vesicle has a hydrodynamic radius between about 20-1000 nm, such as between about 20-100 nm, 20-200 nm, 20-300 nm, 20-400 nm, 20-500 nm, 20-600 nm, 20-700 nm, 20-800 nm, 20-900 nm, 30-100 nm, 30-200 nm, 30-300 nm, 30-400 nm, 30-500 nm, 30-600 nm, 30-700 nm, 30-800 nm, 30-900 nm, 40-100 nm, 40-200 nm, 40-300 nm, 40-400 nm, 40-500 nm, 40-600 nm, 40-700 nm, 40-800 nm, 40-900 nm, 50-150 nm, 50-500 nm, 50-750 nm, 100-200 nm, 100-500 nm, or 500-1000 nm.
In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 90% of the extracellular vesicles have a hydrodynamic radius 20-5000 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 95% of the extracellular vesicles have a hydrodynamic radius 20-5000 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 99% of the extracellular vesicles have a hydrodynamic radius 20-5000 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 90% of the extracellular vesicles have a hydrodynamic radius 20-1000 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 95% of the extracellular vesicles have a hydrodynamic radius 20-1000 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 99% of the extracellular vesicles have a hydrodynamic radius 20-1000 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 90% of the extracellular vesicles have a hydrodynamic radius 20-500 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 95% of the extracellular vesicles have a hydrodynamic radius 20-500 nm. In another embodiment, a population of the extracellular vesicles described herein comprise a population wherein 99% of the extracellular vesicles have a hydrodynamic radius 20-500 nm.
In certain embodiments, the extracellular vesicle is an exosome. In certain embodiments, the extracellular vesicle is a microvesicle.
In some embodiments, the exosome has a hydrodynamic radius between about 20-5000 nm, such as between about 20-150 nm, 20-500 nm, 20-1000 nm, 20-2000, nm, 20-3000 nm, 20-4000 nm, 20-5000 nm, 30-150 nm, 30-500 nm, 30-1000 nm, 30-2000, nm, 30-3000 nm, 30-4000 nm, 30-5000 nm, 40-150 nm, 40-500 nm, 40-1000 nm, 40-2000, nm, 40-3000 nm, 40-4000 nm, 40-5000 nm, 50-150 nm, 50-500 nm, 50-1000 nm, 50-2000, nm, 50-3000 nm, 50-4000 nm, 50-5000 nm, 70-2000, nm, 70-3000 nm, 70-4000 nm, 70-5000 nm, 100-150 nm, 100-500 nm, 100-1000 nm, 100-2000, nm, 100-3000 nm, 100-4000 nm, 100-5000 nm, 500-1000 nm, 500-2000, nm, 500-3000 nm, 500-4000 nm, 500-5000 nm.
In other embodiments, the exosome has a hydrodynamic radius between about 20-1000 nm, such as between about 20-100 nm, 20-200 nm, 20-300 nm, 20-400 nm, 20-500 nm, 20-600 nm, 20-700 nm, 20-800 nm, 20-900 nm, 30-100 nm, 30-200 nm, 30-300 nm, 30-400 nm, 30-500 nm, 30-600 nm, 30-700 nm, 30-800 nm, 30-900 nm, 40-100 nm, 40-200 nm, 40-300 nm, 40-400 nm, 40-500 nm, 40-600 nm, 40-700 nm, 40-800 nm, 40-900 nm, 50-150 nm, 50-500 nm, 50-750 nm, 100-200 nm, 100-500 nm, or 500-1000 nm.
In another embodiment, a population of the exosomes described herein comprise a population wherein 90% of the exosomes have a hydrodynamic radius 20-5000 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 95% of the exosomes have a hydrodynamic radius 20-5000 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 99% of the exosomes have a hydrodynamic radius 20-5000 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 90% of the exosomes have a hydrodynamic radius 20-1000 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 95% of the exosomes have a hydrodynamic radius 20-1000 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 99% of the exosomes have a hydrodynamic radius 20-1000 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 90% of the exosomes have a hydrodynamic radius 20-500 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 95% of the exosomes have a hydrodynamic radius 20-500 nm. In another embodiment, a population of the exosomes described herein comprise a population wherein 99% of the exosomes have a hydrodynamic radius 20-500 nm.
The present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


The present invention is further directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle, wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


In certain embodiments, the extracellular vesicle is an exosome. In certain embodiments, the extracellular vesicle is a microvesicle.
Therefore, a more particular embodiment of the invention is directed to a method for producing a synthetic exosome comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic exosome,
        wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,
        wherein the synthetic exosomes are homogenous in size showing a coefficient of variation in size lower than 13%, and
        wherein the synthetic exosome has a hydrodynamic radius between 70 nm and 5000 nm.
    
    


Another still more particular embodiment of the invention is also directed to a method for producing a synthetic exosome comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic exosome,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the synthetic exosomes are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic exosome has a hydrodynamic radius between 70 nm and 700 nm.

Release and Purification Procedure

    
    


In accordance with optional step d′), the polymer shell is removed from the polymer shell-stabilized synthetic extracellular vesicles. Since the polymer shell is not necessary any more after assembling the vesicles with all the required components, it is actually preferred to perform the step d′) so as to obtain the synthetic extracellular vesicles into an aqueous phase.
The inventors have found that the synthetic extracellular vesicles can be efficiently released from the polymer shell by adding a deemulsifier surfactant to the polymer shell stabilized synthetic extracellular vesicles formed after emulsification. The deemulsifier surfactant destabilizes the structure of the surrounding polymer shell and thus, allows releasing the synthetic extracellular vesicles from the polymer shell into an aqueous buffer, also named “release buffer”.
The deemulsifier surfactant is preferably selected from the group comprising 1H, 1H,2H,2H-perfluoro-1-octanol; 1H, 1H-perfluoro-1-pentanol; 1H, 1H-perfluor-1-octanol; 1H, 1H, 8H-perfluoro-1-octanol.
The deemulsifier surfactant is preferentially added at a ratio ranging from 1:1 to 10:1 with the intraluminal buffer (also named production buffer).
Thereafter, the synthetic extracellular vesicles are usually centrifuged after release from the polymer shell to allow purification from vesicles of unwanted dimensions and other impurities.
The centrifugation can be performed for a time comprised between 5-60 min and at acceleration comprised between 800 g-100,000 g depending on the dimension of the synthetic extracellular vesicles of interest.
Moreover, for synthetic extracellular vesicles with hydrodynamic radius comprised between 100-1000 nm, the centrifugation is preferentially performed at acceleration comprised between 30,000-60,000 g and a time comprised between 10-60 min. For synthetic extracellular vesicles with hydrodynamic radius comprised between 1000-3000 nm, the centrifugation is preferentially performed at acceleration comprised between 10,000-30,000 g and a time comprised between 10-60 min. For synthetic extracellular vesicles with hydrodynamic radius comprised between 3000-5000 nm, the centrifugation is preferentially performed at acceleration comprised between 5,000-20,000 g and a time comprised between 10-60 min.
The synthetic extracellular vesicles synthetized following the inventive method, released into an aqueous medium and then purified by centrifugation (FIG. 1), contained considerably less contaminating aggregates and non-vesicular particles compared to exosomes isolated by standard prior art methods (FIG. 3), i.e. exosomes isolated by differential centrifugation from conditioned K562 erythroleukemia cell media or exosomes from the same cell line obtained from a commercial distributer.
Thus, present invention is directed to method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


A particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 1000 nm.

    
    


A more particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation, wherein the centrifugation is performed at acceleration comprised between 30,000-60,000 g and a time comprised between 10-60 min;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


A more particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation, wherein the centrifugation is performed at acceleration comprised between 30,000-60,000 g and a time comprised between 10-60 min;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


A more particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation, wherein the centrifugation is performed at acceleration comprised between 800 g-100,000 g and a time comprised between 5-60 min;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


A more particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation, wherein the centrifugation is performed at acceleration comprised between 800 g-100,000 g and a time comprised between 5-60 min;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

Protein Associated to the Extracellular Vesicles, Functionalization Procedure

    
    


In the inventive methods, the synthetic extracellular vesicles can be decorated with the proteins of interest after release into an aqueous solution, as described above, wherein the proteins are preferably known to be associated with extracellular vesicles.
The proteins can be coupled to the synthetic extracellular vesicles by applying bio-orthogonal surface chemistry such as N-hydroxysuccinimide ester and/or NTA-poly-histidine tag coupling, or they can be added to the water phase of step a) or can be integrated into or on the polymer shell stabilized synthetic extracellular vesicles by microfluidic technology such as pico-injection.
These procedures allow obtaining synthetic extracellular vesicles comprising proteins at a well-defined ratio protein:lipid, and with very low degree of variation in protein composition between different batches.
Preferred protein:lipid ratios as used herein are between 1:20 to 1:100, 1:40 to 1:100, 1:50 to 1:100, 1:20 to 1:200, 1:40 to 1:200, 1:50 to 1:200, 1:75 to 1:200.
When assessing the exosome protein content, the inventor found that K562-derived exosomes isolated from conditioned media and those provided by a commercial distributer, differed greatly in their protein content, underscoring the degree of variation between different vesicle preparation methods (FIG. 4). Furthermore, when comparing between separately prepared batches of prior art exosomes, a substantial degree of variation in the protein composition could be observed. In contrast, the inventive synthetic exosomes equipped with purified recombinant human forms of exosome's surface markers CD9 and TSG101, attached by nitrilotriacetic acid (NTA)-poly histidine tag chemistry, appeared with a clearly defined band pattern and showed almost identical characteristics between separate preparations. Thus, the method disclosed herein allows obtaining synthetic exosomes that outperforms the exosomes obtained by prior art methods in terms of purity and reproducibility.
Important to mention, by applying bio-orthogonal surface chemistry such as N-hydroxysuccinimide ester and/or NTA-poly-histidine tag coupling, or by using microfluidic technologies, the protein to lipid ratio can be precisely adjusted. This ratio is also very homogenous among the vesicle population.
Thus, the inventive synthetic extracellular vesicles show an outstanding improvement in comparison to the non-adjustable extracellular vesicles obtained by prior art methods, such as differential centrifugation of cell culture medium, or membrane fragmentation of engineered cells.
The wording “extracellular vesicle associated protein” refers to proteins that are enriched in exosomes and extracellular vesicles in comparison to cells. Therefore “extracellular vesicle associated proteins” can also be used as marker of exosomes or other extracellular vesicles. Thus the term “extracellular vesicle associated proteins” has the same meaning as “extracellular vesicle protein marker” or “extracellular vesicle marker”.
Therefore, in specific embodiments, the extracellular vesicles or exosomes comprise one or more proteins on their surface or in their lumen, wherein said proteins are selected from a group of proteins that was recently identified to be enriched on the surface or inside extracellular vesicles, and were thus defined as “extracellular vesicle associated proteins” (Thery et al., 2018, Minimal information for studies of extracellular vesicles 2018; Exocarta Top100 proteins). A list of extracellular vesicle associated proteins suitable for the method and the extracellular vesicles disclosed herein are listed in Table 4.
As used herein the term “fragment” or “active fragment” of a protein refers to a fragment of that protein that retains the ability to be specifically coupled to the extracellular vesicle or exosome. The term “fragment” or “active fragment” of a protein also refers to a fragment of that protein that retains the ability to exert its function in the target cell.
For example, in the case of membrane proteins, a protein fragment refers to a cytosolic domain, a transmembrane domain or an extracellular domain of said protein.
For example, in the case of enzymes, a protein fragment refers to a catalytic domain of that enzyme.
For example, in the case of antibodies, a protein fragment refers to a fragment of the antibody that retains its capacity to bind specifically to the antigen. The antibody or antigen-binding fragment can be derived from natural sources, or partly or wholly synthetically produced. In some embodiments, the antibody is a monoclonal antibody. In some of these embodiments, the monoclonal antibody is an IgG antibody. In certain embodiments, the monoclonal antibody is an IgG1, IgG2, IgG3, or IgG4. In some other embodiments, the antibody is a polyclonal antibody. In certain embodiments, the antibody fragment, also named antigen-binding fragment, is selected from antigen-binding fragment (Fab), Fab′, and F(ab′)2, F(ab)2, a viable fragment (Fv), and Fd fragments. In certain embodiments, the antigen-binding fragment is a Single-chain variable fragment (scFv) or (ScFv)2 fragment. In certain other embodiments, the antibody or antigen-binding fragment is a single-domain antibody. In some embodiments, the antibody or antigen binding fragment is a bispecific or multispecific antibody.
For example, in the case of protein antigens, a protein fragment refers to a fragment of the antigen that retains its capacity to induce an immune response in a human or animal, and/or to be specifically recognized by an antibody.
Preferably, a suitable protein fragment of TSG101 (protein ID Q99816) comprises the amino acids 1-145, a suitable protein fragment of CD9 (protein ID P21926) comprises the amino acids 112-195, a suitable protein fragment of CD81 (protein ID P35762), comprises the amino acids 113-201, a suitable protein fragment of CD63 (protein ID P08962) comprises the amino acids 103-203, a suitable protein fragment of RANK (protein ID O35305) comprises the amino acids 31-214, a suitable protein fragment of FasL (protein ID NM_000639.1) comprises the amino acids 134-281, a suitable protein fragment of ICAM-1 (protein ID P05362) comprises the amino acids 1-480.
As used herein the term protein or a fragment thereof also include “variant” of a protein or of a fragment thereof, and refers to a protein or fragment that shares a certain amino acid sequence identity with the reference protein or fragment upon alignment by a method known in the art. A variant of a protein or of a fragment thereof can include a substitution, insertion, deletion, frameshift or rearrangement in another protein. In some embodiments variants share at least 70%, 80%, 85%, 90%, 95% or 99% sequence identity with the reference protein or with the fragment thereof.
Recitation of any protein provided herein encompasses a functional variant of the protein. The term “functional variant” of a protein refers to a variant of the protein that retains the ability to be specifically targeted to exosomes.
The percentage of “sequence identity” is determined by comparing two optimally aligned protein or polypeptide sequences over a “comparison window” on the full length of the reference sequence. A “comparison window” as used herein, refers to the optimal alignment between the reference and variant sequence after that the two sequences are optimally aligned, wherein the variant nucleic acid or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment. Identity percentage is calculated by determining the number of positions at which the identical amino acid residues occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the full length in amino acid or nucleotide) and multiplying the results by 100 to yield the percentage of sequence identity. Two protein or polypeptide sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when optimally aligned as described above.
The percentage of “sequence identity” can be determined on the comparison window defined above with the help of blastp with the “BLAST 2 Sequences” tool available at the NCBI website. (Tatusova A. et al., FEMS Microbiol Lett. 1999, 174:247-250).
Alternatively, a variant sequence may also be any amino acid sequence resulting from allowed substitutions at any number of positions of the parent sequence according to the formula below:

    
    
        Ser substituted by Ser, Thr, Gly, and Asn;
        Arg substituted by one of Arg, His, Gin, Lys, and Glu;
        Leu substituted by one of Leu, Ile, Phe, Tyr, Met, and Val;
        Pro substituted by one of Pro, Gly, Ala, and Thr;
        Thr substituted by one of Thr, Pro, Ser, Ala, Gly, His, and Gin;
        Ala substituted by one of Ala, Gly, Thr, and Pro;
        Val substituted by one of Val, Met, Tyr, Phe, Ile, and Leu;
        Gly substituted by one of Gly, Ala, Thr, Pro, and Ser;
        Ile substituted by one of Ile, Met, Tyr, Phe, Val, and Leu;
        Phe substituted by one of Phe, Trp, Met, Tyr, lie, Val, and Leu;
        Tyr substituted by one of Tyr, Trp, Met, Phe, Ile, Val, and Leu;
        His substituted by one of His, Glu, Lys, Gin, Thr, and Arg;
        Gin substituted by one of Gin, Glu, Lys, Asn, His, Thr, and Arg;
        Asn substituted by one of Asn, Glu, Asp, Gin, and Ser;
        Lys substituted by one of Lys, Glu, Gin, His, and Arg;
        Asp substituted by one of Asp, Glu, and Asn;
        Glu substituted by one of Glu, Asp, Lys, Asn, Gin, His, and Arg;
        Met substituted by one of Met, Phe, Ile, Val, Leu, and Tyr.
    
    


According to the present invention, the extracellular vesicle associated protein is preferentially selected from the group comprising:

    
    
        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lam in NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


Therefore, one embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:

        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lam in NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinint actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


A further embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:

        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lam in NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


Therefore, one embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle, wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:

        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lam in NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


A further embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:

        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lamin NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


Further extracellular vesicle associated proteins suitable for the method and the synthetic extracellular vesicles disclosed herein are listed in Table 4.
For bio-orthogonal surface chemistry, suitable functional ligands are selected from the group comprising biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator.
Table 2 lists the possible functional ligands that can be attached to the lipids, their function and the interacting moieties.
These functional ligands react with particular moieties at high affinity, as for example the ligand biotin reacts with the moiety streptavidin or avidin. Thus, proteins and other macromolecules of interest can be coupled to the surface of the released extracellular vesicles by using the interaction at high affinity between a functional ligand and the respective reacting moiety.
Thus, a particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle, wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the water phase of step a) comprises at least one lipid coupled to a functional ligand selected from biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and

        wherein the method optionally comprises after step e) the following step:
        f) coupling the synthetic extracellular vesicles with at least one macromolecule comprising at least one moiety reacting with one of said functional ligands, wherein the macromolecule is selected from the group comprising an extracellular vesicle associated protein, or a fragment thereof, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe.
    
    


A more particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm,

wherein the water phase of step a) comprises at least one lipid coupled to a functional ligand selected from biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and

        wherein the method optionally comprises after step e) the following step:
        f) coupling the synthetic extracellular vesicles with at least one macromolecule comprising at least one moiety reacting with one of said functional ligands, wherein the macromolecule is selected from the group comprising an extracellular vesicle associated protein, or a fragment thereof, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe.
    
    


Thus, a particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm,

wherein the water phase of step a) comprises at least one lipid coupled to a functional ligand selected from biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;

        wherein the method optionally comprises after step e) the following step:
        f) coupling the synthetic extracellular vesicles with at least one macromolecule comprising at least one moiety reacting with one of said functional ligands, wherein the macromolecule is selected from the group comprising an extracellular vesicle associated protein, or a fragment thereof, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe; and
        wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:
        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lamin NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


A more particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm,

wherein the water phase of step a) comprises at least one lipid coupled to a functional ligand selected from biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;

        wherein the method optionally comprises after step e) the following step:
        
            f) coupling the synthetic extracellular vesicles with at least one macromolecule comprising at least one moiety reacting with one of said functional ligands, wherein the macromolecule is selected from the group comprising an extracellular vesicle associated protein, or a fragment thereof, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe; and
        
        
        wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:
        
            a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
            a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
            a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
            a protein associated to intracellular compartments selected from the group comprising histone proteins, lamin A/C, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.

Nucleic Acid Molecules and miRNA

        
        
    
    


The phrase “nucleic acid molecule” refers to a single or double-stranded polymer of deoxyribonucleotide or ribonucleotide bases. It includes chromosomal DNA and self-replicating plasmids, vectors, DNA, cDNA, mRNA, siRNA, antisense nucleotide sequence, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) guide RNA.
Abbreviations used in this application include the following: “mRNA” refers to messenger RNA, “miRNA” refers to microRNA, “siRNA” refers to small interfering RNA, “antisense nucleotide sequence” refers to a single stranded sequence that is complementary to a nucleotide sequence of interest, “shRNA” refers to small or short hairpin RNA, “lncRNA” refers to long non-coding RNA, and “dsDNA” refers to double stranded DNA.
As used herein, the term “microRNAs” or “miRNAs” refers to post-transcriptional regulators that typically bind to complementary sequences in the three prime untranslated regions (3′ UTRs) of target messenger RNA transcripts (mRNAs), usually resulting in gene silencing. Typically, miRNAs are short, non-coding ribonucleic acid (RNA) molecules, for example, 21 or 22 nucleotides long. The terms “microRNA” and “miRNA” are used interchangeably.
The content of miRNA molecules is preferably comprised between 75 pg/1012 vesicles-1000 pg/1012 vesicles, between 75 pg/1012 vesicles-5000 pg/1012 vesicles, 75 pg/1012 vesicles-10,000 pg/1012 vesicles, between 75 pg/1012 vesicles-20,000 pg/1012 vesicle, between 75 pg/1012 vesicles-50,000 pg/1012 vesicles, between 75 pg/1012 vesicles-100,000 pg/1012 vesicles, between 75 pg/1012 vesicles-150,000 pg/1012 vesicles, between 75 pg/1012 vesicles-200,000 pg/1012 vesicles, between 75 pg/1012 vesicles-300,000 pg/1012 vesicles, between 500 pg/1012 vesicles-1000 pg/1012 vesicles, between 500 pg/1012 vesicles-5000 pg/1012 vesicles, 500 pg/1012 vesicles-10,000 pg/1012 vesicles, between 500 pg/1012 vesicles-20,000 pg/1012 vesicle, 500 pg/1012 vesicles-50,000 pg/1012 vesicles, between 500 pg/1012 vesicles-100,000 pg/1012 vesicles, between 500 pg/1012 vesicles-150,000 pg/1012 vesicles, between 500 pg/1012 vesicles-200,000 pg/1012 vesicles, between 500 pg/1012 vesicles-300,000 pg/1012 vesicles, between 5000 pg/1012 vesicles-10,000 pg/1012 vesicles, between 5000 pg/1012 vesicles-20,000 pg/1012 vesicle, 5000 pg/1012 vesicles-50,000 pg/1012 vesicles, between 5000 pg/1012 vesicles-100,000 pg/1012 vesicles, between 5000 pg/1012 vesicles-150,000 pg/1012 vesicles, between 5000 pg/1012 vesicles-200,000 pg/1012 vesicles, between 5000 pg/1012 vesicles-300,000 pg/1012 vesicles.
In one aspect, the therapeutic agent is a short interfering RNA, also known as siRNA. Methods to prepare and screen interfering RNA and select for the ability to block polynucleotide expression are known in the art and non-limiting examples of which are shown below. These interfering RNA are provided by this invention alone or in combination with a suitable vector or within a host cell. Compositions containing the RNAi are further provided. RNAi is useful to knock-out or knock-down select functions in a cell or tissue as known in the art.
siRNA sequences can be designed by obtaining the target mRNA sequence and determining an appropriate siRNA complementary sequence. siRNAs of the invention are designed to interact with a target sequence, meaning they complement a target sequence sufficiently to hybridize to that sequence. An siRNA can be 100% identical to the target sequence. However, homology of the siRNA sequence to the target sequence can be less than 100% as long as the siRNA can hybridize to the target sequence. Thus, for example, the siRNA molecule can be at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the target sequence or the complement of the target sequence. Therefore, siRNA molecules with insertions, deletions or single point mutations relative to a target may also be used. The generation of several different siRNA sequences per target mRNA is recommended to allow screening for the optimal target sequence. A homology search, such as a BLAST search, should be performed to ensure that the siRNA sequence does not contain homology to any known mammalian gene.
As a general guide, siRNAs that include one or more of the following conditions are particularly useful in gene silencing in mammalian cells:GC ratio of between 45-55%, no runs of more than 9 G/C residues, G/C at the 5′ end of the sense strand; NU at the 5′ end of the antisense strand; and at least 5 NU residues in the first 7 bases of the 5′ terminal of the antisense strand.
siRNA are, in general, from about 10 to about 30 nucleotides in length. For example, the siRNA can be 10-30 nucleotides long, 12-28 nucleotides long, 15-25 nucleotides long, 19-23 nucleotides long, or 21-23 nucleotides long. When an siRNA contains two strands of different lengths, the longer of the strands designates the length of the siRNA. In this situation, the unpaired nucleotides of the longer strand would form an overhang.
The term siRNA includes short hairpin RNAs (shRNAs). shRNAs comprise a single strand of RNA that forms a stem-loop structure, where the stem consists of the complementary sense and antisense strands that comprise a double-stranded siRNA, and the loop is a linker of varying size. The stem structure of shRNAs generally is from about 10 to about 30 nucleotides long. For example, the stem can be 10-30 nucleotides long, 12-28 nucleotides long, 15-25 nucleotides long, 19-23 nucleotides long, or 21-23 nucleotides long.
Tools to assist siRNA design are readily available to the public. For example, a computer-based siRNA design tool is available on the internet at www.dharmacon.com.
In some embodiments, the extracellular vesicle or exosome delivers their nucleic acid or intracellular protein or functional protein to a cell target. The delivery can occur in vitro or in a subject.
Preferentially, the extracellular vesicles disclosed herein include miRNA molecules selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a.
Furthermore, the extracellular vesicles disclosed herein can include one or more miRNA molecules as listed in Table 3.
Thus, one embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the water phase of step a) comprises one or more nucleic acid molecules selected from the group comprising miRNA molecules miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a.

    
    


Another embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the water phase of step a) comprises one or more nucleic acid molecules selected from the group comprising chromosomal DNA and self-replicating plasmids, vectors, DNA, cDNA, mRNA, siRNA, antisense nucleotide sequence, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) guide RNA.

    
    


A further embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm,

wherein the water phase of step a) comprises one or more nucleic acid molecules selected from the group comprising miRNA molecules miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a, miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a; and

wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:

        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lamin A/C, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


A more particular embodiment of the invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm,

wherein the water phase of step a) comprises at least one lipid coupled to a functional ligand selected from biotin, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimide, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;

        wherein the method optionally comprises after step e) the following step:
        f) coupling the synthetic extracellular vesicles with at least one macromolecule comprising at least one moiety reacting with one of said functional ligands, wherein the macromolecule is selected from the group comprising an extracellular vesicle associated protein, or a fragment thereof, a carbohydrate, a nucleic acid, a polypeptide, a cell receptor, an imaging probe;

wherein the water phase of step a) comprises one or more nucleic acid molecules selected from the group comprising miRNA molecules miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a; and

wherein the extracellular vesicle associated protein, or a fragment thereof is selected from the group comprising:

        a transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), or a fragment thereof;
        a cytosolic protein selected from the group comprising the protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), or a fragment thereof;
        a functional protein selected from the group comprising cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, or a fragment thereof; and
        a protein associated to intracellular compartments selected from the group comprising histone proteins, lamin A/C, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.

Lipid Composition

    
    


Lipids are the major scaffolding components of extracellular vesicles such as exosomes, and pivotal for their signaling capabilities. Therefore, synthetic extracellular vesicles were assembled with lipid compositions resembling those found in natural synthetic extracellular vesicles (FIG. 2), although the technology allows for the integration of an almost unrestricted number of possible lipid types into synthetic extracellular vesicles membrane.
The lipid composition of the final synthetic extracellular vesicles can be easily fine-tuned on the basis of the composition of the initial lipid solution, as no lipid ratio change was observed during the emulsification and release procedures.
This technology also allows to finely regulating the charge of the synthetic extracellular vesicles by adjusting the ratio of cationic, neutral and anionic lipids.
The molar percentage (mol %) of a lipid is measured as the moles of a lipid of interest on the total lipid moles of the vesicle.
In some embodiments, the molar percentage (mol %) of a cationic lipid typically comprises from 0% to 10%, from 10% to 20%, from 10% to 30%, from 10% to 40%, %, from 10% to 50%, from 10% to 60%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60% of the total lipid present in vesicle.
In some embodiments, the molar percentage (mol %) of an anionic lipid typically comprises from 0% to 10%, from 10% to 20%, from 10% to 30%, from 10% to 40%, %, from 10% to 50%, from 10% to 60%, from 20% to 30%, from 20% to 40%, from 20% to 50%, from 20% to 60% of the total lipid present in vesicle.
In some embodiments, the molar percentage (mol %) of neutral lipid typically comprises from 49% to 99%, from 49% to 89%, from 49% to 79%, from 49% to 69%, %, from 59% to 99%, from 59% to 89%, from 59% to 79%, from 59% to 69% of the total lipid present in vesicle.
The present invention is not particularly limited concerning the chemical nature of the at least one lipid contained in the water phase of step a) and thus in the inner space of the polymer shell stabilized synthetic extracellular vesicle, as long as it is able to form a lipid bilayer. Good results are in particular achieved with phospholipids and in particular with a lipid being selected from the group comprising phosphocholine, phosphocholine derivatives, phosphoethanolamine, phosphoethanolamine derivatives, phosphatidylcholine, phosphatidylcholine derivatives, phosphatidylglycerol, phosphatidylglycerol derivatives and arbitrary combinations of two or more of the aforementioned lipids.
At least one of the lipids is an amphiphilic lipid, defined as having a hydrophilic and a hydrophobic portion, typically a hydrophilic head and a hydrophobic tail. The hydrophobic portion typically orients into a hydrophobic phase, e.g., within the bilayer, while the hydrophilic portion typically orients toward the aqueous phase, e.g., outside the bilayer, and possibly between adjacent apposed bilayer surfaces. The hydrophilic portion may comprise polar or charged groups such as carbohydrates, phosphate, carboxylic, sulfato, amino, sulfhydryl, nitro, hydroxy and other like groups. The hydrophobic portion may comprise apolar groups that include without limitation long chain saturated and unsaturated aliphatic hydrocarbon groups and groups substituted by one or more aromatic, cyclo-aliphatic or heterocyclic groups. Examples of amphipathic lipids include, but are not limited to, phospholipids, aminolipids and sphingolipids.
Typically, the lipids are phospholipids. Phospholipids include without limitation phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, and their derivatives. It is to be understood that other lipid membrane components, such as cholesterol, sphingomyelin, cardiolipin, etc. may be used.
Lipids can be “uncharged lipids” or “charged lipids.” “Uncharged lipids” refer to lipids that do not carry any charged or ionizable groups such as phosphate groups or choline groups. Examples of uncharged lipids include, but are not limited to, diacyl glycerols and prostaglandins.
“Charged lipids” include neutrally charged, i.e. zwitterionic lipids, cationic lipids and anionic lipids. Generally, lipids bearing a net positive or negative charge exhibit poor solubility in oil phases.
Neutral lipids exist in an uncharged or neutral zwitterionic form at a selected pH.
“Zwitterionic lipids” carry both positively-charged groups and ionizable groups such as amino groups and choline groups that bear a net positive charge, and negatively-charged groups and ionizable groups, such as phosphates, sulfates and carboxylates. Examples of zwitterionic lipids include, but are not limited to, phosphorylcholine and phosphorylethanolamine
“Anionic lipids” are lipids negatively charged at physiological pH. “Cationic lipids” are lipids positively charged at physiological pH.
Further suitable lipids are pH sensitive lipids. A “pH-sensitive” lipid refers to a lipid whose ability to form and/or maintain formation of a lipid bilayer depends at least in part on the pH of the surrounding environment. Synthetic extracellular vesicles containing such lipids are destabilized under acidic conditions of the endocytotic pathway. Therefore, the encapsulated content is delivered into the intracellular bio-environment through destabilization or its fusion with the endosomal membrane.
Specific examples of the lipids suitable to synthetize the synthetic extracellular vesicles according to the method disclosed herein are listed in Table 1.
Preferably, the lipids are biodegradable in order to allow release of the internal proteins or nucleic acid molecules in vivo and/or in vitro. Biodegradable lipids include but are not limited to 1,2-dioleoyl-sn-glycero-3-phosphocholine (dioleoyl-phosphocholine, DOPC), anionic 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1′-rac-glycerol) (dioleoyl-phosphoglycerol, DOPG), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (distearoyl-phosphoethanolamine, DSPE).
Functionalized Lipids
According to an embodiment of the present invention, the at least one lipid comprised in the water phase of step a) is a lipid coupled with a functional ligand and/or with polyethylenglycol. Specific examples of the suitable functional ligands, the reacting moieties, and of the functionalized lipids containing are listed in Table 2.
Functionalized and non-functionalized lipids are available from a number of commercial sources including Avanti Polar Lipids (Alabaster, Alabama).







TABLE 1







Suitable lipids











Class
Specific example
Abbreviation














Neutral lipids
ceramide

Cer



sphingomyelin
Egg sphingomyelin, brain sphingomyelin,
SM




Milk sphingomyelin, Lyso sphingomyelin,



cholesterol

Chol



cerebrosides
Galactocerebroside, Glucocerebroside
Gal-Cer, Glc-Cer



diacylglycerols
1-oleoyl-2-acetyl-sn-glycerol
DAG, DG



phosphatidylcholines
egg L-α-phosphatidylcholine
EggPC




distearoylphosphatidylcholine
DSPC




1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
POPC




1,2-dimyristoyl-sn-glycero-3-phosphocholine
DMPC




1,2-dipalmitoyl-sn-glycero-3-phosphocholine
DPPC




1,2-dioleoyl-sn-glycero-3-phosphocholine
18:1 DOPC




dioleoylphosphatidylglycerol
DOPG




dipalmitoylphosphatidylglycerol
DPPG




palmitoyloleyolphosphatidylglycerol
POPG



lysophosphatidylcholines
1-palmitoyl-sn-glycero-3-phosphocholine
PC(16:0/0:0)



phosphatidylethanolamines
1-stearoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine
SOPE, 18:0-18:1 PE



(also named “cephalin”)
1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine
DMPE, 14:0 PE




1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine
DPPE




1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
18:1 DOPE



lysophosphatidylethanolamine
1,2-Distearoyl-sn-glycero-3-phosphoethanolamine
DSPE




palmitoyloleoyl-phosphatidylethanolamine
POPE



lysoethanolamines
1-stearoyl-sn-glycero-3-phosphoethanolamine
18:0 Lyso PE, egg





Lyso PE



Inverted Headgroups
2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl
DOCP




hydrogen phosphate




2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl
DOCPe




ethyl phosphate



Sphingosin
(R,E)-2-aminooctadec-4-en-1-ol
3-deoxy sphingosine




(2S,3S,4E)-2-aminooctadec-4-ene-1,3-diol
L-threo-sphingosine





(d18:1)




D-erythro-sphingosine
Sphingosine (d18:1)




D-erythro-sphingosine (C17 base)
Sphingosine (d17:1)




D-erythro-sphingosine (C20 base)
Sphingosine (d20:1)




D-erythro-Sphingosine (C22 base)
Sphingosine (d22:1)




(2S,3R,4E,14Z)-2-aminooctadec-4,14-diene-1,3-diol
4E,14Z-Sphingadiene




(2S,3R,4E,8Z)-2-aminooctadec-4,8-diene-1,3-diol
4E,8Z-Sphingadiene




(2S,3R,4E,11Z)-2-aminooctadec-4,11-diene-1,3-diol
4E,11Z-Sphingadiene




D-erythro-Sphingosine (C16 base)
Sphingosine (d16:1)




D-erythro-Sphingosine (C14 Base)
Sphingosine (d14:1)




Mito-Caged Sphingosine
Mito-So



Sterol-modified phospholipids
1-palmitoyl-2-cholesterylhemisuccinoyl-sn-glycero-
PChemsPC




3-phosphocholine




1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-
OChems PC




3-phosphocholine




1-palmitoyl-2-cholesterylcarbonoyl-sn-glycero-
PChcPC




3-phosphocholine,




1,2-dicholesterylhemisuccinoyl-sn-glycero-
DChemsPC




3-phosphocholine,



Ether ester
1-O-heptadecyl-2-acetyl-sn-glycero-3-
C17 PAF, C17-02:0 PC



lipids
phosphocholine,
(Phosphocholine),




1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine,
C16-02:0 PC,




1-O-hexadecyl-2-oleoyl-sn-glycero-3-phosphocholine,
C16-18:1 PC,




1-O-hexadecyl-2-arachidonoyl-sn-glycero-3-phosphocholine,
C16-20:4 PC,




1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine,
C18-02:0 PC,




1-O-hexadecyl-2-butyryl-sn-glycero-3-phosphocholine,
C16-04:0 PC,




1-O-octadecyl-2-butyryl-sn-glycero-3-phosphocholine,
C18-04:0 PC,




1-O-hexadecyl-2-(8Z,11Z,14Z-eicosatrienoyl)-sn-glycero-
C16-20:3 PC,




3-phosphocholine,
C16-20:5 PC,




1-O-hexadecyl-2-(5Z,8Z,11Z,14Z,17Z-eicosapentaenoyl)-
C16-22:6 PC,




sn-glycero-3-phosphocholine,
C16-18:1 PE




1-O-hexadecyl-2-docosahexaenoyl-sn-glycero-3-




phosphocholine




1-hexadecyl-2-(9Z-octadecenoyl)-sn-glycero-3-




phosphoethanolamine



Diether Lipids
1-O-hexadecanyl-2-O-(9Z-octadecenyl)-sn-glycero-3-
16:0-18:1 Diether PG,




phospho-(1′-rac-glycerol) (ammonium salt)




1-O-hexadecanyl-2-O-(9Z-octadecenyl)-sn-glycero-3-
16:0-18:1 Diether PE




phosphoethanolamine




1-O-hexadecanyl-2-O-(9Z-octadecenyl)-sn-glycero-3-
16:0-18:1 Diether PC




phosphocholine




1,2-di-O-(9Z-octadecenyl)-sn-glycero-3-phosphocholine
18:1 Diether PC




1,2-di-O-octadecyl-sn-glycero-3-phosphocholine
18:0 Diether PC




1,2-di-O-hexadecyl-sn-glycero-3-phosphocholine
16:0 Diether PC




1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine
Edelfosine



Vinyl Ether
1-(1Z-hexadecenyl)-sn-glycero-3-phosphocholine
C16(Plasm) LPC



(Plasmalogen)
1-O-1′-(Z)-octadecenyl-2-hydroxy-sn-glycero-
C18(Plasm) LPC




3-phosphocholine,




1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-
C18(Plasm)-18:1 PC




3-phosphocholine




1-(1Z-octadecenyl)-2-arachidonoyl-sn-glycero-
C18(Plasm)-20:4 PC




3-phosphocholine




1-O-1′-(Z)-octadecenyl-2-hydroxy-sn-glycero-
C18(Plasm) LPE




3-phosphoethanolamine




1-(1Z-octadecenyl)-2-docosahexaenoyl-sn-glycero-
C18(Plasm)-22:6 PC




3-phosphocholine




1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-
C18(Plasm)-18:1 PE




phosphoethanolamine




1-(1Z-octadecenyl)-2-arachidonoyl-sn-glycero-3-
C18(Plasm)-20:4 PE




phosphoethanolamine




1-(1Z-octadecenyl)-2-docosahexaenoyl-sn-glycero-3-
C18(Plasm)-22:6 PE




phosphoethanolamine



N-Acylglycine
N-palmitoylglycine




N-arachidonoylglycine




N-oleoylglycine



Very Long Chain Fatty Acids
14Z,17Z,20Z,23Z,26Z,29Z-dotriacontahexaenoic acid
C32:6 fatty acid



(VLCFA)



Prenols
Coenzyme Q6 (S. cerevisiae)
CoQ6




Coenzyme Q8 (E. coli)
CoQ8




Dolichol Mixture (13~21)




Polyprenol mixture (13~21)




Polyprenal mixture (13~21)



Prostaglandins
Prostaglandin E1
PGE1




Prostaglandin F1α
PGF1α




Prostaglandin F2α (15 beta epimer)
15-beta PGF2α




Prostaglandin F1β
PGF1β




Prostaglandin F1α(15 beta epimer)
15beta-PGF1α




Prostaglandin F1α-d9
PGF1α-d9




Prostaglandin E1-d9
PGE1-d9




Prostaglandin E2 Ethanolamide
PGE2-EA




Prostaglandin A1
PGA1




Prostaglandin E2
PGE2




Prostaglandin F2β
PGF2β




Prostaglandin B1
PGB1




Prostaglandin F2α
PGF2α




15-keto Prostaglandin F2α
15-keto PGF2α



Glycosylated Diacyl Glycerols
1,2-diacyl-3-O-(α-D-glucopyranosyl)-sn-glycerol
MGlc-DAG




(E. coli)




1-oleoyl-2-palmitoyl-3-(α-D-galactosyl)-sn-glycerol
BbGL-2




1-palmitoyl-2-oleoyl-3-(β-D-glucosyl)-sn-glycerol
16:0-18:1 DG glucose



Eicosanoids
5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid
5-OxoETE




17(S)-hydroxy Docosahexaenoic acid
17(S)-HDHA




(±)14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid
14(15) EET




15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid
15(S)-HETE




15(S)-hydroxy-N-(2-hydroxyethyl)-5Z,8Z,11Z,13E-
15(S)-HAEA




eicosatetraenamide




13S-Hydroxy-9Z,11E-octadecadienoic acid
13(S)HODE




13S-Hydroxy-N-(2-hydroxyethyl)-9Z,11E-octadecadienamide
13(S)HODE





Ethanolamide



Palmitic Acid-Hydroxy Stearic
9-(palmitoyloxy)octadecanoic acid
9-PAHSA



Acid, PAHSA
5-(palmitoyloxy)octadecanoic acid
5-PAHSA




9′-(palmitoyloxy)octadecanoic acid
12-PAHSA




1-palmitoyl-2-[9′-(palmitoyloxy)octadecanoyl]-
16:0-(12-PAHSA) PC




sn-glycero-3-phosphoholine


Anionic lipids
phosphatidic acids
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate
16:0-18:1 PA, POPA



lysophosphatidic acids
1-oleoyl-2-hydroxy-sn-glycero-3-phosphate
18:1 Lyso PA




1-stearoyl-2-hydroxy-sn-glycero-3-phosphate
18:0 Lyso PA




1-heptadecanoyl-2-hydroxy-sn-glycero-3-phosphate
17:0 Lyso PA




(sodium salt)




1-arachidonoyl-2-hydroxy-sn-glycero-3-phosphate
20:4 Lyso PA




1-palmitoyl-2-hydroxy-sn-glycero-3-phosphate
16:0 Lyso PA




(sodium salt)




1-myristoyl-2-hydroxy-sn-glycero-3-phosphate
14:0 Lyso PA




(sodium salt)



phosphatidylglycerols
Egg L-α-phosphatidylglycerol
EggPG




1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-
18:1 DOPG




(1′-rac-glycerol), or L-α-Phosphatidyl-DL-glycerol




1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-
POPG




(1′-rac-glycerol)



lysophosphatidylglycerols
1-palmitoyl-2-hydroxy-sn-glycero-3-phospho-
16:0 Lyso PG




(1′-rac-glycerol)



phosphatidylserines
1,2-dioleoyl-sn-glycero-3-phospho-L-serine
DOPS




1-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine
SOPS



lysophosphatidylserines
1-stearoyl-sn-glycero-3-phospho-L-serine
PS (18:1/18:0)



phosphatidylinositols
1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-
18:0/20:4-PI




(1′-myo-inositol)



phosphatidylinositolphosphates
1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-
18:0-20:4 PI(4)P




(1′-myo-inositol-4′phosphate)




1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-
18:0-20:4 PI(4,5)P2




(1′-myo-inositol-4′,5′-bisphosphate)




phosphatidylinositol 4,5-bisphosphate
PIP2



cardiolipins
1′,3′-bis[1,2-dilinoleoyl-sn-glycero-3-
18:1 Cardiolipin




phospho]-sn-glycerol.




1′,3′-bis[1,2-dimyristoleoyl-sn-glycero-
14:1 Cardiolipin




3-phospho]-glycerol




1′,3′-bis[1,2-dipalmitoyl-sn-glycero-3-
16:0 Cardiolipin




phospho]-glycerol




1′,3′-bis[1-Palmitoyl-2-oleoyl-sn-glycero-
16:0-18:1 Cardiolipin




3-phospho]-glycerol




1′,3′-bis[1,2-dipalmitoleoyl-sn-glycero-
16:1 Cardiolipin




3-phospho]-glycerol




1′,3′-bis[1,2-Distearoyl-sn-glycero-3-
18:0 Cardiolipin




phospho]-glycerol



Bis(Monoacylglycero)Phosphate
bis(monomyristoylglycero)phosphate (S, R Isomer)
14:0 BMP (S, R)



(BMP)
(ammonium salt),




sn-(3-myristoyl-2-hydroxy)-glycerol-1-phospho-
14:0 Hemi BMP (S, R)




sn-3′-(1′,2′-dimyristoyl)-glycerol




(ammonium salt)




bis(monooleoylglycero)phosphate (S, R Isomer)
18:1 BMP (S, R)




(ammonium salt)




sn-(3-oleoyl-2-hydroxy)-glycerol-1-phospho-sn-
18:1 Hemi BMP (S, R)




3′-(1′,2′-dioleoyl)-glycerol (ammonium salt)




sn-(3-oleoyl-2-hydroxy)-glycerol-1-phospho-sn-
18:1 BMP (S, S)




1′-(3′-oleoyl-2′-hydroxy)-glycerol




(ammonium salt)




sn-(1-oleoyl-2-hydroxy)-glycerol-3-phospho-sn-
18:1 BMP (R, R)




3′-(1′-oleoyl-2′-hydroxy)-glycerol




(ammonium salt)




sn-[2,3-dioleoyl]-glycerol-1-phospho-sn-
18:1 BDP (S, S)




1′-[2′,3′-dioleoyl]-glycerol




(ammonium salt)


Cationic lipids

2,3-dioleyloxy-N-[2(sperminecarboxamido)
DOSPA




ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate




1,2-dimyristyloxypropyl-3-dimethyl-hydroxy
DMRIE




ethyl ammonium bromide




N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride
DODMA




dioctadecylamidoglycyl carboxyspermine
DOGS




1,2-Dioleoyl-3-dimethylammonium-propane
DODAP




dioleyl-N,N-dimethylammonium chloride
DODAC




N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium
DOTMA




chloride




N,N-distearyl-N,N-dimethylammonium bromide
DDAB




1,2-dioleoyl-3-trimethylammonium-propane
18:1 DOTAP




3β-(N-(N′,N′-dimethylaminoethane)-
DC-Chol




carbamoyl)cholesterol


pH sensitive lipids

N-(4-carboxybenzyl)-N,N-dimethyl-2,3-
DOBAQ (cationic)




bis(oleoyloxy)propan-1-aminium




1,2-distearoyl-3-dimethylammonium-propane
DAP (cationic)




1,2-dipalmitoyl-sn-glycero-3-succinate
16:0 DGS




1,2-dioleoyl-sn-glycero-3-succinate
18:1 DGS




N-palmitoyl homocysteine
PHC


Biodegradable lipids

1,2-dioleoyl-sn-glycero-3-phosphocholine
DOPC




1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-
DOPG




(1′-rac-glycerol)




1,2-distearoyl-sn-glycero-3-phosphoethanolamine
DSPE


Photoswitchable lipid

N-[(E)-4-(4-((4-butylphenyl)diazenyl)phenyl)butanoyl]-
ACe-1




D-erythro-sphingosine




1-stearoyl-2-[(E)-4-(4-((4-
18:0-PhoDAG




butylphenyl)diazenyl)phenyl)butanoyl]-sn-glycerol




1-stearoyl-2-[(E)-4-(4-((4-butylphenyl)diazenyl)phenyl)
18:0-azo PC




butanoyl]-sn-glycero-3-phosphocholine




N-[(E)-4-(4-((4-butylphenyl)diazenyl)phenyl)butanoyl]-
Azo SM




D-erythro-sphingosylphosphorylcholine




(E)-4-(4-((4-butylphenyl)diazenyl)phenyl)-N-(3-hydroxy-
Trans-AzCA4




4-methoxybenzyl)butanamide




4-Butyl-Azo-4:0-Acid-1
Trans-F AAzo-4




1-(E)-4-(4-((4-butylphenyl)diazenyl)phenyl)butanoyl]-
Azo Lyso PA




2-hydroxy-sn-glycero-3-phosphate
















TABLE 2







Functional moieties and examples of functionalized lipid









Functional Ligand
Example
Reacting moiety/Function





biotin
1-oleoyl-2-(12-biotinyl-(aminododecanoyl))-sn-glycero-
Avidin,



3-phosphoethanolamine (18:1-12:0 Biotin PE);
Streptavidin



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-



N-(biotinyl), 16:0 Biotinyl PE



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-



N-(biotinyl), 18:1 Biotinyl PE



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-



N-(cap biotinyl), 18:1 Biotinyl Cap PE;



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-



N-(cap biotinyl), 16:0 Biotinyl Cap PE


N-hydroxysuccinimide
NHS Palmitic acid N-hydroxysuccinimide ester
Amine


ester (NHS),


N-Hydroxysulfosuccinimide


(sulfo-NHS)


nitrilotriacetic
1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-
Histidine (His) tags,


acid (NTA)-nickel
carboxypentyl)iminodiacetic acid) succinyl],
e.g. 6 × His-Tag



18:1 DGS-NTA (Ni)


amines
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-
NHS,



(hexanoylamine)18:1 Caproylamine PE
N-Hydroxysulfosuccinimide



1,2-Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-



N-(hexanoylamine), 16:0 Caproylamine PE



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-



N-(dodecanylamine), 16:0 Dodecanylamine PE



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-



N-(dodecanylamine), 18:1 Dodecanylamine PE


arginylglycylaspartic
1,2-distearoyl-sn-glycero-3-phosphoethanolamine-
Integrin receptors


acid (RGD)
N-[4-(p-(cysarginylglycylaspartate-maleimidomethyl)-
on target cells



cyclohexane-carboxamide], DSPE-RGD


maleimides,
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-
Thiol (e.g.


aromatic maleimides
[4-(p-maleimidomethyl) cyclohexane-carboxamide]
thiolated antibodies)


N-[4-(p-maleimidophenyl)-
(sodium salt), 16:0 PE MCC;


butyryl], MPB;
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-


4-(N-maleimidomethyl)
[4-(p-maleimidomethyl) cyclohexane-carboxamide]


cyclohexane-1-carboxylate,
(sodium salt), 18:1 PE MCC;


MCC
1,2-dioleoyl-sn-glycero-3-phosphocholine



(N-aminoethyl), 18:1 aminoethyl PC;



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-



[4-(p-maleimidophenyl) butyramide] (sodium salt),



18:1 MPB PE



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-



[4-(p-maleimidophenyl) butyramide] (sodium salt),



16:0 MPB PE


pyridyldithiopropionate (PDP)
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-
maleimide-functionalized



[3-(2-pyridyldithio)propionate] (sodium salt),
antibodies bind to sulfhydril



18:1 PDP PE
group obtained after reduction



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-
of a PDP-phopholipid



N-[3-(2-pyridyldithio)propionate] (sodium salt),



16:0 PDP PE


pyridyl disulfide (DPS)

maleimide


dithiopyridinyl 4,4′-dithiodipyridine

maleimide


(4-PDS or 4-DTDP),


N-benzylguanine
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-
SNAP-tag



N-benzylguanine, 18:1 PE-benzylguanine



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-



N-[benzylguanine(polyethylene glycol)-2000],



18:1 PE-PEG2000-benzylguanine


fluorescent dye molecule,
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-


such as lissamine rhodamine
N-(lissamine rhodamine B sulfonyl) (RhB DOPE or


B sulfonyl, Atto488, Alexa
LissRhod PE),


Fluor 488, Alexa Fluor 647,
1,1′-dioctadecyl-3,3,3′,3′-


Fluorescein, N-(7-Nitrobenz-
tetramethylindotricarbocyanine iodide (DiR);


2-Oxa-1,3-Diazol-4-yl (NBD),
1,1′-dioctadecyl-3,3,3′,3′-


Cy5, Cy5.5, Cy7, Topfluor ®
tetramethylindodicarbocyanine (DiD)


Alexa Fluor488, Topfluor ®


Alexa Fluor594


sulfhydryl/thiol group
1,2-Dipalmitoyl-sn-Glycero-3-Phosphothioethanol
Maleimides, lodoacetamides,



(DPPTE)/16:0 Ptd Thioethanol
benzylic halide, and




bromomethylketones,


Carboxyacyl such as Succinyl,
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl)


Glutaryl, dodecanoyl
(sodium salt), 18:1 Succinyl PE;



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl)



(sodium salt), 16:0 Succinyl PE;



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(glutaryl)



(sodium salt), 18:1 Glutaryl PE;



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(glutaryl)



(sodium salt), 16:0 Glutaryl PE;



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(dodecanoyl)



(sodium salt), 18:1 Dodecanyl PE;



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(dodecanoyl)



(sodium salt), 16:0 Dodecanoyl PE


cyanuric chloride
cyanur-DSPE
coupling to amine-containing



cyanur-PEG2000-PE (ammonium salt)
biomolecules such as peptides,



1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-
antibodies, nanoparticles



[cyanur(polyethylene glycol)-2000]



(ammonium salt), DSPE-PEG(2000) Cyanur



1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-



(cyanur), 16:0 Cyanur PE


Folate
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(6-
Folate receptor on



((folate)amino)hexanoyl), 16:0 Folate Cap PE,
cancer cells (endocitosis)


Carbohydrate/Glycan: for example
1,2-dipalmitoyl-sn-glycero-3-phospho((ethyl-1′,2′,3′-
Carbohydrate binding


β-galactose, α-mannose-,
triazole)triethyleneglycolmannose), 16:0 PA-PEG3-mannose
cell receptor


β-mannose-, and α-fucose
β-galactose, α-mannose-, β-mannose-, and α-fucose;



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-lactosyl



(ammonium salt), (18:1 Lactosyl PE)



1,2-diacyl-3-O-(α-D-glucopyranosyl)-sn-glycerol (E. coli),



MGlc-DAG



1-oleoyl-2-palmitoyl-3-(α-D-galactosyl)-sn-glycerol, BbGL-2



1-palmitoyl-2-oleoyl-3-(β-D-glucosyl)-sn-glycerol,



16:0-18:1 DG glucose


Square
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-square,
Square is a dye for



18:1 PE-Square
Resonance Energy Transfer



1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-square,
(RET), Flow Cytometry



18:0 PE-square


Galloyl
1,2-dipalmitoyl-sn-glycero-3-galloyl (16:0 DG Galloyl)
Self-adhering lipid so that




bilayers strongly adhere to




each other


Azide
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-
Photochemically induced cross-



[azido(polyethylene glycol)-
linking with transmembrane



2000] (ammonium salt), DOPE-PEG(2000) Azide
peptides


Carboxylic acid
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-
Amine moieties



[carboxy(polyethylene glycol)-



2000] (sodium salt), DOPE-PEG(2000) Carboxylic acid


Chelator: NTA, diethylenetriamine
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-
gadolinium chelated with


pentaacetic acid, DTPA
diethylenetriaminepentaacetic acid (16:0 PE-DTPA),
diethylenentriaminepentaacetyl



1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-
(DTPA) provides contrast in



carboxypentyl)iminodiacetic acid)
magnetic resonance imaging



succinyl] (18:1 DGS-NTA),



1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-



carboxypentyl)iminodiacetic acid)



succinyl] (Cobalt salt) (18:1 DGS-NTA)(Co),



1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-



carboxypentyl)iminodiacetic acid)



succinyl] (nickel salt) (18:1 DGS-NTA)(Ni),



1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-



N-diethylenetriaminepentaacetic



acid (copper salt), (14:0 PE-DTPA(Cu)),



DTPA-bis(stearylamide) (gadolinium salt), (DTPA-BSA (Gd)),



1,2-distearoyl-sn-glycero-3-phosphoethanolamine-



N-diethylenetriaminepentaacetic



acid (gadolinium salt), (18:0 PE-DTPA (Gd)),



bis(1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine)-N-N′-



diethylenetriaminepentaacetic acid (gadolinium salt)



(bis(14:0 PE)-DTPA(Gd)),



bis(1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine)-N-N′-



diethylenetriaminepentaacetic acid (gadolinium salt)



(bis(16:0 PE)-DTPA(Gd)),



bis(1,2-distearoyl-sn-glycero-3-phosphoethanolamine)-N-N′-



diethylenetriaminepentaacetic acid (gadolinium salt)



(bis(18:0 PE)-DTPA(Gd)),



1,2-distearoyl-sn-glycero-3-phosphoethanolamine-



N-diethylenetriaminepentaacetic



acid (18:0 PE-DTPA).


Magnetic resonance
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-


imaging, MRI imaging
N-diethylenetriaminepentaacetic



acid (gadolinium salt), (16:0 PE-DTPA (Gd)),



1,2-distearoyl-sn-glycero-3-phosphoethanolamine-



N-diethylenetriaminepentaacetic



acid (gadolinium salt), (18:0 PE-DTPA (Gd)),



bis(1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine)-N-N′-



diethylenetriaminepentaacetic acid (gadolinium salt)



(bis(14:0 PE)-DTPA(Gd)),



bis(1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine)-N-N′-



diethylenetriaminepentaacetic acid (gadolinium salt)



(bis(16:0 PE)-DTPA(Gd)),



bis(1,2-distearoyl-sn-glycero-3-phosphoethanolamine)-N-N′-



diethylenetriaminepentaacetic acid (gadolinium salt)



(bis(18:0 PE)-DTPA(Gd)),



1,2-distearoyl-sn-glycero-3-phosphoethanolamine-



N-diethylenetriaminepentaacetic



acid (18:0 PE-DTPA).


polyethylene glycol PEG200,
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-
Surface passivation


PEG350, PEG550, PEG750, PEG1000,
[methoxy(polyethylene glycol)-350], 18:1 PEG350 PE


PEG2000, PEG3000, PEG5000,
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-


PEG20000, PEG50000,
[methoxy(polyethylene glycol)-750], 18:1 PEG750 PE



1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-



[methoxy(polyethylene glycol)-1000], 18:1 PEG1000 PE


Diacetylene
1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphoethanolamine,
Photopolymerization



23:2 Diyne PE [DC(8,9)PE]



1-palmitoyl-2-(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine,



16:0-23:2 Diyne PC



1-palmitoyl-2-(10,12-tricosadiynoyl)-sn-glycero-3-phosphoethanolamine,



16:0-23:2 Diyne PE



1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine,



23:2 Diyne PC [DC(8,9)PC]


Diphytanoyl Lipids
1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine-N-
Lipids containing diphytanoyl



(7-nitro-2-1,3-benzoxadiazol-4-yl), 4ME 16:0 NBD PE (NBD-DPhPE)
fatty acid chains allow to



1,2-diphytanoyl-sn-glycero-3-phosphocholine, 4ME 16:0 PC
produce stable planar lipid



1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine, 4ME 16:0 PE
membranes



1,2-diphytanoyl-sn-glycero-3-phospho-(1′-rac-glycerol),



4ME 16:0 PG



1,2-diphytanoyl-sn-glycero-3-phosphate, 4ME 16:0 PA



1,2-diphytanoyl-sn-glycero-3-phospho-L-serine, 4ME 16:0 PS



phytanoyl Coenzyme A, 4ME 16:0 Coenzyme A



1,2-di-O-phytanyl-sn-glycero-3-phosphocholine, 4ME 16:0 Diether PC



1,2-di-O-phytanyl-sn-glycero-3-phosphoethanolamine,



4ME 16:0 Diether PE



1,2-di-O-phytanyl-sn-glycerol, 4ME 16:0 Diether DG


Fluorinated lipids
1-palmitoyl-2-(16-fluoropalmitoyl)-sn-glycero-3-



phosphocholine, 16:0-16:0 (16-F) PC


Brominated Lipid
1,2-di-(9,10-dibromo)stearoyl-sn-glycero-3-
Fluorescence quenching



phosphocholine, 18:0 (9,10dibromo) PC



1-palmitoyl-2-stearoyl(4,5)dibromo-sn-glycero-



3-phosphocholine, 16:0-18:0(4,5-dibromo) PC



1-palmitoyl-2-(6,7-dibromo)stearoyl-sn-glycero-



3-phosphocholine, 16:0-18:0 (6-7BR) PC



1-palmitoyl-2-(9,10-dibromo)stearoyl-sn-glycero-



3-phosphocholine, 16:0-18:0 (9-10BR) PC



1-palmitoyl-2-(11,12-dibromo)stearoyl-sn-glycero-



3-phosphocholine, 16:0-18:0 (11-12BR) PC









Sulfhydryls, also called thiols, exist in proteins in the side-chain of cysteine (Cys, C) amino acids. Sulfhydryl-reactive chemical groups include haloacetyls, maleimides, aziridines, acryloyls, arylating agents, vinylsulfones, pyridyl disulfides, TNB-thiols and disulfide reducing agents.
Different lipids which are offered for thioether conjugation contain maleimide, aromatic maleimides such as N-[4-(p-maleimidophenyl)-butyryl] (MPB) or 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (MCC) group. The maleimide function group of MCC which contains an aliphatic cyclohexane ring is more stable toward hydrolysis in aqueous reaction environments rather than the aromatic phenyl group of MPB
Carbohydrates are selected from the group comprising β-galactose, α-mannose-, β-mannose-, and α-fucose. It has been shown that said carbohydrates can be conjugated to cholesterols to be incorporated into liposomes, and in vitro results showed that the sugar-conjugated liposomes are efficiently recognized by cells that overexpress carbohydrate-binding receptors on their surface (Rajabi and Mousa, 2016, Current Pharmaceutical Biotechnology, 17, 8).
SNAP-tag is a self-labeling protein tag commercially available in various expression vectors. SNAP-tag is a 182 residues polypeptide (19.4 kDa) that can be fused to any protein of interest and further specifically and covalently tagged with a suitable ligand, such as a fluorescent dye.
A functional ligand for coupling to lipids for carry out the present invention is preferably selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator.
Therefore, one embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the water phase of step a) comprises at least two lipids selected from the group comprising:

        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole.
    
    


A further embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the water phase of step a) comprises at least two lipids selected from the group comprising:

        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine;
        a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole.
    
    


A particular embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the water phase of step a) comprises at least two lipids selected from the group comprising:

        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole.
    
    


A further particular embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for protein conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;
        d′) removing the polymer shell from the polymer shell-stabilized synthetic extracellular vesicles obtained in step d) by adding a surfactant; and
        e) purifying the synthetic extracellular vesicles by centrifugation;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%,

the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm, and

wherein the water phase of step a) comprises at least two lipids selected from the group comprising:

        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator; and
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole.

Suitable Copolymer to Stabilize the Extracellular Vesicles

    
    


In order to allow a good dispersion of the polymer shell stabilized vesicles in the oil phase and in order to allow a good dispersion of the lipid containing aqueous phase within the polymer shell of the vesicle, it is preferred that the polymer shell is made of an amphiphilic copolymer with a hydrophobic end arranged at the outer side and a hydrophilic end arranged at the inner side of the polymer shell.
This may be achieved by forming the polymer shell of the extracellular vesicle, from a diblock copolymer, or a triblock copolymer, to form a water-in-oil droplet.
Good results are particularly obtained, if the polymer shell of the droplet is made of a diblock copolymer consisting of an hydrophobic block arranged at the outer side and a hydrophilic block arranged at the inner side of the polymer shell, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock, so that the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell.
The hydrophobic block may be, but is not restricted to members, e.g. selected from the group consisting of perfluorinated polymers, such as perfluorinated polyethers, polystyrene or poly(olefin oxides), such as poly(propylene oxide), whereas the hydrophilic block may be selected e.g. from polyether glycols, polyetheramine, polyacrylate acid, polymethylacrylate acid or poly[poly(ethylene glycol) methyl ether methacrylate].
Likewise, good results are obtained, if the polymer shell of the droplet is made of a triblock copolymer consisting of two hydrophobic perfluorinated polymer end blocks and therebetween a hydrophilic polyether glycol block, wherein the triblock copolymer is folded so that the hydrophobic perfluorinated polymer blocks are arranged at the outer side and that the hydrophilic polyether glycol block is arranged at the inner side of the polymer shell. Examples for the hydrophobic blocks and the hydrophilic blocks are the same as those mentioned above.
Preferably, the perfluorinated polymer block is a perfluorinated polyether block (PFPE) and more preferably a perfluorinated polyether block having a weight average molecular weight of 1,000 to 10,000 g/mol. Likewise preferably, the polyether glycol (PEG) and polyetheramine (JEFFAMINE) blocks have preferably a weight average molecular weight of 100 to 50,000 g/mol. More specifically, suitable examples for the respective copolymers are PFPE-carboxylic acid (Krytox, MW 2500 or 7000 g/mol) and suitable examples for the respective diblock copolymers are PFPE (7000 g/mol)-PEG (1400 g/mol), PFPE (7000 g/mol)-PEG (600 g/mol), PFPE (2500 g/mol)-PEG (600 g/mol), PFPE (4000 g/mol)-PEG (600 g/mol), PFPE (4000 g/mol)-PEG (1400 g/mol), PFPE (2000 g/mol)-PEG (600 g/mol), PFPE (7000 g/mol)-JEFFAMINE (600 g/mol), PFPE (7000 g/mol)-JEFFAMINE (900 g/mol), PFPE (2500 g/mol)-JEFFAMINE (600 g/mol), PFPE (2500 g/mol)-JEFFAMINE (900 g/mol), PFPE (4000 g/mol)-JEFFAMINE (900 g/mol), PFPE (2500 g/mol)-JEFFAMINE (600 g/mol), PFPE (2000 g/mol)-JEFFAMINE (600 g/mol), PFPE (2000 g/mol)-JEFFAMINE (900 g/mol) and suitable examples for the respective triblock copolymers are PFPE (7000 g/mol)-PEG (1400 g/mol)-PFPE (7000 g/mol), PFPE (7000 g/mol)-PEG (600 g/mol)-PFPE (7000 g/mol), PFPE (4000 g/mol)-PEG (1400 g/mol)-PFPE (4000 g/mol) PFPE (2500 g/mol)-PEG (600 g/mol)-PFPE (2500 g/mol), PFPE (2000 g/mol)-PEG (600 g/mol)-PFPE (2000 g/mol), PFPE (7000 g/mol)-JEFFAMINE (900 g/mol)-PFPE (7000 g/mol) PFPE (7000 g/mol)-JEFFAMINE (600 g/mol)-PFPE (7000 g/mol), PFPE (4000 g/mol)-JEFFAMINE (900 g/mol)-PFPE (4000 g/mol), PFPE (4000 g/mol)-JEFFAMINE (600 g/mol)-PFPE (4000 g/mol), PFPE (2500 g/mol)-JEFFAMINE (900 g/mol)-PFPE (2500 g/mol), PFPE (2500 g/mol)-JEFFAMINE (600 g/mol)-PFPE (2500 g/mol), PFPE (2000 g/mol)-JEFFAMINE (900 g/mol)-PFPE (2000 g/mol) and PFPE (2000 g/mol)-JEFFAMINE (600 g/mol)-PFPE (2000 g/mol). The molecular weight is determined by gel permeation chromatography using a polystyrene standard.
Therefore, the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


Moreover, the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell, wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


In one embodiment, the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase wherein the amphiphilic copolymer is a triblock copolymer consisting of two polyether glycol end blocks and one perfluorinated polymer end block, or of a triblock copolymer consisting of two perfluorinated polymer end blocks and one polyether glycol block, or of a diblock copolymer consisting of one perfluorinated polymer end block and a polyether glycol block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the triblock or diblock copolymer is folded so that the perfluorinated polymer end blocks are arranged at the outer side and that the polyether glycol block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


In one embodiment, the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase wherein the amphiphilic copolymer is a triblock copolymer consisting of two polyether glycol end blocks and one perfluorinated polymer end block, or of a triblock copolymer consisting of two perfluorinated polymer end blocks and one polyether glycol block, or of a diblock copolymer consisting of one perfluorinated polymer end block and a polyether glycol block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the triblock or diblock copolymer is folded so that the perfluorinated polymer end blocks are arranged at the outer side and that the polyether glycol block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

Emulsification Conditions Influencing Extracellular Vesicle Dimension

    
    


One embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier for at least 5 seconds at speed higher than 1,000 rpm;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


Moreover, the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier for at least 5 seconds at speed higher than 1,000 rpm;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


The emulsification procedure is usually performed with a mechanically or electronic emulsifier, for at least 5 seconds at speed higher than 1,000 rpm. This procedure holds the considerable advantage to regulate the vesicle dimension by changing the time and shear stress of emulsification. As shown in Example 2, synthetic extracellular vesicles radii between 292 nm±12 nm, (coefficient of variation (CV)=4.1%; n=3) were obtained by emulsification for 30 sec at 30,000 rpm and radii of 627 nm±15 nm, (CV=2.4%; n=3) were obtained by emulsification for 30 sec at 14,000 rpm.
Notably, this procedure allowed obtaining extracellular vesicles very homogenous in size, as the coefficient of variation of the synthetized extracellular vesicles varied between 2.4%, for vesicles of size 292 nm±12 nm, and 4.1% for vesicles of size 627 nm±15 nm, which are variation levels much lower than observed in the natural exosome samples. Indeed the variation value of commercial K562 exosomes was CV=42.5% for dimensions 468 nm±199 nm, (n=3), and that of exosomes isolated from conditioned K562 cell culture medium was CV=13.3%, for dimensions 240 nm±32 nm (n=3).
Another embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier for at least 20 seconds at speed higher than 10,000 rpm;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


Another particular embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier for at least 20 seconds at speed higher than 10,000 rpm;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle, wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


A further embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, and one or more extracellular vesicle associated proteins, or fragments thereof, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier for at least 20 seconds at speed higher than 14,000 rpm;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

    
    


A further particular embodiment of the present invention is directed to a method for producing synthetic extracellular vesicles comprising:

    
    
        a) providing a water phase comprising at least two lipids, one or more extracellular vesicle associated proteins, or fragments thereof, and one or more nucleic acid molecules, wherein the at least two lipids are a negative charged lipid, and a lipid coupled to a functional ligand for conjugation to an extracellular vesicle associated protein;
        b) providing an amphiphilic copolymer dissolved in an oil phase, wherein the amphiphilic copolymer is a diblock copolymer consisting of a hydrophobic polymer block and a hydrophilic polymer block, or a triblock copolymer consisting of two hydrophobic polymer blocks and a hydrophilic polymer block, and wherein the oil phase comprises a fluorosurfactant triblock;
        c) combining said water phase and said oil phase;
        d) producing polymer shell-stabilized synthetic extracellular vesicles by emulsifying the combined phases of step c) using a mechanic or electronic emulsifier for at least 20 seconds at speed higher than 14,000 rpm;

wherein the amphiphilic copolymer forms a polymer shell stabilizing the synthetic extracellular vesicle,

wherein the one or two hydrophobic polymer blocks are arranged at the outer side and the hydrophilic polymer block is arranged at the inner side of the polymer shell,

wherein the vesicles are homogenous in size showing a coefficient of variation in size lower than 13%, and

wherein the synthetic extracellular vesicles have a hydrodynamic radius between 70 nm and 5000 nm.

Composition of Synthetic Extracellular Vesicles

    
    


A particular embodiment of the present invention is directed to a synthetic extracellular vesicle having a diameter between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole; and
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), glycophorin A (GYPA); acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), intercellular adhesion molecule 1 (CD50, ICAM-1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin A/C, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof.
    
    


A more particular embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), glycophorin A (GYPA); acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), intercellular adhesion molecule 1 (CD50, ICAM-1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin A/C, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof; and one or more nucleic acid molecules selected from the group comprising DNA, cDNA, mRNA, siRNA, antisense nucleotides, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats guide RNA, and miRNA.
    
    


A still more particular embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), glycophorin A (GYPA); acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), intercellular adhesion molecule 1 (CD50, ICAM-1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof; and
        one or more nucleic acid molecules selected from the group comprising DNA, cDNA, mRNA, siRNA, antisense nucleotides, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats guide RNA, miRNA, wherein the miRNA is selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a.
    
    


As mentioned above, in certain embodiments, the synthetic extracellular vesicle is an exosome. In certain embodiments, the synthetic extracellular vesicle is a microvesicle.
A particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above and specifically comprising:

    
    
        a lipid bilayer comprising cholesterol, N-stearoyl-D-erythro-sphingosylphosphorylcholine (SM), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), 1,2-dioleoyl-sn-glycero-3-phospho-ethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt) (PA), diacylglycerol, phosphatidylinositol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+));
        one or more nucleic acid molecules selected from the group comprising miRNA miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132; and
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above and specifically comprising:

    
    
        one or more functional protein nicotinamide phosphoribosyltransferase, or a fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof;
        one or more cytosolic proteins selected from the group comprising Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), tumour susceptibility gene 101 protein (TSG101), or a fragment thereof; and
        wherein the synthetic extracellular vesicle does not comprise transferrin and albumin, or a fragment thereof.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above and specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising MHCII, CD80, and CD86, or a fragment thereof;
        optionally one or more transmembrane proteins selected from the group comprising CD11c, MHCI, integrin α, integrin β-chains, ICAM-1, and CD71, or a fragment thereof; and
        one or more functional proteins selected from the group comprising cytokines, interleukins, interleukin 4, milk fat globule-EGF factor 8 protein (MFGE8), growth factors, Fas, Fas Ligand (FasL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein (CTLA4-Ig), tumor necrosis factor-related apoptosis-inducing ligand (Apo2L, TRAIL), or a fragment thereof.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above and specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+));
        functional protein Fas Ligand, or a fragment thereof; and
        optionally functional protein intercellular adhesion protein-1, or a fragment thereof.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above and specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+)); a fragment of functional protein Fas Ligand;
        optionally functional protein intercellular adhesion protein-1, or a fragment thereof;

wherein the Fas Ligand fragment comprises amino acids Pro134-Leu281 (FasL protein ID NM_000639.1); and

wherein the intercellular adhesion protein-1 fragment comprises amino acids 1-480 of ICAM-1 (protein ID P05362).

    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising CD29, CD44, CD90, CD73, CD44, Sca-1, ora fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63, and CD81, or a fragment thereof;
        one or more functional proteins selected from the group comprising Wnta and Wntb, or a fragment thereof;
        at least one nucleic acid molecule selected from the group comprising miR-140-5p, miR-92a-3p-e;
        one or more nucleic acid molecules selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a, let-7a, miR-21, miR124, miR126, miR-133b, miR-191, miR-222, miR-494, miR-6087, miR-30d-5p; and
        optionally one or more nucleic acid molecules selected from the group comprising miR-33b, miR-451, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-K12-3.
    
    


A further particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+)); and functional protein RANK, or a fragment thereof.
    
    


A further more particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+)); and a fragment of functional protein RANK, wherein said fragment of functional protein RANK comprises amino acids 31-214 (RANK protein ID O35305).

Uses of the Disclosed Extracellular Vesicles

    
    


The examples of the present invention show that the synthetic extracellular vesicles are able to deliver their protein and nucleic acid contents into target cells, thus affecting their gene expression, protein expression, signalling pathways and metabolism.
Thus, the inventive synthetic extracellular pathways can be used for therapy of a wide range of disorders by acting at cellular levels.
For example, it has been here shown that the synthetic extracellular vesicles resembling those of fibrocyte origin can stimulate epithelial cell proliferation, migration, and collagen deposition, ultimately leading to wound healing.
Therefore, one embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole; and
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), glycophorin A (GYPA); acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


A particular embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), glycophorin A (GYPA); acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin A/C, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof; and
        one or more nucleic acid molecules selected from the group comprising DNA, cDNA, mRNA, siRNA, antisense nucleotides, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats guide RNA, and miRNA;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


A more particular embodiment of the present invention is directed to a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N″-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, aromatic maleimid, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, cyanuric chloride, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), glycophorin A (GYPA); acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof; and
        one or more nucleic acid molecules selected from the group comprising DNA, cDNA, mRNA, siRNA, antisense nucleotides, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats guide RNA, miRNA, wherein the miRNA is selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


In certain embodiments, the extracellular vesicle is an exosome. In certain embodiments, the extracellular vesicle is a microvesicle.
One preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising cholesterol, N-stearoyl-D-erythro-sphingosylphosphorylcholine (SM), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), 1,2-dioleoyl-sn-glycero-3-phospho-ethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt) (PA), diacylglycerol, phosphatidylinositol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+));
        one or more nucleic acid molecules selected from the group comprising miRNA miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132; and
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


A preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising cholesterol, N-stearoyl-D-erythro-sphingosylphosphorylcholine (SM), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), 1,2-dioleoyl-sn-glycero-3-phospho-ethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt) (PA), diacylglycerol, phosphatidylinositol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+));
        one or more nucleic acid molecules selected from the group comprising miRNA miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132; and
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising epithelial diseases, cosmetic procedures, coagulation disorders.

    
    


A particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        one or more functional protein nicotinamide phosphoribosyltransferase, or a fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof; and
        one or more cytosolic proteins selected from the group comprising Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), tumour susceptibility gene 101 protein (TSG101), or a fragment thereof;
        wherein the synthetic extracellular vesicle does not comprise transferrin and albumin, or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


A particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        one or more functional protein nicotinamide phosphoribosyltransferase, or a fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof; and
        one or more cytosolic proteins selected from the group comprising Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), tumour susceptibility gene 101 protein (TSG101), or a fragment thereof;
        wherein the synthetic extracellular vesicle does not comprise transferrin and albumin, or a fragment thereof,

for use in the treatment of age-associated disorders.

    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising MHCII, CD80, and CD86, or a fragment thereof;
        optionally one or more transmembrane proteins selected from the group comprising CD11c, MHCI, integrin α, integrin β-chains, ICAM-1, and CD71, or a fragment thereof; and
        one or more functional proteins selected from the group comprising cytokines, interleukins, interleukin 4, milk fat globule-EGF factor 8 protein (MFGE8), growth factors, Fas, Fas ligand (FasL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein (CTLA4-Ig), tumor necrosis factor-related apoptosis-inducing ligand (Apo2L, TRAIL), or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising MHCII, CD80, and CD86, or a fragment thereof;
        optionally one or more transmembrane proteins selected from the group comprising CD11c, MHCI, integrin α, integrin β-chains, ICAM-1, and CD71, or a fragment thereof; and
        one or more functional proteins selected from the group comprising cytokines, interleukins, interleukin 4, milk fat globule-EGF factor 8 protein (MFGE8), growth factors, Fas, Fas ligand (FasL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein (CTLA4-Ig), tumor necrosis factor-related apoptosis-inducing ligand (Apo2L, TRAIL), or a fragment thereof;
        for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, epithelial diseases, autoimmune disorders, infectious diseases, diabetes, age-associated disorders.
    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+));
        functional protein Fas Ligand, or a fragment thereof; and
        optionally functional protein intercellular adhesion protein-1, or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+));
        functional protein Fas Ligand, or a fragment thereof; and
        optionally functional protein intercellular adhesion protein-1, or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, autoimmune disorders, infectious diseases.

    
    


Another particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising CD29, CD44, CD90, CD73, CD44, Sca-1, or a fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63, and CD81, or a fragment thereof;
        one or more functional proteins selected from the group comprising Wnta and Wntb, or a fragment thereof;
        at least one nucleic acid molecule selected from the group comprising miR-140-5p, miR-92a-3p-e;
        one or more nucleic acid molecules selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a, let-7a, miR-21, miR124, miR126, miR-133b, miR-191, miR-222, miR-494, miR-6087, miR-30d-5p; and
        optionally one or more nucleic acid molecules selected from the group comprising miR-33b, miR-451, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-K12-3;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Another more particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+)); and functional protein RANK, or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Another more particularly preferred embodiment of the present invention is directed to a synthetic extracellular vesicle between 70 nm and 5000 nm specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+)); and functional protein RANK, or a fragment thereof;

for use in the treatment of a disorder selected from the group comprising osteoarthritis, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle as disclosed herein, wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.
Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine;
        a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole;
        one or more nucleic acid molecules selected from the group comprising DNA, cDNA, mRNA, siRNA, antisense nucleotides, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) guide RNA, miRNA molecules selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a; miR-21, miR-30d-5p, miR-33b, miR-124, miR-125, miR-126, miR-130, miR-132, miR-133b, miR-140-5p, miR-191, miR-222, miR-451, miR-494, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-6087, miR-92a-3p-e, miR-K12-3, let-7a; and
        one or more extracellular vesicle associated proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle as disclosed herein, wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.
Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl-3-dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine; a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole;
        one or more nucleic acid molecules selected from the group comprising DNA, cDNA, mRNA, siRNA, antisense nucleotides, shRNA, piRNA, snRNA, lncRNA, PNA, left handed DNA, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) guide RNA, miRNA molecules; and
        one or more extracellular vesicle associated proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin A/C, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle as disclosed herein, wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.
Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle having a hydrodynamic radius between 70 nm and 5000 nm, comprising:

    
    
        a lipid bilayer comprising at least two lipids selected from the group comprising:
        a neutral lipid selected from the group comprising ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, lysophosphatidylethanolamine, lysoethanolamines, inverted headgroup lipids, sphingosins, sterol-modified phospholipids, ether ester lipids, diether lipids, vinyl ether (plasmalogen);
        an anionic lipid selected from the group comprising phosphatidic acids, lysophosphatidic acid derivatives, phosphatidylglycerols, lysophosphatidylglycerols, phosphatidylserines, lysophosphatidylserines, phosphatidylinositols, phosphatidylinositolphosphates, cardiolipins, Bis(Monoacylglycero)Phosphate derivatives;
        a cationic lipid selected from the group comprising dioleyl-N,N-dimethylammonium chloride; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; N,N-distearyl-N,N-dimethylammonium bromide; N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride; 3β-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol; 1,2-dimyristyloxypropyl dimethyl-hydroxy ethyl ammonium bromide; 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate; dioctadecylamidoglycyl carboxyspermine; N-(2,3-dioleyloxy)propyl)-N,N-dimethylammonium chloride and 1,2-Dioleoyl dimethylammonium-propane;
        a pH-sensitive lipid selected from the group comprising lipid N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-distearoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-sn-glycero-3-succinate, 1,2-dioleoyl-sn-glycero-3-succinate, N-palmitoyl homocysteine;
        a photoswitchable lipid;
        acylglycine derivatives, prenol derivatives, prostaglandine derivatives, glycosylated diacyl glycerols, eicosanoid derivatives, (palmitoyloxy)octadecanoic acid derivatives, diacetylene derivatives, diphytanoyl derivatives, fluorinated lipids, brominated lipids, lipopolysaccharides;
        one of the aforementioned lipids coupled to a functional ligand selected from the group comprising biotin, N-hydroxysuccinimide ester, nitrilotriacetic acid-nickel, amine, carboxylic acid, maleimides, dithiopyridinyl, pyridyl disulfide, pyridyldithiopropionate, N-benzylguanine, carboxyacyl, cyanur, folate, square, galloyl, glycan, thiol, arginylglycylaspartic acid, a fluorescent dye molecule, a magnetic resonance imaging reagent, a chelator;
        one of the aforementioned lipids coupled to polyethyleneglycol with a molecular weight comprised between 350 and 50,000 g/mole; and one or more extracellular vesicle associated proteins selected from the group comprising tetraspanin proteins CD9, CD37, CD47, CD53, CD63, CD81, CD82, CD151, Tspan8, heterotrimeric G protein subunit alpha (GNA), integrin α-chains, integrin β-chains, transferrin receptor 1 (TfR1, CD71), transferrin receptor 2 (TFR2), lysosome associated membrane proteins (LAMP1, LAMP2), heparan sulfate proteoglycans, syndecans, extracellular matrix metalloproteinase inducer (EMMPRIN, BSG), A Disintegrin And Metalloproteinase Domain 10 (ADAM10), CD3, CD11c, CD14, CD29, CD31, CD41, CD42a, CD44, CD45, CD50 (intercellular adhesion molecule 1, ICAM-1), CD55, CD59, CD73, CD80, CD86, CD90, sonic hedgehog (SHH), major histocompatibility complex I (MHCI), major histocompatibility complex II (MHCII), epidermal growth factor receptor 2 (ERBB2), epithelial cell adhesion molecule (EpCAM), Glycophorin A (GYPA); Acetylcholinesterase S and E (AChE-S, AChE-E), amyloid beta precursor protein (APP), multidrug resistance-associated protein 1 (ABCC1), stem cells antigen-1 (Sca-1), protein complexes endosomal sorting complexes required for transport ESCRT-I, ESCRT-II, and ESCRT-III, tumour susceptibility gene 101 (TSG101), charged multivesicular body protein (CHMP), Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), vacuolar protein sorting 4 homolog A 4A and 4B, arrestin domain-containing protein (ARRDC1), flotillin-1, flotillin-2; caveolins, EH-domain containing 1-4 (EHD1-EHD4), Ras homolog family member A (RHOA), annexins, heat shock proteins, ADP-ribosylation factor 6 (ARF6), syntenin, microtubule-associated protein Tau (MAPT), cytokines, growth factors, interleukins, milk fat globule-EGF factor 8 protein (MFGE8), adhesion proteins, extracellular matrix proteins, nicotinamide phosphoribosyltransferase, signal transduction proteins, Wnta, Wntb, Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein, tumor necrosis factor-related apoptosis-inducing ligand, histone proteins, lamin NC, inner membrane mitochondrial protein (IMMT), cytochrome C-1 (CYC1), mitochondrial import receptor subunit TOM20, calnexin, heat shock protein 90 kDa beta (Grp94), member 1 (HSP90B1), heat shock 70 kDa protein 5 (HSPA5), Golgin A2 (GM130, GOLGA2), Autophagy Related 9A (ATG9A), actinin1, actinin4 (ACTN1, ACTN4), cytokeratin 18 (KRT18), or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above and specifically comprising:

    
    
        a lipid bilayer comprising cholesterol, N-stearoyl-D-erythro-sphingosylphosphorylcholine (SM), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), 1,2-dioleoyl-sn-glycero-3-phospho-ethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt) (PA), diacylglycerol, phosphatidylinositol, 1,2-dioleoyl-sn-glycero phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+));
        one or more nucleic acid molecules selected from the group comprising miRNA miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132; and
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above and specifically comprising:

    
    
        one or more functional protein nicotinamide phosphoribosyltransferase, or a fragment thereof;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63 and CD81, or a fragment thereof;
        one or more cytosolic proteins selected from the group comprising Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), tumour susceptibility gene 101 protein (TSG101), or a fragment thereof; and
        wherein the synthetic extracellular vesicle does not comprise transferrin and albumin, or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above, and specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising MHCII, CD80, and CD86, or a fragment thereof;
        optionally one or more transmembrane proteins selected from the group comprising CD11c, MHCI, integrin α-chains, integrin β-chains, ICAM-1, and CD71, or a fragment thereof; and
        one or more functional proteins selected from the group comprising cytokines, interleukins, interleukin 4, milk fat globule-EGF factor 8 protein (MFGE8), growth factors, Fas, Fas ligand (FasL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein (CTLA4-Ig), tumor necrosis factor-related apoptosis-inducing ligand (Apo2L, TRAIL), or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above, and specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+)); functional protein Fas Ligand, or a fragment thereof; and
        optionally functional protein intercellular adhesion protein-1, or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Also described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above, and specifically comprising:

    
    
        one or more transmembrane proteins selected from the group comprising CD29, CD44, CD90, CD73, CD44, Sca-1, or a fragment thereof;
        one or more functional proteins selected from the group comprising Wnta and Wntb, or a fragment thereof;
        at least one nucleic acid molecule selected from the group comprising miR-140-5p, miR-92a-3p-e;
        one or more transmembrane proteins selected from the group comprising tetraspanin proteins CD9, CD63, and CD81, or a fragment thereof;
        one or more nucleic acid molecules selected from the group comprising miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a, let-7a, miR-21, miR124, miR126, miR-133b, miR-191, miR-222, miR-494, miR-6087, miR-30d-5p; and
        optionally one or more nucleic acid molecules selected from the group comprising miR-33b, miR-451, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-K12-3;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


Further described herein is a method for treating or ameliorating a disorder comprising administering to a patient suffering from said disorder a therapeutically effective amount of a synthetic extracellular vesicle between 70 nm and 5000 nm with the composition described above, and specifically comprising:

    
    
        a lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (LissRhod PE), 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl] (nickel salt) (DGS-NTA(Ni2+)); and functional protein RANK, or a fragment thereof;

wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.

    
    


“Disorder” is any condition that would benefit from treatment with a substance/molecule or method described herein.
“Cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation, such as cancer.
“Cancer” and “cancerous” refer to, or describe a physiological condition in mammals that is typically characterized by a cell proliferative disorder. Cancer generally can include, but is not limited to, carcinoma, lymphoma (e.g., Hodgkin's and non-Hodgkin's lymphoma), blastoma, sarcoma, and leukemia. More specific examples of cancer can include, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, leukemia and other lymphoproliferative disorders, and various types of head and neck cancer.
“Tumour” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer”, “cancerous”, “cell proliferative disorder”, “proliferative disorder”, and “tumour” are not mutually exclusive as referred to herein.
“Cardiovascular disorders” include but are not limited to disorders of the heart and the vascular system like congestive heart failure, myocardial infarction, ischemic diseases of the heart, all kinds of atrial and ventricular arrhythmias, hypertensive vascular diseases, peripheral vascular diseases, and atherosclerosis.
“Metastasis” refers to the spread of cancer and/or tumour from its primary site to other places in the body of an individual.
The term “neurodegenerative disease” or “neurological disorder” or “neuroinflammatory disorder” refers to any disease, disorder, or condition affecting the central or peripheral nervous system. Preferred examples of neurodegenerative diseases and neuroinflammatory disorders are selected from the group comprising or consisting of: Alzheimer's disease, Parkinson's disease, Creutzfeldt Jakob disease (CJD), new variant of Creutzfeldt Jakobs disease (nvCJD), Hallervorden Spatz disease, Huntington's disease, multisystem atrophy, dementia, frontotemporal dementia, motor neuron disorders of multiple spontaneous or genetic background, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, spinocerebellar atrophies (SCAs), schizophrenia, affective disorders, major depression, meningoencephalitis, bacterial meningoencephalitis, viral meningoencephalitis, CNS autoimmune disorders, multiple sclerosis (MS), acute ischemic/hypoxic lesions, stroke, CNS and spinal cord trauma, head and spinal trauma, brain traumatic injuries, arteriosclerosis, atherosclerosis, microangiopathic dementia, Binswanger' disease (Leukoaraiosis), retinal degeneration, cochlear degeneration, macular degeneration, cochlear deafness, AIDS-related dementia, retinitis pigmentosa, fragile X-associated tremor/ataxia syndrome (FXTAS), progressive supranuclear palsy (PSP), striatonigral degeneration (SND), olivopontocerebellear degeneration (OPCD), Shy Drager syndrome (SDS), age dependant memory deficits, neurodevelopmental disorders associated with dementia, Down's Syndrome, synucleinopathies, superoxide dismutase mutations, trinucleotide repeat disorders as Huntington's Disease, trauma, hypoxia, vascular diseases, vascular inflammations, CNS-ageing. Also age dependant decrease of stem cell renewal may be addressed.
“Aging-associated disorders and diseases” are most often seen with increasing frequency with increasing senescence. Examples of aging-associated diseases are atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and Alzheimer's disease. The incidence of all of these diseases increases exponentially with age.
“Rheumatic diseases” are characterized by inflammation that affects the connecting or supporting structures of the body; most commonly the joints, but also sometimes the tendons, ligaments, bones, and muscles. Some rheumatic diseases even affect the organs. These diseases can ultimately cause loss of function in those body parts. Preferred examples of rheumatic diseases and are selected from the group comprising or consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, systemic lupus erythematosus, gout, juvenile idiopathic arthritis, arthritis, scleroderma.
“Epithelial diseases” include acne, atopic eczema, atopic dermatitis, contact dermatitis, impetigo, psoriasis, sunburn, sweating disorders, yeast infections of the mucous membranes.
“Endocrinology disorders” include diabetes, adrenal insufficiency, cushing's disease, gigantism, hyperthyroidism, hypothyroidism, hypopituitarism, polycystic ovary syndrome.
Neuroendocrine disorders are disorders that affect the interaction between the nervous system and the endocrine system. Examples of neuroendocrine disorders include diabetes insipidus, Kallman syndrome, neuroendocrine cancer, and neuroendocrine tumors (NETs), which are neoplasms that arise from cells of the endocrine and nervous systems.
“Bone and cartilage disorders” include diseases or injuries that affect human bones and cartilage.
“Osteoarthritis” is one of the leading causes of disability in adults worldwide. It is a degenerative disease of the joints secondary to many predisposing factors, most notably age, joint injury, altered mechanical stress, and obesity. All these processes cause a local chronic inflammatory response resulting in the progressive joint failure characteristic of osteoarthritis.
“Osteoporosis” is the result of cumulative bone loss during aging. Nevertheless, a wide variety of diseases, medications, and lifestyles can cause or contribute to the development of osteoporosis. In addition, the immune system participates in the regulation of bone homeostasis through production of cytokines and inflammatory mediators with subsequent activation of cartilage-degrading proteinases.
“Paget's disease” is a chronic skeletal disorder, caused by enhanced bone resorption followed by abnormal bone formation, in which a potential cross talk between the bone and the immune system takes place.
Other bone related disorders include renal osteodystrophy, osteopetrosis, rickets.
“Cartilage disorders” include osteoarthritis, costochondritis enchondromatosis, herniation, achondroplasia, relapsing polychondritis, chondroma, chondrosarcoma.
“Treatment”, “treat” or “treating” refer to clinical intervention in an attempt to alter the natural course of a disorder in the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desired results of treatment can include, but are not limited to, preventing occurrence or recurrence of the disorder, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disorder, preventing metastasis, decreasing the rate of progression, amelioration or palliation of a disease state, and remission or improved prognosis. For example, treatment can include administration of a therapeutically effective amount of a pharmaceutical formulation comprising a synthetic extracellular vesicle disclosed herein to a subject to delay development or slow progression of a disorder, wherein the disorder is selected from the group comprising inflammation, cancer, rheumatic disorder, severe graft versus host disease, osteoarthritis, cardiovascular disorder, epithelial diseases, neurodegenerative disorders, autoimmune disorders, bone and cartilage disorders, osteoporosis, renal osteodystrophy, Paget's disease of bone, osteopetrosis, rickets, neurological disorders, intoxication, neuroendocrinology disorders, endocrinology disorders, genetic disorders, infectious diseases, dental disorders, cosmetic procedures, coagulation disorders, dermatoses, diabetes, age-associated disorders.
“Pharmaceutical formulation” refers to a preparation in a form that allows the biological activity of the active ingredient (s) to be effective, and which contain no additional components which are toxic to the subjects to which the formulation is administered.
“Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to the subject to whom it is administered. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
“Therapeutically effective amount” refers to the amount of an active ingredient or agent (e.g., a pharmaceutical formulation) to achieve a desired therapeutic or prophylactic result, e.g., to treat or prevent a disease or disorder in a subject. In the case of a cancer, the therapeutically effective amount of the therapeutic agent is an amount that reduces the number of cancer cells; reduces the primary tumour size; inhibits (i.e. slows to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibits (i.e. slows to some extent and preferably stop) tumour metastasis; inhibits, to some extent, tumour growth; and/or relieves to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy in vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life.
“Individual” or “subject” refers to a mammal, including but not limited to, domesticated animals (e.g. cows, sheep, cats, dogs, and horses), primates (e.g. humans and non-human primates such as monkeys), rabbits, and rodents (e.g. mice and rats).
A “therapeutic agent” or “therapeutic molecule” includes a compound or molecule that, when present in an effective amount, produces a desired therapeutic effect, pharmacologic and/or physiologic effect on a subject in need thereof. It includes any compound, e.g. a small molecule drug, or a biologic (e.g., a polypeptide drug or a nucleic acid drug) that when administered to a subject has a measurable or conveyable effect on the subject, e.g., it alleviates or decreases a symptom of a disease, disorder or condition.
As used herein, the term “antibody” encompasses an immunoglobulin whether natural or partly or wholly synthetically produced, and fragments thereof. The term also covers any protein having a binding domain that is homologous to an immunoglobulin binding domain. “Antibody” further includes a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. Use of the term antibody is meant to include whole antibodies, polyclonal, monoclonal and recombinant antibodies, fragments thereof, and further includes single-chain antibodies, humanized antibodies, murine antibodies, chimeric, mouse-human, mouse-primate, primate-human monoclonal antibodies, anti-idiotype antibodies, antibody fragments, such as, e.g., scFv, (scFv)2, Fab, Fab′, and F(ab′)2, F(abl)2, Fv, dAb, and Fd fragments, diabodies, and antibody-related polypeptides. Antibody includes bispecific antibodies and multispecific antibodies so long as they exhibit the desired biological activity or function.



DESCRIPTION OF THE FIGURES
FIG. 1 shows a schematic representation of the production pipeline for bottom-up assembly of fully synthetic extracellular vesicles within a stabilizing polymer shell.
FIG. 2 shows quantification of lipid ratios (18:1 DOPI, 18:1 DAG, 18:1 PA, 18:1 DOPG, 18:1 DOPE, 18:1 DOPS, 18:1 DOPC, SM, Cholesterol) in the starting small unilamellar vesicles and in the produced synthetic extracellular vesicles as quantified by electrospray-ionization tandem mass spectrometry. These results are compared to the corresponding expected lipid ratio according to design of fully synthetic extracellular vesicles.
FIG. 3 shows transmission electron micrographs of uranyl acetate negative stained natural and synthetic vesicles. Left panel shows extracellular vesicles (black arrows) isolated from 48 hours conditioned K562 cell culture media by differential ultracentrifugation. Middle panel shows extracellular vesicles isolated from conditioned K562 media by a commercial distributer. Right panel shows fully synthetic extracellular vesicles produced with the lipid composition 70 mol % DOPC, 5 mol % DOPE, 20 mol % DOPG, 5 mol % DOPS according to one embodiment of the invention. Scale bars 100 nm, 100 nm and 1 μm, respectively.
FIG. 4 shows denaturating SDS polyacrylamide gel electrophoretic characterization of synthetic extracellular vesicles protein content. 3 μg of two different production batches of K562 Extracellular vesicles isolated by a commercial distributer were loaded on lane 1 and 2. 3 μg extracellular vesicles from two separate isolations of K562 cells were loaded on lane 3 and 4. 500 ng of synthetic extracellular vesicles from two separate assemblies and decorated with the extracellular domains of CD9 (Ser112-Ile195) and TSG101 (Gly1-Pro145) were loaded on lane 5 and 6. Normalized Line profile intensities of respective lanes are shown on the right.
FIG. 5 shows representative confocal microscopy images of fully synthetic extracellular vesicles containing LissRhodamine B PE lipids, Alexa488 labeled CD9 (CD9) and Hoechst 33342 labeled miRNAs miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132. Scale bar is 2 μm.
FIG. 6 shows single plan fluorescence confocal microscopy images of synthetic extracellular vesicles labelled with rhodamine B PE (left panel) and incubated with HaCaT keratynocytes stained with wheat germ agglutinin (WGA)-Alexa647 (middle panel) for 24 hours. Synthetic extracellular vesicles are internalized and co-localized with the WGA stained endosomes (right panel). Scale bar is 5 μm.
FIG. 7 shows (a and b) fluorescence intensity analysis of Hoechst 33342 stained HaCaT keratinocyte cultures to compare the effect of synthetic extracellular vesicles differing for the composition in tetraspanins or miRNAs, after treatment for 48 hours. Results are shown as mean±SD, n=3 technical replicates.
FIG. 8 shows phase contrast images of cell exclusion in vitro wound healing assays after 16 hours of migration of HaCaT monolayers pre-treated with the indicated different synthetic extracellular vesicles for 24 hours.
FIG. 9 shows in vitro quantification of wound healing migration assay of HaCaT keratinocyte monolayers treated for 24 hours with extracellular vesicles decorated with different tetraspanins, showed also in FIG. 7. Box-plots show mean values, 0.75 and 0.25 quantile values, whiskers show maximum and minimum values, n=4 artificial wound sides.
FIG. 10 shows in vitro quantification of wound healing migration assay of HaCaT keratinocyte monolayers treated for 24 hours with extracellular vesicles having different miRNAs, and showed also in FIG. 7. Box-plots show mean values, 0.75 and 0.25 quantile values, whiskers show maximum and minimum values, n=4 artificial wound sides.
FIG. 11 shows enzyme-linked immunosorbent assay analysis of pro-collagen-la deposition of dermal fibroblasts after treatment for 24 hours with CD9, CD63 and CD81 decorated synthetic extracellular vesicles with different miRNA compositions. Results are shown as mean±SD, n=3 technical replicates.
FIG. 12 shows hematoxilin/eosin stained histological sections of epidermal-wounded full thickness human organotypic skin models treated with the synthetic extracellular vesicles (fsEVs) or only the buffer control for 48 hours. Scale bar is 1 mm.
FIG. 13 shows quantification of epidermal wound-bed closure of full thickness human organotypic skin models from FIG. 11 treated with 2% human serum (positive control), buffer treated controls (negative control) and synthetic extracellular vesicles loaded with miRNAs miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132 and decorated with CD9, CD63 and CD81. Results are shown as mean±SD, n=3 individual organotypic cultures.
FIG. 14 shows quantification of epidermal wound-bed closure of full thickness human organotypic skin models treated with synthetic extracellular vesicles or only the soluble miRNA and tetraspanin components for 48 hours. Results are shown as mean±SD, n=3 individual organotypic cultures.
FIG. 15 shows effect of synthetic extracellular vesicles on migration of A431 carcinoma cells, analysed by an in vitro wound healing migration assay of A431 carcinoma monolayers treated for 24 hours with synthetic extracellular vesicle variants. Box-plots show mean, 0.75 and 0.25 quantile, whiskers show maximum and minimum values, n=4 artificial wound sides
FIG. 16 shows effect of synthetic extracellular vesicles on proliferation of A431 carcinoma cells. Fluorescence intensity analysis of Hoechst 33342 stained A431 cells after treatment with synthetic extracellular vesicles of different composition for 48 hours. Results are shown as mean±SD, n=3 technical replicates.
FIG. 17 shows quantification of ERK phosphorylation at amino acids 202/204 in MC-3T3 cells after incubation for 24 hours with RANK presenting synthetic extracellular vesicles of different radii (292 nm, 615 nm) or soluble RANK alone. Bars represent mean values±SD, n=3 technical replicates.
FIG. 18 shows bottom-up assembly of Fas Ligand (FasL) comprising synthetic extracellular vesicles. A) cryo-electron microscospy image of synthetic extracellular vesicles conjugated with recombinant extracellular domain of FasL. B) Live cell fluorescence time laps imaging of HaCaT cells incubated with FasL-synthetic extracellular vesicles (black arrow arrows). Upon contact formation with the synthetic extracellular vesicles (white arrow at 30 min), cells undergo progressive cells death, form blebs and stain positive for propidium iodide (white arrow at 480 min). C) Plate reader quantification of propidium iodide signals of Jurkat T-cells incubated with FasL-synthetic extracellular vesicles (vFasL), or with soluble FasL (sFasL), or left untreated as control. Bars represent mean values±SD, n=3 biological replicates.
FIG. 19 shows caspase-8 activation in human dermal fibroblasts (BJ cells) incubated with Fas Ligand (FasL) comprising synthetic extracellular vesicles (vFasL). a) Analysis by fluorescence microscopy: left column shows staining for activated caspase 8, i.e. cleaved at Asp391 (white arrows), and DAPI stained nuclei. Right column shows corresponding bright field images. b) Time-analysis of staining intensity of propidium iodide of BJ cells incubated with FasL comprising synthetic extracellular vesicles (vFasL) at concentration 28 ng/ml and 5.6 ng/ml (amount of vesicular FasL/ml). c) Time-analysis of staining intensity of propidium iodide of BJ cells incubated with 107 vesicles and 108 vesicles of FasL comprising synthetic extracellular vesicles (vFasL).
FIG. 20 Optimization of FasL-ICAM ratio present on surface of synthetic extracellular vesicles. Jurkat T-cells were incubated with synthetic extracellular vesicles having the different indicated FasL-ICAM ratios for 24 hours and cell death was quantified by propidium iodide (PI) staining. Bars represent mean values±SD, n=3 biological replicates.
FIG. 21 shows assessment of FasL cytotoxicity on Jurkat and K562 cells at different concentrations of Fas Ligand (FasL) comprising synthetic extracellular vesicles (vFasL) or soluble FasL (sFasL). Cells were incubated with the different preparations and propidium iodide staining intensity was quantified after 24 hours.
FIG. 22 shows stability of the extracellular vesicles after storage in human serum at 4° C., calculated as cellular fluorescence retention normalized to untreated control cells (retention=1). fsEV=fully synthetic extracellular vesicles.
FIG. 23 shows assessment of NTA(Ni2+) directed protein density on vesicle membranes. a) Representative transmission electron microscopy images of uranyl acetate negative stained vesicles harboring different NTA(Ni2+) concentrations and incubated with histidine-tagged protein G immobilized IgG conjugated to gold-nanoparticles. Scale bar is 500 nm. A1=0 mol % NTA(Ni2+), A2=1 mol % NTA(Ni2+), A3=2 mol % NTA(Ni2+). Black points are the gold nanoparticles. b) Quantification of the gold nanoparticle density on the surface of vesicles harboring different NTA(Ni2+) concentrations. c) Quantification of PI staining intensity in Jurkat cell cultures treated with 28 ng/ml vFasL on vesicles harbouring 1 mol % and 5 mol % DGS-NTA(Ni2+) after 24 h of incubation. Results are shown as mean±SD from three biological triplicates.



EXAMPLES
Materials
18:1 DOPG 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), 18:1 DOPC 1,2-dioleoyl-sn-glycero-3-phosphocholesteroline, 18:1 DOPE 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, LissRhod PE 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl), 18:1 DGS-NTA(Ni) 1,2-dioleoyl-sn-glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid)succinyl] (nickel salt), 18:1 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol) (ammonium salt), 18:1 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (sodium salt), 18:1 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate (sodium salt), cholesterol, 18:1 1-2-di-(9Z-octadecenoyl)-sn-glycerol, 18:0 N-stearoyl-D-erythro-sphingosylphosphorylcholine and extrude set with 50 nm pore size polycarbonate filter membranes were purchased from Avanti Polar Lipids, USA. All lipids were stored in chloroform at −20° C. and used without further purification. Hoechst 33342, CellTracker Green CMFDA dye, wheat germ agglutinin (WGA)-AlexaFluor conjugates (obtained from Thermo Fisher scientific, Invitrogen), Dulbecco's Modified Eagle Medium (DMEM) high Glucose, heat inactivated as well as exosome depleted fetal bovine serum, recombinant N-terminal His-tagged human CD9 (amino acids 103-203), penicillin-streptomycin (10,000 U/mL), L-Glutamine (200 mM), Alexa Fluor 488 NHS Ester, trypsin-EDTA (0.05%) with phenol red and phosphate buffered saline were purchased from Thermo Fischer Scientific, Germany. 1H,1H,2H,2H-Perfluoro-1-octanol (PFO) de-emulsifier and human male plasma serum were purchased from Sigma Aldrich, Germany. Bovine albumin fraction V (BSA) was purchased from Carl Roth, Germany. HaCaT cells were obtained from CLS cell line service, Germany. A431, K562, MC 3T3, and BJ cell lines as well as Iscove's Modified Dulbecco's Medium were obtained from ATCC, USA. Atto488 conjugated 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine was purchased from Atto-Tec GmbH, Germany. Caspase 8 (Cleaved Asp391) monoclonal antibody (clone S.147.8) was purchased from Thermo Fischer Scientific, Germany. Purified Mouse Anti-ERK1/2 (pT202/pY204) was purchased from BD biosciences (Cat. No. 612358). Recombinant N-terminal His-tagged human CD9 (protein ID P21926 amino acids 112-195) was purchased from Novus Biologicals, Germany. Recombinant N-terminal His-tagged human TSG101 (protein ID Q99816, amino acids 1-145) was purchased from Fitzgerald, USA. Recombinant N-terminal His-tagged human CD81 (protein ID P35762, amino acids 113-201) was purchased from MyBioSource, USA. Recombinant N-terminal His-tagged human CD63 (protein ID P08962, amino acids Ala 103-Val 203) was purchased from Thermo Fischer Scientific, Germany. Recombinant His-tagged RANK (protein ID O35305, amino acids 31-214) was obtained from Abcam, Germany. Recombinant his-tagged FasL amino acids N-Met-His8 (Pro134-Leu281) (protein ID NM_000639.1) was obtained from BioLegend, USA. His tagged ICAM-1 (protein ID P05362) recombinant human protein (Met 1-Glu 480), was obtained from Thermo Fischer Scientific, Germany. miRIDIAN micro RNA mimics (hsa-miR-21-5p, hsa-miR124-3p, hsa-miR-125b-5p, hsa-miR-126-5p, hsa-miR-130a-3p, hsa-miR-132-3p) were purchased from Horizon Dharmacon, USA. K562 exosomes (HBM-K562) were obtained from Hansa BioMed Lonza, Switzerland. 4-well cell exclusion inserts were purchased from Ibidi, Germany. Pre-wounded full thickness human organotypic skin cultures, respective culture media and histological sample preparation services were purchased from MatTek Cooperation, USA. FC-40 oil was purchased from Iolitec, Germany. ELISA kit for quantification of human pro-collagen I alpha was obtained from Abcam, UK.
Methods
Exosome Isolation from K562 Cell Cultures
K562 extracellular vesicles were isolated from conditioned cell culture medium by differential centrifugation. For this, K562 cells were cultured in 50 ml of Iscove's modified Dulbecco's Medium for 48 hours in suspension with 10% exosome free serum at 37° C. and 5% CO2 atmosphere. The final cell concentration was 5×105 cells/ml. After incubation, the cell suspension was centrifuged at 300 g at 4° C. for 10 minutes to remove the cells. The supernatant was filtered through a 0.22 μm filter and centrifuged at 125,000 g at 4° C. for 75 min with a Beckmann Coulter Optima XE-100 ultracentrifuge in a JA-20 fixed angle rotor (k-factor 770). The pellet was washed with 50 ml ice-cold PBS and centrifuged again under the same conditions. The exosome pellet was resuspended in 1 ml PBS. The total protein concentration of this exosome suspension was assessed by measuring the absorbance at 280 nm with a Nanodrop ND-1000 spectrophotometer.
Confocal and Bright Field Microscopy
Confocal microscopy was performed with a laser scanning microscope LSM 800 (Carl Zeiss AG). Images were acquired with a 20× (Objective Plan-Apochromat 20×/0.8 M27, Carl Zeiss AG) and a 63× immersion oil objective (Plan-Apochromat 63×/1.40 Oil DIC, Carl Zeiss AG). Images were analyzed with ImageJ (NIH) and adjustments of image brightness and contrast or background corrections were performed always on the whole image and special care was taken not to obscure or eliminate any information from the original image. For bright field imaging a Leica DMi8 inverted fluorescent microscope equipped with a sCMOS camera and 10×HC PL Fluotar (NA 0.32, PH1) objective was used.
For analysis of extracellular vesicle uptake into HaCaT cells, rhodamine B labeled extracellular vesicles were incubated with HaCaT cells in Nunc LabTek 8-well chambers. Immediately after addition of the extracellular vesicles to the cells, 5 μg/ml of AlexaFluor (obtained from Thermo Fischer Scientific, Invitrogen) conjugated wheat germ agglutinin (WGA) was added to the medium. Cells were incubated for 24 hours and subsequently imaged by confocal laser scanning microscopy. WGA binds to specific sugar residues on the outer cell membrane and is endocytosed along with them during membrane turn-over and endocytotic processes, staining intracellular endosomal vesicles.
Alexa488 labelled CD9 was produced by incubating NHS functionalized Alexa488 with recombinant CD9 in a twofold molar excess for 2 hours at 37° C. in PBS. Subsequently, free NHS was quenched by adding a 10-fold molar excess of glycine.
Staining of HaCaT cells with CellTracker Green was performed by incubating 20 μM of cell Tracker Green CMFDA dye for 60 min. To remove excess dye and non-uptaken synthetic extracellular vesicles, cells were rinsed twice with PBS.
Transmission Electron Microscopy
For analysis of synthetic extracellular vesicles conjugated with recombinant extracellular domain of FasL (FIG. 18a), cryo-electron microscopy samples were prepared by applying 2.5 μL of vesicle solution onto a glow-discharged 200 mesh C-flat holey carbon-coated multihole grid. Subsequently, blotting was performed for 4 s. Plunge-freezing was performed in liquid ethane using a Vitrobot Mark IV at 100% humidity and grids were stored under liquid nitrogen. The samples were imaged with a FEI Tecnai G2 T20 twin transmission electron microscope operated at 200 kV. A FEI Eagle 4k HS, 200 kV CCD camera was used to record electron micrographs with a total dose of ≈40 electrons/A2.
The protein to lipid ratio on vesicle membranes (FIG. 23a) was evaluated through negative staining of gold nanoparticles on the vesicle membranes and transmission electron microscopy analysis. To this aim, vesicles were incubated with 6×-Histidine tagged Protein G for 15 min. Subsequently, gold nanoparticle conjugated antibodies (Anti-goat IgG (whole molecule)-gold antibody produced in rabbit; Sigma Aldrich #G5402). Vesicle solutions were subsequently prefixed with 0.5% osmium tetroxide. Subsequently a negative staining was performed using 1% uranyl acetate and imaging was performed with a Zeiss EM 10 CR transmission electron microscope. ImageJ (NIH) software was used to measure the total vesicle area from electron micrographs. Additionally, gold nanoparticles on the vesicles were manually counted.
Dynamic Light Scattering
Analysis of the hydrodynamic radius of vesicles was performed with a Malvern Zetasizer Nano ZS system. Samples were diluted to a final lipid concentration of 15 μM in PBS filtered with through a 0.22 μm filter. The temperature equilibration time was set to 300 s at 25° C. Three individual measurements for each sample were performed at a scattering angle of 173° based on the built-in automatic run-number selection. The material refractive index was set to 1.4233 and solvent properties were set to η=0.8882, n=1.33 and ε=79.0.
Polydispersion Index Determination
Size polydispersion index (PDI) was assessed from hydrodynamic radius measurements based on dynamic light scattering. A Malvern Zetasizer Nano ZS was used to perform dynamic light scattering (DLS) measurements and PDI was derived from the automatically calculated size distribution analysis.
Cell Culture
HaCaT, BJ and A431 cells were cultured in Dulbecco's Modified Eagle Medium supplemented with 4.5 g/I glucose, 1% L-glutamine, 1% penicillin/streptomycin and 10% fetal bovine serum. Cells were routinely cultured at 37° C. and 5% CO2 atmosphere and passaged at approx. 80% confluency using 0.05% trypsin/EDTA treatment. K562 cells were cultured in suspension in Iscove's modified Dulbecco's Medium supplemented with 10% exosomes free fetal bovine serum. K562 cells were splitted every other day by transferring 3 ml of cell suspension to 10 ml of fresh cell culture medium.
To evaluate serum stability (FIG. 22), 100,000 HaCaT cells/well were seeded in 96-flat bottom transparent well plates. After 24 hours, synthetic extracellular vesicles harbouring fluorescent Rhodamine B lipids, preserved in serum at 4° C. for 2 days or 63 days, were added for 24 hours to the cells. Subsequently, fluorescence intensity in every well was measured by microplate-reader analysis. The cells were then washed 3 times with 100 μl PBS and remaining fluorescence intensity in each well (corresponding to the uptaken or strongly bound vesicles) was measured again by microplate reader. The fluorescence intensity after washing was divided by the fluorescence intensity before washing for each well and normalized to the untreated control value.
Assessment of Cell Proliferation
For proliferation analysis, a previously reported Hoechst 33342 intensity analysis was applied. To this end, HaCaT and A431 cells were seeded at a density of 15.000 cells/well in a flat-bottom transparent 96-well plate in 200 μl culture medium. Cells were seeded together with corresponding extracellular vesicles and incubated for 48 hours. Subsequently, cells were washed twice with 100 μl PBS and incubated for 10 min with icecold culture medium supplemented with 10 μM Hoechst 33342. After removal of the culture medium and 2× washing with PBS, Hoechst 33342 intensity was measured at four individual positions in each well using an Infinite M200 TECAN plate reader controlled by TECAN iControl software with an in-built gain optimization and excitation/emission setting adjusted to 380/460 nm. Measurements were performed in triplicates.
Cell Exclusion Assay
For in vitro 2D wound healing assays, 4-well silicone cell exclusion cell culture inserts with a gap width of 500 μm were used in 12-well plastic plates. Cells were seeded at a cell density of 40,000 cells/well and allowed to adhere overnight in 110 μl culture medium (2 ml of culture medium were added to the well outside of the inserts). Extracellular vesicles were incubated (at final lipid concentration of 10 μM) with the cell monolayer for 24 hours. Subsequently, the inserts were carefully removed using sterile tweezers and the wound was allowed to close for 16 hours. For quantification, culture medium was removed and cell layers were fixed with ice-cold 4% paraformaldehyde for a minimum of 20 min. The wound sides were then imaged by phase contract microscopy and the cell free area was quantified manually with ImageJ software.
Organotypic Dermal Cultures
For analysis of human organotypic full thickness skin models, pre-wounded human epidermal keratinocytes (obtained from neonatal-foreskin normal tissue of a single donor) and fibroblasts 3D cultures were obtained from a commercial distributer (MatTek corporation). Skins were cultured at an air-liquid interface following manufacturer's suggestions. For wound closure analysis, tissues were allowed to equilibrate for 16 hours after arrival at 37° C. in a 5% CO2 atmosphere. Subsequently, 2 μl of the extracellular vesicle solution (or respective buffer controls) were pipetted onto the wound side and the wound was allowed to heal for 48 hours at 37° C. in a 5% CO2 atmosphere. Tissues were then fixed with 10% formalin solution overnight at 4° C. Wound size was quantified from histological H/E slices. For each wound, six individual slices and three individual wounds were analyzed.
Protein Analysis by Gel-Electrophoresis
For gel-electrophoretic analysis of protein content of K562 exosomes and synthetic extracellular vesicles, a NuPAGE bold Bis-Tris 4-12% gradient gel was used with MES running buffer. Electrophoresis was performed at 200V for 35 min under denaturating conditions with a total of 3 μg (for natural exosomes) or 500 ng (for synthetic extracellular vesicles) of protein loaded onto each lane. Protein staining was performed with Coomassie R250. Line intensity profiles of the respective lanes were measured by ImageJ software.
Quantitative Assessment of Collagen Deposition
For quantification of in vitro collagen deposition, BJ dermal fibroblast were seeded in 96-well flat bottom transparent cell culture plates at a density of 20,000 cells/well. 24 hours after seeding, cells were washed twice with PBS and 200 μl of fresh cell culture medium was added together with synthetic extracellular vesicles (to a final lipids concentration of 10 μM) to the cells. Cells were incubated for 24 hours with synthetic extracellular vesicles. Subsequently human pro-collagen I alpha in the medium was quantified by enzyme-linked immunosorbent assay (Abcam ELISA Kit) following the manufacturer's instructions.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the scope of the invention.
Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the scope of the invention as described in the following claims.
Example 1. Production of Biomimetic Fully Synthetic Extracellular Vesicles
Synthetic extracellular vesicles were produced by shear stress emulsification (FIG. 1). At first, a solution of small unilamellar vesicles was prepared as follows: lipids dissolved in chloroform stock solutions were mixed at the desired lipid ratio in glass vials and subsequently dried under a gentle nitrogen stream. The obtained lipid film was rehydrated to a final lipid concentration of 6 mM in PBS for 15 min and afterwards shaken for 5 min at 1000 rpm. This solution of small unilamellar vesicles was extruded at least 9 time through a 50 nm pore size filter.
The so obtained solution, representing the water phase of step a), was then diluted to a final concentration of 3 mM with PBS, or eventually PBS containing the desired miRIDIAN miRNA mimic components at concentration 40-145 nM.
In this example, polymer shell-stabilized extracellular vesicles were produced from small unilamellar vesicles containing 41 mol % cholesterol, 16 mol % SM, 15 mol % DOPC, 11 mol % DOPS, 6 mol % DOPE, 5 mol % DOPG, 2 mol % PA, 1 mol % DAG, 1 mol % PI, 1 mol % LissRhod PE, 1 mol % DGS-NTA(Ni2+) in PBS containing miRIDIAN RNA (40-145 nM). This lipid composition resembles that of natural extracellular vesicles. However, the technology allows for the integration of an almost unrestricted number of possible lipid types into synthetic exosome membrane.
This water phase was then combined with an oil phase at a ratio 1:2. The oil phase consisted of FC-40 oil containing the fluorosurfactant triblock PEG2500-PFPE600-PEG2500 at a final concentration of 1.25 mM.
The combined water phase and oil phase was then emulsified using an Ultra Turrax IKA T10 basic emulsifier for, exemplarily, 60 sec at approx. 26,300 rpm. The resulting polymer shell stabilized synthetic extracellular vesicles were incubated for at least 2 hours at 4° C. in the dark.
Release of the polymer shell stabilized extracellular vesicles into an aqueous release buffer was performed by removing excess oil phase and adding the release buffer (PBS) and 1H,1H,2H,2H-perfluoro-1-octanol (PFO) to the mixture in a 1:1:1 ratio of aqueous release buffer:PFO. aqueous intraluminal buffer. After 30 min of equilibration, the layer containing the extracellular vesicles was transferred into a 2 ml microtube and PBS was added to a final volume of 2 ml.
This solution was centrifuged at >10,000 g for 15 min.
The supernatant was discarded and the extracellular vesicle pellet was resuspended in PBS. The extracellular vesicles were also released into PBS containing 0.1% BSA to block unspecific protein-lipid interactions
In order to conjugate the released extracellular vesicles with CD peptides, the total amount of NTA(Ni2+) functionalized lipids was calculated according to the lipid ratio. Thus, the His-tagged CD-peptides (CD9, TSG101, or CD63, or CD81) were added to the extracellular vesicle solution in a 1:2 excess and allowed to conjugate for 1 hour at 37° C. protected from light. After this phase, 500 nM Hoechst33342 was eventually added to the extracellular vesicles to visualize nucleic acids by confocal microscopy analysis.
The extracellular vesicle solution was subsequently centrifuged at >10,000 rpm for 15 min. The supernatant containing unbound peptides was disposed and the extracellular vesicle pellet resuspended in PBS.
In order to compare the lipid ratio of the formed extracellular vesicles, and that of the small unilamellar vesicles, the total lipid concentration of the extracellular vesicles was determined by quantifying the fluorescence from the integrated rhodamine B or Atto488 conjugated lipids, which was referenced to a small unilamellar vesicle standard dilution curve.
The results of quantitative electrospray-ionization tandem mass spectrometry revealed that fully synthetic extracellular vesicles had the lipid composition cholesterol:SM:DOPC:DOPS:DOPE:DOPG:PA:DAG:PI 43:16:15:11:6:5:2:1:1, resembling not only the lipid composition of natural extracellular vesicles, but also that of the original small unilamellar vesicles (FIG. 2), proving that no lipid ratio change occurs during the emulsification and release procedures. Therefore, the lipid composition of the extracellular vesicles can be easily fine-tuned by changing the lipid formulation of the original small unilamellar vesicles.
Example 2. Comparison with Exosomes Obtained by State of the Art Methods
The fully synthetic extracellular vesicles produced as described in Example 1 were compared to natural extracellular vesicles in term of purity, protein composition, dimension, and variability between different batches.
Interestingly, the fully synthetic extracellular vesicles produced according to the invention contained considerably less contaminating aggregates and non-vesicular particles compared to exosomes isolated by differential centrifugation from conditioned K562 erythroleukemia cell media or commercially available exosomes from the same cell line (see FIG. 3).
Moreover, when assessing the protein content of the respective vesicles by denaturating polyacrylamide gel-electrophoresis, it was found that exosomes isolated from conditioned K562 media and K562 commercial exosomes, differed greatly in their protein content, underscoring the degree of variation between different vesicle preparation methods (FIG. 4). Furthermore, when considering the variation between different exosome batches prepared with the same method (column 1 vs 2 and 3 vs 4 of FIG. 4), a substantial degree of variation in the protein composition could be observed. In contrast, fully synthetic extracellular vesicles equipped with purified recombinant human forms of exosome's surface markers CD9 and TSG101, attached by nitrilotriacetic acid (NTA)-poly histidine tag chemistry, appeared with a clearly defined band pattern and showed almost identical characteristics between separate preparations (column 5 vs 6 of FIG. 4). Thus, polymer shell stabilized extracellular vesicles can be considered as a more defined and robust platform for extracellular vesicles research that outperforms extracellular vesicles isolates from natural sources in terms of purity and reproducibility.
Additionally the biophysical similarity of fully synthetic extracellular vesicles to natural extracellular vesicles was evaluated by dynamic light scattering. The results showed that the size of polymer shell stabilized extracellular vesicles and therefore the hydrodynamic radius of fully synthetic extracellular vesicles can be fine-tuned by adjusting the shear stress used during emulsification, producing fully synthetic extracellular vesicles radii between 292 nm±12 nm, (CV=4.1%; n=3) by emulsification for 30 sec at 30,000 rpm, and radii between 627 nm±15 nm, (CV=2.4%; n=3) by emulsification for 30 sec at 14,000 rpm. The zeta potential of synthetic extracellular vesicles containing the above-mentioned lipid formulation was −12.3 mV (±0.7 mV, n=3). Thus, size and zeta potential of the fully synthetic extracellular vesicles are comparable to those of natural extracellular vesicles reported in literature (Vogel, R. et al. High-Resolution Single Particle Zeta Potential Characterization of Biological Nanoparticles using Tunable Resistive Pulse Sensing, Scientific reports 7, 2017).
Moreover, the hydrodynamic radius values of the synthetic extracellular vesicles were very similar to those of commercial K562 exosomes (468 nm±199 nm, CV=42.5%, and −11.8 mV±0.9 mV, n=3) and of exosomes isolated from conditioned K562 cell culture medium (240 nm±32 nm, CV=13.3%, and −11.3 mV±0.5 mV, n=3).
With respect to particle size distribution characterization, a parameter used to define the size range of the lipidic carrier systems is called the “polydispersity index” (PDI). PDI is basically a representation of the distribution of size populations within a given sample. The term “polydispersity” (or “dispersity” as recommended by IUPAC) is used to describe the degree of non-uniformity of a size distribution of particles (Danaei et al., Pharmaceutics 2018, 10, 57). Also known as the heterogeneity index, PDI is a number calculated from a two-parameter fit to the correlation data (the cumulants analysis). This index is dimensionless. The numerical value of PDI ranges from 0.0 (for a perfectly uniform sample with respect to the particle size) to 1.0 (for a highly polydisperse sample with multiple particle size populations). In drug delivery applications using lipid-based carriers, such as liposome and nanoliposome formulations, a PDI of 0.3 and below is considered to be acceptable and indicates a homogenous population of phospholipid vesicles.
Dynamic scattering analysis showed that the polydispersion index of an exemplary sample of fully synthetic extracellular vesicles is 0.098, demonstrating that the vesicles are homogenous in size.
Vesicle stability was evaluated by measuring the uptake rate by target cells of two synthetic extracellular vesicle samples preserved for two different time intervals (FIG. 22). The two samples of fluorescently labeled vesicles (see Methods) were used after storage in 2% human serum at 4° C. for 2 days or 63 days. Vesicle uptake was measured as fluorescence retention normalized to untreated cells. The results show that no significant difference in the uptake of the synthetic extracellular vesicles by cells can be detected after 63 days of storage in serum.
These results confirm that fully synthetic extracellular vesicles can be assembled from individually adjustable synthetic lipid precursors to precisely match the lipid composition and therefore biophysical characteristic (membrane charge, dimensions) of natural extracellular vesicles. Importantly, the fully synthetic extracellular vesicles prepared according to the inventive method showed the technical advantage to be much more reproducible, pure, stable and homogenous in size (coefficient of variation and PDI) in comparison with the exosomes obtained according to prior art methods.
Example 3. Building of Fully Synthetic Extracellular Vesicles Resembling the Protein and Nucleic Acid Composition of Natural Exosomes
Although lipids play an important role in extracellular vesicle communication, for therapeutic applications the main physiological functions of extracellular vesicles is commonly attributed to their micro RNA (miRNA) cargo and to the peripheral membrane proteins and receptor ligands on their surface.
The inventors have here produced synthetic exosomes miming fibrocyte-derived exosomes, in order to show the potential of the inventive method to produce synthetic exosomes for therapeutic application.
Natural fibrocyte-derived exosomes contain miRNAs including miR-21, miR-124, miR-125, miR-126, miR-130 and miR-132 and protein components including CD9, CD63 and CD81, and have been shown to promote wound-healing. Therefore, synthetic exosomes where prepared using synthetic miRIDIAN mimics of the miRNA described in the natural exosomes at a concentration typically found in natural exosomes (750 pg/1012 vesicles), by mixing the miRNA solution with the initial water phase containing the lipids (FIG. 1). Following the release of the synthetic exosomes from the surrounding polymer shell into an aqueous solution, synthetic exosomes were decorated with recombinant extracellular domains of human tetraspanins CD9, CD63 and CD81 via poly-Histidine-tag chemistry at a 1:100 protein to lipid ratio, at a similar protein to lipid ratio as described for natural exosomes.
Confocal microscopy analysis of the prepared synthetic exosomes showed luminal distribution of the miRNAs and peripheral distribution of Alexa-488 labeled CD9, overlapping with the lipid fluorescence of Liss Rhodamin PE integrated into the lipid bilayer (FIG. 5), thus demonstrating the correct bottom-up assembly of miRNA loaded and protein decorated extracellular vesicles.
Example 4. Interaction Between Synthetic Extracellular Vesicles and Target Cells
The interaction of fully synthetic extracellular vesicles synthetized as explained in Example 3 with target cells was analysed by incubating the keratinocytes HaCaT cells with said vesicles for 24 hours. These experiments showed that fluorescently labeled synthetic extracellular vesicles are internalized by HaCaT cells via an endosomal pathway (FIG. 6).
Importantly, these results suggest that the content of the fully synthetic extracellular vesicles is delivered into the target cells, so that they could be used for intracellular cargo delivery and for therapy of different disorders.
Example 5. Effect of Synthetic Extracellular Vesicles on Wound Healing
It has been shown that human fibrocyte-derived exosomes can have pro-proliferative effect, accelerates the collective migratory behavior of dermal keratinocytes and enhances collagen deposition of dermal fibroblasts, ultimately promoting wound closure in a diabetic mice model. Therefore, the wound healing effect of the synthetic extracellular vesicles synthetized as in Example 3 was tested studying their effect on cell proliferation, migration and collagen deposition, which is crucial for wound closure and healing.
The pro-proliferative effect on spontaneously immortalized keratinocytes Hacat cells, was assessed by quantifying keratinocyte number via nuclear staining after 48 h of incubation with the fully synthetic extracellular vesicles.
In order to decipher the contribution of the individual biomolecular components of the fully synthetic extracellular vesicles, fully synthetic extracellular vesicles lacking miRNAs, but decorated with the single tetraspanins or combinations of them were produced and analysed. Interestingly, co-presentation of CD9 and CD63 or CD9 and CD81 leaded to a synergistic effect on proliferation (FIG. 7a). However, the pro-proliferative effect was most pronounced when CD9, CD63 and CD81 where all co-presented, inducing a more than 2.7-fold increase compared to cultures treated with naive vesicles. The addition of the soluble tetraspanin protein variants alone to the HaCaT cells did not show a comparable effect. Therefore, these results reveal that the sole presentation of the CD9, CD63 and CD81 extracellular domain on synthetically assembled vesicles, has a pro-proliferative effect on keratinocytes, which can be considered as an essential requirement to promote wound healing.
The contribution of the single miRNAs was further evaluated by producing CD9, CD63 and CD81 biofunctionalized synthetic extracellular vesicles loaded with the individual human miRNA mimics (FIG. 7b). Interestingly, the results revealed that each individual miRNA enhanced to some extend the pro-proliferative effect. Slightly higher enhancement (1.7-fold) was observed in case of miR-125 or miR-126 loaded fully synthetic extracellular vesicles. However, the highest pro-proliferative effect (2.5-fold) was achieved when fully synthetic extracellular vesicles were loaded with a combination of all six miRNAs compared to non-loaded CD9, CD63, CD81-biofunctionalized fully synthetic extracellular vesicles. Generally, miRNAs modulate a broad spectrum of cell activities by translational regulation of intracellular signaling pathways.
Thus, these results show that fully synthetic extracellular vesicles can act as appropriate carriers to convey miRNA-based signaling information and thereby acting on post-transcriptional gene regulation by which they mirror a central mechanism of extracellular vesicle signaling.
The effect of extracellular vesicles on epithelial cell migration was assessed performing in vitro cell exclusion wound healing assays of collectively migrating keratinocyte monolayers treated for 24 h with the fully synthetic extracellular vesicles (FIG. 8). By quantifying the cell free area 16 hours after removal of the exclusion-inserts, the fully synthetic extracellular vesicles resulted able to promote keratinocyte migration into the cell free area and therefore closure of the artificial wound side (FIG. 9). Similarly to the results obtained for the pro-proliferative effect, co-presentation of all three tetraspanins on the fully synthetic extracellular vesicles showed a more pronounced enhancement of collective cell migration compared to single presentation of the proteins. When analyzing the effects of the individual miRNAs, miRNA132 resulted to especially improve the migratory behavior, and co-encapsulation of all six miRNAs could further increase collective cell migration compared to treatment with fully synthetic extracellular vesicles functionalized with CD9, CD63, CD81 only (FIG. 10).
Building on these observation, the ratios of the different miRNAs and tetraspanins could be varied, in order to assess the influence of individual signaling pathways.
The effect of fully synthetic extracellular vesicles on pro-collagen-la deposition of BJ dermal fibroblasts was assessed by enzyme-linked immunosorbent assay (ELISA) after a 24 hours treatment with the synthetic extracellular vesicles (FIG. 11). Although individual miRNA constituents showed no significant effect, a higher collagen deposition was obtained by treatment with fully synthetic extracellular vesicles containing all six miRNAs and tetraspanins.
Taken all these finding together, the in vitro assembled vesicles, like their natural equivalents, comprise the ability to boost three of the very fundamental processes critical for wound healing: proliferation, migration and collagen deposition.
Example 6. Effect of Biomimetic Fully Synthetic Extracellular Vesicles on Epithelial Regeneration
In order to assess the ability of fully synthetic extracellular vesicles to promote epithelial regeneration of wounded skin, wounded organotypic full-thickness human skin models (FIG. 12) were treated by applying synthetic extracellular vesicles for 48 hours on the wound site (see Methods). Closure of the 3 mm epidermal wound was assessed by quantification of the epithelial wound bed size from hematoxylin-eosin (H/E) stained histological samples (FIG. 13). The treatment with synthetic extracellular vesicles substantially augmented the healing processes compared to buffer treated controls and application of the single soluble constituents was not as effective as the fully synthetic extracellular vesicles (FIG. 14).
Example 7. Migration Promotion of Fully Synthetic Extracellular Vesicles
It is known that proliferation, migration and collagen deposition play a critical role in development and progression of epithelial carcinomas. Therefore, the effect of fully synthetic extracellular vesicles miming the fibrocyte derived vesicle was additionally tested on A431 human vulvar squamous carcinoma cells.
The results revealed that A431 carcinoma cells responded to fully synthetic extracellular vesicle treatment by accelerated in vitro collective migration, a central requirement for tumor invasion and metastasis, but displayed an altered sensitivity for the respective fully synthetic extracellular vesicle surface proteins (FIG. 15). Moreover, the fully synthetic extracellular vesicles increased A431 cells proliferation of 1.8-fold (FIG. 16).
Example 8. Extracellular Vesicles for Age-Related Disorders
The inventive method was applied to produce synthetic extracellular vesicles containing a nicotinamide phosphoribosyltransferase intracellular protein, as previous studies showed that these vesicles play a role in treatment of age-related disorders, and increase of lifespan.
Therefore, the inventors have here produced synthetic extracellular vesicles according to the inventive method and specifically comprising the functional protein nicotinamide phosphoribosyltransferase, and cytosolic proteins such as Apoptosis-Linked Gene 2-Interacting Protein X (ALIX), tumour susceptibility gene 101 protein (TSG101). These synthetic extracellular vesicles did not comprise transferrin and albumin.
Example 9. Synthesis of Immunoregulatory Extracellular Vesicles
The inventors aimed to synthetize synthetic extracellular vesicles with immunoregulatory properties that could be used to treat immune disorders, autoimmune disorders, inflammatory disorders, such as rheumatoid arthritis, and cancer, e.g. by cancer immunotherapy.
This type of synthetic extracellular vesicles can comprise transmembrane proteins such as MHCII, CD80, CD86, CD11c, MHCI, integrin α-chains, integrin β-chains, ICAM-1, and CD71; functional proteins such as cytokines, interleukins, IL4, growth factors, milk fat globule-EGF factor 8 protein (MFGE8), Fas, Fas Ligand (FasL), RANK, RANK Ligand (RANKL), indolamin-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein (CTLA4-Ig), tumor necrosis factor-related apoptosis-inducing ligand (Apo2L, TRAIL).
Fas (also named CD95, Apo-1) is a membrane receptor from the TNF family expressed on surface of almost all cells in the human body. Upon activation by Fas ligand (FasL), Fas induces apoptosis by activation of caspase signalling. Fas mediated apoptosis plays a major role in immunobiology, and especially by death induction of infected and cancerous cells mediated by cytotoxic T-cells and by natural killer cells (NK-cells). Moreover, Fas induced apoptosis is crucial for regulation of T-cell physiology in inflammatory diseases. Major producers of FasL are T-cells and NK-cells which release FasL primarily from intracellular reservoirs in a form bound to extracellular vesicles resembling exosomes.
Synthetic extracellular vesicles presenting FasL could therefore be useful not only to investigate further Fas-signalling, but also to provide new therapy option in immune disorders, inflammatory disorders, neurodegenerative disorders, or cancer.
In order to produce synthetic extracellular vesicles presenting FasL, synthetic extracellular vesicles were produced by the inventive method based on mechanical emulsification at 14,000 rpm for 30 sec with the following composition: 20 mol % DOPG, 78 mol % DOPC, 1 mol % DGS-NTA(Ni2+) and 1 mol % LissRhod PE. Obtained synthetic extracellular vesicles had a mean hydrodynamic radius of 606 nm, as measured by dynamic light scattering (DLS). Recombinant his-tagged FasL amino acids N-Met-His8 (BioLegend, USA) was coupled on the surface of these synthetic extracellular vesicles by applying bio-orthogonal surface chemistry NTA-poly-histidine tag coupling. The FasL present on synthetic extracellular vesicles is referred to as vesicular FasL to differentiate from soluble FasL (sFasL). Cryo-electron microscopy analysis demonstrated correct coupling of FasL on vesicle surface (FIG. 18a). The pro-apoptotic activity of FasL-synthetic extracellular vesicles was then tested on human keratinocytes by following cell positivity for propidium iodide by live-cell time lapse imaging (FIG. 18b). Upon contact formation with the FasL presenting synthetic vesicles, target cells stained progressively positive for propidium iodide (PI), demonstrating the pro-apoptotic activity of FasL-synthetic vesicles on target cells.
FasL-synthetic vesicles were then tested for their pro-apoptotic activity on T-cells, which is important for therapy of inflammatory and autoimmune diseases. To this aim, Jurkat T-cells were incubated for 24 hours with FasL-synthetic vesicles and apoptotis was quantified by measuring propidium iodide (PI) staining intensity on a plate reader. Results showed that vesicle bound recombinant FasL is able to induce apoptosis in the T-cells, but not soluble FasL (FIG. 18c).
Thereafter, FasL-synthetic vesicles were tested for their ability to activate caspase-8, which has been shown also for natural FasL-vesicles. To this aim, human dermal fibroblast BJ cells were incubated with FasL-synthetic vesicles for 2 hours and then stained with antibodies recognizing activated caspase-8, i.e. cleaved at Asp391 (FIG. 19). The results confirmed activation of caspase 8 in the BJ cells treated with FasL-synthetic vesicles. Activation of caspase-8 was directly proportional to the vesicle concentration (FIG. 19c), and to the concentration of vesicular FasL in solution after a given time (FIG. 19b). The concentration of FasL is calculated in these experiments as the total amount of FasL in the vesicle sample/ml, considering that FasL molar concentration is the same as that of NTA(Ni2+) lipids in the membrane (i.e. both 1 mol %=10 μM).
We further evaluated the pro-apoptotic concentration range of FasL presenting synthetic vesicles on Jurkat T-cells and on K562 granulocytic cells, which are frequently used to assess FasL mediated apoptosis on NK cells. We again found that the addition of soluble FasL (sFasL) did not display any cytotoxic effect at all tested concentrations (FIG. 21). However, FasL bound on synthetic vesicle surface could induce substantial cell death in both cell line, at the lowest tested amount of 5.6 ng/ml. Highest pro-apoptotic efficiency could be observed for the highest tested amount of 56 ng/ml FasL presenting synthetic vesicle.
Thereafter, the inventive method was used to assemble pro-apoptotic synthetic vesicles exposing not only FasL but also the intercellular adhesion molecule ICAM-1, which is presented on natural occurring extracellular vesicles with immunological activity. Synthetic extracellular vesicles presenting FasL and ICAM-1, were produced as described above by mechanical emulsification at 14,000 rpm for 30 sec. Obtained synthetic extracellular vesicles had a mean hydrodynamic radius of 606 nm. The pro-apoptotic potential of these vesicles was tested on Jurkat T-cells using different FasL to ICAM-1 ratios, and measuring cell death by propidium iodide (PI) staining It was found that the killing efficiency of the synthetic vesicles depends on the FasL to ICAM-1 ratio (FIG. 20). Such quantitative optimization of protein composition in extracellular vesicles is not feasible using natural derived extracellular vesicles. It was found that a FasL to ICAM-1 ratio of 5:5 is optimal and can induce cells apoptosis at a similar level as vesicles presenting only FasL (10:0=double as much FasL on the vesicle surface). In other words, we could increase pro-apoptotic signalling by a factor of 2 through this initial optimization. Interestingly, ICAM-1 is not cytotoxic by itself but when present as adhesion protein on cell derived vesicles. This demonstrates that adhesion proteins like ICAM-1 can further increase the cytotoxicity of FasL exposing vesicles, probably because they mediate and facilitate the adhesion of the vesicles to the target cells.
Moreover, in order to analyse the effect of vesicle membrane density of FasL on the pro-apoptotic potential, vesicles harbouring 5 mol % DGS-NTA(Ni2+) were compared to vesicles with 1 mol % DGS-NTA(Ni2+). Jurkat cells were incubated with FasL-extracellular vesicles (vFasL) with 1 mol % DGS-NTA(Ni2+) at 1×108 vesicles/ml or vFasL) with 5 mol % DGS-NTA(Ni2+) at 2×107 vesicles/ml, in order to have the same final FasL concentration in the two samples. Results showed that vesicles with higher FasL density (5 mol % DGS-NTA(Ni2+)) displayed reduced killing-efficiency.
The molar percentage of DGS-NTA(Ni2+) is a measure of the density of FasL on the vesicles as confirmed by labelling the vesicles with gold-nanoparticle conjugated antibodies and subsequent transmission electron microscopy imaging (FIG. 23a, 23b).
Example 10. Synthetic Extracellular Vesicles Resembling Mesenchymal Stem-Cell Derived Extracellular Vesicles
The inventive method was applied to produce synthetic extracellular vesicles resembling those derived from mesenchymal stem cells. Natural extracellular vesicles derived from mesenchymal stem cells have been shown to have a wide range of potential therapeutic effects, such as alleviation of severe graft versus host disease, osteoarthritis and promotion of cartilage extracellular matrix homeostasis.
The synthetic extracellular vesicles resembling those of mesenchymal stem cell origin were prepared with transmembrane proteins such as CD29, CD44, CD90, CD73, Sca-1, tetraspanin proteins CD9, CD63, and CD81, functional proteins such as Wnta and Wntb, nucleic acid molecules such as miR-140-5p, miR-92a-3p-e, nucleic acid molecules such as miRNAs miR-33b, miR-451, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-K12-3.
Example 11. Synthetic Extracellular Vesicles for Treatment of Stroke, Angiogenesis, and Other Cardiovascular Disorders
Emerging evidence suggests that stem cell derived exosomes and their microRNA cargo mediate cell therapy derived neurorestorative effects in patients after stroke. In particular, these exosomes can play a role in angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level.
In order to reproduce exosomes with such properties, the inventive method was applied to produce synthetic extracellular vesicle specifically comprising: transmembrane proteins such as CD29, CD44, CD90, CD73, CD44, Sca-1, tetraspanin proteins CD9, CD63, and CD81; nucleic acid molecules such as miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, miR-92a, let-7a, miR-21, miR124, miR126, miR-133b, miR-191, miR-222, miR-494, miR-6087, miR-30d-5p; miR-33b, miR-451, miR-575, miR-630, miR-638, miR-1202, miR-1207-5p, miR-1225-5p, miR-1268, miR-K12-3.
Example 12. Synthetic Extracellular Vesicles for Treatment of Osteoporosis and Other Bone Diseases
Osteoclast to osteoblast signalling is crucial for bone homeostasis in order to assure correct bone formation and resorption. Receptor activator of nuclear factor-κB (RANK) is pivotal for this interaction. It has been shown, that maturing osteoclasts secrete vesicles presenting RANK on their surface, which then binds to RANKL on osteoblast surface, thus boosting mineralization of osteoblasts by activation of “reverse signalling”. After RANK ligand (RANKL)-RANK binding, downstream MAP-kinase signalling is activated. The RANK-exposing vesicles have been shown to be crucial for physiological signalling and represent potential therapeutic targets to treat bone diseases such as osteoporosis.
Therefore, synthetic extracellular vesicles exposing RANK on their surface were produced applying the inventive method based on emulsification using a mechanic emulsifier, and tested for their activating effect on pre-osteoblast cells.
Synthetic extracellular vesicles were produced the following lipid composition: 20 mol % DOPG, 78 mol % DOPC, 1 mol % DGS-NTA(Ni2+) and 1 mol % LissRhod PE. Recombinant His-tagged RANK (amino acids 31-214) (protein ID O35305) was coupled on the surface of these synthetic extracellular vesicles by applying bio-orthogonal surface chemistry NTA-poly-histidine tag coupling, at a protein lipid (LissRhodPE) ratio of 1:100. Two samples of such synthetic extracellular vesicles were produced having hydrodynamic radii of 292 nm (emulsification at 30,000 rpm, 30 sec) and 615 nm (emulsification at 14,000 rpm, 30 sec), respectively, in order to optimize the vesicle dimension for maximal functionality. Synthetic extracellular vesicles were incubated with MC 3T3 cells, a model of pre-osteoblast cells, for 24 hours in 96 well plates at concentration 10 μM (vesicle lipid moles/medium volume). Cell samples were subsequently stained for p(202/204) ERK with an anti-p(202/204) ERK1/2-Alexa488 conjugated antibody and staining intensity was quantified using an Infinite M200 TECAN plate reader controlled by TECAN iControl software with an in-built gain optimization and excitation/emission setting adjusted to 488/512 nm. Here, phosphorylation of ERK at amino acids 202/204 was quantified as a measure of vesicular RANK potency in specific pre-osteoblast cell activation. As a control, soluble RANK was added to control cells at the same concentration as used to produce vesicular RANK (soluble or vesicle RANK/medium volume=100 ng/ml).
The results revealed that RANK exposed on synthetic extracellular vesicles can induce RANK signalling more strongly compared to soluble RANK (FIG. 17). Moreover, we found that smaller RANK vesicles are stronger inducers compared to large vesicles. These data demonstrate that RANK presenting synthetic extracellular vesicles could be used for bone remodelling therapy in bone diseases such as osteoporosis. Moreover, the inventive RANK presenting synthetic extracellular vesicles could be used to further investigate the physiology of bone formation and remodeling.







TABLE 3







Suitable miRNA molecules












MIRNA ID
ENTREZ ID
MIRNA ID
ENTREZ ID
MIRNA ID
ENTREZ ID















let-7a
406881
miR-30c-2*
407032
miR-141
406933


let-7b
406884
miR-30d
407033
miR-143
406935


let-7c
406885
miR-30e
407034
miR-145
406937


let-7d
406886
miR-30e-3p
407034
miR-146a
406938


let-7e
406887
miR-31
407035
miR-146b
574447


let-7f
406888
miR-32
407036
miR-147
406939


let-7g
406890
miR-33a
407039
miR-148a
406940


let-7i
406891
miR-33b
693120
miR-148b
442892


miR-1
406952
miR-34a
407040
miR-149
406941


miR-7-1*
407043
miR-34B
407041
miR-150
406942


miR-10a
406902
miR-92a-1
407048
miR-151
442893


miR-10b
406903
miR-92A2
407049
miR-152
406943


miR-15a
406948
miR-92b
693235
miR-153-1
406944


miR-15b
406949
miR-93
407050
miR-153-2
406945


miR-16
51573
miR-95
407052
miR-154
406946


miR-16-1
406950
miR-96
407053
miR-155
406947


miR-16-2
406951
miR-98
407054
miR-181a-2
406954


miR-17
406952
miR-99a
407055
miR-181a-1
406995


miR-17-3p
406952
miR-99b
407056
miR-181B2
406956


miR-17-5p
406952
miR-17-92a-1
407975
miR-181c
406957


miR-18a
406953
miR-100
406892
miR-181d
574457


miR-18b
574033
miR-101
406893
miR-182
406958


miR-19a
406979
miR-103A1
406895
miR-183
406959


miR-19b
406980
miR-103A2
406896
miR-184
406960


miR-19b-1*
406980
miR-103b-1
100302238
miR-185
406961


miR-19B2
406981
miR-103b-2
100302282
miR-186
406962


miR-20a
406982
miR-105-1
406897
miR-187
406963


miR-20b
574032
miR-105-2
406898
miR-188
406964


miR-21
406991
miR-106a
406899
miR-190
406965


miR-22
407004
miR-106b
406900
miR-190A
406965


miR-23a
407010
miR-107
406901
miR-191
406966


miR-23b
407011
miR-122
406906
miR-192
406967


miR-24
407012
miR-125a
406910
miR-193a
406968


miR-24
407013
miR-125B1
406911
miR-193b
574455


miR-25
407014
miR-125B2
406912
miR-194
406969


miR-26a
407015
miR-126
406913
miR-194-2
406970


miR-26A1
407015
miR-128-1
406915
miR-195
406971


miR-26A2
407016
miR-128-2
406916
miR-196a
406972


miR-26b
407017
miR-130a
406919
miR-196A2
406973


miR-27a
407018
miR-130b
406920
miR-196b
442920


miR-27b
407019
miR-132
406921
miR-197
406974


miR-28
407020
miR-133a
128826
miR-198
406975


miR-29a
407021
miR-134
406924
miR-199A2
406977


miR-29b
407024
miR-135a-1
406925
miR-199B
406978


miR-29b-2
407025
miR-135a-2
406926
miR-200a
406983


miR-29B1
407024
miR-135b
442891
miR-200b
406984


miR-29c
407026
miR-136
406927
miR-200c
406985


miR-30a
407029
miR-137
406928
miR-202
574448


miR-30a-3p
407029
miR-138
406929
miR-203
406986


miR-30a-5p
407029
miR-138-2
406930
miR-204
406987


miR-30b
407030
miR-139
406931
miR-205
406988


miR-30C1
407031
miR-140
406932
miR-2052
100302260


miR-206
406989
miR-373
442918
miR-500
574502


miR-210
406992
miR-374a
442919
miR-500A
574502


miR-214
406996
miR-374b
100126317
miR-501
574503


miR-215
406997
miR-375
494324
miR-502
574504


miR-217
406999
miR-376A1
494325
miR-503
574506


miR-218-1
407000
miR-376C
442913
miR-504
574507


miR-219-1
407002
miR-377
494326
miR-505
574508


miR-219b
100616335
miR-378
494327
miR-507
574512


miR-221
407006
miR-378A
494327
miR-510
574515


miR-222
407007
miR-379
494328
miR-511
574445


miR-223
407008
miR-380
494329
miR-513
574510


miR-224
407009
miR-380-3p
494329
miR-513b
100313822


miR-296
407022
miR-381
494330
miR-513c
100302114


miR-297
100126354
miR-382
494331
miR-516b-2
574485


miR-299
407023
miR-383
494332
miR-516b-1
574490


miR-301a
407027
miR-384
494333
miR-517c
574492


miR-301b
100126318
miR-409
574413
miR-5189
100847057


miR-302a
407028
miR-410
574434
miR-518c*
574477


miR-320b-1
100302117
miR-411
693121
miR-518d-3p
574489


miR-320c-1
100302135
miR-412
574433
miR-518e*
574487


miR-320d-2
100302169
miR-421
693122
miR-518f
574472


miR-320c-2
100302195
miR-422a
494334
miR-519b
574469


miR-320b-2
100313769
miR-423
494335
miR-520b
574473


miR-320d-1
100313896
miR-424
494336
miR-520e
574461


miR-320A
407037
miR-425
494337
miR-521
574481


miR-323A
442897
miR-429
554210
miR-521
574494


miR-323B
574410
miR-431*
574038
miR-522
574495


miR-324
442898
miR-432
574451
miR-526a
574475


miR-324-3p
442898
miR-433
574034
miR-526a
574486


miR-324-5p
442898
miR-448
554212
miR-527
574497


miR-325
442899
miR-449a
554213
miR-532
693124


miR-326
442900
miR-450a-1
554214
miR-539
664612


miR-328
442901
miR-450a-2
574505
miR-541
100126308


miR-331
442903
miR-450B
100126302
miR-542
664617


miR-335
442904
miR-451
574411
miR-543
100126335


miR-335-5p
442904
miR-452
574412
miR-548c-5p
693129


miR-337
442905
miR-323b
574410
miR-548d-5p
693130


miR-338
442906
miR-454
768216
miR-548d-5p
693131


miR-339
442907
miR-455
619556
miR-550*
693133


miR-340
442908
miR-483
619552
miR-550a-1
693133


miR-342
442909
miR-484
619553
miR-550a-2
693134


miR-342-3p
442909
miR-485
574436
miR-551b
693136


miR-345
442910
miR-486
619554
miR-557
693142


miR-346
442911
miR-486-5p
619554
miR-561
693146


miR-361
494323
miR-487A
619555
miR-564
693149


miR-362
574030
miR-487b
664616
miR-571
693156


miR-363
574031
miR-492
574449
miR-573
693158


miR-365
100126355
miR-493
574450
miR-574
693159


miR-369
442914
miR-494
574452
miR-574-3p
693159


miR-369-3p
442914
miR-495
574453
miR-575
693160


miR-370
442915
miR-496
574454
miR-577
693162


miR-371
442916
miR-498
574460
miR-578
693163


miR-581
693166
miR-671
768213
miR-1276
100302121


miR-582
693167
miR-708
100126333
miR-1278
100302163


miR-583
693168
miR-718
100313781
miR-1279
100302182


miR-584
693169
miR-744
100126313
miR-1284
100302112


miR-585
693170
miR-758
768212
miR-1286
100302118


miR-588
693173
miR-760
100126348
miR-1288
100302124


miR-589
693174
miR-762
100313837
miR-1287
100302133


miR-590
693175
miR-765
768220
miR-1281
100302237


miR-592
693177
miR-766
768218
miR-1282
100302254


miR-593
693178
miR-769
768217
miR-1281
100302237


miR-595
693180
miR-770
768222
miR-1295a
100302178


miR-598
693183
miR-874
100126343
miR-1290
100302276


miR-601
693186
miR-877
100126314
miR-1291
100302221


miR-603
693188
miR-887
100126347
miR-1293
100302220


miR-609
693194
miR-889
100126345
miR-1294
100302181


miR-610
693195
miR-890
100126303
miR-1296
100302150


miR-612
693197
miR-892b
100126307
miR-1297
100302187


miR-615
693200
miR-921
100126349
miR-1298
100302153


miR-617
693202
miR-924
100126323
miR-1299
100302167


miR-618
693203
miR-935
100126325
miR-1301
100302246


miR-622
693207
miR-936
100126326
miR-1305
100302270


miR-623
693208
miR-939
100126351
miR-1321
100302171


miR-624*
693209
miR-940
100126328
miR-1322
100302166


miR-625
693210
miR-942
100126331
miR-1323
100302255


miR-627
693212
miR-943
100126332
miR-1343
100616437


miR-628
693213
miR-1180
100302256
miR-1468
100302115


miR-629
693214
miR-1181
100302213
miR-1471
100302126


miR-630
693215
miR-1182
100302132
miR-1537
100302139


miR-631
693216
miR-1183
100302122
miR-1538
100302119


miR-632
693217
miR-1185-1
100302157
miR-1539
100302257


miR-634
693219
miR-1193
100422837
miR-1587
100616251


miR-637
693222
miR-1197
100302250
miR-1825
100302183


miR-638
693223
miR-1200
100302113
miR-1827
100302217


miR-639
693224
miR-1202
100302259
miR-1908
100302263


miR-641
693226
miR-1204
100302185
miR-1910
100302261


miR-642
693227
miR-1205
100302161
miR-1912
100302144


miR-645
693230
miR-1208
100302281
miR-1913
100302141


miR-647
693232
miR-1225-5p
100188847
miR-1976
100302190


miR-648
693233
miR-1226*
100302232
miR-2110
100302224


miR-649
693234
miR-122a
406906
miR-2113
100302164


miR-651
723779
miR-1231
100302158
miR-2116
100313886


miR-652
724022
miR-1244
100302285
miR-2117
100313779


miR-654
724024
miR-1246
100302142
miR-2278
100313780


miR-655
724025
miR-1248
100302143
miR-2355
100423036


miR-656
724026
miR-1249
100302149
miR-2467
100616360


miR-657
724027
miR-1251
100302289
miR-2861
100422910


miR-658
724028
miR-1254
100302273
miR-3115
100422866


miR-659
724029
miR-1261
100302228
miR-3117
100422871


miR-660
724030
miR-1262
100302279
miR-3125
100422986


miR-662
724032
miR-1264
100302251
miR-3137
100422926


miR-663
724033
miR-1270
100302179
miR-3138
100423011


miR-665
100126315
miR-1275
100302123
miR-3143
100422934


miR-3146
100422967
miR-4279
100422874
miR-6087
102464835


miR-3147
100422939
miR-4281
100422962
miR-6131
102465138


miR-3149
100422921
miR-4286
100422982
miR-7112
102465906


miR-3152
100422869
miR-4290
100422963
miR-7704
102465802


miR-3155A
100422989
miR-4292
100422860
miR-7705
102466854


miR-3161
100423000
miR-4297
100422873
miR-7706
102465803


miR-3168
100422878
miR-4303
100422924
miR-7974
102465856


miR-3169
100422973
miR-4306
100422861


miR-3170
100422881
miR-4311
100422905


miR-3174
100422841
miR-4312
100422971


miR-3175
100422995
miR-4316
100422851


miR-3176
100423037
miR-4317
100422840


miR-3182
100422853
miR-4322
100422925


miR-3188
100422833
miR-4323
100422980


miR-3198
100423025
miR-4325
100422883


miR-3200
100422912
miR-4326
100422945


miR-3605
100500853
miR-4327
100422891


miR-3609
100500819
miR-4424
100616328


miR-3615
100500847
miR-4429
100616469


miR-3621
100500811
miR-4443
100616407


miR-3648
100500862
miR-4447
100616485


miR-3652
100500842
miR-4448
100616127


miR-3653
100500833
miR-4454
100616234


miR-3655
100500820
miR-4455
100616111


miR-3656
100500840
miR-4461
100616209


miR-3657
100500889
miR-4467
100616367


miR-3661
100500905
miR-4482-1
100616323


miR-3662
100500880
miR-4485
100616263


miR-3686
100500839
miR-4488
100616470


miR-3687
100500815
miR-4492
100616376


miR-3691
100500900
miR-4497
100616454


miR-3714
100500913
miR-4508
100616275


miR-3907
100500835
miR-4520-1
100616401


miR-3909
100500826
miR-4520-2
100616466


miR-3911
100500872
miR-4524a
100616316


miR-3912
100500831
miR-4536-1
100616155


miR-3924
100500834
miR-4644
100616430


miR-3928
100500901
miR-4645
100616285


miR-3937
100500822
miR-4657
100616393


miR-3939
100500857
miR-4710
100616300


miR-3943
100500829
miR-4785
100616364


miR-3945
100500818
miR-4792
100616448


miR-3960
100616250
miR-5000
100846995


miR-3972
100616188
miR-5094
100847059


miR-4253
100422914
miR-5100
100847014


miR-4254
100423028
miR-5190
100847080


miR-4257
100422997
miR-5192
100847087


miR-4258
100423020
miR-5572
100847042


miR-4259
100422852
miR-5690
100847048


miR-4265
100422863
miR-5698
100847024


miR-4268
100422959
miR-5704
100847040


miR-4274
100422826
miR-6089
102464837
















TABLE 4







Suitable extracellular vesicle associated proteins








Gene Name
Gene Symbol





alpha-1-B glycoprotein
A1BG


alpha-2-macroglobulin
A2M


alpha-2-macroglobulin-like 1
A2ML1


achalasia, adrenocortical insufficiency,
AAAS


alacrimia


acetoacetyl-CoA synthetase
AACS


AAR2 splicing factor homolog (S. cerevisiae)
AAR2


alanyl-tRNA synthetase
AARS


alanyl-tRNA synthetase domain containing
AARSD1


1


aminoadipate-semialdehyde
AASDHPPT


dehydrogenase-phosphopantetheinyl


transferase


ATP-binding cassette, sub-family A
ABCA7


(ABC1), member 7


ATP-binding cassette, sub-family B
ABCB1


(MDR/TAP), member 1


ATP-binding cassette, sub-family B
ABCB11


(MDR/TAP), member 11


ATP-binding cassette, sub-family B
ABCB4


(MDR/TAP), member 4


ATP-binding cassette, sub-family B
ABCB6


(MDR/TAP), member 6 (Langereis blood


group)


ATP-binding cassette, sub-family C
ABCC1


(CFTR/MRP), member 1


ATP-binding cassette, sub-family C
ABCC11


(CFTR/MRP), member 11


ATP-binding cassette, sub-family C
ABCC2


(CFTR/MRP), member 2


ATP-binding cassette, sub-family C
ABCC4


(CFTR/MRP), member 4


ATP-binding cassette, sub-family C
ABCC5


(CFTR/MRP), member 5


ATP-binding cassette, sub-family C
ABCC9


(CFTR/MRP), member 9


ATP-binding cassette, sub-family D (ALD),
ABCD2


member 2


ATP-binding cassette, sub-family E
ABCE1


(OABP), member 1


ATP-binding cassette, sub-family F
ABCF1


(GCN20), member 1


ATP-binding cassette, sub-family F
ABCF2


(GCN20), member 2


ATP-binding cassette, sub-family F
ABCF3


(GCN20), member 3


ATP-binding cassette, sub-family G
ABCG2


(WHITE), member 2 (Junior blood group)


abhydrolase domain containing 11
ABHD11


abhydrolase domain containing 14B
ABHD14B


abhydrolase domain containing 16A
ABHD16A


abhydrolase domain containing 17A
ABHD17A


abhydrolase domain containing 17B
ABHD17B


abl-interactor 1
ABH


abl-interactor 2
ABI2


ABI family, member 3
ABI3


ABI family, member 3 (NESH) binding
ABI3BP


protein


activator of basal transcription 1
ABT1


acetyl-CoA acyltransferase 1
ACAA1


acetyl-CoA acyltransferase 2
ACAA2


acetyl-CoA carboxylase alpha
ACACA


acetyl-CoA carboxylase beta
ACACB


acyl-CoA dehydrogenase family, member 8
ACAD8


acyl-CoA dehydrogenase, C-4 to C-12
ACADM


straight chain


ArfGAP with coiled-coil, ankyrin repeat and
ACAP1


PH domains 1


acetyl-CoA acetyltransferase 1
ACAT1


acetyl-CoA acetyltransferase 2
ACAT2


acyl-CoA binding domain containing 3
ACBD3


angiotensin I converting enzyme
ACE


angiotensin I converting enzyme 2
ACE2


ATP citrate lyase
ACLY


aconitase 1, soluble
ACO1


aconitase 2, mitochondrial
ACO2


acyl-CoA thioesterase 1
ACOT1


acyl-CoA thioesterase 11
ACOT11


acyl-CoA thioesterase 7
ACOT7


acid phosphatase 1, soluble
ACP1


acid phosphatase 2, lysosomal
ACP2


acid phosphatase, prostate
ACPP


acyl-CoA synthetase long-chain family
ACSL1


member 1


acyl-CoA synthetase long-chain family
ACSL3


member 3


acyl-CoA synthetase long-chain family
ACSL4


member 4


acyl-CoA synthetase long-chain family
ACSL5


member 5


acyl-CoA synthetase long-chain family
ACSL6


member 6


acyl-CoA synthetase medium-chain family
ACSM1


member 1


acyl-CoA synthetase short-chain family
ACSS2


member 2


actin, alpha 1, skeletal muscle
ACTA1


actin, alpha 2, smooth muscle, aorta
ACTA2


actin, beta
ACTB


actin, beta-like 2
ACTBL2


actin, alpha, cardiac muscle 1
ACTC1


actin gamma 1
ACTG1


actin, gamma 2, smooth muscle, enteric
ACTG2


actin-like 6A
ACTL6A


actinin, alpha 1
ACTN1


actinin, alpha 2
ACTN2


actinin, alpha 3 (gene/pseudogene)
ACTN3


actinin, alpha 4
ACTN4


actin-related protein 10 homolog
ACTR10


(S. cerevisiae)


ARP1 actin-related protein 1 homolog A,
ACTR1A


centractin alpha (yeast)


ARP1 actin-related protein 1 homolog B,
ACTR1B


centractin beta (yeast)


ARP2 actin-related protein 2 homolog
ACTR2


(yeast)


ARP3 actin-related protein 3 homolog
ACTR3


(yeast)


ARP3 actin-related protein 3 homolog B
ACTR3B


(yeast)


ARP3 actin-related protein 3 homolog C
ACTR3C


(yeast)


ARP5 actin-related protein 5 homolog
ACTR5


(yeast)


ARP8 actin-related protein 8 homolog
ACTR8


(yeast)


activin A receptor, type I
ACVR1


activin A receptor, type IB
ACVR1B


aminoacylase 1
ACY1


aminoacylase 3
ACY3


adenosine deaminase
ADA


ADAM metallopeptidase domain 10
ADAM10


ADAM metallopeptidase domain 15
ADAM15


ADAM metallopeptidase domain 17
ADAM17


ADAM metallopeptidase domain 30
ADAM30


ADAM metallopeptidase domain 9
ADAM9


ADAM metallopeptidase with
ADAMTS1


thrombospondin type 1 motif, 1


ADAM metallopeptidase with
ADAMTS12


thrombospondin type 1 motif, 12


ADAM metallopeptidase with
ADAMTS13


thrombospondin type 1 motif, 13


ADAM metallopeptidase with
ADAMTS2


thrombospondin type 1 motif, 2


ADAM metallopeptidase with
ADAMTS3


thrombospondin type 1 motif, 3


adenosine deaminase, RNA-specific
ADAR


adenylate cyclase 1 (brain)
ADCY1


adenylate cyclase 6
ADCY6


adenylate cyclase 9
ADCY9


adducin 1 (alpha)
ADD1


adducin 2 (beta)
ADD2


adhesion G protein-coupled receptor E5
ADGRE5


adhesion G protein-coupled receptor G1
ADGRG1


adhesion G protein-coupled receptor G2
ADGRG2


adhesion G protein-coupled receptor G4
ADGRG4


adhesion G protein-coupled receptor G6
ADGRG6


adhesion G protein-coupled receptor L2
ADGRL2


adhesion G protein-coupled receptor L3
ADGRL3


adhesion G protein-coupled receptor V1
ADGRV1


alcohol dehydrogenase 1A (class I), alpha
ADH1A


polypeptide


alcohol dehydrogenase 1B (class I), beta
ADH1B


polypeptide


alcohol dehydrogenase 1C (class I),
ADH1C


gamma polypeptide


alcohol dehydrogenase 5 (class III), chi
ADH5


polypeptide


alcohol dehydrogenase 6 (class V)
ADH6


adipogenesis regulatory factor
ADIRF


adenosine kinase
ADK


ADP-ribosylhydrolase like 2
ADPRHL2


adrenergic, beta, receptor kinase 1
ADRBK1


adhesion regulating molecule 1
ADRM1


adenylosuccinate lyase
ADSL


adenylosuccinate synthase
ADSS


AE binding protein 1
AEBP1


afamin
AFM


alpha-fetoprotein
AFP


ATP/GTP binding protein-like 3
AGBL3


acylglycerol kinase
AGK


amylo-alpha-1,6-glucosidase, 4-alpha-
AGL


glucanotransferase


argonaute RISC catalytic component 2
AGO2


alkylglycerone phosphate synthase
AGPS


anterior gradient 2
AGR2


anterior gradient 3
AGR3


agrin
AGRN


angiotensinogen (serpin peptidase
AGT


inhibitor, clade A, member 8)


angiotensin II receptor-associated protein
AGTRAP


AT hook containing transcription factor 1
AHCTF1


adenosylhomocysteinase
AHCY


adenosylhomocysteinase-like 1
AHCYL1


adenosylhomocysteinase-like 2
AHCYL2


AHNAK nucleoprotein
AHNAK


AHNAK nucleoprotein 2
AHNAK2


aryl-hydrocarbon receptor repressor
AHRR


AHA1, activator of heat shock 90 kDa
AHSA1


protein ATPase homolog 1 (yeast)


alpha-2-HS-glycoprotein
AHSG


axin interactor, dorsalization associated
AIDA


allograft inflammatory factor 1-like
AIF1L


apoptosis-inducing factor, mitochondrion-
AIFM2


associated, 2


aminoacyl tRNA synthetase complex-
AIMP1


interacting multifunctional protein 1


aminoacyl tRNA synthetase complex-
AIMP2


interacting multifunctional protein 2


adenylate kinase 1
AK1


adenylate kinase 2
AK2


adenylate kinase 4
AK4


A kinase (PRKA) anchor protein 12
AKAP12


A kinase (PRKA) anchor protein 9
AKAP9


aldo-keto reductase family 1, member A1
AKR1A1


(aldehyde reductase)


aldo-keto reductase family 1, member B1
AKR1B1


(aldose reductase)


aldo-keto reductase family 1, member B10
AKR1B10


(aldose reductase)


aldo-keto reductase family 1, member C1
AKR1C1


aldo-keto reductase family 1, member C3
AKR1C3


aldo-keto reductase family 1, member E2
AKR1E2


aldo-keto reductase family 7, member A2
AKR7A2


(aflatoxin aldehyde reductase)


aldo-keto reductase family 7, member A3
AKR7A3


(aflatoxin aldehyde reductase)


aldo-keto reductase family 7-like
AKR7L


(gene/pseudogene)


v-akt murine thymoma viral oncogene
AKT1


homolog 1


v-akt murine thymoma viral oncogene
AKT2


homolog 2


aminolevulinate dehydratase
ALAD


albumin
ALB


activated leukocyte cell adhesion molecule
ALCAM


aldehyde dehydrogenase 16 family,
ALDH16A1


member A1


aldehyde dehydrogenase 18 family,
ALDH18A1


member A1


aldehyde dehydrogenase 1 family, member
ALDH1A1


A1


aldehyde dehydrogenase 1 family, member
ALDH1A3


A3


aldehyde dehydrogenase 1 family, member
ALDH1L1


L1


aldehyde dehydrogenase 2 family
ALDH2


(mitochondrial)


aldehyde dehydrogenase 3 family, member
ALDH3A1


A1


aldehyde dehydrogenase 3 family, member
ALDH3A2


A2


aldehyde dehydrogenase 3 family, member
ALDH3B1


B1


aldehyde dehydrogenase 5 family, member
ALDH5A1


A1


aldehyde dehydrogenase 6 family, member
ALDH6A1


A1


aldehyde dehydrogenase 7 family, member
ALDH7A1


A1


aldehyde dehydrogenase 8 family, member
ALDH8A1


A1


aldehyde dehydrogenase 9 family, member
ALDH9A1


A1


aldolase A, fructose-bisphosphate
ALDOA


aldolase B, fructose-bisphosphate
ALDOB


aldolase C, fructose-bisphosphate
ALDOC


anaplastic lymphoma receptor tyrosine
ALK


kinase


AlkB family member 5, RNA demethylase
ALKBH5


arachidonate 12-lipoxygenase
ALOX12


arachidonate 12-lipoxygenase pseudogene
ALOX12P2


2


alkaline phosphatase, liver/bone/kidney
ALPL


alkaline phosphatase, placental
ALPP


alkaline phosphatase, placental-like 2
ALPPL2


Aly/REF export factor
ALYREF


alpha-1-microglobulin/bikunin precursor
AMBP


amnion associated transmembrane protein
AMN


antagonist of mitotic exit network 1
AMN1


homolog (S. cerevisiae)


adenosine monophosphate deaminase 2
AMPD2


amylase, alpha 1A (salivary)
AMY1A


amylase, alpha 1B (salivary)
AMY1B


amylase, alpha 1C (salivary)
AMY1C


amylase, alpha 2A (pancreatic)
AMY2A


amylase, alpha 2B (pancreatic)
AMY2B


anaphase promoting complex subunit 1
ANAPC1


anaphase promoting complex subunit 2
ANAPC2


anaphase promoting complex subunit 5
ANAPC5


anaphase promoting complex subunit 7
ANAPC7


angiogenin, ribonuclease, RNase A family,
ANG


5


angiopoietin 1
ANGPT1


angiopoietin-like 1
ANGPTL1


angiopoietin-like 2
ANGPTL2


angiopoietin-like 3
ANGPTL3


angiopoietin-like 4
ANGPTL4


angiopoietin-like 7
ANGPTL7


ankyrin 1, erythrocytic
ANK1


ankyrin repeat and FYVE domain
ANKFY1


containing 1


ANKH inorganic pyrophosphate transport
ANKH


regulator


ankyrin repeat domain 13A
ANKRD13A


ankyrin repeat domain 18B
ANKRD18B


ankyrin repeat domain 23
ANKRD23


ankyrin repeat domain 24
ANKRD24


ankyrin repeat domain 26
ANKRD26


ankyrin repeat domain 28
ANKRD28


ankyrin repeat domain 36
ANKRD36


ankyrin repeat domain 44
ANKRD44


ankyrin repeat and sterile alpha motif
ANKS1A


domain containing 1A


ankyrin repeat and sterile alpha motif
ANKS1B


domain containing 1B


anillin, actin binding protein
ANLN


anoctamin 1, calcium activated chloride
ANO1


channel


anoctamin 6
ANO6


acidic (leucine-rich) nuclear
ANP32A


phosphoprotein 32 family, member A


acidic (leucine-rich) nuclear
ANP32B


phosphoprotein 32 family, member B


acidic (leucine-rich) nuclear
ANP32E


phosphoprotein 32 family, member E


alanyl (membrane) aminopeptidase
ANPEP


anthrax toxin receptor 1
ANTXR1


anthrax toxin receptor 2
ANTXR2


annexin A1
ANXA1


annexin A11
ANXA11


annexin A13
ANXA13


annexin A2
ANXA2


annexin A2 pseudogene 1
ANXA2P1


annexin A2 pseudogene 2
ANXA2P2


annexin A3
ANXA3


annexin A4
ANXA4


annexin A5
ANXA5


annexin A6
ANXA6


annexin A7
ANXA7


annexin A8
ANXA8


amine oxidase, copper containing 1
AOC1


aldehyde oxidase 1
AOX1


adaptor-related protein complex 1, beta 1
AP1B1


subunit


adaptor-related protein complex 1, gamma
AP1G1


1 subunit


adaptor-related protein complex 1, mu 1
AP1M1


subunit


adaptor-related protein complex 1, mu 2
AP1M2


subunit


adaptor-related protein complex 1, sigma 1
AP1S1


subunit


adaptor-related protein complex 2, alpha 1
AP2A1


subunit


adaptor-related protein complex 2, alpha 2
AP2A2


subunit


adaptor-related protein complex 2, beta 1
AP2B1


subunit


adaptor-related protein complex 2, mu 1
AP2M1


subunit


adaptor-related protein complex 2, sigma 1
AP2S1


subunit


adaptor-related protein complex 3, beta 1
AP3B1


subunit


adaptor-related protein complex 3, delta 1
AP3D1


subunit


adaptor-related protein complex 3, mu 1
AP3M1


subunit


adaptor-related protein complex 3, sigma 2
AP3S2


subunit


adaptor-related protein complex 4, mu 1
AP4M1


subunit


adaptor-related protein complex 5, beta 1
AP5B1


subunit


adaptor-related protein complex 5, mu 1
AP5M1


subunit


adaptor-related protein complex 5, zeta 1
AP5Z1


subunit


apoptotic peptidase activating factor 1
APAF1


amyloid beta (A4) precursor protein-
APBB1IP


binding, family B, member 1 interacting


protein


amyloid P component, serum
APCS


acylaminoacyl-peptide hydrolase
APEH


APEX nuclease (multifunctional DNA repair
APEX1


enzyme) 1


APH1A gamma secretase subunit
APH1A


apoptosis inhibitor 5
API5


amyloid beta (A4) precursor-like protein 2
APLP2


adipocyte plasma membrane associated
APMAP


protein


apolipoprotein A-I
APOA1


apolipoprotein A-II
APOA2


apolipoprotein A-IV
APOA4


apolipoprotein A-V
APOA5


apolipoprotein B
APOB


apolipoprotein B mRNA editing enzyme,
APOBEC3A


catalytic polypeptide-like 3A


APOBEC3A and APOBEC3B deletion
APOBEC3A_B


hybrid


apolipoprotein B mRNA editing enzyme,
APOBEC3B


catalytic polypeptide-like 3B


apolipoprotein B mRNA editing enzyme,
APOBEC3C


catalytic polypeptide-like 3C


apolipoprotein C-II
APOC2


apolipoprotein C-III
APOC3


apolipoprotein D
APOD


apolipoprotein E
APOE


apolipoprotein H (beta-2-glycoprotein I)
APOH


apolipoprotein L, 1
APOL1


apolipoprotein L, 2
APOL2


apolipoprotein M
APOM


amyloid beta (A4) precursor protein
APP


adaptor protein, phosphotyrosine
APPL1


interaction, PH domain and leucine zipper


containing 1


adaptor protein, phosphotyrosine
APPL2


interaction, PH domain and leucine zipper


containing 2


adenine phosphoribosyltransferase
APRT


aquaporin 1 (Colton blood group)
AQP1


aquaporin 2 (collecting duct)
AQP2


aquaporin 5
AQP5


aquarius intron-binding spliceosomal factor
AQR


androgen receptor
AR


A-Raf proto-oncogene, serine/threonine
ARAF


kinase


ArfGAP with RhoGAP domain, ankyrin
ARAP1


repeat and PH domain 1


ArfGAP with RhoGAP domain, ankyrin
ARAP3


repeat and PH domain 3


archain 1
ARCN1


amphiregulin
AREG


ADP-ribosylation factor 1
ARF1


ADP-ribosylation factor 3
ARF3


ADP-ribosylation factor 4
ARF4


ADP-ribosylation factor 5
ARF5


ADP-ribosylation factor 6
ARF6


ADP-ribosylation factor GTPase activating
ARFGAP3


protein 3


ADP-ribosylation factor guanine
ARFGEF2


nucleotide-exchange factor 2 (brefeldin A-


inhibited)


ADP-ribosylation factor interacting protein
ARFIP1


1


arginase 1
ARG1


Rho GTPase activating protein 1
ARHGAP1


Rho GTPase activating protein 15
ARHGAP15


Rho GTPase activating protein 18
ARHGAP18


Rho GTPase activating protein 23
ARHGAP23


Rho GTPase activating protein 26
ARHGAP26


Rho GTPase activating protein 33
ARHGAP33


Rho GTPase activating protein 35
ARHGAP35


Rho GTPase activating protein 4
ARHGAP4


Rho GTPase activating protein 6
ARHGAP6


Rho GTPase activating protein 8
ARHGAP8


Rho GTPase activating protein 9
ARHGAP9


Rho GDP dissociation inhibitor (GDI) alpha
ARHGDIA


Rho GDP dissociation inhibitor (GDI) beta
ARHGDIB


Rho guanine nucleotide exchange factor
ARHGEF1


(GEF) 1


Rho guanine nucleotide exchange factor
ARHGEF12


(GEF) 12


Rho guanine nucleotide exchange factor
ARHGEF16


(GEF) 16


Rho guanine nucleotide exchange factor
ARHGEF17


(GEF) 17


Rho/Rac guanine nucleotide exchange
ARHGEF18


factor (GEF) 18


Rho/Rac guanine nucleotide exchange
ARHGEF2


factor (GEF) 2


Rho guanine nucleotide exchange factor
ARHGEF39


(GEF) 39


Rac/Cdc42 guanine nucleotide exchange
ARHGEF6


factor (GEF) 6


Rho guanine nucleotide exchange factor
ARHGEF7


(GEF) 7


AT rich interactive domain 1A (SWI-like)
ARID1A


AT rich interactive domain 5B (MRF1-like)
ARID5B


ADP-ribosylation factor-like 1
ARL1


ADP-ribosylation factor-like 15
ARL15


ADP-ribosylation factor-like 2
ARL2


ADP-ribosylation factor-like 3
ARL3


ADP-ribosylation factor-like 6
ARL6


ADP-ribosylation factor-like 6 interacting
ARL6IP1


protein 1


ADP-ribosylation factor-like 6 interacting
ARL6IP5


protein 5


ADP-ribosylation factor-like 8A
ARL8A


ADP-ribosylation factor-like 8B
ARL8B


armadillo repeat containing 3
ARMC3


armadillo repeat containing 5
ARMC5


armadillo repeat containing 6
ARMC6


armadillo repeat containing 8
ARMC8


armadillo repeat containing 9
ARMC9


age-related maculopathy susceptibility 2
ARMS2


acidic residue methyltransferase 1
ARMT1


actin related protein 2/3 complex, subunit
ARPC1A


1A, 41 kDa


actin related protein 2/3 complex, subunit
ARPC1B


1B, 41 kDa


actin related protein 2/3 complex, subunit
ARPC2


2, 34 kDa


actin related protein 2/3 complex, subunit
ARPC3


3, 21 kDa


actin related protein 2/3 complex, subunit
ARPC4


4, 20 kDa


ARPC4-TTLL3 readthrough
ARPC4-TTLL3


actin related protein 2/3 complex, subunit
ARPC5


5, 16 kDa


actin related protein 2/3 complex, subunit
ARPC5L


5-like


cAMP-regulated phosphoprotein, 19 kDa
ARPP19


arrestin 3, retinal (X-arrestin)
ARR3


arrestin domain containing 1
ARRDC1


arrestin domain containing 3
ARRDC3


arylsulfatase B
ARSB


arylsulfatase E (chondrodysplasia punctata
ARSE


1)


arylsulfatase F
ARSF


armadillo repeat gene deleted in
ARVCF


velocardiofacial syndrome


N-acylsphingosine amidohydrolase (acid
ASAH1


ceramidase) 1


ArfGAP with SH3 domain, ankyrin repeat
ASAP1


and PH domain 1


ArfGAP with SH3 domain, ankyrin repeat
ASAP2


and PH domain 2


ankyrin repeat and SOCS box containing
ASB15


15


activating signal cointegrator 1 complex
ASCC3


subunit 3


ash1 (absent, small, or homeotic)-like
ASH1L


(Drosophila)


argininosuccinate lyase
ASL


acetylserotonin O-methyltransferase-like
ASMTL


arsA arsenite transporter, ATP-binding,
ASNA1


homolog 1 (bacterial)


asparagine synthetase (glutamine-
ASNS


hydrolyzing)


aspartate beta-hydroxylase
ASPH


asporin
ASPN


argininosuccinate synthase 1
ASS1


ATPase family, AAA domain containing 2
ATAD2


ATPase family, AAA domain containing 2B
ATAD2B


ATPase family, AAA domain containing 3A
ATAD3A


ATPase family, AAA domain containing 3B
ATAD3B


ATPase family, AAA domain containing 3C
ATAD3C


autophagy related 3
ATG3


autophagy related 7
ATG7


autophagy related 9A
ATG9A


5-aminoimidazole-4-carboxamide
ATIC


ribonucleotide formyltransferase/IMP


cyclohydrolase


atlastin GTPase 2
ATL2


atlastin GTPase 3
ATL3


ATPase, class V, type 10A
ATP10A


ATPase, class V, type 10D
ATP10D


ATPase, class VI, type 11A
ATP11A


ATPase, class VI, type 11C
ATP11C


ATPase, H+/K+ transporting, nongastric,
ATP12A


alpha polypeptide


ATPase type 13A3
ATP13A3


ATPase, Na+/K+ transporting, alpha 1
ATP1A1


polypeptide


ATPase, Na+/K+ transporting, alpha 2
ATP1A2


polypeptide


ATPase, Na+/K+ transporting, alpha 3
ATP1A3


polypeptide


ATPase, Na+/K+ transporting, alpha 4
ATP1A4


polypeptide


ATPase, Na+/K+ transporting, beta 1
ATP1B1


polypeptide


ATPase, Na+/K+ transporting, beta 3
ATP1B3


polypeptide


ATPase, Ca++ transporting, cardiac
ATP2A2


muscle, slow twitch 2


ATPase, Ca++ transporting, ubiquitous
ATP2A3


ATPase, Ca++ transporting, plasma
ATP2B1


membrane 1


ATPase, Ca++ transporting, plasma
ATP2B2


membrane 2


ATPase, Ca++ transporting, plasma
ATP2B3


membrane 3


ATPase, Ca++ transporting, plasma
ATP2B4


membrane 4


ATPase, Ca++ transporting, type 2C,
ATP2C1


member 1


ATPase, H+/K+ exchanging, alpha
ATP4A


polypeptide


ATP synthase, H+ transporting,
ATP5A1


mitochondrial F1 complex, alpha subunit 1,


cardiac muscle


ATP synthase, H+ transporting,
ATP5B


mitochondrial F1 complex, beta


polypeptide


ATP synthase, H+ transporting,
ATP5C1


mitochondrial F1 complex, gamma


polypeptide 1


ATP synthase, H+ transporting,
ATP5D


mitochondrial F1 complex, delta subunit


ATP synthase, H+ transporting,
ATP5H


mitochondrial Fo complex, subunit d


ATP synthase, H+ transporting,
ATP5I


mitochondrial Fo complex, subunit E


ATP synthase, H+ transporting,
ATP5L


mitochondrial Fo complex, subunit G


ATP synthase, H+ transporting,
ATP5O


mitochondrial F1 complex, O subunit


ATPase, H+ transporting, lysosomal
ATP6AP1


accessory protein 1


ATPase, H+ transporting, lysosomal
ATP6AP2


accessory protein 2


ATPase, H+ transporting, lysosomal V0
ATP6V0A1


subunit a1


ATPase, H+ transporting, lysosomal V0
ATP6V0A2


subunit a2


ATPase, H+ transporting, lysosomal V0
ATP6V0A4


subunit a4


ATPase, H+ transporting, lysosomal
ATP6V0C


16 kDa, V0 subunit c


ATPase, H+ transporting, lysosomal
ATP6V0D1


38 kDa, V0 subunit d1


ATPase, H+ transporting, lysosomal
ATP6V0D2


38 kDa, V0 subunit d2


ATPase, H+ transporting, lysosomal
ATP6V1A


70 kDa, V1 subunit A


ATPase, H+ transporting, lysosomal
ATP6V1B1


56/58 kDa, V1 subunit B1


ATPase, H+ transporting, lysosomal
ATP6V1B2


56/58 kDa, V1 subunit B2


ATPase, H+ transporting, lysosomal
ATP6V1C1


42 kDa, V1 subunit C1


ATPase, H+ transporting, lysosomal
ATP6V1C2


42 kDa, V1 subunit C2


ATPase, H+ transporting, lysosomal
ATP6V1D


34 kDa, V1 subunit D


ATPase, H+ transporting, lysosomal
ATP6V1E1


31 kDa, V1 subunit E1


ATPase, H+ transporting, lysosomal
ATP6V1F


14 kDa, V1 subunit F


ATPase, H+ transporting, lysosomal
ATP6V1G1


13 kDa, V1 subunit G1


ATPase, H+ transporting, lysosomal
ATP6V1H


50/57 kDa, V1 subunit H


ATPase, Cu++ transporting, alpha
ATP7A


polypeptide


ATPase, Cu++ transporting, beta
ATP7B


polypeptide


ATPase, aminophospholipid transporter
ATP8A1


(APLT), class I, type 8A, member 1


ATPase, aminophospholipid transporter,
ATP8A2


class I, type 8A, member 2


ATPase, aminophospholipid transporter,
ATP8B1


class I, type 8B, member 1


ATPase, aminophospholipid transporter,
ATP8B3


class I, type 8B, member 3


ATPase, class II, type 9A
ATP9A


ATPase, class II, type 9B
ATP9B


attractin
ATRN


ataxin 1
ATXN1


ataxin 10
ATXN10


ataxin 2-like
ATXN2L


AXL receptor tyrosine kinase
AXL


alpha-2-glycoprotein 1, zinc-binding
AZGP1


alpha-2-glycoprotein 1, zinc-binding
AZGP1P1


pseudogene 1


azurocidin 1
AZU1


beta-2-microglobulin
B2M


beta-1,3-glucuronyltransferase 3
B3GAT3


UDP-GlcNAc: betaGal beta-1,3-N-
B3GNT2


acetylglucosaminyltransferase 2


UDP-Gal: betaGlcNAc beta 1,4-
B4GALT1


galactosyltransferase, polypeptide 1


UDP-Gal: betaGlcNAc beta 1,4-
B4GALT3


galactosyltransferase, polypeptide 3


UDP-Gal: betaGlcNAc beta 1,4-
B4GALT4


galactosyltransferase, polypeptide 4


UDP-Gal: betaGlcNAc beta 1,4-
B4GALT5


galactosyltransferase, polypeptide 5


xylosylprotein beta 1,4-
B4GALT7


galactosyltransferase, polypeptide 7


BRISC and BRCA1 A complex member 1
BABAM1


beta-site APP-cleaving enzyme 2
BACE2


BTB and CNC homology 1, basic leucine
BACH2


zipper transcription factor 2


BCL2-associated athanogene
BAG1


BCL2-associated athanogene 2
BAG2


BCL2-associated athanogene 5
BAG5


BCL2-associated athanogene 6
BAG6


BAI1-associated protein 2
BAIAP2


BAI1-associated protein 2-like 1
BAIAP2L1


BAI1-associated protein 2-like 2
BAIAP2L2


barrier to autointegration factor 1
BANF1


brain abundant, membrane attached signal
BASP1


protein 1


BCL2-associated X protein
BAX


bromodomain adjacent to zinc finger
BAZ1B


domain, 1B


butyrobetaine (gamma), 2-oxoglutarate
BBOX1


dioxygenase (gamma-butyrobetaine


hydroxylase) 1


Bardet-Biedl syndrome 4
BBS4


basal cell adhesion molecule (Lutheran
BCAM


blood group)


B-cell receptor-associated protein 31
BCAP31


breast carcinoma amplified sequence 2
BCAS2


branched chain amino-acid transaminase
BCAT1


1, cytosolic


BRCA2 and CDKN1A interacting protein
BCCIP


butyrylcholinesterase
BCHE


B-cell CLL/lymphoma 11A (zinc finger
BCL11A


protein)


BCL2-like 12 (proline rich)
BCL2L12


breakpoint cluster region
BCR


3-hydroxybutyrate dehydrogenase, type 2
BDH2


brain-derived neurotrophic factor
BDNF


BEN domain containing 7
BEND7


biglycan
BGN


basic helix-loop-helix domain containing,
BHLHB9


class B, 9


betaine--homocysteine S-
BHMT


methyltransferase


betaine--homocysteine S-
BHMT2


methyltransferase 2


BicC family RNA binding protein 1
BICC1


bridging integrator 1
BIN1


bridging integrator 2
BIN2


BLK proto-oncogene, Src family tyrosine
BLK


kinase


Bloom syndrome, RecQ helicase-like
BLM


bleomycin hydrolase
BLMH


biogenesis of lysosomal organelles
BLOC1S5


complex-1, subunit 5, muted


biliverdin reductase A
BLVRA


biliverdin reductase B
BLVRB


bone morphogenetic protein 15
BMP15


bone morphogenetic protein 3
BMP3


bone morphogenetic protein 4
BMP4


bone morphogenetic protein 7
BMP7


bone morphogenetic protein receptor, type
BMPR2


II (serine/threonine kinase)


bolA family member 2
BOLA2


bolA family member 2B
BOLA2B


block of proliferation 1
BOP1


bactericidal/permeability-increasing protein
BPI


BPI fold containing family A, member 1
BPIFA1


BPI fold containing family A, member 2
BPIFA2


BPI fold containing family B, member 1
BPIFB1


3′(2′),5′-bisphosphate nucleotidase 1
BPNT1


BRCA1-associated ATM activator 1
BRAT1


breast cancer 2, early onset
BRCA2


bromodomain containing 4
BRD4


brain and reproductive organ-expressed
BRE


(TNFRSF1A modulator)


BRI3 binding protein
BRI3BP


BRX1, biogenesis of ribosomes
BRIX1


BRICK1, SCAR/WAVE actin-nucleating
BRK1


complex subunit


breast cancer metastasis suppressor 1
BRMS1


BRO1 domain and CAAX motif containing
BROX


basigin (Ok blood group)
BSG


bone marrow stromal cell antigen 1
BST1


bone marrow stromal cell antigen 2
BST2


BTAF1 RNA polymerase II, B-TFIID
BTAF1


transcription factor-associated, 170 kDa


basic transcription factor 3
BTF3


B-cell translocation gene 1, anti-
BTG1


proliferative


BTG family, member 2
BTG2


Bruton agammaglobulinemia tyrosine
BTK


kinase


butyrophilin, subfamily 1, member A1
BTN1A1


butyrophilin, subfamily 2, member A1
BTN2A1


butyrophilin, subfamily 3, member A1
BTN3A1


butyrophilin, subfamily 3, member A2
BTN3A2


butyrophilin, subfamily 3, member A3
BTN3A3


BUB3 mitotic checkpoint protein
BUB3


basic leucine zipper and W2 domains 1
BZW1


basic leucine zipper and W2 domains 2
BZW2


chromosome 10 open reading frame 54
C10orf54


chromosome 10 open reading frame 90
C10orf90


chromosome 11 open reading frame 52
C11orf52


chromosome 11 open reading frame 54
C11orf54


chromosome 12 open reading frame 10
C12orf10


chromosome 12 open reading frame 57
C12orf57


chromosome 14 open reading frame 1
C14orf1


chromosome 14 open reading frame 166
C14orf166


chromosome 15 open reading frame 52
C15orf52


chromosome 16 open reading frame 13
C16orf13


chromosome 16 open reading frame 54
C16orf54


chromosome 16 open reading frame 62
C16orf62


chromosome 16 open reading frame 87
C16orf87


chromosome 16 open reading frame 89
C16orf89


chromosome 17 open reading frame 75
C17orf75


chromosome 17 open reading frame 80
C17orf80


chromosome 19 open reading frame 18
C19orf18


C1GALT1-specific chaperone 1
C1GALT1C1


chromosome 1 open reading frame 116
C1orf116


chromosome 1 open reading frame 198
C1orf198


complement component 1, q
C1QA


subcomponent, A chain


complement component 1, q
C1QB


subcomponent, B chain


complement component 1, q
C1QBP


subcomponent binding protein


complement component 1, q
C1QC


subcomponent, C chain


C1q and tumor necrosis factor related
C1QTNF1


protein 1


C1q and tumor necrosis factor related
C1QTNF3


protein 3


complement component 1, r
C1R


subcomponent


complement component 1, r
C1RL


subcomponent-like


complement component 1, s
C1S


subcomponent


chromosome 21 open reading frame 59
C21orf59


C2 calcium-dependent domain containing
C2CD5


5


chromosome 2 open reading frame 16
C2orf16


chromosome 2 open reading frame 74
C2orf74


chromosome 2 open reading frame 88
C2orf88


complement component 3
C3


complement component 4A (Rodgers
C4A


blood group)


complement component 4B (Chido blood
C4B


group)


complement component 4 binding protein,
C4BPA


alpha


complement component 4 binding protein,
C4BPB


beta


complement component 5
C5


chromosome 5 open reading frame 15
C5orf15


chromosome 5 open reading frame 24
C5orf24


chromosome 5 open reading frame 46
C5orf46


chromosome 5 open reading frame 51
C5orf51


complement component 6
C6


chromosome 6 open reading frame 10
C6orf10


chromosome 6 open reading frame 163
C6orf163


complement component 7
C7


chromosome 7 open reading frame 50
C7orf50


complement component 8, alpha
C8A


polypeptide


complement component 8, gamma
C8G


polypeptide


chromosome 8 open reading frame 33
C8orf33


complement component 9
C9


chromosome 9 open reading frame 64
C9orf64


chromosome 9 open reading frame 91
C9orf91


carbonic anhydrase I
CA1


carbonic anhydrase XII
CA12


carbonic anhydrase XIV
CA14


carbonic anhydrase II
CA2


carbonic anhydrase IV
CA4


carbonic anhydrase VI
CA6


carbonic anhydrase IX
CA9


calcium binding protein 39
CAB39


calcium binding protein 39-like
CAB39L


calcium binding protein 1
CABP1


calcium channel, voltage-dependent, R
CACNA1E


type, alpha 1E subunit


calcium channel, voltage-dependent, L
CACNA1S


type, alpha 1S subunit


calcium channel, voltage-dependent, alpha
CACNA2D1


2/delta subunit 1


calcium channel, voltage-dependent, alpha
CACNA2D2


2/delta subunit 2


calcium channel, voltage-dependent, alpha
CACNA2D4


2/delta subunit 4


calcyclin binding protein
CACYBP


carbamoyl-phosphate synthetase 2,
CAD


aspartate transcarbamylase, and


dihydroorotase


cell adhesion molecule 1
CADM1


cell adhesion molecule 4
CADM4


calbindin 1, 28 kDa
CALB1


calmodulin 1 (phosphorylase kinase, delta)
CALM1


calmodulin 2 (phosphorylase kinase, delta)
CALM2


calmodulin 3 (phosphorylase kinase, delta)
CALM3


calmodulin-like 3
CALML3


calmodulin-like 5
CALML5


calreticulin
CALR


calumenin
CALU


calcium/calmodulin-dependent protein
CAMK2D


kinase II delta


calcium/calmodulin-dependent protein
CAMK2G


kinase II gamma


calcium/calmodulin-dependent protein
CAMK4


kinase IV


calcium/calmodulin-dependent protein
CAMKK2


kinase kinase 2, beta


CaM kinase-like vesicle-associated
CAMKV


cathelicidin antimicrobial peptide
CAMP


calmodulin binding transcription activator 1
CAMTA1


cullin-associated and neddylation-
CAND1


dissociated 1


cullin-associated and neddylation-
CAND2


dissociated 2 (putative)


calcium activated nucleotidase 1
CANT1


calnexin
CANX


CAP, adenylate cyclase-associated protein
CAP1


1 (yeast)


capping protein (actin filament), gelsolin-
CAPG


like


calpain 1, (mu/I) large subunit
CAPN1


calpain 2, (m/II) large subunit
CAPN2


calpain 5
CAPN5


calpain 7
CAPN7


calpain, small subunit 1
CAPNS1


calpain, small subunit 2
CAPNS2


cell cycle associated protein 1
CAPRIN1


calcyphosine
CAPS


calcyphosine 2
CAPS2


capping protein (actin filament) muscle Z-
CAPZA1


line, alpha 1


capping protein (actin filament) muscle Z-
CAPZA2


line, alpha 2


capping protein (actin filament) muscle Z-
CAPZB


line, beta


caspase recruitment domain family,
CARD9


member 9


calcium regulated heat stable protein 1,
CARHSP1


24 kDa


carbohydrate kinase domain containing
CARKD


cysteinyl-tRNA synthetase
CARS


cancer susceptibility candidate 4
CASC4


calcium/calmodulin-dependent serine
CASK


protein kinase (MAGUK family)


caspase 14, apoptosis-related cysteine
CASP14


peptidase


caspase 3, apoptosis-related cysteine
CASP3


peptidase


caspase 6, apoptosis-related cysteine
CASP6


peptidase


caspase 9, apoptosis-related cysteine
CASP9


peptidase


catalase
CAT


caveolin 1, caveolae protein, 22 kDa
CAV1


caveolin 2
CAV2


Cbl proto-oncogene, E3 ubiquitin protein
CBL


ligase


carbonyl reductase 1
CBR1


carbonyl reductase 3
CBR3


cystathionine-beta-synthase
CBS


chromobox homolog 1
CBX1


chromobox homolog 3
CBX3


chromobox homolog 5
CBX5


chromobox homolog 8
CBX8


coiled-coil and C2 domain containing 1A
CC2D1A


coiled-coil and C2 domain containing 1B
CC2D1B


cell division cycle and apoptosis regulator
CCAR1


1


cell cycle and apoptosis regulator 2
CCAR2


cysteine conjugate-beta lyase 2
CCBL2


coiled-coil domain containing 105
CCDC105


coiled-coil domain containing 115
CCDC115


coiled-coil domain containing 129
CCDC129


coiled-coil domain containing 132
CCDC132


coiled-coil domain containing 158
CCDC158


coiled-coil domain containing 171
CCDC171


coiled-coil domain containing 175
CCDC175


coiled-coil domain containing 22
CCDC22


coiled-coil domain containing 25
CCDC25


coiled-coil domain containing 33
CCDC33


coiled-coil domain containing 47
CCDC47


coiled-coil domain containing 50
CCDC50


coiled-coil domain containing 64B
CCDC64B


coiled-coil domain containing 88B
CCDC88B


coiled-coil domain containing 93
CCDC93


chemokine (C-C motif) ligand 2
CCL2


chemokine (C-C motif) ligand 20
CCL20


chemokine (C-C motif) ligand 22
CCL22


chemokine (C-C motif) ligand 28
CCL28


chemokine (C-C motif) ligand 7
CCL7


cerebral cavernous malformation 2
CCM2


cyclin D-type binding-protein 1
CCNDBP1


cyclin Y
CCNY


cyclin Y-like 1
CCNYL1


cell cycle progression 1
CCPG1


chemokine (C-C motif) receptor 4
CCR4


chemokine (C-C motif) receptor 5
CCR5


(gene/pseudogene)


copper chaperone for superoxide
CCS


dismutase


chaperonin containing TCP1, subunit 2
CCT2


(beta)


chaperonin containing TCP1, subunit 3
CCT3


(gamma)


chaperonin containing TCP1, subunit 4
CCT4


(delta)


chaperonin containing TCP1, subunit 5
CCT5


(epsilon)


chaperonin containing TCP1, subunit 6A
CCT6A


(zeta 1)


chaperonin containing TCP1, subunit 6B
CCT6B


(zeta 2)


chaperonin containing TCP1, subunit 7
CCT7


(eta)


chaperonin containing TCP1, subunit 8
CCT8


(theta)


CD101 molecule
CD101


CD109 molecule
CD109


CD14 molecule
CD14


CD151 molecule (Raph blood group)
CD151


CD163 molecule
CD163


CD163 molecule-like 1
CD163L1


CD19 molecule
CD19


CD1a molecule
CD1A


CD1b molecule
CD1B


CD1c molecule
CD1C


CD2 molecule
CD2


CD200 molecule
CD200


CD209 molecule
CD209


CD22 molecule
CD22


CD226 molecule
CD226


CD24 molecule
CD24


CD247 molecule
CD247


CD248 molecule, endosialin
CD248


CD274 molecule
CD274


CD276 molecule
CD276


CD2-associated protein
CD2AP


CD2 (cytoplasmic tail) binding protein 2
CD2BP2


CD300a molecule
CD300A


CD320 molecule
CD320


CD33 molecule
CD33


CD36 molecule (thrombospondin receptor)
CD36


CD37 molecule
CD37


CD38 molecule
CD38


CD3d molecule, delta (CD3-TCR complex)
CD3D


CD3e molecule, epsilon (CD3-TCR
CD3E


complex)


CD3g molecule, gamma (CD3-TCR
CD3G


complex)


CD4 molecule
CD4


CD40 molecule, TNF receptor superfamily
CD40


member 5


CD40 ligand
CD40LG


CD44 molecule (Indian blood group)
CD44


CD46 molecule, complement regulatory
CD46


protein


CD47 molecule
CD47


CD48 molecule
CD48


CD5 molecule
CD5


CD53 molecule
CD53


CD55 molecule, decay accelerating factor
CD55


for complement (Cromer blood group)


CD58 molecule
CD58


CD59 molecule, complement regulatory
CD59


protein


CD5 molecule-like
CD5L


CD6 molecule
CD6


CD63 molecule
CD63


CD68 molecule
CD68


CD70 molecule
CD70


CD74 molecule, major histocompatibility
CD74


complex, class II invariant chain


CD79b molecule, immunoglobulin-
CD79B


associated beta


CD80 molecule
CD80


CD81 molecule
CD81


CD82 molecule
CD82


CD84 molecule
CD84


CD86 molecule
CD86


CD8a molecule
CD8A


CD8b molecule
CD8B


CD9 molecule
CD9


CD99 molecule
CD99


CD99 molecule-like 2
CD99L2


cell division cycle 16
CDC16


cell division cycle 23
CDC23


cell division cycle 25B
CDC25B


cell division cycle 27
CDC27


cell division cycle 37
CDC37


cell division cycle 42
CDC42


CDC42 binding protein kinase alpha
CDC42BPA


(DMPK-like)


CDC42 binding protein kinase beta
CDC42BPB


(DMPK-like)


CDC42 binding protein kinase gamma
CDC42BPG


(DMPK-like)


cell division cycle 42 pseudogene 6
CDC42P6


CDC42 small effector 2
CDC42SE2


cell division cycle 5-like
CDC5L


cell division cycle associated 3
CDCA3


cell division cycle associated 8
CDCA8


CUB domain containing protein 1
CDCP1


cadherin 1, type 1, E-cadherin (epithelial)
CDH1


cadherin 11, type 2, OB-cadherin
CDH11


(osteoblast)


cadherin 13
CDH13


cadherin 17, LI cadherin (liver-intestine)
CDH17


cadherin 2, type 1, N-cadherin (neuronal)
CDH2


cadherin-related 23
CDH23


cadherin 3, type 1, P-cadherin (placental)
CDH3


cadherin 6, type 2, K-cadherin (fetal
CDH6


kidney)


cadherin 9, type 2 (T1-cadherin)
CDH9


cadherin-related family member 2
CDHR2


cadherin-related family member 5
CDHR5


CDP-diacylglycerol--inositol 3-
CDIPT


phosphatidyltransferase


cyclin-dependent kinase 1
CDK1


cyclin-dependent kinase 11B
CDK11B


cyclin-dependent kinase 12
CDK12


cyclin-dependent kinase 13
CDK13


cyclin-dependent kinase 14
CDK14


cyclin-dependent kinase 16
CDK16


cyclin-dependent kinase 17
CDK17


cyclin-dependent kinase 18
CDK18


cyclin-dependent kinase 2
CDK2


cyclin-dependent kinase 3
CDK3


cyclin-dependent kinase 4
CDK4


cyclin-dependent kinase 5
CDK5


cyclin-dependent kinase 5, regulatory
CDK5R2


subunit 2 (p39)


CDK5 regulatory subunit associated
CDK5RAP2


protein 2


cyclin-dependent kinase 6
CDK6


cyclin-dependent kinase 9
CDK9


CDP-diacylglycerol synthase
CDS2


(phosphatidate cytidylyltransferase) 2


corneodesmosin
CDSN


CDV3 homolog (mouse)
CDV3


carcinoembryonic antigen-related cell
CEACAM1


adhesion molecule 1 (biliary glycoprotein)


carcinoembryonic antigen-related cell
CEACAM5


adhesion molecule 5


carcinoembryonic antigen-related cell
CEACAM8


adhesion molecule 8


cat eye syndrome chromosome region,
CECR5


candidate 5


carboxyl ester lipase
CEL


CUGBP, Elav-like family member 1
CELF1


CUGBP, Elav-like family member 2
CELF2


cell migration inducing protein, hyaluronan
CEMIP


binding


centromere protein E, 312 kDa
CENPE


centromere protein V
CENPV


centrosomal protein 131 kDa
CEP131


centrosomal protein 250 kDa
CEP250


centrosomal protein 350 kDa
CEP350


centrosomal protein 55 kDa
CEP55


centrosomal protein 97 kDa
CEP97


ceramide synthase 1
CERS1


carboxylesterase 2
CES2


carboxylesterase 3
CES3


cholesteryl ester transfer protein, plasma
CETP


cilia and flagella associated protein 20
CFAP20


cilia and flagella associated protein 43
CFAP43


cilia and flagella associated protein 44
CFAP44


cilia and flagella associated protein 58
CFAP58


cilia and flagella associated protein 70
CFAP70


complement factor B
CFB


complement factor D (adipsin)
CFD


complement factor H
CFH


complement factor H-related 3
CFHR3


complement factor I
CFI


cofilin 1 (non-muscle)
CFL1


cofilin 2 (muscle)
CFL2


cystic fibrosis transmembrane conductance
CFTR


regulator (ATP-binding cassette sub-family


C, member 7)


coiled-coil-helix-coiled-coil-helix domain
CHCHD3


containing 3


chromodomain helicase DNA binding
CHD1L


protein 1-like


chromodomain helicase DNA binding
CHD4


protein 4


chromodomain helicase DNA binding
CHD6


protein 6


chromodomain helicase DNA binding
CHD9


protein 9


chitinase domain containing 1
CHID1


charged multivesicular body protein 1A
CHMP1A


charged multivesicular body protein 1B
CHMP1B


charged multivesicular body protein 2A
CHMP2A


charged multivesicular body protein 2B
CHMP2B


charged multivesicular body protein 3
CHMP3


charged multivesicular body protein 4A
CHMP4A


charged multivesicular body protein 4B
CHMP4B


charged multivesicular body protein 4C
CHMP4C


charged multivesicular body protein 5
CHMP5


charged multivesicular body protein 6
CHMP6


cysteine and histidine-rich domain
CHORDC1


(CHORD) containing 1


calcineurin-like EF-hand protein 1
CHP1


chordin-like 2
CHRDL2


cholinergic receptor, nicotinic, alpha 3
CHRNA3


(neuronal)


carbohydrate (keratan sulfate Gal-6)
CHST1


sulfotransferase 1


carbohydrate (chondroitin 4)
CHST12


sulfotransferase 12


carbohydrate (N-acetylgalactosamine 4-0)
CHST14


sulfotransferase 14


CTF18, chromosome transmission fidelity
CHTF18


factor 18 homolog (S. cerevisiae)


conserved helix-loop-helix ubiquitous
CHUK


kinase


cytosolic iron-sulfur assembly component 1
CIAO1


calcium and integrin binding 1 (calmyrin)
CIB1


cold inducible RNA binding protein
CIRBP


CDGSH iron sulfur domain 2
CISD2


citron rho-interacting serine/threonine
CIT


kinase


Cbp/p300-interacting transactivator, with
CITED1


Glu/Asp-rich carboxy-terminal domain, 1


cytoskeleton-associated protein 4
CKAP4


cytoskeleton associated protein 5
CKAP5


creatine kinase, brain
CKB


creatine kinase, mitochondrial 1A
CKMT1A


creatine kinase, mitochondrial 1B
CKMT1B


cytoplasmic linker associated protein 1
CLASP1


cytoplasmic linker associated protein 2
CLASP2


Charcot-Leyden crystal galectin
CLC


chloride channel accessory 4
CLCA4


chloride channel, voltage-sensitive 3
CLCN3


chloride channel, voltage-sensitive 4
CLCN4


chloride channel, voltage-sensitive 5
CLCN5


chloride channel, voltage-sensitive 7
CLCN7


claudin 1
CLDN1


claudin 12
CLDN12


claudin 18
CLDN18


claudin 2
CLDN2


claudin 3
CLDN3


claudin 4
CLDN4


claudin 5
CLDN5


claudin 6
CLDN6


claudin 7
CLDN7


claudin domain containing 1
CLDND1


C-type lectin domain family 11, member A
CLEC11A


C-type lectin domain family 1, member B
CLEC1B


C-type lectin domain family 3, member B
CLEC3B


chloride intracellular channel 1
CLIC1


chloride intracellular channel 2
CLIC2


chloride intracellular channel 3
CLIC3


chloride intracellular channel 4
CLIC4


chloride intracellular channel 5
CLIC5


chloride intracellular channel 6
CLIC6


clathrin interactor 1
CLINT1


CAP-GLY domain containing linker protein
CLIP2


2


ceroid-lipofuscinosis, neuronal 3
CLN3


chloride channel, nucleotide-sensitive, 1A
CLNS1A


caseinolytic mitochondrial matrix peptidase
CLPX


chaperone subunit


clarin 3
CLRN3


calsyntenin 1
CLSTN1


clathrin, light chain A
CLTA


clathrin, light chain B
CLTB


clathrin, heavy chain (Hc)
CLTC


clathrin, heavy chain-like 1
CLTCL1


clusterin
CLU


clustered mitochondria (cluA/CLU1)
CLUH


homolog


clavesin 2
CLVS2


carboxymethylenebutenolidase homolog
CMBL


(Pseudomonas)


c-Maf inducing protein
CMIP


cytidine monophosphate (UMP-CMP)
CMPK1


kinase 1, cytosolic


cytidine monophosphate (UMP-CMP)
CMPK2


kinase 2, mitochondrial


cap methyltransferase 1
CMTR1


cardiomyopathy associated 5
CMYA5


CNDP dipeptidase 2 (metallopeptidase
CNDP2


M20 family)


cyclic nucleotide gated channel beta 1
CNGB1


connector enhancer of kinase suppressor
CNKSR2


of Ras 2


CNKSR family member 3
CNKSR3


calponin 1, basic, smooth muscle
CNN1


calponin 2
CNN2


calponin 3, acidic
CNN3


cyclin and CBS domain divalent metal
CNNM2


cation transport mediator 2


cyclin and CBS domain divalent metal
CNNM3


cation transport mediator 3


cyclin and CBS domain divalent metal
CNNM4


cation transport mediator 4


CCR4-NOT transcription complex, subunit
CNOT1


1


CCR4-NOT transcription complex, subunit
CNOT11


11


CCR4-NOT transcription complex, subunit
CNOT7


7


2′,3′-cyclic nucleotide 3′ phosphodiesterase
CNP


canopy FGF signaling regulator 2
CNPY2


ciliary neurotrophic factor receptor
CNTFR


centlein, centrosomal protein
CNTLN


contactin 1
CNTN1


contactin 5
CNTN5


contactin associated protein-like 4
CNTNAP4


CoA synthase
COASY


cordon-bleu WH2 repeat protein-like 1
COBLL1


cochlin
COCH


component of oligomeric golgi complex 1
COG1


component of oligomeric golgi complex 2
COG2


component of oligomeric golgi complex 3
COG3


component of oligomeric golgi complex 4
COG4


component of oligomeric golgi complex 5
COG5


component of oligomeric golgi complex 6
COG6


component of oligomeric golgi complex 7
COG7


collagen, type XI, alpha 1
COL11A1


collagen, type XII, alpha 1
COL12A1


collagen, type XIV, alpha 1
COL14A1


collagen, type XV, alpha 1
COL15A1


collagen, type XVI, alpha 1
COL16A1


collagen, type XVIII, alpha 1
COL18A1


collagen, type I, alpha 1
COL1A1


collagen, type I, alpha 2
COL1A2


collagen, type XXI, alpha 1
COL21A1


collagen, type XXIV, alpha 1
COL24A1


collagen, type II, alpha 1
COL2A1


collagen, type III, alpha 1
COL3A1


collagen, type IV, alpha 1
COL4A1


collagen, type IV, alpha 2
COL4A2


collagen, type IV, alpha 3 (Goodpasture
COL4A3


antigen)


collagen, type V, alpha 1
COL5A1


collagen, type V, alpha 2
COL5A2


collagen, type VI, alpha 1
COL6A1


collagen, type VI, alpha 2
COL6A2


collagen, type VI, alpha 3
COL6A3


collagen, type VII, alpha 1
COL7A1


collectin sub-family member 10 (C-type
COLEC10


lectin)


collectin sub-family member 12
COLEC12


collagen beta(1-O)galactosyltransferase 1
COLGALT1


COMM domain containing 3
COMMD3


cartilage oligomeric matrix protein
COMP


catechol-O-methyltransferase
COMT


coatomer protein complex, subunit alpha
COPA


coatomer protein complex, subunit beta 1
COPB1


coatomer protein complex, subunit beta 2
COPB2


(beta prime)


coatomer protein complex, subunit epsilon
COPE


coatomer protein complex, subunit gamma 1
COPG1


coatomer protein complex, subunit gamma 2
COPG2


COP9 signalosome subunit 2
COPS2


COP9 signalosome subunit 3
COPS3


COP9 signalosome subunit 4
COPS4


COP9 signalosome subunit 5
COPS5


COP9 signalosome subunit 6
COPS6


COP9 signalosome subunit 8
COPS8


coatomer protein complex, subunit zeta 1
COPZ1


coenzyme Q6 monooxygenase
COQ6


coronin, actin binding protein, 1A
CORO1A


coronin, actin binding protein, 1B
CORO1B


coronin, actin binding protein, 1C
CORO1C


coronin 7
CORO7


CORO7-PAM16 readthrough
CORO7-PAM16


coactosin-like F-actin binding protein 1
COTL1


cytochrome c oxidase subunit IV isoform 1
COX4I1


cytochrome c oxidase subunit Vb
COX5B


ceruloplasmin (ferroxidase)
CP


carboxypeptidase A1 (pancreatic)
CPA1


carboxypeptidase B1 (tissue)
CPB1


carboxypeptidase D
CPD


carboxypeptidase M
CPM


carboxypeptidase N, polypeptide 2
CPN2


copine I
CPNE1


copine II
CPNE2


copine III
CPNE3


copine V
CPNE5


copine VI (neuronal)
CPNE6


copine VIII
CPNE8


coproporphyrinogen oxidase
CPOX


carbamoyl-phosphate synthase 1,
CPS1


mitochondrial


cleavage and polyadenylation specific
CPSF1


factor 1, 160 kDa


cleavage and polyadenylation specific
CPSF3


factor 3, 73 kDa


cleavage and polyadenylation specific
CPSF3L


factor 3-like


cleavage and polyadenylation specific
CPSF6


factor 6, 68 kDa


cleavage and polyadenylation specific
CPSF7


factor 7, 59 kDa


carboxypeptidase, vitellogenic-like
CPVL


complement component (3b/4b) receptor 1
CR1


(Knops blood group)


complement component (3d/Epstein Barr
CR2


virus) receptor 2


cellular retinoic acid binding protein 2
CRABP2


crumbs family member 2
CRB2


crumbs family member 3
CRB3


cAMP responsive element binding protein 5
CREB5


cellular repressor of E1A-stimulated genes 1
CREG1


cysteine-rich protein 2
CRIP2


cysteine-rich PDZ-binding protein
CRIPT


cysteine-rich secretory protein LCCL
CRISPLD1


domain containing 1


v-crk avian sarcoma virus CT10 oncogene
CRK


homolog


v-crk avian sarcoma virus CT10 oncogene
CRKL


homolog-like


cytokine receptor-like factor 3
CRLF3


collapsin response mediator protein 1
CRMP1


crooked neck pre-mRNA splicing factor 1
CRNKL1


cornulin
CRNN


ciliary rootlet coiled-coil, rootletin
CROCC


ciliary rootlet coiled-coil, rootletin family
CROCC2


member 2


cartilage associated protein
CRTAP


CREB regulated transcription coactivator 2
CRTC2


crystallin, alpha A
CRYAA


crystallin, alpha B
CRYAB


crystallin, lambda 1
CRYL1


crystallin, mu
CRYM


crystallin, zeta (quinone reductase)
CRYZ


crystallin, zeta (quinone reductase)-like 1
CRYZL1


citrate synthase
CS


cold shock domain containing E1, RNA-
CSDE1


binding


CSE1 chromosome segregation 1-like
CSE1L


(yeast)


colony stimulating factor 1 (macrophage)
CSF1


colony stimulating factor 2 (granulocyte-
CSF2


macrophage)


colony stimulating factor 3 (granulocyte)
CSF3


c-src tyrosine kinase
CSK


CUB and Sushi multiple domains 2
CSMD2


casein alpha s1
CSN1S1


casein beta
CSN2


casein kappa
CSN3


casein kinase 1, alpha 1
CSNK1A1


casein kinase 1, delta
CSNK1D


casein kinase 1, gamma 1
CSNK1G1


casein kinase 1, gamma 3
CSNK1G3


casein kinase 2, alpha 1 polypeptide
CSNK2A1


casein kinase 2, alpha prime polypeptide
CSNK2A2


casein kinase 2, beta polypeptide
CSNK2B


chondroitin sulfate proteoglycan 4
CSPG4


chondroitin sulfate proteoglycan 5
CSPG5


(neuroglycan C)


cysteine and glycine-rich protein 1
CSRP1


cysteine and glycine-rich protein 2
CSRP2


cystatin C
CST3


cystatin S
CST4


cystatin D
CST5


cystatin A (stefin A)
CSTA


cystatin B (stefin B)
CSTB


cleavage stimulation factor, 3′ pre-RNA,
CSTF1


subunit 1, 50 kDa


cleavage stimulation factor, 3′ pre-RNA,
CSTF3


subunit 3, 77 kDa


C-terminal binding protein 1
CTBP1


C-terminal binding protein 2
CTBP2


CTD nuclear envelope phosphatase 1
CTDNEP1


CTD (carboxy-terminal domain, RNA
CTDSP1


polymerase II, polypeptide A) small


phosphatase 1


CTD (carboxy-terminal domain, RNA
CTDSPL


polymerase II, polypeptide A) small


phosphatase-like


cystathionine gamma-lyase
CTH


cytotoxic T-lymphocyte-associated protein
CTLA4-Ig


4-immunoglobulin fusion protein


catenin (cadherin-associated protein),
CTNNA1


alpha 1, 102 kDa


catenin (cadherin-associated protein),
CTNNA2


alpha 2


catenin (cadherin-associated protein), beta 1,
CTNNB1


88 kDa


catenin (cadherin-associated protein), delta 1
CTNND1


catenin (cadherin-associated protein), delta 2
CTNND2


cystinosin, lysosomal cystine transporter
CTNS


CTP synthase 1
CTPS1


CTP synthase 2
CTPS2


CTR9, Paf1/RNA polymerase II complex
CTR9


component


cathepsin A
CTSA


cathepsin B
CTSB


cathepsin C
CTSC


cathepsin D
CTSD


cathepsin G
CTSG


cathepsin H
CTSH


cathepsin L
CTSL


cathepsin V
CTSV


cathepsin Z
CTSZ


cortactin
CTTN


cubilin (intrinsic factor-cobalamin receptor)
CUBN


cullin 1
CUL1


cullin 2
CUL2


cullin 3
CUL3


cullin 4A
CUL4A


cullin 4B
CUL4B


cullin 5
CUL5


cutA divalent cation tolerance homolog
CUTA


(E. coli)


cut-like homeobox 2
CUX2


CWC25 spliceosome-associated protein
CWC25


homolog (S. cerevisiae)


CWF19-like 1, cell cycle control (S. pombe)
CWF19L1


coxsackie virus and adenovirus receptor
CXADR


chemokine (C-X-C motif) ligand 16
CXCL16


chemokine (C-X-C motif) ligand 2
CXCL2


chemokine (C-X-C motif) ligand 8
CXCL8


chemokine (C-X-C motif) receptor 4
CXCR4


cytochrome b5 type A (microsomal)
CYB5A


cytochrome b5 type B (outer mitochondrial
CYB5B


membrane)


cytochrome b5 reductase 1
CYB5R1


cytochrome b5 reductase 3
CYB5R3


cytochrome b-245, beta polypeptide
CYBB


cytochrome b reductase 1
CYBRD1


cytochrome c-1
CYC1


cytoplasmic FMR1 interacting protein 1
CYFIP1


cytoplasmic FMR1 interacting protein 2
CYFIP2


cytochrome P450, family 17, subfamily A,
CYP17A1


polypeptide 1


cytochrome P450, family 2, subfamily D,
CYP2D6


polypeptide 6


cysteine-rich, angiogenic inducer, 61
CYR61


cysteine-rich tail protein 1
CYSRT1


cysteine-rich transmembrane module
CYSTM1


containing 1


cytohesin 2
CYTH2


cytohesin 3
CYTH3


dishevelled associated activator of
DAAM1


morphogenesis 1


Dab, mitogen-responsive phosphoprotein,
DAB2


homolog 2 (Drosophila)


dishevelled-binding antagonist of beta-
DACT1


catenin 1


defender against cell death 1
DAD1


dystroglycan 1 (dystrophin-associated
DAG1


glycoprotein 1)


dual adaptor of phosphotyrosine and 3-
DAPP1


phosphoinositides


aspartyl-tRNA synthetase
DARS


DBF4 zinc finger B
DBF4B


dopamine beta-hydroxylase (dopamine
DBH


beta-monooxygenase)


diazepam binding inhibitor (GABA receptor
DBI


modulator, acyl-CoA binding protein)


drebrin 1
DBN1


drebrin-like
DBNL


DDB1 and CUL4 associated factor 7
DCAF7


discoidin, CUB and LCCL domain
DCBLD2


containing 2


dermcidin
DCD


dachsous cadherin-related 2
DCHS2


deoxycytidine kinase
DCK


doublecortin-like kinase 1
DCLK1


doublecortin-like kinase 2
DCLK2


decorin
DON


dopachrome tautomerase
DOT


dynactin 1
DCTN1


dynactin 2 (p50)
DCTN2


dynactin 3 (p22)
DCTN3


dCTP pyrophosphatase 1
DCTPP1


DCN1, defective in cullin neddylation 1,
DCUN1D3


domain containing 3


dicarbonyl/L-xylulose reductase
DCXR


dimethylarginine dimethylaminohydrolase 1
DDAH1


dimethylarginine dimethylaminohydrolase 2
DDAH2


damage-specific DNA binding protein 1, 127 kDa
DDB1


dopa decarboxylase (aromatic L-amino
DDC


acid decarboxylase)


dendrin
DDN


dolichyl-diphosphooligosaccharide--protein
DDOST


glycosyltransferase subunit (non-catalytic)


discoidin domain receptor tyrosine kinase 1
DDR1


discoidin domain receptor tyrosine kinase 2
DDR2


DDRGK domain containing 1
DDRGK1


D-dopachrome tautomerase
DDT


DEAD (Asp-Glu-Ala-Asp) box helicase 1
DDX1


DEAD (Asp-Glu-Ala-Asp) box helicase 17
DDX17


DEAD (Asp-Glu-Ala-Asp) box polypeptide 18
DDX18


DEAD (Asp-Glu-Ala-Asp) box polypeptide 19A
DDX19A


DEAD (Asp-Glu-Ala-Asp) box polypeptide 19B
DDX19B


DEAD (Asp-Glu-Ala-Asp) box helicase 21
DDX21


DEAD (Asp-Glu-Ala-Asp) box polypeptide 23
DDX23


DEAD (Asp-Glu-Ala-Asp) box polypeptide 27
DDX27


DEAD (Asp-Glu-Ala-Asp) box polypeptide 39A
DDX39A


DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B
DDX39B


DEAD (Asp-Glu-Ala-Asp) box helicase 3, X-linked
DDX3X


DEAD (Asp-Glu-Ala-Asp) box helicase 3, Y-linked
DDX3Y


DEAD (Asp-Glu-Ala-Asp) box polypeptide 4
DDX4


DEAD (Asp-Glu-Ala-Asp) box polypeptide 46
DDX46


DEAD (Asp-Glu-Ala-Asp) box polypeptide 47
DDX47


DEAD (Asp-Glu-Ala-Asp) box polypeptide 49
DDX49


DEAD (Asp-Glu-Ala-Asp) box helicase 5
DDX5


DEAD (Asp-Glu-Ala-Asp) box polypeptide 50
DDX50


DEAD (Asp-Glu-Ala-Asp) box polypeptide 58
DDX58


DEAD (Asp-Glu-Ala-Asp) box helicase 6
DDX6


DEAD (Asp-Glu-Ala-Asp) box polypeptide 60
DDX60


2,4-dienoyl CoA reductase 1, mitochondrial
DECR1


differentially expressed in FDCP 6
DEF6


homolog (mouse)


defensin, alpha 1
DEFA1


defensin, alpha 1B
DEFA1B


defensin, alpha 3, neutrophil-specific
DEFA3


DEK proto-oncogene
DEK


DENN/MADD domain containing 3
DENND3


DENN/MADD domain containing 6A
DENND6A


density-regulated protein
DENR


DEP domain containing 1B
DEPDC1B


deoxyribose-phosphate aldolase (putative)
DERA


derlin 1
DERL1


desmin
DES


deafness, autosomal dominant 5
DFNA5


diacylglycerol kinase, alpha 80 kDa
DGKA


24-dehydrocholesterol reductase
DHCR24


7-dehydrocholesterol reductase
DHCR7


dihydrofolate reductase
DHFR


dehydrogenase/reductase (SDR family)
DHRS1


member 1


dehydrogenase/reductase (SDR family)
DHRS7


member 7


DEAH (Asp-Glu-Ala-His) box helicase 15
DHX15


DEAH (Asp-Glu-Ala-His) box polypeptide 16
DHX16


DEAH (Asp-Glu-Ala-His) box helicase 30
DHX30


DEAH (Asp-Glu-Ala-His) box polypeptide 34
DHX34


DEAH (Asp-Glu-Ala-His) box polypeptide 36
DHX36


DEAH (Asp-Glu-Ala-His) box helicase 9
DHX9


diaphanous-related formin 1
DIAPH1


diaphanous-related formin 3
DIAPH3


DIM1 dimethyladenosine transferase 1
DIMT1


homolog (S. cerevisiae)


DIP2 disco-interacting protein 2 homolog A
DIP2A


(Drosophila)


DIP2 disco-interacting protein 2 homolog B
DIP2B


(Drosophila)


DIP2 disco-interacting protein 2 homolog C
DIP2C


(Drosophila)


DIRAS family, GTP-binding RAS-like 2
DIRAS2


DIS3 exosome endoribonuclease and 3′-5′
DIS3


exoribonuclease


DIS3 like 3′-5′ exoribonuclease 2
DIS3L2


disrupted in schizophrenia 1
DISC1


dyskeratosis congenita 1, dyskerin
DKC1


dickkopf WNT signaling pathway inhibitor 1
DKK1


dickkopf WNT signaling pathway inhibitor 3
DKK3


dihydrolipoamide S-acetyltransferase
DLAT


DLC1 Rho GTPase activating protein
DLC1


dihydrolipoamide dehydrogenase
DLD


discs, large homolog 1 (Drosophila)
DLG1


discs, large homolog 2 (Drosophila)
DLG2


discs, large homolog 3 (Drosophila)
DLG3


dihydrolipoamide S-succinyltransferase
DLST


(E2 component of 2-oxo-glutarate


complex)


DNA methyltransferase 1 associated
DMAP1


protein 1


deleted in malignant brain tumors 1
DMBT1


dystrophin
DMD


dynein, axonemal, assembly factor 5
DNAAF5


dynein, axonemal, heavy chain 12
DNAH12


dynein, axonemal, heavy chain 17
DNAH17


dynein, axonemal, heavy chain 2
DNAH2


dynein, axonemal, heavy chain 5
DNAH5


dynein, axonemal, heavy chain 7
DNAH7


dynein, axonemal, heavy chain 8
DNAH8


DnaJ (Hsp40) homolog, subfamily A,
DNAJA1


member 1


DnaJ (Hsp40) homolog, subfamily A,
DNAJA2


member 2


DnaJ (Hsp40) homolog, subfamily B,
DNAJB1


member 1


DnaJ (Hsp40) homolog, subfamily B,
DNAJB11


member 11


DnaJ (Hsp40) homolog, subfamily B,
DNAJB3


member 3


DnaJ (Hsp40) homolog, subfamily B,
DNAJB6


member 6


DnaJ (Hsp40) homolog, subfamily B,
DNAJB9


member 9


DnaJ (Hsp40) homolog, subfamily C,
DNAJC10


member 10


DnaJ (Hsp40) homolog, subfamily C,
DNAJC13


member 13


DnaJ (Hsp40) homolog, subfamily C,
DNAJC19


member 19


DnaJ (Hsp40) homolog, subfamily C,
DNAJC2


member 2


DnaJ (Hsp40) homolog, subfamily C,
DNAJC3


member 3


DnaJ (Hsp40) homolog, subfamily C,
DNAJC5


member 5


DnaJ (Hsp40) homolog, subfamily C,
DNAJC7


member 7


DnaJ (Hsp40) homolog, subfamily C,
DNAJC8


member 8


DnaJ (Hsp40) homolog, subfamily C,
DNAJC9


member 9


deoxyribonuclease l-like 1
DNASE1L1


dynamin 1
DNM1


dynamin 1-like
DNM1L


dynamin 2
DNM2


dynamin 3
DNM3


DNA (cytosine-5-)-methyltransferase 1
DNMT1


DNA (cytosine-5-)-methyltransferase 3
DNMT3A


alpha


aspartyl aminopeptidase
DNPEP


2′-deoxynucleoside 5′-phosphate N-
DNPH1


hydrolase 1


DNA nucleotidylexotransferase
DNTT


dedicator of cytokinesis 1
DOCK1


dedicator of cytokinesis 10
DOCK10


dedicator of cytokinesis 11
DOCK11


dedicator of cytokinesis 2
DOCK2


dedicator of cytokinesis 5
DOCK5


dedicator of cytokinesis 7
DOCK7


dedicator of cytokinesis 8
DOCK8


dedicator of cytokinesis 9
DOCK9


docking protein 1, 62 kDa (downstream of
DOK1


tyrosine kinase 1)


docking protein 2, 56 kDa
DOK2


docking protein 3
DOK3


docking protein 7
DOK7


dopey family member 2
DOPEY2


dipeptidase 1 (renal)
DPEP1


dipeptidase 3
DPEP3


dipeptidyl-peptidase 3
DPP3


dipeptidyl-peptidase 4
DPP4


dipeptidyl-peptidase 7
DPP7


dpy-30 homolog (C. elegans)
DPY30


dihydropyrimidinase
DPYS


dihydropyrimidinase-like 2
DPYSL2


dihydropyrimidinase-like 3
DPYSL3


developmentally regulated GTP binding
DRG1


protein 1


developmentally regulated GTP binding
DRG2


protein 2


desmocollin 1
DSC1


desmocollin 2
DSC2


desmocollin 3
DSC3


Down syndrome critical region 3
DSCR3


desmoglein 1
DSG1


desmoglein 2
DSG2


desmoglein 3
DSG3


DSN1, MIS12 kinetochore complex
DSN1


component


desmoplakin
DSP


dystonin
DST


destrin (actin depolymerizing factor)
DSTN


deltex 3 like, E3 ubiquitin ligase
DTX3L


deoxythymidylate kinase (thymidylate
DTYMK


kinase)


dual oxidase 2
DUOX2


dihydrouridine synthase 3-like
DUS3L


(S. cerevisiae)


dual specificity phosphatase 26 (putative)
DUSP26


dual specificity phosphatase 3
DUSP3


deoxyuridine triphosphatase
DUT


dynein, cytoplasmic 1, heavy chain 1
DYNC1H1


dynein, cytoplasmic 1, intermediate chain 2
DYNC1I2


dynein, cytoplasmic 1, light intermediate
DYNC1LI1


chain 1


dynein, cytoplasmic 1, light intermediate
DYNC1LI2


chain 2


dynein, cytoplasmic 2, heavy chain 1
DYNC2H1


dynein, light chain, LC8-type 1
DYNLL1


dynein, light chain, roadblock-type 1
DYNLRB1


dynein, light chain, Tctex-type 1
DYNLT1


dysferlin
DYSF


dystrotelin
DYTN


EBNA1 binding protein 2
EBNA1BP2


endothelin converting enzyme 1
ECE1


enoyl CoA hydratase 1, peroxisomal
ECH1


ethylmalonyl-CoA decarboxylase 1
ECHDC1


enoyl CoA hydratase, short chain, 1,
ECHS1


mitochondrial


extracellular matrix protein 1
ECM1


enhancer of mRNA decapping 3
EDC3


enhancer of mRNA decapping 4
EDC4


endothelial differentiation-related factor 1
EDF1


EGF-like repeats and discoidin l-like
EDIL3


domains 3


endothelin receptor type B
EDNRB


early endosome antigen 1
EEA1


eukaryotic translation elongation factor 1
EEF1A1


alpha 1


eukaryotic translation elongation factor 1
EEF1A1P5


alpha 1 pseudogene 5


eukaryotic translation elongation factor 1
EEF1A2


alpha 2


eukaryotic translation elongation factor 1
EEF1B2


beta 2


eukaryotic translation elongation factor 1
EEF1D


delta (guanine nucleotide exchange protein)


eukaryotic translation elongation factor 1
EEF1E1


epsilon 1


eukaryotic translation elongation factor 1
EEF1G


gamma


eukaryotic translation elongation factor 2
EEF2


eukaryotic elongation factor,
EEFSEC


selenocysteine-tRNA-specific


EF-hand calcium binding domain 5
EFCAB5


EGF containing fibulin-like extracellular
EFEMP1


matrix protein 1


EGF containing fibulin-like extracellular
EFEMP2


matrix protein 2


EF-hand domain family, member D2
EFHD2


ephrin-B1
EFNB1


EFR3 homolog A (S. cerevisiae)
EFR3A


elongation factor Tu GTP binding domain
EFTUD1


containing 1


elongation factor Tu GTP binding domain
EFTUD2


containing 2


epidermal growth factor
EGF


EGF-like-domain, multiple 7
EGFL7


epidermal growth factor receptor
EGFR


EH domain binding protein 1-like 1
EHBP1L1


EH-domain containing 1
EHD1


EH-domain containing 2
EHD2


EH-domain containing 3
EHD3


EH-domain containing 4
EHD4


enoyl-CoA, hydratase/3-hydroxyacyl CoA
EHHADH


dehydrogenase


euchromatic histone-lysine N-
EHMT2


methyltransferase 2


eukaryotic translation initiation factor 1A,
EIF1AY


Y-linked


eukaryotic translation initiation factor 2A,
EIF2A


65 kDa


eukaryotic translation initiation factor 2-
EIF2AK2


alpha kinase 2


eukaryotic translation initiation factor 2B,
EIF2B1


subunit 1 alpha, 26 kDa


eukaryotic translation initiation factor 2B,
EIF2B2


subunit 2 beta, 39 kDa


eukaryotic translation initiation factor 2B,
EIF2B3


subunit 3 gamma, 58 kDa


eukaryotic translation initiation factor 2B,
EIF2B4


subunit 4 delta, 67 kDa


eukaryotic translation initiation factor 2B,
EIF2B5


subunit 5 epsilon, 82 kDa


eukaryotic translation initiation factor 2D
EIF2D


eukaryotic translation initiation factor 2,
EIF2S1


subunit 1 alpha, 35 kDa


eukaryotic translation initiation factor 2,
EIF2S2


subunit 2 beta, 38 kDa


eukaryotic translation initiation factor 2,
EIF2S3


subunit 3 gamma, 52 kDa


eukaryotic translation initiation factor 3,
EIF3A


subunit A


eukaryotic translation initiation factor 3,
EIF3B


subunit B


eukaryotic translation initiation factor 3,
EIF3C


subunit C


eukaryotic translation initiation factor 3,
EIF3CL


subunit C-like


eukaryotic translation initiation factor 3,
EIF3D


subunit D


eukaryotic translation initiation factor 3,
EIF3E


subunit E


eukaryotic translation initiation factor 3,
EIF3F


subunit F


eukaryotic translation initiation factor 3,
EIF3G


subunit G


eukaryotic translation initiation factor 3,
EIF3H


subunit H


eukaryotic translation initiation factor 3,
EIF3I


subunit I


eukaryotic translation initiation factor 3,
EIF3J


subunit J


eukaryotic translation initiation factor 3,
EIF3K


subunit K


eukaryotic translation initiation factor 3,
EIF3L


subunit L


eukaryotic translation initiation factor 3,
EIF3M


subunit M


eukaryotic translation initiation factor 4A1
EIF4A1


eukaryotic translation initiation factor 4A2
EIF4A2


eukaryotic translation initiation factor 4A3
EIF4A3


eukaryotic translation initiation factor 4B
EIF4B


eukaryotic translation initiation factor 4E
EIF4E


eukaryotic translation initiation factor 4
EIF4G1


gamma, 1


eukaryotic translation initiation factor 4H
EIF4H


eukaryotic translation initiation factor 5
EIF5


eukaryotic translation initiation factor 5A
EIF5A


eukaryotic translation initiation factor 5A2
EIF5A2


eukaryotic translation initiation factor 5A-
EIF5AL1


like 1


eukaryotic translation initiation factor 5B
EIF5B


eukaryotic translation initiation factor 6
EIF6


elastase, neutrophil expressed
ELANE


ELAV like RNA binding protein 1
ELAVL1


engulfment and cell motility 1
ELMO1


engulfment and cell motility 2
ELMO2


engulfment and cell motility 3
ELMO3


elongator acetyltransferase complex
ELP2


subunit 2


elongator acetyltransferase complex
ELP3


subunit 3


embigin
EMB


emerin
EMD


essential meiotic structure-specific
EME2


endonuclease subunit 2


EMG1 N1-specific pseudouridine
EMG1


methyltransferase


elastin microfibril interfacer 1
EMILIN1


elastin microfibril interfacer 2
EMILIN2


echinoderm microtubule associated protein
EML3


like 3


echinoderm microtubule associated protein
EML4


like 4


echinoderm microtubule associated protein
EML5


like 5


enabled homolog (Drosophila)
ENAH


endonuclease domain containing 1
ENDOD1


endoglin
ENG


endo-beta-N-acetylglucosaminidase
ENGASE


enolase 1, (alpha)
ENO1


enolase 2 (gamma, neuronal)
ENO2


enolase 3 (beta, muscle)
ENO3


glutamyl aminopeptidase (aminopeptidase A)
ENPEP


ectonucleotide
ENPP1


pyrophosphatase/phosphodiesterase 1


ectonucleotide
ENPP3


pyrophosphatase/phosphodiesterase 3


ectonucleotide
ENPP4


pyrophosphatase/phosphodiesterase 4


(putative)


ectonucleotide
ENPP6


pyrophosphatase/phosphodiesterase 6


ectonucleotide
ENPP7


pyrophosphatase/phosphodiesterase 7


ectonucleoside triphosphate
ENTPD1


diphosphohydrolase 1


ectonucleoside triphosphate
ENTPD2


diphosphohydrolase 2


ectonucleoside triphosphate
ENTPD4


diphosphohydrolase 4


erythrocyte membrane protein band 4.1
EPB41


erythrocyte membrane protein band 4.1-
EPB41L1


like 1


erythrocyte membrane protein band 4.1-
EPB41L2


like 2


erythrocyte membrane protein band 4.1-
EPB41L3


like 3


erythrocyte membrane protein band 4.1
EPB41L4B


like 4B


erythrocyte membrane protein band 4.1
EPB41L5


like 5


erythrocyte membrane protein band 4.2
EPB42


epithelial cell adhesion molecule
EPCAM


EPH receptor A1
EPHA1


EPH receptor A2
EPHA2


EPH receptor A3
EPHA3


EPH receptor A4
EPHA4


EPH receptor A5
EPHA5


EPH receptor B1
EPHB1


EPH receptor B2
EPHB2


EPH receptor B3
EPHB3


EPH receptor B4
EPHB4


epoxide hydrolase 1, microsomal
EPHX1


(xenobiotic)


epoxide hydrolase 2, cytoplasmic
EPHX2


epsin 2
EPN2


epsin 3
EPN3


erythropoietin
EPO


epiplakin 1
EPPK1


glutamyl-prolyl-tRNA synthetase
EPRS


epidermal growth factor receptor pathway
EPS15


substrate 15


epidermal growth factor receptor pathway
EPS15L1


substrate 15-like 1


epidermal growth factor receptor pathway
EPS8


substrate 8


EPS8-like 1
EPS8L1


EPS8-like 2
EPS8L2


EPS8-like 3
EPS8L3


eosinophil peroxidase
EPX


endoplasmic reticulum aminopeptidase 1
ERAP1


erb-b2 receptor tyrosine kinase 2
ERBB2


erbb2 interacting protein
ERBB2IP


erb-b2 receptor tyrosine kinase 3
ERBB3


erb-b2 receptor tyrosine kinase 4
ERBB4


excision repair cross-complementation
ERCC2


group 2


endoplasmic reticulum-golgi intermediate
ERGIC1


compartment (ERGIC) 1


ERGIC and golgi 2
ERGIC2


ER lipid raft associated 1
ERLIN1


ER lipid raft associated 2
ERLIN2


erythroblast membrane-associated protein
ERMAP


(Scianna blood group)


ermin, ERM-like protein
ERMN


endoplasmic reticulum metallopeptidase 1
ERMP1


ERO1-like (S. cerevisiae)
ERO1L


endoplasmic reticulum protein 29
ERP29


endoplasmic reticulum protein 44
ERP44


endogenous retrovirus group FRD,
ERVFRD-2


member 2


endogenous retrovirus group K, member 6
ERVK-6


endothelial cell adhesion molecule
ESAM


esterase D
ESD


endothelial cell-specific molecule 1
ESM1


epithelial splicing regulatory protein 1
ESRP1


epithelial splicing regulatory protein 2
ESRP2


extended synaptotagmin-like protein 1
ESYT1


extended synaptotagmin-like protein 2
ESYT2


eukaryotic translation termination factor 1
ETF1


electron-transfer-flavoprotein, alpha
ETFA


polypeptide


electron-transfer-flavoprotein, beta
ETFB


polypeptide


ethylmalonic encephalopathy 1
ETHE1


eva-1 homolog A (C. elegans)
EVA1A


eva-1 homolog B (C. elegans)
EVA1B


ecotropic viral integration site 2B
EVI2B


Enah/Vasp-like
EVL


envoplakin
EVPL


exocyst complex component 1
EXOC1


exocyst complex component 2
EXOC2


exocyst complex component 3
EXOC3


exocyst complex component 3-like 4
EXOC3L4


exocyst complex component 4
EXOC4


exocyst complex component 5
EXOC5


exocyst complex component 6
EXOC6


exocyst complex component 6B
EXOC6B


exocyst complex component 7
EXOC7


exocyst complex component 8
EXOC8


exosome component 1
EXOSC1


exosome component 3
EXOSC3


exosome component 4
EXOSC4


exosome component 5
EXOSC5


exosome component 6
EXOSC6


exosome component 7
EXOSC7


exostosin glycosyltransferase 2
EXT2


exostosin-like glycosyltransferase 2
EXTL2


eyes shut homolog (Drosophila)
EYS


ezrin
EZR


coagulation factor X
F10


coagulation factor XI
F11


F11 receptor
F11R


coagulation factor XIII, A1 polypeptide
F13A1


coagulation factor II (thrombin)
F2


coagulation factor II (thrombin) receptor
F2R


coagulation factor II (thrombin) receptor-
F2RL3


like 3


coagulation factor III (thromboplastin,
F3


tissue factor)


coagulation factor V (proaccelerin, labile
F5


factor)


coagulation factor VII (serum prothrombin
F7


conversion accelerator)


coagulation factor VIII, procoagulant
F8


component


coagulation factor IX
F9


fatty acid binding protein 1, liver
FABP1


fatty acid binding protein 3, muscle and
FABP3


heart


fatty acid binding protein 5 (psoriasis-
FABP5


associated)


fatty acid binding protein 5 pseudogene 7
FABP5P7


Fas (TNFRSF6)-associated via death
FADD


domain


Fas (TNFRSF6) associated factor 1
FAF1


fumarylacetoacetate hydrolase
FAH


(fumarylacetoacetase)


fumarylacetoacetate hydrolase domain
FAHD2A


containing 2A


family with sequence similarity 104,
FAM104A


member A


family with sequence similarity 120A
FAM120A


family with sequence similarity 120B
FAM120B


family with sequence similarity 129,
FAM129A


member A


family with sequence similarity 129,
FAM129B


member B


family with sequence similarity 151,
FAM151A


member A


family with sequence similarity 160,
FAM160A2


member A2


family with sequence similarity 171,
FAM171A1


member A1


family with sequence similarity 171,
FAM171A2


member A2


family with sequence similarity 174,
FAM174A


member A


family with sequence similarity 174,
FAM174B


member B


family with sequence similarity 175,
FAM175B


member B


family with sequence similarity 177,
FAM177A1


member A1


family with sequence similarity 178,
FAM178B


member B


family with sequence similarity 179,
FAM179B


member B


family with sequence similarity 184,
FAM184A


member A


family with sequence similarity 186,
FAM186A


member A


family with sequence similarity 193,
FAM193B


member B


family with sequence similarity 208,
FAM208B


member B


family with sequence similarity 209,
FAM209A


member A


family with sequence similarity 20,
FAM20A


member A


family with sequence similarity 20,
FAM20C


member C


family with sequence similarity 213,
FAM213A


member A


family with sequence similarity 213,
FAM213B


member B


family with sequence similarity 3,
FAM3B


member B


family with sequence similarity 3,
FAM3C


member C


family with sequence similarity 49,
FAM49A


member A


family with sequence similarity 49,
FAM49B


member B


family with sequence similarity 63,
FAM63A


member A


family with sequence similarity 63,
FAM63B


member B


family with sequence similarity 64,
FAM64A


member A


family with sequence similarity 65,
FAM65A


member A


family with sequence similarity 65,
FAM65C


member C


family with sequence similarity 71,
FAM71F1


member F1


family with sequence similarity 83,
FAM83F


member F


family with sequence similarity 83,
FAM83H


member H


family with sequence similarity 84,
FAM84B


member B


family with sequence similarity 91,
FAM91A1


member A1


family with sequence similarity 98,
FAM98A


member A


family with sequence similarity 98,
FAM98B


member B


Fanconi anemia, complementation group I
FANCI


Fanconi anemia, complementation group M
FANCM


fibroblast activation protein, alpha
FAP


FERM, RhoGEF (ARHGEF) and pleckstrin
FARP1


domain protein 1 (chondrocyte-derived)


phenylalanyl-tRNA synthetase, alpha
FARSA


subunit


phenylalanyl-tRNA synthetase, beta
FARSB


subunit


Fas cell surface death receptor
FAS


Fas ligand (TNF superfamily, member 6)
FASLG


fatty acid synthase
FASN


FAT atypical cadherin 1
FAT1


FAT atypical cadherin 2
FAT2


FAT atypical cadherin 4
FAT4


fibrillarin
FBL


fibulin 1
FBLN1


fibulin 2
FBLN2


fibrillin 1
FBN1


fibrillin 2
FBN2


fibrillin 3
FBN3


fructose-1,6-bisphosphatase 1
FBP1


fructose-1,6-bisphosphatase 2
FBP2


F-box and leucine-rich repeat protein 12
FBXL12


F-box and leucine-rich repeat protein 20
FBXL20


F-box and leucine-rich repeat protein 4
FBXL4


F-box and leucine-rich repeat protein 8
FBXL8


F-box protein 15
FBXO15


F-box protein 17
FBXO17


F-box protein 2
FBXO2


F-box protein 22
FBXO22


F-box protein 45
FBXO45


F-box protein 6
FBXO6


F-box and WD repeat domain containing 8
FBXW8


Fc fragment of IgE, high affinity I, receptor
FCER1G


for; gamma polypeptide


Fc fragment of IgE, low affinity II, receptor
FCER2


for (CD23)


Fc fragment of IgG binding protein
FCGBP


Fc fragment of IgG, low affinity Ila, receptor
FCGR2A


(CD32)


Fc fragment of IgG, low affinity IIc, receptor
FCGR2C


for (CD32) (gene/pseudogene)


Fc fragment of IgG, receptor, transporter,
FCGRT


alpha


ficolin (collagen/fibrinogen domain
FCN1


containing) 1


ficolin (collagen/fibrinogen domain
FCN2


containing lectin) 2


ficolin (collagen/fibrinogen domain
FCN3


containing) 3


Fc receptor-like A
FCRLA


farnesyl-diphosphate farnesyltransferase 1
FDFT1


farnesyl diphosphate synthase
FDPS


flap structure-specific endonuclease 1
FEN1


fermitin family member 2
FERMT2


fermitin family member 3
FERMT3


FES proto-oncogene, tyrosine kinase
FES


fibrinogen alpha chain
FGA


fibrinogen beta chain
FGB


FYVE, RhoGEF and PH domain containing 2
FGD2


FYVE, RhoGEF and PH domain containing 4
FGD4


fibroblast growth factor 16
FGF16


fibroblast growth factor 18
FGF18


fibroblast growth factor 19
FGF19


fibroblast growth factor binding protein 1
FGFBP1


fibroblast growth factor receptor 1
FGFR1


fibroblast growth factor receptor 2
FGFR2


fibroblast growth factor receptor 3
FGFR3


fibroblast growth factor receptor 4
FGFR4


fibroblast growth factor receptor-like 1
FGFRL1


fibrinogen gamma chain
FGG


fibrinogen-like 2
FGL2


FGR proto-oncogene, Src family tyrosine
FGR


kinase


fumarate hydratase
FH


forkhead-associated (FHA)
FHAD1


phosphopeptide binding domain 1


four and a half LIM domains 1
FHL1


four and a half LIM domains 5
FHL5


formin homology 2 domain containing 1
FHOD1


fidgetin-like 1
FIGNL1


FK506 binding protein 15, 133 kDa
FKBP15


FK506 binding protein 1A, 12 kDa
FKBP1A


FK506 binding protein 3, 25 kDa
FKBP3


FK506 binding protein 4, 59 kDa
FKBP4


FK506 binding protein 5
FKBP5


filaggrin family member 2
FLG2


flightless I homolog (Drosophila)
FLII


filamin A, alpha
FLNA


filamin B, beta
FLNB


filamin C, gamma
FLNC


flotillin 1
FLOT1


flotillin 2
FLOT2


fms-related tyrosine kinase 1
FLT1


feline leukemia virus subgroup C cellular
FLVCR1


receptor 1


formin 1
FMN1


formin-like 1
FMNL1


formin-like 2
FMNL2


formin-like 3
FMNL3


fibromodulin
FMOD


fibronectin 1
FN1


fructosamine 3 kinase
FN3K


fructosamine 3 kinase related protein
FN3KRP


formin binding protein 1-like
FNBP1L


fibronectin type III domain containing 1
FNDC1


farnesyltransferase, CAAX box, alpha
FNTA


folate hydrolase (prostate-specific
FOLH1


membrane antigen) 1


folate receptor 1 (adult)
FOLR1


forkhead box F1
FOXF1


fucose-1-phosphate guanylyltransferase
FPGT


frequently rearranged in advanced T-cell
FRAT1


lymphomas 1


FRAS1 related extracellular matrix protein 2
FREM2


FRAS1 related extracellular matrix 3
FREM3


fyn-related Src family tyrosine kinase
FRK


FERM domain containing 5
FRMD5


FERM domain containing 8
FRMD8


FERM and PDZ domain containing 3
FRMPD3


FRY-like
FRYL


fascin actin-bundling protein 1
FSCN1


fibronectin type III and SPRY domain
FSD2


containing 2


fibrous sheath interacting protein 2
FSIP2


follistatin
FST


formimidoyltransferase cyclodeaminase
FTCD


ferritin, heavy polypeptide 1
FTH1


ferritin, light polypeptide
FTL


ferritin, light polypeptide pseudogene 3
FTLP3


FtsJ homolog 3 (E. coli)
FTSJ3


far upstream element (FUSE) binding
FUBP1


protein 1


far upstream element (FUSE) binding
FUBP3


protein 3


fucosidase, alpha-L-1, tissue
FUCA1


fucosidase, alpha-L-2, plasma
FUCA2


fucokinase
FUK


furin (paired basic amino acid cleaving
FURIN


enzyme)


FUS RNA binding protein
FUS


fucosyltransferase 2 (secretor status
FUT2


included)


fucosyltransferase 3 (galactoside 3(4)-L-
FUT3


fucosyltransferase, Lewis blood group)


fucosyltransferase 6 (alpha (1,3)
FUT6


fucosyltransferase)


fucosyltransferase 8 (alpha (1,6)
FUT8


fucosyltransferase)


fuzzy planar cell polarity protein
FUZ


fragile X mental retardation, autosomal
FXR1


homolog 1


fragile X mental retardation, autosomal
FXR2


homolog 2


FXYD domain containing ion transport
FXYD2


regulator 2


FXYD domain containing ion transport
FXYD3


regulator 3


FYN binding protein
FYB


FYVE and coiled-coil domain containing 1
FYCO1


FYN proto-oncogene, Src family tyrosine
FYN


kinase


frizzled class receptor 2
FZD2


frizzled class receptor 6
FZD6


frizzled class receptor 7
FZD7


GTPase activating protein (SH3 domain)
G3BP1


binding protein 1


GTPase activating protein (SH3 domain)
G3BP2


binding protein 2


glucose-6-phosphate dehydrogenase
G6PD


glucosidase, alpha; acid
GAA


GABA(A) receptor-associated protein-like 2
GABARAPL2


GA binding protein transcription factor,
GABPA


alpha subunit 60 kDa


gamma-aminobutyric acid (GABA) A
GABRB2


receptor, beta 2


cyclin G associated kinase
GAK


galactose-3-O-sulfotransferase 4
GAL3ST4


UDP-galactose-4-epimerase
GALE


galactokinase 1
GALK1


galactose mutarotase (aldose 1-
GALM


epimerase)


polypeptide N-
GALNT13


acetylgalactosaminyltransferase 13


polypeptide N-
GALNT2


acetylgalactosaminyltransferase 2


polypeptide N-
GALNT3


acetylgalactosaminyltransferase 3


polypeptide N-
GALNT4


acetylgalactosaminyltransferase 4


polypeptide N-
GALNT5


acetylgalactosaminyltransferase 5


polypeptide N-
GALNT7


acetylgalactosaminyltransferase 7


glucosidase, alpha; neutral AB
GANAB


glyceraldehyde-3-phosphate
GAPDH


dehydrogenase


glyceraldehyde-3-phosphate
GAPDHS


dehydrogenase, spermatogenic


GAR1 ribonucleoprotein
GAR1


glycyl-tRNA synthetase
GARS


phosphoribosylglycinamide
GART


formyltransferase,


phosphoribosylglycinamide synthetase,


phosphoribosylaminoimidazole synthetase


growth arrest-specific 6
GAS6


GATS protein-like 3
GATSL3


glucosidase, beta, acid
GBA


glucan (1,4-alpha-), branching enzyme 1
GBE1


golgi brefeldin A resistant guanine
GBF1


nucleotide exchange factor 1


guanylate binding protein 1, interferon-
GBP1


inducible


guanylate binding protein family, member 6
GBP6


group-specific component (vitamin D
GC


binding protein)


grancalcin, EF-hand calcium binding
GCA


protein


glutamate-cysteine ligase, modifier subunit
GCLM


GCN1 general control of amino-acid
GCN1L1


synthesis 1-like 1 (yeast)


glucosaminyl (N-acetyl) transferase 2, I-
GCNT2


branching enzyme (I blood group)


glucosaminyl (N-acetyl) transferase 3,
GCNT3


mucin type


guanine deaminase
GDA


growth differentiation factor 1
GDF1


growth differentiation factor 11
GDF11


growth differentiation factor 15
GDF15


growth differentiation factor 2
GDF2


growth differentiation factor 3
GDF3


growth differentiation factor 5
GDF5


growth differentiation factor 9
GDF9


GDP dissociation inhibitor 1
GDI1


GDP dissociation inhibitor 2
GDI2


glycerophosphodiester phosphodiesterase
GDPD3


domain containing 3


glycerophosphodiester phosphodiesterase
GDPD5


domain containing 5


gem (nuclear organelle) associated protein 2
GEMIN2


gem (nuclear organelle) associated protein 4
GEMIN4


gem (nuclear organelle) associated protein 5
GEMIN5


golgi to ER traffic protein 4 homolog
GET4


(S. cerevisiae)


glial fibrillary acidic protein
GFAP


G elongation factor, mitochondrial 1
GFM1


G elongation factor, mitochondrial 2
GFM2


glutamine--fructose-6-phosphate
GFPT1


transaminase 1


glutamine-fructose-6-phosphate
GFPT2


transaminase 2


GDNF family receptor alpha 1
GFRA1


GDNF family receptor alpha 3
GFRA3


golgi-associated, gamma adaptin ear
GGA1


containing, ARF binding protein 1


golgi-associated, gamma adaptin ear
GGA3


containing, ARF binding protein 3


gamma-glutamylamine cyclotransferase
GGACT


gamma-glutamylcyclotransferase
GGCT


gamma-glutamyl hydrolase (conjugase,
GGH


folylpolygammaglutamyl hydrolase)


gamma-glutamyltransferase 1
GGT1


gamma-glutamyltransferase 2
GGT2


gamma-glutamyltransferase 3 pseudogene
GGT3P


gamma-glutamyltransferase light chain 1
GGTLC1


gamma-glutamyltransferase light chain 2
GGTLC2


growth hormone inducible transmembrane
GHITM


protein


GID complex subunit 8
GID8


GTPase, IMAP family member 4
GIMAP4


GTPase, IMAP family member 8
GIMAP8


GIPC PDZ domain containing family,
GIPC1


member 1


GIPC PDZ domain containing family,
GIPC2


member 2


gap junction protein, alpha 1, 43 kDa
GJA1


gap junction protein, beta 1, 32 kDa
GJB1


gap junction protein, gamma 1, 45 kDa
GJC1


glycerol kinase 2
GK2


galactosidase, alpha
GLA


galactosidase, beta 1
GLB1


glycine dehydrogenase (decarboxylating)
GLDC


golgi glycoprotein 1
GLG1


GLI pathogenesis-related 2
GLIPR2


glomulin, FKBP associated protein
GLMN


glyoxalase I
GLO1


glutaredoxin (thioltransferase)
GLRX


glutaredoxin 3
GLRX3


glutaminase
GLS


glycosyltransferase 8 domain containing 1
GLT8D1


glutamate dehydrogenase 1
GLUD1


glutamate-ammonia ligase
GLUL


glyoxylate reductase 1 homolog
GLYR1


(Arabidopsis)


GM2 ganglioside activator
GM2A


GDP-mannose 4,6-dehydratase
GMDS


glia maturation factor, gamma
GMFG


GDP-mannose pyrophosphorylase A
GMPPA


GDP-mannose pyrophosphorylase B
GMPPB


guanosine monophosphate reductase 2
GMPR2


guanine monphosphate synthase
GMPS


guanine nucleotide binding protein (G
GNA11


protein), alpha 11 (Gq class)


guanine nucleotide binding protein (G
GNA12


protein) alpha 12


guanine nucleotide binding protein (G
GNA13


protein), alpha 13


guanine nucleotide binding protein (G
GNA14


protein), alpha 14


guanine nucleotide binding protein (G
GNAW


protein), alpha 15 (Gq class)


guanine nucleotide binding protein (G
GNAI1


protein), alpha inhibiting activity


polypeptide 1


guanine nucleotide binding protein (G
GNAI2


protein), alpha inhibiting activity


polypeptide 2


guanine nucleotide binding protein (G
GNAI3


protein), alpha inhibiting activity


polypeptide 3


guanine nucleotide binding protein (G
GNAL


protein), alpha activating activity


polypeptide, olfactory type


guanine nucleotide binding protein (G
GNAO1


protein), alpha activating activity


polypeptide O


guanine nucleotide binding protein (G
GNAQ


protein), q polypeptide


GNAS complex locus
GNAS


guanine nucleotide binding protein (G
GNAT1


protein), alpha transducing activity


polypeptide 1


guanine nucleotide binding protein (G
GNAT2


protein), alpha transducing activity


polypeptide 2


guanine nucleotide binding protein, alpha
GNAT3


transducing 3


guanine nucleotide binding protein (G
GNAZ


protein), alpha z polypeptide


guanine nucleotide binding protein (G
GNB1


protein), beta polypeptide 1


guanine nucleotide binding protein (G
GNB1L


protein), beta polypeptide 1-like


guanine nucleotide binding protein (G
GNB2


protein), beta polypeptide 2


guanine nucleotide binding protein (G
GNB2L1


protein), beta polypeptide 2-like 1


guanine nucleotide binding protein (G
GNB3


protein), beta polypeptide 3


guanine nucleotide binding protein (G
GNB4


protein), beta polypeptide 4


guanine nucleotide binding protein (G
GNB5


protein), beta 5


glucosamine (UDP-N-acetyl)-2-
GNE


epimerase/N-acetylmannosamine kinase


guanine nucleotide binding protein (G
GNG10


protein), gamma 10


guanine nucleotide binding protein (G
GNG11


protein), gamma 11


guanine nucleotide binding protein (G
GNG12


protein), gamma 12


guanine nucleotide binding protein (G
GNG2


protein), gamma 2


guanine nucleotide binding protein (G
GNG5


protein), gamma 5


guanine nucleotide binding protein (G
GNG7


protein), gamma 7


guanine nucleotide binding protein-like 1
GNL1


guanine nucleotide binding protein-like 2
GNL2


(nucleolar)


guanine nucleotide binding protein-like 3
GNL3


(nucleolar)


glucosamine-6-phosphate deaminase 1
GNPDA1


glucosamine-6-phosphate deaminase 2
GNPDA2


glucosamine-phosphate N-
GNPNAT1


acetyltransferase 1


N-acetylglucosamine-1-phosphate
GNPTG


transferase, gamma subunit


glucosamine (N-acetyl)-6-sulfatase
GNS


golgin A2
GOLGA2


golgin A3
GOLGA3


golgin A5
GOLGA5


golgin A7
GOLGA7


golgin B1
GOLGB1


golgi integral membrane protein 4
GOLIM4


golgi membrane protein 1
GOLM1


golgi phosphoprotein 3 (coat-protein)
GOLPH3


golgin, RAB6-interacting
GORAB


golgi reassembly stacking protein 2, 55 kDa
GORASP2


golgi SNAP receptor complex member 1
GOSR1


glutamic-oxaloacetic transaminase 1,
GOT1


soluble


glutamic-oxaloacetic transaminase 2,
GOT2


mitochondrial


glycoprotein Ib (platelet), alpha polypeptide
GP1BA


glycoprotein Ib (platelet), beta polypeptide
GP1BB


glycoprotein V (platelet)
GP5


glycoprotein VI (platelet)
GP6


glycoprotein IX (platelet)
GP9


glycoprotein A33 (transmembrane)
GPA33


glypican 1
GPC1


glypican 3
GPC3


glypican 4
GPC4


glypican 5
GPC5


glypican 6
GPC6


glycerol-3-phosphate dehydrogenase 1
GPD1


(soluble)


glycerol-3-phosphate dehydrogenase 1-like
GPD1L


glucose-6-phosphate isomerase
GPI


glycoprotein M6A
GPM6A


glycoprotein (transmembrane) nmb
GPNMB


G protein-coupled receptor 107
GPR107


G protein-coupled receptor 143
GPR143


G protein-coupled receptor 155
GPR155


G protein-coupled receptor 176
GPR176


G protein-coupled receptor 179
GPR179


G protein-coupled receptor, class C,
GPRC5A


group 5, member A


G protein-coupled receptor, class C,
GPRC5B


group 5, member B


G protein-coupled receptor, class C,
GPRC5C


group 5, member C


G protein pathway suppressor 1
GPS1


glutamic-pyruvate transaminase (alanine
GPT


aminotransferase)


glutathione peroxidase 1
GPX1


glutathione peroxidase 2
GPX2


glutathione peroxidase 3
GPX3


glutathione peroxidase 4
GPX4


GRB2-related adaptor protein 2
GRAP2


growth factor receptor-bound protein 2
GRB2


gremlin 1, DAN family BMP antagonist
GREM1


glyoxylate reductase/hydroxypyruvate
GRHPR


reductase


glutamate receptor, ionotropic, delta 1
GRID1


glutamate receptor, ionotropic, N-methyl D-
GRIN1


aspartate 1


glutamate receptor interacting protein 2
GRIP2


GRIP1 associated protein 1
GRIPAP1


G protein-coupled receptor kinase 5
GRK5


G protein-coupled receptor kinase 6
GRK6


glutamate receptor, metabotropic 2
GRM2


glutamate receptor, metabotropic 3
GRM3


glutamate receptor, metabotropic 7
GRM7


granulin
GRN


growth hormone regulated TBC protein 1
GRTP1


glutamate-rich WD repeat containing 1
GRWD1


gasdermin A
GSDMA


gasdermin D
GSDMD


Gse1 coiled-coil protein
GSE1


glycogen synthase kinase 3 alpha
GSK3A


glycogen synthase kinase 3 beta
GSK3B


gelsolin
GSN


G1 to S phase transition 1
GSPT1


G1 to S phase transition 2
GSPT2


glutathione reductase
GSR


glutathione synthetase
GSS


glutathione S-transferase alpha 1
GSTA1


glutathione S-transferase alpha 2
GSTA2


glutathione S-transferase alpha 3
GSTA3


glutathione S-transferase alpha 5
GSTA5


glutathione S-transferase, C-terminal
GSTCD


domain containing


glutathione S-transferase kappa 1
GSTK1


glutathione S-transferase mu 1
GSTM1


glutathione S-transferase mu 2 (muscle)
GSTM2


glutathione S-transferase mu 3 (brain)
GSTM3


glutathione S-transferase mu 5
GSTM5


glutathione S-transferase omega 1
GSTO1


glutathione S-transferase omega 2
GSTO2


glutathione S-transferase pi 1
GSTP1


general transcription factor IIB
GTF2B


general transcription factor IIi
GTF2I


general transcription factor IIIC,
GTF3C5


polypeptide 5, 63 kDa


GTP binding protein 1
GTPBP1


GTP binding protein 2
GTPBP2


G-2 and S-phase expressed 1
GTSE1


glucuronidase, beta
GUSB


glycosyltransferase-like 1B
GYLTL1B


glycophorin C (Gerbich blood group)
GYPC


glycogen synthase 1 (muscle)
GYS1


glycogen synthase 2 (liver)
GYS2


granzyme A (granzyme 1, cytotoxic T-
GZMA


lymphocyte-associated serine esterase 3)


H1 histone family, member 0
H1F0


H1 histone family, member O, oocyte-
H1FOO


specific


H1 histone family, member X
H1FX


H2A histone family, member J
H2AFJ


H2A histone family, member V
H2AFV


H2A histone family, member X
H2AFX


H2A histone family, member Y
H2AFY


H2A histone family, member Y2
H2AFY2


H2A histone family, member Z
H2AFZ


H3 histone, family 3A
H3F3A


H3 histone, family 3B (H3.3B)
H3F3B


H3 histone, family 3C
H3F3C


3-hydroxyacyl-CoA dehydratase 3
HACD3


hydroxyacyl-CoA dehydrogenase
HADH


hydroxyacyl-CoA dehydrogenase/3-
HADHA


ketoacyl-CoA thiolase/enoyl-CoA


hydratase (trifunctional protein),


alpha subunit


hydroxyacyl-CoA dehydrogenase/3-
HADHB


ketoacyl-CoA thiolase/enoyl-CoA


hydratase (trifunctional protein),


beta subunit


histidine ammonia-lyase
HAL


hyaluronan and proteoglycan link protein 1
HAPLN1


hyaluronan and proteoglycan link protein 3
HAPLN3


histidyl-tRNA synthetase
HARS


histidyl-tRNA synthetase 2, mitochondrial
HARS2


hyaluronan synthase 1
HAS1


histone acetyltransferase 1
HAT1


HAUS augmin-like complex, subunit 5
HAUS5


hemoglobin, alpha 1
HBA1


hemoglobin, alpha 2
HBA2


hemoglobin, beta
HBB


hemoglobin, delta
HBD


hemoglobin, epsilon 1
HBE1


hemoglobin, gamma A
HBG1


hemoglobin, gamma G
HBG2


HBS1-like translational GTPase
HBS1L


host cell factor C1
HCFC1


HCK proto-oncogene, Src family tyrosine
HCK


kinase


hyperpolarization activated cyclic
HCN3


nucleotide gated potassium channel 3


histone deacetylase 1
HDAC1


histone deacetylase 2
HDAC2


histone deacetylase 3
HDAC3


histone deacetylase 5
HDAC5


histone deacetylase 6
HDAC6


hepatoma-derived growth factor
HDGF


haloacid dehalogenase-like hydrolase
HDHD2


domain containing 2


high density lipoprotein binding protein
HDLBP


heme binding protein 1
HEBP1


heme binding protein 2
HEBP2


HECT domain containing E3 ubiquitin
HECTD3


protein ligase 3


HECT domain containing E3 ubiquitin
HECTD4


protein ligase 4


heart development protein with EGF-like
HEG1


domains 1


helicase, lymphoid-specific
HELLS


hephaestin
HEPH


HECT and RLD domain containing E3
HERC5


ubiquitin protein ligase 5


hexosaminidase A (alpha polypeptide)
HEXA


hexosaminidase B (beta polypeptide)
HEXB


homogentisate 1,2-dioxygenase
HGD


hepatocyte growth factor (hepapoietin A;
HGF


scatter factor)


HGF activator
HGFAC


hepatocyte growth factor-regulated
HGS


tyrosine kinase substrate


hypermethylated in cancer 2
HIC2


HID1 domain containing
HID1


histidine triad nucleotide binding protein 1
HINT1


histidine triad nucleotide binding protein 3
HINT3


histone cluster 1, H1a
HIST1H1A


histone cluster 1, H1b
HIST1H1B


histone cluster 1, H1c
HIST1H1C


histone cluster 1, H1d
HIST1H1D


histone cluster 1, H1e
HIST1H1E


histone cluster 1, H1t
HIST1H1T


histone cluster 1, H2aa
HIST1H2AA


histone cluster 1, H2ab
HIST1H2AB


histone cluster 1, H2ac
HIST1H2AC


histone cluster 1, H2ad
HIST1H2AD


histone cluster 1, H2ae
HIST1H2AE


histone cluster 1, H2ag
HIST1H2AG


histone cluster 1, H2ah
HIST1H2AH


histone cluster 1, H2ai
HIST1H2AI


histone cluster 1, H2aj
HIST1H2AJ


histone cluster 1, H2ak
HIST1H2AK


histone cluster 1, H2al
HIST1H2AL


histone cluster 1, H2am
HIST1H2AM


histone cluster 1, H2ba
HIST1H2BA


histone cluster 1, H2bb
HIST1H2BB


histone cluster 1, H2bc
HIST1H2BC


histone cluster 1, H2bd
HIST1H2BD


histone cluster 1, H2be
HIST1H2BE


histone cluster 1, H2bf
HIST1H2BF


histone cluster 1, H2bg
HIST1H2BG


histone cluster 1, H2bh
HIST1H2BH


histone cluster 1, H2bi
HIST1H2BI


histone cluster 1, H2bj
HIST1H2BJ


histone cluster 1, H2bk
HIST1H2BK


histone cluster 1, H2bl
HIST1H2BL


histone cluster 1, H2bm
HIST1H2BM


histone cluster 1, H2bn
HIST1H2BN


histone cluster 1, H2bo
HIST1H2BO


histone cluster 1, H3a
HIST1H3A


histone cluster 1, H3b
HIST1H3B


histone cluster 1, H3c
HIST1H3C


histone cluster 1, H3d
HIST1H3D


histone cluster 1, H3e
HIST1H3E


histone cluster 1, H3f
HIST1H3F


histone cluster 1, H3g
HIST1H3G


histone cluster 1, H3h
HIST1H3H


histone cluster 1, H3i
HIST1H3I


histone cluster 1, H3j
HIST1H3J


histone cluster 1, H4a
HIST1H4A


histone cluster 1, H4b
HIST1H4B


histone cluster 1, H4c
HIST1H4C


histone cluster 1, H4d
HIST1H4D


histone cluster 1, H4e
HIST1H4E


histone cluster 1, H4f
HIST1H4F


histone cluster 1, H4g
HIST1H4G


histone cluster 1, H4h
HIST1H4H


histone cluster 1, H4i
HIST1H4I


histone cluster 1, H4j
HIST1H4J


histone cluster 1, H4k
HIST1H4K


histone cluster 1, H4I
HIST1H4L


histone cluster 2, H2aa3
HIST2H2AA3


histone cluster 2, H2aa4
HIST2H2AA4


histone cluster 2, H2ab
HIST2H2AB


histone cluster 2, H2ac
HIST2H2AC


histone cluster 2, H2bc (pseudogene)
HIST2H2BC


histone cluster 2, H2be
HIST2H2BE


histone cluster 2, H2bf
HIST2H2BF


histone cluster 2, H3a
HIST2H3A


histone cluster 2, H3c
HIST2H3C


histone cluster 2, H3d
HIST2H3D


histone cluster 2, H4a
HIST2H4A


histone cluster 2, H4b
HIST2H4B


histone cluster 3, H2a
HIST3H2A


histone cluster 3, H2bb
HIST3H2BB


histone cluster 3, H3
HIST3H3


histone cluster 4, H4
HIST4H4


human immunodeficiency virus type I
HIVEP1


enhancer binding protein 1


human immunodeficiency virus type I
HIVEP3


enhancer binding protein 3


hexokinase 1
HK1


major histocompatibility complex, class I, A
HLA-A


major histocompatibility complex, class I, B
HLA-B


major histocompatibility complex, class I, C
HLA-C


major histocompatibility complex, class II,
HLA-DMB


DM beta


major histocompatibility complex, class II,
HLA-DPB1


DP beta 1


major histocompatibility complex, class II,
HLA-DQA1


DQ alpha 1


major histocompatibility complex, class II,
HLA-DQB1


DQ beta 1


major histocompatibility complex, class II,
HLA-DRA


DR alpha


major histocompatibility complex, class II,
HLA-DRB1


DR beta 1


major histocompatibility complex, class II,
HLA-DRB3


DR beta 3


major histocompatibility complex, class II,
HLA-DRB5


DR beta 5


major histocompatibility complex, class I, E
HLA-E


major histocompatibility complex, class I, G
HLA-G


major histocompatibility complex, class I, H
HLA-H


(pseudogene)


histocompatibility (minor) 13
HM13


hydroxymethylbilane synthase
HMBS


hemicentin 1
HMCN1


high mobility group AT-hook 1
HMGA1


high mobility group AT-hook 2
HMGA2


high mobility group box 1
HMGB1


high mobility group box 2
HMGB2


high mobility group box 3
HMGB3


3-hydroxy-3-methylglutaryl-CoA synthase 1
HMGCS1


(soluble)


3-hydroxy-3-methylglutaryl-CoA synthase 2
HMGCS2


(mitochondrial)


histocompatibility (minor) HA-1
HMHA1


heme oxygenase 2
HMOX2


hematological and neurological expressed 1
HN1


hematological and neurological expressed 1-like
HN1L


histamine N-methyltransferase
HNMT


heterogeneous nuclear ribonucleoprotein A0
HNRNPA0


heterogeneous nuclear ribonucleoprotein A1
HNRNPA1


heterogeneous nuclear ribonucleoprotein A2/B1
HNRNPA2B1


heterogeneous nuclear ribonucleoprotein A3
HNRNPA3


heterogeneous nuclear ribonucleoprotein A/B
HNRNPAB


heterogeneous nuclear ribonucleoprotein C
HNRNPC


(C1/C2)


heterogeneous nuclear ribonucleoprotein
HNRNPCL1


C-like 1


heterogeneous nuclear ribonucleoprotein
HNRNPCL2


C-like 2


heterogeneous nuclear ribonucleoprotein
HNRNPCL3


C-like 3


heterogeneous nuclear ribonucleoprotein
HNRNPCL4


C-like 4


heterogeneous nuclear ribonucleoprotein D
HNRNPD


(AU-rich element RNA binding protein 1,


37 kDa)


heterogeneous nuclear ribonucleoprotein
HNRNPDL


D-like


heterogeneous nuclear ribonucleoprotein F
HNRNPF


heterogeneous nuclear ribonucleoprotein
HNRNPH1


H1 (H)


heterogeneous nuclear ribonucleoprotein
HNRNPH2


H2 (H′)


heterogeneous nuclear ribonucleoprotein
HNRNPH3


H3 (2H9)


heterogeneous nuclear ribonucleoprotein K
HNRNPK


heterogeneous nuclear ribonucleoprotein L
HNRNPL


heterogeneous nuclear ribonucleoprotein M
HNRNPM


heterogeneous nuclear ribonucleoprotein R
HNRNPR


heterogeneous nuclear ribonucleoprotein U
HNRNPU


(scaffold attachment factor A)


heterogeneous nuclear ribonucleoprotein
HNRNPUL1


U-like 1


heterogeneous nuclear ribonucleoprotein
HNRNPUL2


U-like 2


homer scaffolding protein 3
HOMER3


homeobox B3
HOXB3


homeobox B7
HOXB7


haptoglobin
HP


heterochromatin protein 1, binding protein 3
HP1BP3


hippocalcin
HPCA


hippocalcin-like 1
HPCAL1


4-hydroxyphenylpyruvate dioxygenase
HPD


4-hydroxyphenylpyruvate dioxygenase-like
HPDL


hydroxyprostaglandin dehydrogenase 15-
HPGD


(NAD)


haptoglobin-related protein
HPR


hypoxanthine phosphoribosyltransferase 1
HPRT1


Hermansky-Pudlak syndrome 6
HPS6


heparanase
HPSE


hemopexin
HPX


Harvey rat sarcoma viral oncogene
HRAS


homolog


histidine-rich glycoprotein
HRG


hornerin
HRNR


heat-responsive protein 12
HRSP12


heparan sulfate 2-O-sulfotransferase 1
HS2ST1


hydroxysteroid (17-beta) dehydrogenase 10
HSD17B10


hydroxysteroid (17-beta) dehydrogenase 12
HSD17B12


hydroxysteroid (17-beta) dehydrogenase 4
HSD17B4


hydroxysteroid dehydrogenase like 2
HSDL2


hematopoietic SH2 domain containing
HSH2D


heat shock protein 90 kDa alpha (cytosolic),
HSP90AA1


class A member 1


heat shock protein 90 kDa alpha (cytosolic),
HSP90AA2P


class A member 2, pseudogene


heat shock protein 90 kDa alpha (cytosolic),
HSP90AA4P


class A member 4, pseudogene


heat shock protein 90 kDa alpha (cytosolic),
HSP90AB1


class B member 1


heat shock protein 90 kDa alpha (cytosolic),
HSP90AB2P


class B member 2, pseudogene


heat shock protein 90 kDa alpha (cytosolic),
HSP90AB3P


class B member 3, pseudogene


heat shock protein 90 kDa alpha (cytosolic),
HSP90AB6P


class B member 6, pseudogene


heat shock protein 90 kDa beta (Grp94),
HSP90B1


member 1


heat shock 70 kDa protein 12A
HSPA12A


heat shock 70 kD protein 12B
HSPA12B


heat shock protein 70 kDa family, member 13
HSPA13


heat shock 70 kDa protein 1A
HSPA1A


heat shock 70 kDa protein 1B
HSPA1B


heat shock 70 kDa protein 1-like
HSPA1L


heat shock 70 kDa protein 2
HSPA2


heat shock 70 kDa protein 4
HSPA4


heat shock 70 kDa protein 4-like
HSPA4L


heat shock 70 kDa protein 5 (glucose-
HSPA5


regulated protein, 78 kDa)


heat shock 70 kDa protein 6 (HSP70B′)
HSPA6


heat shock 70 kDa protein 7 (HSP70B)
HSPA7


heat shock 70 kDa protein 8
HSPA8


heat shock 70 kDa protein 9 (mortalin)
HSPA9


heat shock 27 kDa protein 1
HSPB1


heat shock 27 kDa protein 1 pseudogene 1
HSPB1P1


heat shock 22 kDa protein 8
HSPB8


heat shock 60 kDa protein 1 (chaperonin)
HSPD1


heat shock 60 kDa protein 1 (chaperonin)
HSPD1P1


pseudogene 1


heat shock 60 kDa protein 1 (chaperonin)
HSPD1P4


pseudogene 4


heat shock 60 kDa protein 1 (chaperonin)
HSPD1P5


pseudogene 5


heat shock 60 kDa protein 1 (chaperonin)
HSPD1P6


pseudogene 6


heat shock 10 kDa protein 1
HSPE1


heparan sulfate proteoglycan 2
HSPG2


heat shock 105 kDa/110 kDa protein 1
HSPH1


HIV-1 Tat interactive protein 2, 30 kDa
HTATIP2


HIV-1 Tat specific factor 1
HTATSF1


HtrA serine peptidase 1
HTRA1


HtrA serine peptidase 3
HTRA3


huntingtin
HTT


HECT, UBA and WWE domain containing 1,
HUWE1


E3 ubiquitin protein ligase


hyaluronoglucosaminidase 2
HYAL2


hydroxypyruvate isomerase (putative)
HYI


hypoxia up-regulated 1
HYOU1


isoleucyl-tRNA synthetase
IARS


inhibitor of Bruton agammaglobulinemia
IBTK


tyrosine kinase


intercellular adhesion molecule 1
ICAM1


intercellular adhesion molecule 2
ICAM2


intercellular adhesion molecule 3
ICAM3


intercellular adhesion molecule 5,
ICAM5


telencephalin


insulin-degrading enzyme
IDE


isocitrate dehydrogenase 1 (NADP+),
IDH1


soluble


isocitrate dehydrogenase 2 (NADP+),
IDH2


mitochondrial


isocitrate dehydrogenase 3 (NAD+) alpha
IDH3A


isocitrate dehydrogenase 3 (NAD+) beta
IDH3B


isopentenyl-diphosphate delta isomerase 1
IDI1


idnK, gluconokinase homolog (E. coli)
IDNK


indolamin-2,3-dioxygenase
IDO


interferon, gamma-inducible protein 16
IFI16


interferon-induced protein with
IFIT1


tetratricopeptide repeats 1


interferon-induced protein with
IFIT3


tetratricopeptide repeats 3


interferon-induced protein with
IFIT5


tetratricopeptide repeats 5


interferon induced transmembrane protein 1
IFITM1


interferon induced transmembrane protein 2
IFITM2


interferon induced transmembrane protein 3
IFITM3


interferon, gamma
IFNG


interferon gamma receptor 1
IFNGR1


interferon-related developmental regulator 1
IFRD1


intraflagellar transport 140
IFT140


insulin-like growth factor 1 receptor
IGF1R


insulin-like growth factor 2
IGF2


insulin-like growth factor 2 mRNA binding
IGF2BP2


protein 2


insulin-like growth factor 2 mRNA binding
IGF2BP3


protein 3


insulin-like growth factor 2 receptor
IGF2R


insulin-like growth factor binding protein,
IGFALS


acid labile subunit


insulin-like growth factor binding protein 2,
IGFBP2


36 kDa


insulin-like growth factor binding protein 3
IGFBP3


insulin-like growth factor binding protein 4
IGFBP4


insulin-like growth factor binding protein 6
IGFBP6


insulin-like growth factor binding protein 7
IGFBP7


IGF-like family member 1
IGFL1


immunoglobulin heavy locus
IGH


immunoglobulin heavy constant alpha 1
IGHA1


immunoglobulin heavy constant alpha 2
IGHA2


(A2m marker)


immunoglobulin heavy constant gamma 1
IGHG1


(G1m marker)


immunoglobulin heavy constant gamma 2
IGHG2


(G2m marker)


immunoglobulin heavy constant gamma 3
IGHG3


(G3m marker)


immunoglobulin heavy constant gamma 4
IGHG4


(G4m marker)


immunoglobulin heavy constant mu
IGHM


immunoglobulin heavy variable 3-11
IGHV3-11


(gene/pseudogene)


immunoglobulin heavy variable 3-7
IGHV3-7


immunoglobulin heavy variable 4-31
IGHV4-31


immunoglobulin kappa locus
IGK


immunoglobulin kappa constant
IGKC


immunoglobulin kappa variable 1-5
IGKV1-5


immunoglobulin kappa variable 2-24
IGKV2-24


immunoglobulin kappa variable 3-20
IGKV3-20


immunoglobulin kappa variable 3D-15
IGKV3D-15


(gene/pseudogene)


immunoglobulin kappa variable 4-1
IGKV4-1


immunoglobulin lambda locus
IGL


immunoglobulin lambda constant 1 (Mcg
IGLC1


marker)


immunoglobulin lambda constant 2 (Kern-
IGLC2


Oz-marker)


immunoglobulin lambda constant 3 (Kern-
IGLC3


Oz+ marker)


immunoglobulin lambda constant 6
IGLC6


(Kern + Oz-marker, gene/pseudogene)


immunoglobulin lambda constant 7
IGLC7


immunoglobulin lambda-like polypeptide 5
IGLL5


immunoglobulin lambda variable 1-40
IGLV1-40


immunoglobulin lambda variable 1-44
IGLV1-44


immunoglobulin lambda variable 2-11
IGLV2-11


immunoglobulin lambda variable 3-21
IGLV3-21


immunoglobulin lambda variable 4-3
IGLV4-3


immunoglobulin superfamily, member 3
IGSF3


immunoglobulin superfamily, member 8
IGSF8


inhibitor of kappa light polypeptide gene
IKBKAP


enhancer in B-cells, kinase complex-


associated protein


inhibitor of kappa light polypeptide gene
IKBKB


enhancer in B-cells, kinase beta


inhibitor of kappa light polypeptide gene
IKBKG


enhancer in B-cells, kinase gamma


IKAROS family zinc finger 5 (Pegasus)
IKZF5


interleukin 10
IL10


interleukin 11
IL11


interleukin 13
IL13


interleukin 13 receptor, alpha 2
IL13RA2


interleukin 15 receptor, alpha
IL15RA


interleukin 17B
IL17B


interleukin 17 receptor C
IL17RC


interleukin 19
IL19


interleukin 1 receptor accessory protein
IL1RAP


interleukin 1 receptor accessory protein-
IL1RAPL1


like 1


interleukin 1 receptor-like 2
IL1RL2


interleukin 1 receptor antagonist
IL1RN


interleukin 22 receptor, alpha 1
IL22RA1


interleukin 23, alpha subunit p19
IL23A


interleukin 27 receptor, alpha
IL27RA


interleukin 3
IL3


interleukin 36, gamma
IL36G


interleukin 4 induced 1
IL4I1


interleukin 5
IL5


interleukin 6 signal transducer
IL6ST


interleukin 7
IL7


immunoglobulin-like domain containing
ILDR1


receptor 1


interleukin enhancer binding factor 2
ILF2


interleukin enhancer binding factor 3,
ILF3


90 kDa


integrin-linked kinase
ILK


integrin-linked kinase-associated
ILKAP


serine/threonine phosphatase


inner membrane protein, mitochondrial
IMMT


IMP3, U3 small nucleolar ribonucleoprotein
IMP3


inositol(myo)-1(or 4)-monophosphatase 1
IMPA1


inositol(myo)-1(or 4)-monophosphatase 2
IMPA2


inositol monophosphatase domain
IMPAD1


containing 1


IMP (inosine 5′-monophosphate)
IMPDH1


dehydrogenase 1


IMP (inosine 5′-monophosphate)
IMPDH2


dehydrogenase 2


internexin neuronal intermediate filament
INA


protein, alpha


InaD-like (Drosophila)
INADL


inverted formin, FH2 and WH2 domain
INF2


containing


inhibin, beta A
INHBA


inhibin, beta B
INHBB


INO80 complex subunit B
INO80B


inositol polyphosphate-1-phosphatase
INPP1


inositol polyphosphate-4-phosphatase,
INPP4A


type I, 107 kDa


inositol polyphosphate-5-phosphatase,
INPP5A


40 kDa


inositol polyphosphate-5-phosphatase,
INPP5B


75 kDa


inositol polyphosphate-5-phosphatase,
INPP5D


145 kDa


inositol polyphosphate phosphatase-like 1
INPPL1


insulin
INS


insulinoma-associated 2
INSM2


insulin receptor
INSR


insulin receptor-related receptor
INSRR


integrator complex subunit 1
INTS1


integrator complex subunit 3
INTS3


importin 11
IPO11


importin 4
IPO4


importin 5
IPO5


importin 7
IPO7


importin 8
IPO8


importin 9
IPO9


IQ motif containing G
IQCG


IQ motif containing GTPase activating
IQGAP1


protein 1


IQ motif containing GTPase activating
IQGAP2


protein 2


IQ motif containing GTPase activating
IQGAP3


protein 3


interleukin-1 receptor-associated kinase 1
IRAK1BP1


binding protein 1


interferon regulatory factor 6
IRF6


insulin receptor substrate 2
IRS2


insulin receptor substrate 4
IRS4


iron-sulfur cluster assembly enzyme
ISCU


ISG15 ubiquitin-like modifier
ISG15


interferon stimulated exonuclease gene
ISG20L2


20 kDa-like 2


increased sodium tolerance 1 homolog
IST1


(yeast)


ISY1 splicing factor homolog
ISY1


(S. cerevisiae)


ISY1-RAB43 readthrough
ISY1-RAB43


inositol-3-phosphate synthase 1
ISYNA1


itchy E3 ubiquitin protein ligase
ITCH


integrin alpha FG-GAP repeat containing 3
ITFG3


integrin, alpha 1
ITGA1


integrin, alpha 11
ITGA11


integrin, alpha 2 (CD49B, alpha 2 subunit
ITGA2


of VLA-2 receptor)


integrin, alpha 2b (platelet glycoprotein IIb
ITGA2B


of IIb/IIIa complex, antigen CD41)


integrin, alpha 3 (antigen CD49C, alpha 3
ITGA3


subunit of VLA-3 receptor)


integrin, alpha 4 (antigen CD49D, alpha 4
ITGA4


subunit of VLA-4 receptor)


integrin, alpha 5 (fibronectin receptor,
ITGA5


alpha polypeptide)


integrin, alpha 6
ITGA6


integrin, alpha 9
ITGA9


integrin, alpha L (antigen CD11A (p180),
ITGAL


lymphocyte function-associated antigen 1;


alpha polypeptide)


integrin, alpha M (complement component
ITGAM


3 receptor 3 subunit)


integrin, alpha V
ITGAV


integrin, alpha X (complement component
ITGAX


3 receptor 4 subunit)


integrin, beta 1 (fibronectin receptor, beta
ITGB1


polypeptide, antigen CD29 includes MDF2,


MSK12)


integrin, beta 2 (complement component 3
ITGB2


receptor 3 and 4 subunit)


integrin, beta 3 (platelet glycoprotein IIIa,
ITGB3


antigen CD61)


integrin, beta 4
ITGB4


integrin, beta 5
ITGB5


integrin, beta 6
ITGB6


integrin, beta 7
ITGB7


integrin, beta 8
ITGB8


inter-alpha-trypsin inhibitor heavy chain 1
ITIH1


inter-alpha-trypsin inhibitor heavy chain 2
ITIH2


inter-alpha-trypsin inhibitor heavy chain 3
ITIH3


inter-alpha-trypsin inhibitor heavy chain
ITIH4


family, member 4


IL2-inducible T-cell kinase
ITK


intelectin 1 (galactofuranose binding)
ITLN1


integral membrane protein 2B
ITM2B


integral membrane protein 2C
ITM2C


inosine triphosphatase (nucleoside
ITPA


triphosphate pyrophosphatase)


inositol 1,4,5-trisphosphate receptor, type 2
ITPR2


inositol 1,4,5-trisphosphate receptor, type 3
ITPR3


inositol 1,4,5-trisphosphate receptor
ITPRIPL2


interacting protein-like 2


intersectin 1 (SH3 domain protein)
ITSN1


intersectin 2
ITSN2


involucrin
IVL


jade family PHD finger 2
JADE2


jagged 1
JAG1


Janus kinase 1
JAK1


Janus kinase 2
JAK2


Janus kinase 3
JAK3


janus kinase and microtubule interacting
JAKMIP1


protein 1


junctional adhesion molecule 3
JAM3


joining chain of multimeric IgA and IgM
JCHAIN


jumonji domain containing 1C
JMJD1C


junctophilin 3
JPH3


junction plakoglobin
JUP


kalirin, RhoGEF kinase
KALRN


lysyl-tRNA synthetase
KARS


katanin p60 subunit A-like 2
KATNAL2


kelch repeat and BTB (POZ) domain
KBTBD11


containing 11


potassium channel, voltage gated
KCNAB2


subfamily A regulatory beta subunit 2


potassium channel, voltage gated modifier
KCNG2


subfamily G, member 2


potassium channel, calcium activated
KCNN4


intermediate/small conductance subfamily


N alpha, member 4


potassium voltage-gated channel, modifier
KCNS3


subfamily S, member 3


potassium channel, sodium activated
KCNT1


subfamily T, member 1


potassium channel tetramerization domain
KCTD12


containing 12


potassium channel tetramerization domain
KCTD14


containing 14


potassium channel tetramerization domain
KCTD21


containing 21


KDEL (Lys-Asp-Glu-Leu) endoplasmic
KDELR2


reticulum protein retention receptor 2


lysine (K)-specific demethylase 1A
KDM1A


lysine (K)-specific demethylase 6B
KDM6B


KH domain containing, RNA binding, signal
KHDRBS1


transduction associated 1


ketohexokinase (fructokinase)
KHK


KH-type splicing regulatory protein
KHSRP


KIAA0020
KIAA0020


KIAA0195
KIAA0195


KIAA0196
KIAA0196


KIAA0319-like
KIAA0319L


KIAA0368
KIAA0368


KIAA0513
KIAA0513


KIAA1033
KIAA1033


KIAA1161
KIAA1161


KIAA1217
KIAA1217


KIAA1324
KIAA1324


KIAA1468
KIAA1468


KIAA1522
KIAA1522


KIAA1524
KIAA1524


KIAA1598
KIAA1598


KIAA2013
KIAA2013


kinase D-interacting substrate, 220 kDa
KIDINS220


kinesin family member 12
KIF12


kinesin family member 13A
KIF13A


kinesin family member 13B
KIF13B


kinesin family member 15
KIF15


kinesin family member 17
KIF17


kinesin family member 18B
KIF18B


kinesin family member 1B
KIF1B


KIF1 binding protein
KIF1BP


kinesin family member 21A
KIF21A


kinesin family member 23
KIF23


kinesin family member 26A
KIF26A


kinesin heavy chain member 2A
KIF2A


kinesin family member 3A
KIF3A


kinesin family member 3B
KIF3B


kinesin family member 3C
KIF3C


kinesin family member 4A
KIF4A


kinesin family member 5A
KIF5A


kinesin family member 5B
KIF5B


kinesin family member 5C
KIF5C


kinesin family member 6
KIF6


kinesin family member 9
KIF9


kinesin family member C1
KIFC1


kinesin family member C3
KIFC3


kin of IRRE like (Drosophila)
KIRREL


v-kit Hardy-Zuckerman 4 feline sarcoma
KIT


viral oncogene homolog


klotho
KL


kinesin light chain 1
KLC1


kinesin light chain 2
KLC2


kinesin light chain 4
KLC4


KLF3 antisense RNA 1
KLF3-AS1


kelch domain containing 10
KLHDC10


kelch-like family member 14
KLHL14


kelch-like family member 22
KLHL22


kallikrein 1
KLK1


kallikrein-related peptidase 10
KLK10


kallikrein-related peptidase 11
KLK11


kallikrein-related peptidase 5
KLK5


kallikrein-related peptidase 6
KLK6


kallikrein-related peptidase 7
KLK7


kallikrein-related peptidase 8
KLK8


kallikrein B, plasma (Fletcher factor) 1
KLKB1


killer cell lectin-like receptor subfamily G,
KLRG2


member 2


lysine (K)-specific methyltransferase 2C
KMT2C


lysine (K)-specific methyltransferase 2D
KMT2D


kininogen 1
KNG1


karyopherin alpha 1 (importin alpha 5)
KPNA1


karyopherin alpha 2 (RAG cohort 1,
KPNA2


importin alpha 1)


karyopherin alpha 4 (importin alpha 3)
KPNA4


karyopherin alpha 6 (importin alpha 7)
KPNA6


karyopherin (importin) beta 1
KPNB1


keratinocyte proline-rich protein
KPRP


Kirsten rat sarcoma viral oncogene
KRAS


homolog


KRIT1, ankyrin repeat containing
KRIT1


KRR1, small subunit (SSU) processome
KRR1


component, homolog (yeast)


keratin 1, type II
KRT1


keratin 10, type I
KRT10


keratin 12, type I
KRT12


keratin 13, type I
KRT13


keratin 14, type I
KRT14


keratin 15, type I
KRT15


keratin 16, type I
KRT16


keratin 16 pseudogene 2
KRT16P2


keratin 17, type I
KRT17


keratin 17 pseudogene 3
KRT17P3


keratin 18, type I
KRT18


keratin 18 pseudogene 19
KRT18P19


keratin 19, type I
KRT19


keratin 2, type II
KRT2


keratin 20, type I
KRT20


keratin 24, type I
KRT24


keratin 25, type I
KRT25


keratin 27, type I
KRT27


keratin 28, type I
KRT28


keratin 3, type II
KRT3


keratin 31, type I
KRT31


keratin 33B, type I
KRT33B


keratin 36, type I
KRT36


keratin 37, type I
KRT37


keratin 38, type I
KRT38


keratin 4, type II
KRT4


keratin 5, type II
KRT5


keratin 6A, type II
KRT6A


keratin 6B, type II
KRT6B


keratin 6C, type II
KRT6C


keratin 7, type II
KRT7


keratin 71, type II
KRT71


keratin 72, type II
KRT72


keratin 73, type II
KRT73


keratin 74, type II
KRT74


keratin 75, type II
KRT75


keratin 76, type II
KRT76


keratin 77, type II
KRT77


keratin 78, type II
KRT78


keratin 79, type II
KRT79


keratin 8, type II
KRT8


keratin 80, type II
KRT80


keratin 84, type II
KRT84


keratin 8 pseudogene 45
KRT8P45


keratin 8 pseudogene 9
KRT8P9


keratin 9, type I
KRT9


keratinocyte differentiation-associated
KRTDAP


protein


kinectin 1 (kinesin receptor)
KTN1


L1 cell adhesion molecule
L1CAM


lacritin
LACRT


ladinin 1
LAD1


laminin, alpha 1
LAMA1


laminin, alpha 3
LAMA3


laminin, alpha 4
LAMA4


laminin, alpha 5
LAMA5


laminin, beta 1
LAMB1


laminin, beta 2 (laminin S)
LAMB2


laminin, beta 3
LAMB3


laminin, gamma 1 (formerly LAMB2)
LAMC1


laminin, gamma 2
LAMC2


lysosomal-associated membrane protein 1
LAMP1


lysosomal-associated membrane protein 2
LAMP2


late endosomal/lysosomal adaptor, MAPK
LAMTOR1


and MTOR activator 1


late endosomal/lysosomal adaptor, MAPK
LAMTOR3


and MTOR activator 3


late endosomal/lysosomal adaptor, MAPK
LAMTOR4


and MTOR activator 4


LanC lantibiotic synthetase component C-
LANCL1


like 1 (bacterial)


LanC lantibiotic synthetase component C-
LANCL2


like 2 (bacterial)


leucine aminopeptidase 3
LAP3


lysosomal protein transmembrane 5
LAPTM5


La ribonucleoprotein domain family,
LARP7


member 7


leucyl-tRNA synthetase
LARS


LAS1-like (S. cerevisiae)
LAS1L


LIM and SH3 protein 1
LASP1


linker for activation of T cells
LAT


linker for activation of T cells family,
LAT2


member 2


lipopolysaccharide binding protein
LBP


lamin B receptor
LBR


LCK proto-oncogene, Src family tyrosine
LCK


kinase


leucine carboxyl methyltransferase 1
LCMT1


lipocalin 1
LCN1


lipocalin 1 pseudogene 1
LCN1P1


lipocalin 2
LCN2


lymphocyte cytosolic protein 1 (L-plastin)
LCP1


lymphocyte cytosolic protein 2 (SH2
LCP2


domain containing leukocyte protein of


76 kDa)


lactate dehydrogenase A
LDHA


lactate dehydrogenase A-like 6B
LDHAL6B


lactate dehydrogenase B
LDHB


low density lipoprotein receptor
LDLR


leptin receptor
LEPR


leptin receptor overlapping transcript-like 1
LEPROTL1


leucine zipper-EF-hand containing
LETM1


transmembrane protein 1


LFNG O-fucosylpeptide 3-beta-N-
LFNG


acetylglucosaminyltransferase


lectin, galactoside-binding, soluble, 1
LGALS1


lectin, galactoside-binding, soluble, 3
LGALS3


lectin, galactoside-binding, soluble, 3
LGALS3BP


binding protein


lectin, galactoside-binding, soluble, 4
LGALS4


lectin, galactoside-binding, soluble, 7
LGALS7


lectin, galactoside-binding, soluble, 7B
LGALS7B


lectin, galactoside-binding, soluble, 8
LGALS8


lectin, galactoside-binding, soluble, 9B
LGALS9B


lectin, galactoside-binding-like
LGALSL


leucine-rich repeat containing G protein-
LGR4


coupled receptor 4


leucine-rich repeat containing G protein-
LGR6


coupled receptor 6


lipoma HMGIC fusion partner-like 2
LHFPL2


leukemia inhibitory factor
LIF


ligase I, DNA, ATP-dependent
LIG1


ligase III, DNA, ATP-dependent
LIG3


LIM domain and actin binding 1
LIMA1


Lck interacting transmembrane adaptor 1
LIME1


LIM and senescent cell antigen-like
LIMS1


domains 1


LIM and senescent cell antigen-like
LIMS2


domains 2


LIM and senescent cell antigen-like
LIMS3L


domains 3-like


lin-7 homolog A (C. elegans)
LIN7A


lin-7 homolog C (C. elegans)
LIN7C


long intergenic non-protein coding RNA
LINC00488


488


leucine rich repeat and Ig domain
LINGO1


containing 1


lethal giant larvae homolog 1 (Drosophila)
LLGL1


lethal giant larvae homolog 2 (Drosophila)
LLGL2


lectin, mannose-binding, 1
LMAN1


lectin, mannose-binding 2
LMAN2


LMBR1 domain containing 1
LMBRD1


LIM and cysteine-rich domains 1
LMCD1


lamin A/C
LMNA


lamin B1
LMNB1


lamin B2
LMNB2


leucyl/cystinyl aminopeptidase
LNPEP


small nuclear ribonucleoprotein Sm D1
LOC100129492


pseudogene


Ig kappa chain V-l region Walker-like
LOC100130100


related RAS viral (r-ras) oncogene
LOC100133211


homolog 2 pseudogene


LOC100499484-C9orf174 readthrough
LOC100499484-C9ORF174


uncharacterized LOC100996720
LOC100996720


uncharacterized LOC100996740
LOC100996740


uncharacterized LOC101060400
LOC101060400


DNA-directed RNA polymerase III subunit
LOC101060521


RPC5


40S ribosomal protein S26
LOC101929876


uroplakin-3b-like protein-like
LOC102724187


histone H2B type F—S-like
LOC102724334


cystathionine beta-synthase
LOC102724560


splicing factor U2AF 35 kDa subunit
LOC102724594


alpha-crystallin A chain
LOC102724652


40S ribosomal protein S8 pseudogene
LOC102724737


immunoglobulin superfamily member 3-like
LOC102724844


pyridoxal-dependent decarboxylase
LOC102724985


domain-containing protein 1


peptidylprolyl isomerase A (cyclophilin A)
LOC128192


pseudogene


heat shock 70 kDa protein 5 (glucose-
LOC400750


regulated protein, 78 kDa) pseudogene


uncharacterized LOC440786
LOC440786


vitamin K epoxide reductase complex,
LOC441241


subunit 1-like 1 pseudogene


uncharacterized LOC442497
LOC442497


uncharacterized LOC642441
LOC642441


telomeric repeat-binding factor 1
LOC646127


pseudogene


IST1 homolog
LOC728533


exonuclease NEF-sp
LOC81691


Ion peptidase 1, mitochondrial
LONP1


lysyl oxidase-like 2
LOXL2


lysyl oxidase-like 4
LOXL4


lipoprotein, Lp(a)
LPA


lysophosphatidylcholine acyltransferase 3
LPCAT3


lysophosphatidylglycerol acyltransferase 1
LPGAT1


lipin 3
LPIN3


lipoprotein lipase
LPL


lactoperoxidase
LPO


LIM domain containing preferred
LPP


translocation partner in lipoma


LPS-responsive vesicle trafficking, beach
LRBA


and anchor containing


leucine-rich alpha-2-glycoprotein 1
LRG1


low density lipoprotein receptor-related
LRP1


protein 1


low density lipoprotein receptor-related
LRP10


protein 10


low density lipoprotein receptor-related
LRP1B


protein 1B


low density lipoprotein receptor-related
LRP2


protein 2


low density lipoprotein receptor-related
LRP4


protein 4


low density lipoprotein receptor-related
LRP5


protein 5


low density lipoprotein receptor-related
LRP6


protein 6


leucine-rich pentatricopeptide repeat
LRPPRC


containing


leucine rich repeat containing 1
LRRC1


leucine rich repeat containing 15
LRRC15


leucine rich repeat containing 16A
LRRC16A


leucine rich repeat containing 26
LRRC26


leucine rich repeat containing 32
LRRC32


leucine rich repeat containing 47
LRRC47


leucine rich repeat containing 57
LRRC57


leucine rich repeat containing 59
LRRC59


leucine rich repeat containing 75A
LRRC75A


leucine rich repeat containing 8 family,
LRRC8A


member A


leucine rich repeat containing 8 family,
LRRC8C


member C


leucine rich repeat containing 8 family,
LRRC8D


member D


leucine rich repeat containing 8 family,
LRRC8E


member E


leucine rich repeat (in FLII) interacting
LRRFIP1


protein 1


leucine rich repeat (in FLII) interacting
LRRFIP2


protein 2


leucine-rich repeat kinase 2
LRRK2


leucine rich repeat and sterile alpha motif
LRSAM1


containing 1


LSM12 homolog (S. cerevisiae)
LSM12


LSM2 homolog, U6 small nuclear RNA
LSM2


associated (S. cerevisiae)


LSM3 homolog, U6 small nuclear RNA
LSM3


associated (S. cerevisiae)


LSM6 homolog, U6 small nuclear RNA
LSM6


associated (S. cerevisiae)


lymphocyte-specific protein 1
LSP1


lipolysis stimulated lipoprotein receptor
LSR


lanosterol synthase (2,3-oxidosqualene-
LSS


lanosterol cyclase)


leukocyte specific transcript 1
LST1


leukotriene A4 hydrolase
LTA4H


leukotriene B4 receptor
LTB4R


latent transforming growth
LTBP1


factor beta binding protein 1


latent transforming growth
LTBP2


factor beta binding protein 2


latent transforming growth
LTBP3


factor beta binding protein 3


latent transforming growth
LTBP4


factor beta binding protein 4


lactotransferrin
LTF


leukocyte receptor tyrosine
LTK


kinase


listerin E3 ubiquitin protein
LTN1


ligase 1


LUC7-like (S. cerevisiae)
LUC7L


lumican
LUM


lymphocyte antigen 6
LY6G6F


complex, locus G6F


lymphocyte antigen 75
LY75


LY75-CD302 readthrough
LY75-CD302


lymphocyte antigen 9
LY9


Ly1 antibody reactive
LYAR


LYN proto-oncogene, Src
LYN


family tyrosine kinase


LY6/PLAUR domain
LYPD3


containing 3


lysophospholipase I
LYPLA1


lysophospholipase II
LYPLA2


lysophospholipase-like 1
LYPLAL1


lysozyme
LYZ


leucine-zipper-like
LZTR1


transcription regulator 1


mannose-6-phosphate
M6PR


receptor (cation dependent)


microtubule-actin crosslinking
MACF1


factor 1


MAP-kinase activating death
MADD


domain


melanoma antigen family A4
MAGEA4


melanoma antigen family B17
MAGEB17


melanoma antigen family B2
MAGEB2


melanoma antigen family D2
MAGED2


membrane associated
MAGI3


guanylate kinase, WW and


PDZ domain containing 3


mago-nashi homolog B
MAGOHB


(Drosophila)


magnesium transporter 1
MAGT1


mal, T-cell differentiation
MAL2


protein 2 (gene/pseudogene)


MALT1 paracaspase
MALT1


MAM domain containing 2
MAMDC2


mannosidase, alpha, class
MAN1A1


1A, member 1


mannosidase, alpha, class
MAN1A2


1A, member 2


mannosidase, alpha, class
MAN1B1


1B, member 1


mannosidase, alpha, class
MAN2A1


2A, member 1


mannosidase, alpha, class
MAN2B1


2B, member 1


mesencephalic astrocyte-
MANF


derived neurotrophic factor


microtubule-associated
MAP1A


protein 1A


microtubule-associated
MAP1B


protein 1B


microtubule-associated
MAP1S


protein 1S


microtubule-associated
MAP2


protein 2


microtubule-associated
MAPT


protein Tau


mitogen-activated protein
MAP2K1


kinase kinase 1


mitogen-activated protein
MAP2K2


kinase kinase 2


mitogen-activated protein
MAP2K3


kinase kinase 3


mitogen-activated protein
MAP2K4


kinase kinase 4


mitogen-activated protein
MAP2K6


kinase kinase 6


mitogen-activated protein
MAP2K7


kinase kinase 7


mitogen-activated protein
MAP3K1


kinase kinase kinase 1, E3


ubiquitin protein ligase


mitogen-activated protein
MAP3K19


kinase kinase kinase 19


microtubule-associated
MAP4


protein 4


mitogen-activated protein
MAP4K4


kinase kinase kinase kinase 4


microtubule-associated
MAP7


protein 7


mitogen-activated protein
MAPK1


kinase 1


mitogen-activated protein
MAPK14


kinase 14


mitogen-activated protein
MAPK1IP1L


kinase 1 interacting protein 1-


like


mitogen-activated protein
MAPK3


kinase 3


mitogen-activated protein
MAPK8


kinase 8


mitogen-activated protein
MAPK8IP1


kinase 8 interacting protein 1


mitogen-activated protein
MAPK9


kinase 9


mitogen-activated protein
MAPKAPK2


kinase-activated protein


kinase 2


microtubule-associated
MAPRE1


protein, RP/EB family,


member 1


microtubule-associated
MAPRE2


protein, RP/EB family,


member 2


myristoylated alanine-rich
MARCKS


protein kinase C substrate


MARCKS-like 1
MARCKSL1


MAP/microtubule affinity-
MARK2


regulating kinase 2


MAP/microtubule affinity-
MARK3


regulating kinase 3


methionyl-tRNA synthetase
MARS


MARVEL domain containing 2
MARVELD2


mannan-binding lectin serine
MASP1


peptidase 1 (C4/C2 activating


component of Ra-reactive


factor)


mannan-binding lectin serine
MASP2


peptidase 2


methionine
MAT1A


adenosyltransferase I, alpha


methionine
MAT2A


adenosyltransferase II, alpha


methionine
MAT2B


adenosyltransferase II, beta


matrilin 2
MATN2


matrin 3
MATR3


mitochondrial antiviral
MAVS


signaling protein


methyl-CpG binding domain
MBD3


protein 3


methyl-CpG binding domain
MBD3L5


protein 3-like 5


methyl-CpG binding domain
MBD5


protein 5


mannose-binding lectin
MBL2


(protein C) 2, soluble


metallo-beta-lactamase
MBLAC2


domain containing 2


muscleblind-like splicing
MBNL1


regulator 1


melanocortin 1 receptor
MC1R


(alpha melanocyte stimulating


hormone receptor)


melanoma cell adhesion
MCAM


molecule


mutated in colorectal cancers
MCC


methylcrotonoyl-CoA
MCCC1


carboxylase 1 (alpha)


MCF.2 cell line derived
MCF2L2


transforming sequence-like 2


minichromosome
MCM10


maintenance complex


component 10


minichromosome
MCM2


maintenance complex


component 2


minichromosome
MCM3


maintenance complex


component 3


minichromosome
MCM4


maintenance complex


component 4


minichromosome
MCM5


maintenance complex


component 5


minichromosome
MCM6


maintenance complex


component 6


minichromosome
MCM7


maintenance complex


component 7


minichromosome
MCMBP


maintenance complex binding


protein


mucolipin 1
MCOLN1


malignant T cell amplified
MCTS1


sequence 1


malate dehydrogenase 1,
MDH1


NAD (soluble)


malate dehydrogenase 2,
MDH2


NAD (mitochondrial)


midkine (neurite growth-
MDK


promoting factor 2)


MDN1, midasin homolog
MDN1


(yeast)


magnesium-dependent
MDP1


phosphatase 1


malic enzyme 1, NADP(+)-
ME1


dependent, cytosolic


malic enzyme 3, NADP(+)-
ME3


dependent, mitochondrial


methyl CpG binding protein 2
MECP2


mediator complex subunit 20
MED20


mediator complex subunit 23
MED23


multiple EGF-like-domains 10
MEGF10


multiple EGF-like-domains 8
MEGF8


mediator of cell motility 1
MEMO1


multiple endocrine neoplasia I
MEN1


meprin A, alpha (PABA
MEP1A


peptide hydrolase)


meprin A, beta
MEP1B


mesoderm specific transcript
MEST


MET proto-oncogene,
MET


receptor tyrosine kinase


methionyl aminopeptidase 2
METAP2


meteorin, glial cell
METRNL


differentiation regulator-like


methyltransferase like 13
METTL13


methyltransferase like 16
METTL16


mex-3 RNA binding family
MEX3B


member B


microfibrillar-associated
MFAP4


protein 4


milk fat globule-EGF factor 8
MFGE8


protein


antigen p97 (melanoma
MFI2


associated) identified by


monoclonal antibodies 133.2


and 96.5


major facilitator superfamily
MFSD1


domain containing 1


major facilitator superfamily
MFSD2B


domain containing 2B


maltase-glucoamylase
MGAM


mannosyl (alpha-1,3-)-
MGAT1


glycoprotein beta-1,2-N-


acetylglucosaminyltransferase


mannosyl (alpha-1,3-)-
MGAT4A


glycoprotein beta-1,4-N-


acetylglucosaminyltransferase,


isozyme A


mannosyl (alpha-1,6-)-
MGAT5


glycoprotein beta-1,6-N-


acetyl-


glucosaminyltransferase


monoglyceride lipase
MGLL


O-6-methylguanine-DNA
MGMT


methyltransferase


matrix Gla protein
MGP


mahogunin ring finger 1, E3
MGRN1


ubiquitin protein ligase


microsomal glutathione S-
MGST2


transferase 2


microsomal glutathione S-
MGST3


transferase 3


mindbomb E3 ubiquitin
MIB2


protein ligase 2


MHO class I polypeptide-
MICA


related sequence A


microtubule associated
MICAL1


monooxygenase, calponin


and LIM domain containing 1


midline 2
MID2


mesoderm induction early
MIER3


response 1, family member 3


macrophage migration
MIF


inhibitory factor (glycosylation-


inhibiting factor)


MIF antisense RNA 1
MIF-AS1


misshapen-like kinase 1
MINK1


mitotic spindle positioning
MISP


MIT, microtubule interacting
MITD1


and transport, domain


containing 1


makorin ring finger protein 1
MKRN1


melan-A
MLANA


megalencephalic
MLC1


leukoencephalopathy with


subcortical cysts 1


malectin
MLEC


myeloid leukemia factor 2
MLF2


mutL homolog 1
MLH1


myeloid/lymphoid or mixed-
MLLT3


lineage leukemia (trithorax


homolog, Drosophila);


translocated to, 3


myeloid/lymphoid or mixed-
MLLT4


lineage leukemia (trithorax


homolog, Drosophila);


translocated to, 4


MTOR associated protein,
MLST8


LST8 homolog (S. cerevisiae)


membrane metallo-
MME


endopeptidase


matrix metallopeptidase 1
MMP1


matrix metallopeptidase 10
MMP10


matrix metallopeptidase 14
MMP14


(membrane-inserted)


matrix metallopeptidase 15
MMP15


(membrane-inserted)


matrix metallopeptidase 2
MMP2


matrix metallopeptidase 24
MMP24


(membrane-inserted)


matrix metallopeptidase 25
MMP25


matrix metallopeptidase 3
MMP3


matrix metallopeptidase 7
MMP7


matrix metallopeptidase 9
MMP9


multimerin 1
MMRN1


multimerin 2
MMRN2


MMS19 nucleotide excision
MMS19


repair homolog (S. cerevisiae)


myeloid cell nuclear
MNDA


differentiation antigen


MOB kinase activator 1A
MOB1A


MOB kinase activator 1B
MOB1B


MOB kinase activator 2
MOB2


molybdenum cofactor
MOCS3


synthesis 3


mannosyl-oligosaccharide
MOGS


glucosidase


MON2 homolog
MON2


(S. cerevisiae)


MORC family CW-type zinc
MORC3


finger 3


v-mos Moloney murine
MOS


sarcoma viral oncogene


homolog


Mov10 RISC complex RNA
MOV10


helicase


monooxygenase, DBH-like 1
MOXD1


mannose phosphate
MPI


isomerase


MPL proto-oncogene,
MPL


thrombopoietin receptor


myeloperoxidase
MPO


membrane protein,
MPP1


palmitoylated 1, 55 kDa


membrane protein,
MPP5


palmitoylated 5 (MAGUK p55


subfamily member 5)


membrane protein,
MPP6


palmitoylated 6 (MAGUK p55


subfamily member 6)


membrane protein,
MPP7


palmitoylated 7 (MAGUK p55


subfamily member 7)


metallophosphoesterase 1
MPPE1


mercaptopyruvate
MPST


sulfurtransferase


myelin protein zero-like 1
MPZL1


myelin protein zero-like 2
MPZL2


mannose receptor, C type 2
MRC2


MRE11 meiotic recombination
MRE11A


11 homolog A (S. cerevisiae)


methylthioribose-1-phosphate
MRI1


isomerase 1


maestro heat-like repeat
MROH1


family member 1


mitochondrial ribosomal
MRPS17


protein S17


mitochondrial ribosomal
MRPS22


protein S22


mRNA turnover 4 homolog
MRTO4


(S. cerevisiae)


murine retrovirus integration
MRVI1


site 1 homolog


membrane-spanning 4-
MS4A1


domains, subfamily A,


member 1


mutS homolog 2
MSH2


mutS homolog 3
MSH3


mutS homolog 6
MSH6


musashi RNA-binding protein 2
MSI2


male-specific lethal 1 homolog
MSL1


(Drosophila)


mesothelin
MSLN


methylsterol monooxygenase 1
MSMO1


microseminoprotein, prostate
MSMP


associated


moesin
MSN


methionine sulfoxide
MSRA


reductase A


macrophage stimulating 1
MST1R


receptor


metastasis associated 1
MTA2


family, member 2


metastasis associated 1
MTA3


family, member 3


methylthioadenosine
MTAP


phosphorylase


mitochondrial carrier 2
MTCH2


methylenetetrahydrofolate
MTHFD1


dehydrogenase (NADP+


dependent) 1,


methenyltetrahydrofolate


cyclohydrolase,


formyltetrahydrofolate


synthetase


methylenetetrahydrofolate
MTHFD1L


dehydrogenase (NADP+


dependent) 1-like


myotubularin related protein 10
MTMR10


myotubularin related protein 12
MTMR12


mechanistic target of
MTOR


rapamycin (serine/threonine


kinase)


myotrophin
MTPN


metastasis suppressor 1
MTSS1


microsomal triglyceride
MTTP


transfer protein


microtubule associated tumor
MTUS2


suppressor candidate 2


mucin 1, cell surface
MUC1


associated


mucin 13, cell surface
MUC13


associated


mucin 16, cell surface
MUC16


associated


mucin 17, cell surface
MUC17


associated


mucin 4, cell surface
MUC4


associated


mucin 5AC, oligomeric
MUC5AC


mucus/gel-forming


mucin 6, oligomeric
MUC6


mucus/gel-forming


mucin 7, secreted
MUC7


melanoma associated antigen
MUM1L1


(mutated) 1-like 1


multivesicular body subunit 12A
MVB12A


multivesicular body subunit 12B
MVB12B


mevalonate (diphospho)
MVD


decarboxylase


mevalonate kinase
MVK


major vault protein
MVP


MX dynamin-like GTPase 1
MX1


MX dynamin-like GTPase 2
MX2


matrix-remodelling associated 5
MXRA5


matrix-remodelling associated 8
MXRA8


myeloid-associated
MYADM


differentiation marker


MYB binding protein (P160) 1a
MYBBP1A


myosin binding protein C, fast type
MYBPC2


MYC binding protein 2, E3
MYCBP2


ubiquitin protein ligase


MYCBP associated protein
MYCBPAP


myc target 1
MYCT1


myeloid differentiation primary
MYD88


response 88


myeloid-derived growth factor
MYDGF


myosin, heavy chain 10, non-
MYH10


muscle


myosin, heavy chain 11,
MYH11


smooth muscle


myosin, heavy chain 13,
MYH13


skeletal muscle


myosin, heavy chain 14, non-
MYH14


muscle


myosin, heavy chain 3,
MYH3


skeletal muscle, embryonic


myosin, heavy chain 7,
MYH7


cardiac muscle, beta


myosin, heavy chain 8,
MYH8


skeletal muscle, perinatal


myosin, heavy chain 9, non-
MYH9


muscle


myosin, light chain 1, alkali;
MYL1


skeletal, fast


myosin, light chain 12A,
MYL12A


regulatory, non-sarcomeric


myosin, light chain 12B,
MYL12B


regulatory


myosin, light chain 3, alkali;
MYL3


ventricular, skeletal, slow


myosin, light chain 6, alkali,
MYL6


smooth muscle and non-


muscle


myosin, light chain 6B, alkali,
MYL6B


smooth muscle and non-


muscle


myosin, light chain 9,
MYL9


regulatory


myosin light chain kinase
MYLK


myosin light chain kinase 2
MYLK2


myosin light chain kinase 3
MYLK3


myosin XVA
MYO15A


myosin XVI
MYO16


myosin XVIIIA
MYO18A


myosin IA
MYO1A


myosin IB
MYO1B


myosin IC
MYO1C


myosin ID
MYO1D


myosin IE
MYO1E


myosin IF
MYO1F


myosin IG
MYO1G


myosin IIIB
MYO3B


myosin VA (heavy chain 12,
MYO5A


myoxin)


myosin VB
MYO5B


myosin VI
MYO6


myosin VIIA
MYO7A


myosin IXB
MYO9B


myocilin, trabecular meshwork
MYOC


inducible glucocorticoid


response


myoferlin
MYOF


myozenin 2
MYOZ2


NEDD4 binding protein 2-like 2
N4BP2L2


N(alpha)-acetyltransferase 10,
NAA10


NatA catalytic subunit


N(alpha)-acetyltransferase 15,
NAA15


NatA auxiliary subunit


N(alpha)-acetyltransferase 16,
NAA16


NatA auxiliary subunit


N(alpha)-acetyltransferase 50,
NAA50


NatE catalytic subunit


N-acetylated alpha-linked
NAALAD2


acidic dipeptidase 2


NGFI-A binding protein 2
NAB2


(EGR1 binding protein 2)


nascent polypeptide-
NACA


associated complex alpha


subunit


nascent polypeptide-
NACA2


associated complex alpha


subunit 2


NEDD8 activating enzyme E1
NAE1


subunit 1


N-acetylgalactosaminidase,
NAGA


alpha-


N-acetylglucosamine kinase
NAGK


N-acetylglucosaminidase,
NAGLU


alpha


nicotinamide
NAMPT


phosphoribosyltransferase


N-acetylneuraminic acid
NANS


synthase


nucleosome assembly protein
NAP1L1


1-like 1


nucleosome assembly protein
NAP1L4


1-like 4


N-ethylmaleimide-sensitive
NAPA


factor attachment protein,


alpha


N-acyl
NAPEPLD


phosphatidylethanolamine


phospholipase D


N-ethylmaleimide-sensitive
NAPG


factor attachment protein,


gamma


Nicotinate
NAPRT


phosphoribosyltransferase


napsin A aspartic peptidase
NAPSA


asparaginyl-tRNA synthetase
NARS


nuclear autoantigenic sperm
NASP


protein (histone-binding)


N-acetyltransferase 1
NAT1


(arylamine N-


acetyltransferase)


N-acetyltransferase 10
NAT10


(GCN5-related)


N-acetyltransferase 8-like
NAT8L


(GCN5-related, putative)


neuron navigator 1
NAV1


neurobeachin-like 2
NBEAL2


neuroblastoma 1, DAN family
NBL1


BMP antagonist


neighbor of BRCA1 gene 1
NBR1


neurocalcin delta
NCALD


neural cell adhesion molecule 1
NCAM1


non-SMC condensin I
NCAPD2


complex, subunit D2


non-SMC condensin I
NCAPG


complex, subunit G


non-SMC condensin II
NCAPG2


complex, subunit G2


non-SMC condensin I
NCAPH


complex, subunit H


nuclear cap binding protein
NCBP1


subunit 1, 80 kDa


nuclear cap binding protein
NCBP2


subunit 2, 20 kDa


non-specific cytotoxic cell
NCCRP1


receptor protein 1 homolog


(zebrafish)


neutral cholesterol ester
NCEH1


hydrolase 1


neutrophil cytosolic factor 2
NCF2


neutrophil cytosolic factor 4,
NCF4


40 kDa


NCK adaptor protein 1
NCK1


NCK adaptor protein 2
NCK2


NCK-associated protein 1
NCKAP1


NCK-associated protein 1-like
NCKAP1L


nucleolin
NCL


nuclear receptor coactivator 4
NCOA4


neuronal calcium sensor 1
NCS1


nicastrin
NCSTN


nudE neurodevelopment
NDE1


protein 1


necdin-like 2
NDNL2


N-myc downstream regulated 1
NDRG1


NDRG family member 2
NDRG2


NDRG family member 3
NDRG3


NADH dehydrogenase
NDUFS2


(ubiquinone) Fe&endash;S protein 2,


49 kDa (NADH-coenzyme Q


reductase)


nebulin
NEB


nebulette
NEBL


neural precursor cell
NEDD1


expressed, developmentally


down-regulated 1


neural precursor cell
NEDD4


expressed, developmentally


down-regulated 4, E3


ubiquitin protein ligase


neural precursor cell
NEDD4L


expressed, developmentally


down-regulated 4-like, E3


ubiquitin protein ligase


neural precursor cell
NEDD8


expressed, developmentally


down-regulated 8


neural precursor cell
NEDD9


expressed, developmentally


down-regulated 9


neurofilament, heavy
NEFH


polypeptide


neurofilament, light
NEFL


polypeptide


neurofilament, medium
NEFM


polypeptide


NIMA-related kinase 10
NEK10


NIMA-related kinase 7
NEK7


NIMA-related kinase 9
NEK9


negative elongation factor
NELFB


complex member B


negative elongation factor
NELFCD


complex member C/D


negative elongation factor
NELFE


complex member E


neogenin 1
NEO1


nestin
NES


sialidase 1 (lysosomal
NEU1


sialidase)


neurofibromin 1
NF1


neurofibromin 2 (merlin)
NF2


nuclear factor of activated T-
NFATC1


cells, cytoplasmic, calcineurin-


dependent 1


nuclear factor of activated T-
NFATC4


cells, cytoplasmic, calcineurin-


dependent 4


nuclear factor I/A
NFIA


nuclear factor, interleukin 3
NFIL3


regulated


nuclear factor of kappa light
NFKB2


polypeptide gene enhancer in


B-cells 2 (p49/p100)


nerve growth factor receptor
NGFR


N-glycanase 1
NGLY1


NHL repeat containing 2
NHLRC2


NHP2 ribonucleoprotein
NHP2


NHP2 non-histone
NHP2L1


chromosome protein 2-like 1


(S. cerevisiae)


Nance-Horan syndrome
NHS


(congenital cataracts and


dental anomalies)


nidogen 1
NID1


nidogen 2 (osteonidogen)
NID2


NIF3 NGG1 interacting factor
NIF3L1


3-like 1 (S. cerevisiae)


nucleolar protein interacting
NIFK


with the FHA domain of


MKI67


ninein (GSK3B interacting
NIN


protein)


ninjurin 1
NINJ1


Nipped-B homolog
NIPBL


(Drosophila)


nipsnap homolog 1 (C.
NIPSNAP1


elegans)


nischarin
NISCH


nitrilase 1
NIT1


nitrilase family, member 2
NIT2


NFKB repressing factor
NKRF


NK6 homeobox 1
NKX6-1


NLR family, pyrin domain
NLRP8


containing 8


NMD3 ribosome export
NMD3


adaptor


NME/NM23 nucleoside
NME1


diphosphate kinase 1


NME1-NME2 readthrough
NME1-NME2


NME/NM23 nucleoside
NME2


diphosphate kinase 2


NME/NM23 nucleoside
NME2P1


diphosphate kinase 2


pseudogene 1


NmrA-like family domain
NMRAL1


containing 1


N-myristoyltransferase 1
NMT1


N-myristoyltransferase 2
NMT2


nucleotide-binding
NOD1


oligomerization domain


containing 1


nucleolar protein 9
NOL9


nucleolar and coiled-body
NOLC1


phosphoprotein 1


NODAL modulator 1
NOMO1


NODAL modulator 2
NOMO2


NODAL modulator 3
NOMO3


non-POU domain containing,
NONO


octamer-binding


NOP10 ribonucleoprotein
NOP10


NOP14 nucleolar protein
NOP14


NOP16 nucleolar protein
NOP16


NOP2 nucleolar protein
NOP2


NOP56 ribonucleoprotein
NOP56


NOP58 ribonucleoprotein
NOP58


NOP9 nucleolar protein
NOP9


nitric oxide synthase
NOSTRIN


trafficking


notch 1
NOTCH1


notch 2
NOTCH2


NADPH oxidase 3
NOX3


Niemann-Pick disease, type
NPC1


C1


aminopeptidase puromycin
NPEPPS


sensitive


nephrosis 1, congenital,
NPHS1


Finnish type (nephrin)


nephrosis 2, idiopathic,
NPHS2


steroid-resistant (podocin)


nuclear protein localization 4
NPLOC4


homolog (S. cerevisiae)


nucleophosmin (nucleolar
NPM1


phosphoprotein B23,


numatrin)


nucleophosmin/nucleoplasmin 3
NPM3


nephronectin
NPNT


natriuretic peptide receptor 1
NPR1


natriuretic peptide receptor 3
NPR3


neuroplastin
NPTN


NAD(P)H dehydrogenase,
NQO1


quinone 1


NAD(P)H dehydrogenase,
NQO2


quinone 2


nuclear receptor subfamily 3,
NR3C1


group C, member 1


(glucocorticoid receptor)


neuroblastoma RAS viral (v-
NRAS


ras) oncogene homolog


nuclear respiratory factor 1
NRF1


neuregulin 2
NRG2


neuropilin 1
NRP1


neuropilin 2
NRP2


NAD(P) dependent steroid
NSDHL


dehydrogenase-like


N-ethylmaleimide-sensitive
NSF


factor


NSFL1 (p97) cofactor (p47)
NSFL1C


NOP2/Sun RNA
NSUN2


methyltransferase family,


member 2


5′,3′-nucleotidase, cytosolic
NT5C


5′-nucleotidase, cytosolic II
NT5C2


5′-nucleotidase domain
NT5DC1


containing 1


5′-nucleotidase, ecto (CD73)
NT5E


N-terminal Xaa-Pro-Lys N-
NTMT1


methyltransferase 1


nucleoside-triphosphatase,
NTPCR


cancer-related


neurotrophic tyrosine kinase,
NTRK2


receptor, type 2


negative regulator of ubiquitin-
NUB1


like proteins 1


nucleotide binding protein 2
NUBP2


nucleobindin 1
NUCB1


nucleobindin 2
NUCB2


nuclear casein kinase and
NUCKS1


cyclin-dependent kinase


substrate 1


nudC nuclear distribution
NUDC


protein


NudC domain containing 1
NUDCD1


NudC domain containing 2
NUDCD2


nudix (nucleoside
NUDT16L1


diphosphate linked moiety X)-


type motif 16-like 1


nudix (nucleoside
NUDT21


diphosphate linked moiety X)-


type motif 21


nudix (nucleoside
NUDT4


diphosphate linked moiety X)-


type motif 4


nudix (nucleoside
NUDT5


diphosphate linked moiety X)-


type motif 5


nudix (nucleoside
NUDT9


diphosphate linked moiety X)-


type motif 9


nuclear mitotic apparatus
NUMA1


protein 1


numb homolog (Drosophila)
NUMB


numb homolog (Drosophila)-
NUMBL


like


nucleoporin 160 kDa
NUP160


nucleoporin 205 kDa
NUP205


nucleoporin 210 kDa
NUP210


nucleoporin 43 kDa
NUP43


nucleoporin 88 kDa
NUP88


nucleoporin 93 kDa
NUP93


nucleoporin like 2
NUPL2


nucleolar and spindle
NUSAP1


associated protein 1


nuclear transport factor 2
NUTF2


nuclear RNA export factor 1
NXF1


nucleoredoxin
NXN


neurexophilin and PC-
NXPE4


esterase domain family,


member 4


O-acyl-ADP-ribose deacylase 1
OARD1


2′-5′-oligoadenylate
OAS2


synthetase 2, 69/71 kDa


2′-5′-oligoadenylate
OAS3


synthetase 3, 100 kDa


ornithine aminotransferase
OAT


oligonucleotide/oligosaccharid
OBFC1


e-binding fold containing 1


odorant binding protein 2A
OBP2A


obscurin, cytoskeletal
OBSCN


calmodulin and titin-


interacting RhoGEF


OCIA domain containing 2
OCIAD2


occludin
OCLN


oculocerebrorenal syndrome
OCRL


of Lowe


oral-facial-digital syndrome 1
OFD1


opioid growth factor receptor
OGFR


osteoglycin
OGN


O-linked N-acetylglucosamine
OGT


(GlcNAc) transferase


oncoprotein induced transcript
OIT3


3


Obg-like ATPase 1
OLA1


olfactomedin 4
OLFM4


olfactomedin-like 3
OLFML3


oxidized low density
OLR1


lipoprotein (lectin-like)


receptor 1


optic atrophy 1 (autosomal
OPA1


dominant)


optic atrophy 3 (autosomal
OPA3


recessive, with chorea and


spastic paraplegia)


opiate receptor-like 1
OPRL1


opioid receptor, mu 1
OPRM1


optineurin
OPTN


olfactory receptor, family 11,
OR11L1


subfamily L, member 1


olfactory receptor, family 2,
OR2A4


subfamily A, member 4


olfactory receptor, family 2,
OR2T8


subfamily T, member 8


ORAI calcium release-
ORAI1


activated calcium modulator 1


orosomucoid 1
ORM1


ORMDL sphingolipid
ORMDL1


biosynthesis regulator 1


ORMDL sphingolipid
ORMDL2


biosynthesis regulator 2


ORMDL sphingolipid
ORMDL3


biosynthesis regulator 3


osteosarcoma amplified 9,
OS9


endoplasmic reticulum lectin


oxysterol binding protein
OSBP


oxysterol binding protein-like 1A
OSBPL1A


O-sialoglycoprotein
OSGEP


endopeptidase


oncostatin M
OSM


oncostatin M receptor
OSMR


oligosaccharyltransferase
OSTC


complex subunit (non-


catalytic)


osteoclast stimulating factor 1
OSTF1


ornithine
OTC


carbamoyltransferase


OTU deubiquitinase, ubiquitin
OTUB1


aldehyde binding 1


OTU deubiquitinase 7A
OTUD7A


OTU deubiquitinase 7B
OTUD7B


oxidoreductase NAD-binding
OXNAD1


domain containing 1


oxidative stress responsive 1
OXSR1


oxytocin receptor
OXTR


purinergic receptor P2X,
P2RX1


ligand gated ion channel, 1


purinergic receptor P2X,
P2RX4


ligand gated ion channel, 4


purinergic receptor P2X,
P2RX5


ligand gated ion channel, 5


purinergic receptor P2Y, G-
P2RY12


protein coupled, 12


purinergic receptor P2Y, G-
P2RY2


protein coupled, 2


prolyl 3-hydroxylase 1
P3H1


prolyl 4-hydroxylase, alpha
P4HA1


polypeptide I


prolyl 4-hydroxylase, beta
P4HB


polypeptide


proliferation-associated 2G4,
PA2G4


38kDa


poly(A) binding protein,
PABPC1


cytoplasmic 1


poly(A) binding protein,
PABPC1L


cytoplasmic 1-like


poly(A) binding protein,
PABPC3


cytoplasmic 3


poly(A) binding protein,
PABPC4


cytoplasmic 4 (inducible form)


poly(A) binding protein,
PABPC5


cytoplasmic 5


protein kinase C and casein
PACSIN2


kinase substrate in neurons 2


protein kinase C and casein
PACSIN3


kinase substrate in neurons 3


peptidyl arginine deiminase,
PADI2


type II


Paf1, RNA polymerase II
PAF1


associated factor, homolog


(S. cerevisiae)


platelet-activating factor
PAFAH1B1


acetylhydrolase 1b, regulatory


subunit 1 (45 kDa)


platelet-activating factor
PAFAH1B2


acetylhydrolase 1b, catalytic


subunit 2 (30 kDa)


platelet-activating factor
PAFAH1B3


acetylhydrolase 1b, catalytic


subunit 3 (29 kDa)


P antigen family, member 2
PAGE2


(prostate associated)


phenylalanine hydroxylase
PAH


phosphoribosylaminoimidazole
PAICS


carboxylase,


phosphoribosylaminoimidazole


succinocarboxamide


synthetase


p21 protein (Cdc42/Rac)-
PAK2


activated kinase 2


p21 protein (Cdc42/Rac)-
PAK4


activated kinase 4


p21 protein (Cdc42/Rac)-
PAK6


activated kinase 6


phosphatase domain
PALD1


containing, paladin 1


paralemmin
PALM


peptidylglycine alpha-
PAM


amidating monooxygenase


peptidase domain containing
PAMR1


associated with muscle


regeneration 1


PAN3 poly(A) specific
PAN3


ribonuclease subunit


pantothenate kinase 2
PANK2


pantothenate kinase 4
PANK4


pannexin 1
PANX1


pregnancy-associated plasma
PAPPA


protein A, pappalysin 1


PAPPA antisense RNA 1
PAPPA-AS1


3′-phosphoadenosine 5′-
PAPSS1


phosphosulfate synthase 1


3′-phosphoadenosine 5′-
PAPSS2


phosphosulfate synthase 2


par-3 family cell polarity
PARD3


regulator


par-6 family cell polarity
PARD6B


regulator beta


parkinson protein 7
PARK7


poly (ADP-ribose) polymerase
PARP1


1


poly (ADP-ribose) polymerase
PARP10


family, member 10


poly (ADP-ribose) polymerase
PARP12


family, member 12


poly (ADP-ribose) polymerase
PARP14


family, member 14


poly (ADP-ribose) polymerase
PARP16


family, member 16


poly (ADP-ribose) polymerase
PARP4


family, member 4


poly (ADP-ribose) polymerase
PARP9


family, member 9


parvin, alpha
PARVA


parvin, beta
PARVB


parvin, gamma
PARVG


protein associated with
PATL1


topoisomerase II homolog 1


(yeast)


phenazine biosynthesis-like
PBLD


protein domain containing


polybromo 1
PBRM1


pyruvate carboxylase
PC


pterin-4 alpha-carbinolamine
PCBD1


dehydratase/dimerization


cofactor of hepatocyte nuclear


factor 1 alpha


poly(rC) binding protein 1
PCBP1


poly(rC) binding protein 2
PCBP2


poly(rC) binding protein 3
PCBP3


protocadherin 1
PCDH1


protocadherin gamma
PCDHGB5


subfamily B, 5


PCF11 cleavage and
PCF11


polyadenylation factor subunit


PCI domain containing 2
PCID2


PDX1 C-terminal inhibiting
PCIF1


factor 1


phosphoenolpyruvate
PCK1


carboxykinase 1 (soluble)


piccolo presynaptic cytomatrix
PCLO


protein


protein-L-isoaspartate (D-
PCMT1


aspartate) O-


methyltransferase


proliferating cell nuclear
PCNA


antigen


procollagen C-endopeptidase
PCOLCE


enhancer


proprotein convertase
PCSK6


subtilisin/kexin type 6


proprotein convertase
PCSK9


subtilisin/kexin type 9


prenylcysteine oxidase 1
PCYOX1


phosphate cytidylyltransferase
PCYT1B


1, choline, beta


phosphate cytidylyltransferase
PCYT2


2, ethanolamine


programmed cell death 10
PDCD10


programmed cell death 2
PDCD2


programmed cell death 2-like
PDCD2L


programmed cell death 4
PDCD4


(neoplastic transformation


inhibitor)


programmed cell death 5
PDCD5


programmed cell death 6
PDCD6


programmed cell death 6
PDCD6IP,ALIX


interacting protein (Apoptosis-


Linked Gene 2-lnteracting


Protein X


Parkinson disease 7 domain
PDDC1


containing 1


phosphodiesterase 12
PDE12


phosphodiesterase 1C,
PDE1C


calmodulin-dependent 70 kDa


phosphodiesterase 4D
PDE4DIP


interacting protein


phosphodiesterase 5A,
PDE5A


cGMP-specific


phosphodiesterase 8A
PDE8A


platelet-derived growth factor
PDGFA


alpha polypeptide


platelet derived growth factor
PDGFC


C


platelet-derived growth factor
PDGFRB


receptor, beta polypeptide


pyruvate dehydrogenase
PDHA1


(lipoamide) alpha 1


protein disulfide isomerase
PDIA2


family A, member 2


protein disulfide isomerase
PDIA3


family A, member 3


protein disulfide isomerase
PDIA4


family A, member 4


protein disulfide isomerase
PDIA5


family A, member 5


protein disulfide isomerase
PDIA6


family A, member 6


PDZ and LIM domain 1
PDLIM1


PDZ and LIM domain 5
PDLIM5


PDZ and LIM domain 7
PDLIM7


(enigma)


PDS5 cohesin associated
PDS5A


factor A


PDS5 cohesin associated
PDS5B


factor B


pyridoxal-dependent
PDXDC1


decarboxylase domain


containing 1


pyridoxal (pyridoxine, vitamin
PDXK


B6) kinase


PDZ domain containing 1
PDZK1


PDZK1 interacting protein 1
PDZK1IP1


pseudopodium-enriched
PEAK1


atypical kinase 1


platelet endothelial
PEAR1


aggregation receptor 1


phosphatidylethanolamine
PEBP1


binding protein 1


platelet/endothelial cell
PECAM1


adhesion molecule 1


penta-EF-hand domain
PEF1


containing 1


pellino E3 ubiquitin protein
PELI1


ligase 1


pellino E3 ubiquitin protein
PELI2


ligase family member 2


pelota homolog (Drosophila)
PELO


proline, glutamate and leucine
PELP1


rich protein 1


peptidase D
PEPD


pescadillo ribosomal
PES1


biogenesis factor 1


peroxisomal biogenesis factor 1
PEX1


peroxisomal biogenesis factor 3
PEX3


phosphoribosylformylglycinamidine
PFAS


synthase


prefoldin subunit 2
PFDN2


prefoldin subunit 4
PFDN4


prefoldin subunit 5
PFDN5


6-phosphofructo-2-
PFKFB2


kinase/fructose-2,6-


biphosphatase 2


6-phosphofructo-2-
PFKFB3


kinase/fructose-2,6-


biphosphatase 3


phosphofructokinase, liver
PFKL


phosphofructokinase, muscle
PFKM


phosphofructokinase, platelet
PFKP


profilin 1
PFN1


profilin 2
PFN2


phosphoglycerate mutase 1
PGAM1


(brain)


phosphoglycerate mutase 2
PGAM2


(muscle)


phosphoglycerate mutase
PGAM4


family member 4


phosphoglycerate mutase
PGAM5


family member 5


phosphogluconate
PGD


dehydrogenase


phosphoglycerate kinase 1
PGK1


phosphoglycerate kinase 2
PGK2


6-phosphogluconolactonase
PGLS


peptidoglycan recognition
PGLYRP1


protein 1


peptidoglycan recognition
PGLYRP2


protein 2


phosphoglucomutase 1
PGM1


phosphoglucomutase 2
PGM2


phosphoglucomutase 2-like 1
PGM2L1


phosphoglucomutase 3
PGM3


phosphoglucomutase 5
PGM5


progesterone receptor
PGRMC1


membrane component 1


progesterone receptor
PGRMC2


membrane component 2


phosphatase and actin
PHACTR4


regulator 4


prohibitin
PHB


prohibitin 2
PHB2


PHD finger protein 23
PHF23


PHD finger protein 5A
PHF5A


phosphoglycerate
PHGDH


dehydrogenase


phosphorylase kinase, alpha
PHKA1


1 (muscle)


phosphorylase kinase, alpha
PHKA2


2 (liver)


phosphorylase kinase, beta
PHKB


pleckstrin homology-like
PHLDA1


domain, family A, member 1


pleckstrin homology-like
PHLDA2


domain, family A, member 2


pleckstrin homology-like
PHLDB1


domain, family B, member 1


pleckstrin homology-like
PHLDB2


domain, family B, member 2


phosphohistidine
PHPT1


phosphatase 1


phosphatidylinositol 4-kinase
PI4K2A


type 2 alpha


phosphatidylinositol 4-kinase,
PI4KA


catalytic, alpha


phosphatidylinositol 4-kinase,
PI4KB


catalytic, beta


phosphatidylinositol binding
PICALM


clathrin assembly protein


polymeric immunoglobulin
PIGR


receptor


phosphatidylinositol-4-
PIK3C2A


phosphate 3-kinase, catalytic


subunit type 2 alpha


phosphatidylinositol-4-
PIK3C2B


phosphate 3-kinase, catalytic


subunit type 2 beta


phosphatidylinositol 3-kinase,
PIK3C3


catalytic subunit type 3


phosphatidylinositol-4,5-
PIK3CA


bisphosphate 3-kinase,


catalytic subunit alpha


phosphatidylinositol-4,5-
PIK3CB


bisphosphate 3-kinase,


catalytic subunit beta


phosphoinositide-3-kinase,
PIK3R1


regulatory subunit 1 (alpha)


phosphoinositide-3-kinase,
PIK3R4


regulatory subunit 4


paired immunoglobin-like type
PILRA


2 receptor alpha


peptidylprolyl cis/trans
PIN1


isomerase, NIMA-interacting 1


peptidylprolyl cis/trans
PIN4


isomerase, NIMA-interacting 4


prolactin-induced protein
PIP


phosphatidylinositol-5-
PIP4K2A


phosphate 4-kinase, type II,


alpha


phosphatidylinositol-5-
PIP4K2B


phosphate 4-kinase, type II,


beta


phosphatidylinositol-5-
PIP4K2C


phosphate 4-kinase, type II,


gamma


phosphatidylinositol-4-
PIP5K1A


phosphate 5-kinase, type I,


alpha


pirin (iron-binding nuclear
PIR


protein)


PITH (C-terminal proteasome-
PITHD1


interacting domain of


thioredoxin-like) domain


containing 1


phosphatidylinositol transfer
PITPNA


protein, alpha


phosphatidylinositol transfer
PITPNB


protein, beta


phosphatidylinositol transfer
PITPNM1


protein, membrane-


associated 1


polycystic kidney disease 1
PKD1


(autosomal dominant)


polycystic kidney disease 1-
PKD1L3


like 3


polycystic kidney disease 2
PKD2


(autosomal dominant)


polycystic kidney disease 2-
PKD2L2


like 2


polycystic kidney and hepatic
PKHD1


disease 1 (autosomal


recessive)


polycystic kidney and hepatic
PKHD1L1


disease 1 (autosomal


recessive)-like 1


pyruvate kinase, liver and
PKLR


RBC


pyruvate kinase, muscle
PKM


protein kinase N2
PKN2


protein kinase N3
PKN3


plakophilin 2
PKP2


plakophilin 3
PKP3


plakophilin 4
PKP4


phospholipase A2, group IIA
PLA2G2A


(platelets, synovial fluid)


phospholipase A2-activating
PLAA


protein


plasminogen activator, tissue
PLAT


plasminogen activator,
PLAU


urokinase


plasminogen activator,
PLAUR


urokinase receptor


phospholipase B domain
PLBD2


containing 2


phospholipase C, beta 1
PLCB1


(phosphoinositide-specific)


phospholipase C, beta 3
PLCB3


(phosphatidylinositol-specific)


phospholipase C, beta 4
PLCB4


phospholipase C, delta 1
PLCD1


phospholipase C, delta 3
PLCD3


phospholipase C, epsilon 1
PLCE1


phospholipase C, gamma 1
PLCG1


phospholipase C, gamma 2
PLCG2


(phosphatidylinositol-specific)


phospholipase C-like 1
PLCL1


phospholipase C-like 2
PLCL2


phospholipase D1,
PLD1


phosphatidylcholine-specific


phospholipase D family,
PLD3


member 3


plectin
PLEC


pleckstrin
PLEK


pleckstrin 2
PLEK2


pleckstrin homology domain
PLEKHA1


containing, family A


(phosphoinositide binding


specific) member 1


pleckstrin homology domain
PLEKHA4


containing, family A


(phosphoinositide binding


specific) member 4


pleckstrin homology domain
PLEKHA7


containing, family A member 7


pleckstrin homology domain
PLEKHB2


containing, family B (evectins)


member 2


pleckstrin homology domain
PLEKHF1


containing, family F (with


FYVE domain) member 1


pleckstrin homology domain
PLEKHF2


containing, family F (with


FYVE domain) member 2


pleckstrin homology domain
PLEKHG3


containing, family G (with


RhoGef domain) member 3


pleckstrin homology domain
PLEKHG4B


containing, family G (with


RhoGef domain) member 4B


pleckstrin homology domain
PLEKHO2


containing, family O member 2


plasminogen
PLG


perilipin 2
PLIN2


perilipin 3
PLIN3


procollagen-lysine, 2-
PLOD1


oxoglutarate 5-dioxygenase 1


procollagen-lysine, 2-
PLOD2


oxoglutarate 5-dioxygenase 2


procollagen-lysine, 2-
PLOD3


oxoglutarate 5-dioxygenase 3


proteolipid protein 1
PLP1


proteolipid protein 2 (colonic
PLP2


epithelium-enriched)


pleiotropic regulator 1
PLRG1


plastin 1
PLS1


plastin 3
PLS3


phospholipid scramblase 1
PLSCR1


phospholipid scramblase 3
PLSCR3


phospholipid transfer protein
PLTP


plasmalemma vesicle
PLVAP


associated protein


plexin domain containing 2
PLXDC2


plexin A1
PLXNA1


plexin A2
PLXNA2


plexin A3
PLXNA3


plexin A4
PLXNA4


plexin B1
PLXNB1


plexin B2
PLXNB2


plexin B3
PLXNB3


plexin C1
PLXNC1


plexin D1
PLXND1


peptidase M20 domain
PM20D1


containing 1


peptidase M20 domain
PM20D2


containing 2


premelanosome protein
PMEL


polyamine modulated factor 1
PMFBP1


binding protein 1


phosphomannomutase 2
PMM2


phosphomevalonate kinase
PMVK


polynucleotide kinase 3′-
PNKP


phosphatase


pinin, desmosome associated
PNN


protein


partner of NOB1 homolog (S.
PNO1


cerevisiae)


purine nucleoside
PNP


phosphorylase


patatin-like phospholipase
PNPLA1


domain containing 1


patatin-like phospholipase
PNPLA6


domain containing 6


podocan
PODN


podocalyxin-like
PODXL


protein O-fucosyltransferase 2
POFUT2


polymerase (DNA directed),
POLB


beta


polymerase (DNA directed),
POLD1


delta 1, catalytic subunit


polymerase (DNA directed),
POLD2


delta 2, accessory subunit


polymerase (DNA directed) nu
POLN


polymerase (RNA) I
POLR1C


polypeptide C, 30 kDa


polymerase (RNA) I
POLR1D


polypeptide D, 16 kDa


polymerase (RNA) II (DNA
POLR2A


directed) polypeptide A,


220 kDa


polymerase (RNA) II (DNA
POLR2B


directed) polypeptide B,


140 kDa


polymerase (RNA) II (DNA
POLR2C


directed) polypeptide C,


33 kDa


polymerase (RNA) II (DNA
POLR2E


directed) polypeptide E,


25 kDa


polymerase (RNA) II (DNA
POLR2H


directed) polypeptide H


polymerase (RNA) II (DNA
POLR2L


directed) polypeptide L,


7.6 kDa


polymerase (RNA) III (DNA
POLR3A


directed) polypeptide A,


155 kDa


polymerase (RNA) III (DNA
POLR3B


directed) polypeptide B


polymerase (RNA) III (DNA
POLR3C


directed) polypeptide C


(62 kD)


polymerase (RNA) III (DNA
POLR3E


directed) polypeptide E


(80 kD)


polymerase (RNA)
POLRMT


mitochondrial (DNA directed)


paraoxonase 1
PON1


paraoxonase 3
PON3


processing of precursor 1,
POP1


ribonuclease P/MRP subunit


(S. cerevisiae)


P450 (cytochrome)
POR


oxidoreductase


periostin, osteoblast specific
POSTN


factor


POTE ankyrin domain family,
POTEB2


member B2


POTE ankyrin domain family,
POTEB3


member B3


POTE ankyrin domain family,
POTEE


member E


POTE ankyrin domain family,
POTEF


member F


POTE ankyrin domain family,
POTEI


member I


POTE ankyrin domain family,
POTEJ


member J


POTE ankyrin domain family,
POTEKP


member K, pseudogene


POTE ankyrin domain family,
POTEM


member M


POU class 2 homeobox 2
POU2F2


pyrophosphatase (inorganic) 1
PPA1


pyrophosphatase (inorganic) 2
PPA2


phosphatidic acid
PPAP2A


phosphatase type 2A


phosphatidic acid
PPAP2B


phosphatase type 2B


phosphatidic acid
PPAP2C


phosphatase type 2C


peroxisome proliferator-
PPARG


activated receptor gamma


phosphoribosyl
PPAT


pyrophosphate


amidotransferase


pro-platelet basic protein
PPBP


(chemokine (C-X-C motif)


ligand 7)


protein tyrosine phosphatase,
PPFIA1


receptor type, f polypeptide


(PTPRF), interacting protein


(liprin), alpha 1


protein tyrosine phosphatase,
PPFIA2


receptor type, f polypeptide


(PTPRF), interacting protein


(liprin), alpha 2


protein tyrosine phosphatase,
PPFIA3


receptor type, f polypeptide


(PTPRF), interacting protein


(liprin), alpha 3


PTPRF interacting protein,
PPFIBP1


binding protein 1 (liprin beta 1)


PTPRF interacting protein,
PPFIBP2


binding protein 2 (liprin beta 2)


peptidylprolyl isomerase A
PPIA


(cyclophilin A)


peptidylprolyl isomerase A
PPIAP22


(cyclophilin A) pseudogene 22


peptidylprolyl isomerase A
PPIAP31


(cyclophilin A) pseudogene 31


peptidylprolyl isomerase B
PPIB


(cyclophilin B)


peptidylprolyl isomerase C
PPIC


(cyclophilin C)


peptidylprolyl isomerase D
PPID


peptidylprolyl isomerase E
PPIE


(cyclophilin E)


peptidylprolyl isomerase H
PPIH


(cyclophilin H)


peptidylprolyl isomerase
PPIL1


(cyclophilin)-like 1


diphosphoinositol
PPIP5K2


pentakisphosphate kinase 2


periplakin
PPL


protein phosphatase,
PPM1A


Mg2+/Mn2+ dependent, 1A


protein phosphatase,
PPM1B


Mg2+/Mn2+ dependent, 1B


protein phosphatase,
PPM1G


Mg2+/Mn2+ dependent, 1G


protein phosphatase,
PPM1L


Mg2+/Mn2+ dependent, 1L


protein phosphatase
PPME1


methylesterase 1


protein phosphatase 1,
PPP1CA


catalytic subunit, alpha


isozyme


protein phosphatase 1,
PPP1CB


catalytic subunit, beta


isozyme


protein phosphatase 1,
PPP1CC


catalytic subunit, gamma


isozyme


protein phosphatase 1,
PPP1R12B


regulatory subunit 12B


protein phosphatase 1,
PPP1R21


regulatory subunit 21


protein phosphatase 1,
PPP1R7


regulatory subunit 7


protein phosphatase 2,
PPP2CA


catalytic subunit, alpha


isozyme


protein phosphatase 2,
PPP2CB


catalytic subunit, beta


isozyme


protein phosphatase 2,
PPP2R1A


regulatory subunit A, alpha


protein phosphatase 2,
PPP2R1B


regulatory subunit A, beta


protein phosphatase 2,
PPP2R2A


regulatory subunit B, alpha


protein phosphatase 2,
PPP2R2B


regulatory subunit B, beta


protein phosphatase 2,
PPP2R2C


regulatory subunit B, gamma


protein phosphatase 2,
PPP2R2D


regulatory subunit B, delta


protein phosphatase 2A
PPP2R4


activator, regulatory subunit 4


protein phosphatase 2,
PPP2R5C


regulatory subunit B′, gamma


protein phosphatase 2,
PPP2R5E


regulatory subunit B′, epsilon


isoform


protein phosphatase 3,
PPP3CA


catalytic subunit, alpha


isozyme


protein phosphatase 4,
PPP4C


catalytic subunit


protein phosphatase 4,
PPP4R1


regulatory subunit 1


protein phosphatase 5,
PPP5C


catalytic subunit


protein phosphatase 6,
PPP6C


catalytic subunit


protein phosphatase 6,
PPP6R1


regulatory subunit 1


palmitoyl-protein thioesterase 1
PPT1


prolylcarboxypeptidase
PRCP


(angiotensinase C)


PR domain containing 16
PRDM16


peroxiredoxin 1
PRDX1


peroxiredoxin 2
PRDX2


peroxiredoxin 3
PRDX3


peroxiredoxin 4
PRDX4


peroxiredoxin 5
PRDX5


peroxiredoxin 6
PRDX6


proline/arginine-rich end
PRELP


leucine-rich repeat protein


prolyl endopeptidase
PREP


proteoglycan 4
PRG4


protein kinase, AMP-
PRKAA1


activated, alpha 1 catalytic


subunit


protein kinase, AMP-
PRKAA2


activated, alpha 2 catalytic


subunit


protein kinase, AMP-
PRKAB2


activated, beta 2 non-catalytic


subunit


protein kinase, cAMP-
PRKACA


dependent, catalytic, alpha


protein kinase, cAMP-
PRKACB


dependent, catalytic, beta


protein kinase, AMP-
PRKAG1


activated, gamma 1 non-


catalytic subunit


protein kinase, AMP-
PRKAG2


activated, gamma 2 non-


catalytic subunit


protein kinase, cAMP-
PRKAR1A


dependent, regulatory, type I,


alpha


protein kinase, cAMP-
PRKAR2A


dependent, regulatory, type II,


alpha


protein kinase, cAMP-
PRKAR2B


dependent, regulatory, type II,


beta


protein kinase C, alpha
PRKCA


protein kinase C, beta
PRKCB


protein kinase C, delta
PRKCD


protein kinase C, gamma
PRKCG


protein kinase C, eta
PRKCH


protein kinase C, iota
PRKCI


protein kinase C, theta
PRKCQ


protein kinase C substrate
PRKCSH


80K-H


protein kinase C, zeta
PRKCZ


protein kinase D1
PRKD1


protein kinase D2
PRKD2


protein kinase D3
PRKD3


protein kinase, DNA-
PRKDC


activated, catalytic


polypeptide


protein kinase, interferon-
PRKRA


inducible double stranded


RNA dependent activator


PRKR interacting protein 1
PRKRIP1


(IL11 inducible)


protein kinase, X-linked
PRKX


protein arginine
PRMT1


methyltransferase 1


protein arginine
PRMT5


methyltransferase 5


prion protein
PRNP


protein C receptor, endothelial
PROCR


prominin 1
PROM1


prominin 2
PROM2


protein S (alpha)
PROS1


protein Z, vitamin K-
PROZ


dependent plasma


glycoprotein


pre-mRNA processing factor 19
PRPF19


pre-mRNA processing factor 31
PRPF31


pre-mRNA processing factor 38B
PRPF38B


pre-mRNA processing factor 4
PRPF4


PRP40 pre-mRNA processing
PRPF40A


factor 40 homolog A


(S. cerevisiae)


pre-mRNA processing factor 4B
PRPF4B


pre-mRNA processing factor 6
PRPF6


pre-mRNA processing factor 8
PRPF8


peripherin
PRPH


peripherin 2 (retinal
PRPH2


degeneration, slow)


phosphoribosyl
PRPS1


pyrophosphate synthetase 1


phosphoribosyl
PRPS1L1


pyrophosphate synthetase 1-


like 1


phosphoribosyl
PRPS2


pyrophosphate synthetase 2


phosphoribosyl
PRPSAP1


pyrophosphate synthetase-


associated protein 1


phosphoribosyl
PRPSAP2


pyrophosphate synthetase-


associated protein 2


proline rich 14-like
PRR14L


proline rich 27
PRR27


proline rich 36
PRR36


proline rich 4 (lacrimal)
PRR4


proline-rich coiled-coil 2A
PRRC2A


proline rich Gla (G-
PRRG1


carboxyglutamic acid) 1


proline-rich transmembrane
PRRT3


protein 3


protease, serine, 16 (thymus)
PRSS16


protease, serine, 22
PRSS22


protease, serine, 23
PRSS23


protease, serine, 3
PRSS3


protease, serine, 48
PRSS48


protease, serine, 8
PRSS8


proteinase 3
PRTN3


prosaposin
PSAP


phosphoserine
PSAT1


aminotransferase 1


prostate stem cell antigen
PSCA


PC4 and SFRS1 interacting
PSIP1


protein 1


proteasome (prosome,
PSMA1


macropain) subunit, alpha


type, 1


proteasome (prosome,
PSMA2


macropain) subunit, alpha


type, 2


proteasome (prosome,
PSMA3


macropain) subunit, alpha


type, 3


proteasome (prosome,
PSMA4


macropain) subunit, alpha


type, 4


proteasome (prosome,
PSMA5


macropain) subunit, alpha


type, 5


proteasome (prosome,
PSMA6


macropain) subunit, alpha


type, 6


proteasome (prosome,
PSMA7


macropain) subunit, alpha


type, 7


proteasome (prosome,
PSMA8


macropain) subunit, alpha


type, 8


proteasome (prosome,
PSMB1


macropain) subunit, beta


type, 1


proteasome (prosome,
PSMB10


macropain) subunit, beta


type, 10


proteasome (prosome,
PSMB11


macropain) subunit, beta


type, 11


proteasome (prosome,
PSMB2


macropain) subunit, beta


type, 2


proteasome (prosome,
PSMB3


macropain) subunit, beta


type, 3


proteasome (prosome,
PSMB4


macropain) subunit, beta


type, 4


proteasome (prosome,
PSMB5


macropain) subunit, beta


type, 5


proteasome (prosome,
PSMB6


macropain) subunit, beta


type, 6


proteasome (prosome,
PSMB7


macropain) subunit, beta


type, 7


proteasome (prosome,
PSMB8


macropain) subunit, beta


type, 8


proteasome (prosome,
PSMB9


macropain) subunit, beta


type, 9


proteasome (prosome,
PSMC1


macropain) 26S subunit,


ATPase, 1


proteasome (prosome,
PSMC2


macropain) 26S subunit,


ATPase, 2


proteasome (prosome,
PSMC3


macropain) 26S subunit,


ATPase, 3


proteasome (prosome,
PSMC4


macropain) 26S subunit,


ATPase, 4


proteasome (prosome,
PSMC5


macropain) 26S subunit,


ATPase, 5


proteasome (prosome,
PSMC6


macropain) 26S subunit,


ATPase, 6


proteasome (prosome,
PSMD1


macropain) 26S subunit, non-


ATPase, 1


proteasome (prosome,
PSMD10


macropain) 26S subunit, non-


ATPase, 10


proteasome (prosome,
PSMD11


macropain) 26S subunit, non-


ATPase, 11


proteasome (prosome,
PSMD12


macropain) 26S subunit, non-


ATPase, 12


proteasome (prosome,
PSMD13


macropain) 26S subunit, non-


ATPase, 13


proteasome (prosome,
PSMD14


macropain) 26S subunit, non-


ATPase, 14


proteasome (prosome,
PSMD2


macropain) 26S subunit, non-


ATPase, 2


proteasome (prosome,
PSMD3


macropain) 26S subunit, non-


ATPase, 3


proteasome (prosome,
PSMD4


macropain) 26S subunit, non-


ATPase, 4


proteasome (prosome,
PSMD5


macropain) 26S subunit, non-


ATPase, 5


proteasome (prosome,
PSMD6


macropain) 26S subunit, non-


ATPase, 6


proteasome (prosome,
PSMD7


macropain) 26S subunit, non-


ATPase, 7


proteasome (prosome,
PSMD8


macropain) 26S subunit, non-


ATPase, 8


proteasome (prosome,
PSMD9


macropain) 26S subunit, non-


ATPase, 9


proteasome (prosome,
PSME1


macropain) activator subunit 1


(PA28 alpha)


proteasome (prosome,
PSME2


macropain) activator subunit 2


(PA28 beta)


proteasome (prosome,
PSME3


macropain) activator subunit 3


(PA28 gamma; Ki)


proteasome (prosome,
PSME4


macropain) activator subunit 4


proteasome (prosome,
PSMG1


macropain) assembly


chaperone 1


proteasome (prosome,
PSMG2


macropain) assembly


chaperone 2


paraspeckle component 1
PSPC1


phosphoserine phosphatase
PSPH


proline-serine-threonine
PSTPIP1


phosphatase interacting


protein 1


proline-serine-threonine
PSTPIP2


phosphatase interacting


protein 2


polypyrimidine tract binding
PTBP1


protein 1


polypyrimidine tract binding
PTBP3


protein 3


phosphotriesterase related
PTER


prostaglandin E synthase 2
PTGES2


prostaglandin E synthase 3
PTGES3


(cytosolic)


PTGES3L-AARSD1
PTGES3L-AARSD1


readthrough


prostaglandin F2 receptor
PTGFRN


inhibitor


prostaglandin reductase 1
PTGR1


prostaglandin reductase 2
PTGR2


prostaglandin-endoperoxide
PTGS1


synthase 1 (prostaglandin


G/H synthase and


cyclooxygenase)


protein tyrosine kinase 2
PTK2


protein tyrosine kinase 2 beta
PTK2B


protein tyrosine kinase 7
PTK7


(inactive)


prothymosin, alpha
PTMA


parathymosin
PTMS


protein tyrosine phosphatase
PTP4A1


type IVA, member 1


protein tyrosine phosphatase
PTP4A2


type IVA, member 2


protein tyrosine phosphatase,
PTPN1


non-receptor type 1


protein tyrosine phosphatase,
PTPN11


non-receptor type 11


protein tyrosine phosphatase,
PTPN13


non-receptor type 13 (APO-


1/CD95 (Fas)-associated


phosphatase)


protein tyrosine phosphatase,
PTPN18


non-receptor type 18 (brain-


derived)


protein tyrosine phosphatase,
PTPN2


non-receptor type 2


protein tyrosine phosphatase,
PTPN23


non-receptor type 23


protein tyrosine phosphatase,
PTPN6


non-receptor type 6


protein tyrosine phosphatase,
PTPN7


non-receptor type 7


protein tyrosine phosphatase,
PTPN9


non-receptor type 9


protein tyrosine phosphatase,
PTPRA


receptor type, A


protein tyrosine phosphatase,
PTPRB


receptor type, B


protein tyrosine phosphatase,
PTPRC


receptor type, C


protein tyrosine phosphatase,
PTPRCAP


receptor type, C-associated


protein


protein tyrosine phosphatase,
PTPRF


receptor type, F


protein tyrosine phosphatase,
PTPRG


receptor type, G


protein tyrosine phosphatase,
PTPRJ


receptor type, J


protein tyrosine phosphatase,
PTPRK


receptor type, K


protein tyrosine phosphatase,
PTPRO


receptor type, O


protein tyrosine phosphatase,
PTPRS


receptor type, S


polymerase I and transcript
PTRF


release factor


peptidyl-tRNA hydrolase 2
PTRH2


pituitary tumor-transforming 1
PTTG1IP


interacting protein


pentraxin 3, long
PTX3


poly-U binding splicing factor
PUF60


60 KDa


purine-rich element binding
PURA


protein A


purine-rich element binding
PURB


protein B


pseudouridylate synthase 1
PUS1


poliovirus receptor
PVR


poliovirus receptor-related 2
PVRL2


(herpesvirus entry mediator B)


peroxidasin
PXDN


paxillin
PXN


pyrroline-5-carboxylate
PYCRL


reductase-like


phosphorylase, glycogen;
PYGB


brain


phosphorylase, glycogen, liver
PYGL


phosphorylase, glycogen,
PYGM


muscle


pregnancy-zone protein
PZP


glutaminyl-tRNA synthetase
QARS


quinoid dihydropteridine
QDPR


reductase


glutaminyl-peptide
QPCT


cyclotransferase


glutaminyl-peptide
QPCTL


cyclotransferase-like


quinolinate
QPRT


phosphoribosyltransferase


quiescin Q6 sulfhydryl
QSOX1


oxidase 1


quiescin Q6 sulfhydryl
QSOX2


oxidase 2


queuine tRNA-
QTRT1


ribosyltransferase 1


RAB10, member RAS
RAB10


oncogene family


RAB11A, member RAS
RAB11A


oncogene family


RAB11B, member RAS
RAB11B


oncogene family


RAB11 family interacting
RAB11FIP1


protein 1 (class I)


RAB12, member RAS
RAB12


oncogene family


RAB13, member RAS
RAB13


oncogene family


RAB14, member RAS
RAB14


oncogene family


RAB15, member RAS
RAB15


oncogene family


RAB17, member RAS
RAB17


oncogene family


RAB18, member RAS
RAB18


oncogene family


RAB19, member RAS
RAB19


oncogene family


RAB1A, member RAS
RAB1A


oncogene family


RAB1B, member RAS
RAB1B


oncogene family


RAB1C, member RAS
RAB1C


oncogene family pseudogene


RAB20, member RAS
RAB20


oncogene family


RAB21, member RAS
RAB21


oncogene family


RAB22A, member RAS
RAB22A


oncogene family


RAB23, member RAS
RAB23


oncogene family


RAB25, member RAS
RAB25


oncogene family


RAB27A, member RAS
RAB27A


oncogene family


RAB27B, member RAS
RAB27B


oncogene family


RAB29, member RAS
RAB29


oncogene family


RAB2A, member RAS
RAB2A


oncogene family


RAB2B, member RAS
RAB2B


oncogene family


RAB30, member RAS
RAB30


oncogene family


RAB32, member RAS
RAB32


oncogene family


RAB33A, member RAS
RAB33A


oncogene family


RAB33B, member RAS
RAB33B


oncogene family


RAB34, member RAS
RAB34


oncogene family


RAB35, member RAS
RAB35


oncogene family


RAB37, member RAS
RAB37


oncogene family


RAB38, member RAS
RAB38


oncogene family


RAB39A, member RAS
RAB39A


oncogene family


RAB39B, member RAS
RAB39B


oncogene family


RAB3A, member RAS
RAB3A


oncogene family


RAB3B, member RAS
RAB3B


oncogene family


RAB3C, member RAS
RAB3C


oncogene family


RAB3D, member RAS
RAB3D


oncogene family


RAB3 GTPase activating
RAB3GAP1


protein subunit 1 (catalytic)


RAB3 GTPase activating
RAB3GAP2


protein subunit 2 (non-


catalytic)


RAB43, member RAS
RAB43


oncogene family


RAB4A, member RAS
RAB4A


oncogene family


RAB4B, member RAS
RAB4B


oncogene family


RAB5A, member RAS
RAB5A


oncogene family


RAB5B, member RAS
RAB5B


oncogene family


RAB5C, member RAS
RAB5C


oncogene family


RAB6A, member RAS
RAB6A


oncogene family


RAB6B, member RAS
RAB6B


oncogene family


RAB6C, member RAS
RAB6C


oncogene family


RAB7A, member RAS
RAB7A


oncogene family


RAB8A, member RAS
RAB8A


oncogene family


RAB8B, member RAS
RAB8B


oncogene family


RAB9A, member RAS
RAB9A


oncogene family


RAB9B, member RAS
RAB9B


oncogene family


RAB GTPase activating
RABGAP1


protein 1


ras-related C3 botulinum toxin
RAC1


substrate 1 (rho family, small


GTP binding protein Rac1)


ras-related C3 botulinum toxin
RAC2


substrate 2 (rho family, small


GTP binding protein Rac2)


ras-related C3 botulinum toxin
RAC3


substrate 3 (rho family, small


GTP binding protein Rac3)


Rac GTPase activating
RACGAP1


protein 1


RAD21 homolog (S. pombe)
RAD21


RAD23 homolog B
RAD23B


(S. cerevisiae)


RAD50 homolog
RAD50


(S. cerevisiae)


ribonucleic acid export 1
RAE1


Raf-1 proto-oncogene,
RAF1


serine/threonine kinase


retinoic acid induced 14
RAI14


v-ral simian leukemia viral
RALA


oncogene homolog A (ras


related)


v-ral simian leukemia viral
RALB


oncogene homolog B


Ral GTPase activating
RALGAPB


protein, beta subunit (non-


catalytic)


RALY heterogeneous nuclear
RALY


ribonucleoprotein


RALY RNA binding protein-
RALYL


like


RAN, member RAS oncogene
RAN


family


RAN binding protein 1
RANBP1


RAN binding protein 10
RANBP10


RAN binding protein 2
RANBP2


RAN binding protein 3
RANBP3


RAN binding protein 9
RANBP9


Ran GTPase activating
RANGAP1


protein 1


RAN, member RAS oncogene
RANP1


family pseudogene 1


RAP1 A, member of RAS
RAP1A


oncogene family


RAP1B, member of RAS
RAP1B


oncogene family


RAP1B, member of RAS
RAP1BL


oncogene family pseudogene


RAP1 GTPase activating
RAP1GAP2


protein 2


RAP1, GTP-GDP dissociation
RAP1GDS1


stimulator 1


RAP2A, member of RAS
RAP2A


oncogene family


RAP2B, member of RAS
RAP2B


oncogene family


RAP2C, member of RAS
RAP2C


oncogene family


Rap guanine nucleotide
RAPGEF1


exchange factor (GEF) 1


Rap guanine nucleotide
RAPGEF3


exchange factor (GEF) 3


Rap guanine nucleotide
RAPGEF6


exchange factor (GEF) 6


retinoic acid receptor, alpha
RARA


retinoic acid receptor
RARRES1


responder (tazarotene


induced) 1


arginyl-tRNA synthetase
RARS


RAS p21 protein activator
RASA1


(GTPase activating protein) 1


RAS p21 protein activator 2
RASA2


RAS p21 protein activator 3
RASA3


RAS p21 protein activator 4
RASA4


RAS p21 protein activator 4C,
RASA4CP


pseudogene


RAS protein activator like 1
RASAL1


(GAP1 like)


RAS protein activator like 3
RASAL3


RAS guanyl releasing protein 2
RASGRP2


(calcium and DAG-regulated)


Ras association (RalGDS/AF-6)
RASSF2


domain family member 2


RB1-inducible coiled-coil 1
RB1CC1


retinoblastoma binding protein 4
RBBP4


retinoblastoma binding protein 6
RBBP6


retinoblastoma binding protein 7
RBBP7


retinoblastoma-like 2
RBL2


RNA binding motif protein 12
RBM12


RNA binding motif protein 14
RBM14


RBM14-RBM4 readthrough
RBM14-RBM4


RNA binding motif protein 19
RBM19


RNA binding motif protein 22
RBM22


RNA binding motif protein 25
RBM25


RNA binding motif protein 28
RBM28


RNA binding motif (RNP1,
RBM3


RRM) protein 3


RNA binding motif protein 39
RBM39


RNA binding motif protein 4
RBM4


RNA binding motif protein 6
RBM6


RNA binding motif protein 8A
RBM8A


RNA binding motif protein, X-
RBMX


linked


retinol binding protein 1,
RBP1


cellular


retinol binding protein 4,
RBP4


plasma


retinol binding protein 5,
RBP5


cellular


ring-box 1, E3 ubiquitin
RBX1


protein ligase


ring finger and CCCH-type
RC3H1


domains 1


regulator of chromosome
RCC1


condensation 1


regulator of chromosome
RCC2


condensation 2


RNA terminal phosphate
RCL1


cyclase-like 1


reticulocalbin 1, EF-hand
RCN1


calcium binding domain


reticulocalbin 2, EF-hand
RCN2


calcium binding domain


REST corepressor 2
RCOR2


retinol dehydrogenase 11 (all-
RDH11


trans/9-cis/11-cis)


retinol dehydrogenase 14 (all-
RDH14


trans/9-cis/11-cis)


retinol dehydrogenase 5 (11-
RDH5


cis/9-cis)


radixin
RDX


RecQ helicase-like
RECQL


receptor accessory protein 5
REEP5


regenerating islet-derived
REG4


family, member 4


v-rel avian
REL


reticuloendotheliosis viral


oncogene homolog


RELT-like 1
RELL1


reelin
RELN


renin binding protein
RENBP


retention in endoplasmic
RER1


reticulum sorting receptor 1


ret proto-oncogene
RET


resistin
RETN


replication factor C (activator
RFC1


1) 1, 145 kDa


replication factor C (activator
RFC2


1) 2, 40 kDa


replication factor C (activator
RFC3


1) 3, 38 kDa


replication factor C (activator
RFC4


1) 4, 37 kDa


replication factor C (activator
RFC5


1) 5, 36.5 kDa


ring finger and FYVE-like
RFFL


domain containing E3


ubiquitin protein ligase


raftlin, lipid raft linker 1
RFTN1


regucalcin
RGN


regulator of G-protein
RGS10


signaling 10


regulator of G-protein
RGS16


signaling 16


regulator of G-protein
RGS18


signaling 18


regulator of G-protein
RGS20


signaling 20


regulator of G-protein
RGS3


signaling 3


regulator of G-protein
RGS6


signaling 6


rhomboid 5 homolog 1
RHBDF1


(Drosophila)


rhomboid 5 homolog 2
RHBDF2


(Drosophila)


Rh family, C glycoprotein
RHCG


Ras homolog enriched in
RHEB


brain


ras homolog family member A
RHOA


ras homolog family member B
RHOB


Rho-related BTB domain
RHOBTB3


containing 3


ras homolog family member C
RHOC


ras homolog family member F
RHOF


(in filopodia)


ras homolog family member G
RHOG


ras homolog family member Q
RHOQ


rhophilin, Rho GTPase
RHPN2


binding protein 2


RIC8 guanine nucleotide
RIC8A


exchange factor A


RIC8 guanine nucleotide
RIC8B


exchange factor B


RPTOR independent
RICTOR


companion of MTOR,


complex 2


RIO kinase 3
RIOK3


RGD motif, leucine rich
RLTPR


repeats, tropomodulin domain


and proline-rich containing


regulator of microtubule
RMDN2


dynamics 2


required for meiotic nuclear
RMND5A


division 5 homolog A


(S. cerevisiae)


ribonuclease, RNase A family, 2
RNASE2


(liver, eosinophil-derived


neurotoxin)


ribonuclease, RNase A family, 4
RNASE4


ribonuclease, RNase A family, 7
RNASE7


ribonuclease H2, subunit A
RNASEH2A


RNF103-CHMP3 readthrough
RNF103-CHMP3


ring finger protein 11
RNF11


ring finger protein 123
RNF123


ring finger protein 149
RNF149


ring finger protein 20, E3
RNF20


ubiquitin protein ligase


ring finger protein 213
RNF213


ring finger protein 40, E3
RNF40


ubiquitin protein ligase


RNA guanylyltransferase and
RNGTT


5′-phosphatase


ribonuclease/angiogenin
RNH1


inhibitor 1


arginyl aminopeptidase
RNPEP


(aminopeptidase B)


RNA binding protein S1,
RNPS1


serine-rich domain


roundabout, axon guidance
ROBO2


receptor, homolog 2


(Drosophila)


Rho-associated, coiled-coil
ROCK1


containing protein kinase 1


Rho-associated, coiled-coil
ROCK2


containing protein kinase 2


rogdi homolog (Drosophila)
ROGDI


receptor tyrosine kinase-like
ROR1


orphan receptor 1


retinitis pigmentosa 2 (X-
RP2


linked recessive)


replication protein A1, 70 kDa
RPA1


replication protein A2, 32 kDa
RPA2


RPGRIP1-like
RPGRIP1L


ribose 5-phosphate isomerase A
RPIA


ribosomal protein L10
RPL10


ribosomal protein L10a
RPL10A


ribosomal protein L10a
RPL10AP6


pseudogene 6


ribosomal protein L10a
RPL10AP9


pseudogene 9


ribosomal protein L10-like
RPL10L


ribosomal protein L11
RPL11


ribosomal protein L12
RPL12


ribosomal protein L12
RPL12P14


pseudogene 14


ribosomal protein L12
RPL12P19


pseudogene 19


ribosomal protein L12
RPL12P2


pseudogene 2


ribosomal protein L12
RPL12P32


pseudogene 32


ribosomal protein L12
RPL12P35


pseudogene 35


ribosomal protein L12
RPL12P6


pseudogene 6


ribosomal protein L13
RPL13


ribosomal protein L13a
RPL13A


ribosomal protein L14
RPL14


ribosomal protein L15
RPL15


ribosomal protein L15
RPL15P17


pseudogene 17


ribosomal protein L15
RPL15P18


pseudogene 18


ribosomal protein L15
RPL15P22


pseudogene 22


ribosomal protein L15
RPL15P3


pseudogene 3


ribosomal protein L15
RPL15P7


pseudogene 7


ribosomal protein L17
RPL17


RPL17-C18orf32 readthrough
RPL17-C18orf32


ribosomal protein L18
RPL18


ribosomal protein L18a
RPL18A


ribosomal protein L19
RPL19


ribosomal protein L21
RPL21


ribosomal protein L22
RPL22


ribosomal protein L22-like 1
RPL22L1


ribosomal protein L23
RPL23


ribosomal protein L23a
RPL23A


ribosomal protein L23a
RPL23AP32


pseudogene 32


ribosomal protein L23a
RPL23AP42


pseudogene 42


ribosomal protein L23
RPL23P6


pseudogene 6


ribosomal protein L24
RPL24


ribosomal protein L26
RPL26


ribosomal protein L26-like 1
RPL26L1


ribosomal protein L27
RPL27


ribosomal protein L27a
RPL27A


ribosomal protein L28
RPL28


ribosomal protein L29
RPL29


ribosomal protein L29
RPL29P11


pseudogene 11


ribosomal protein L29
RPL29P12


pseudogene 12


ribosomal protein L29
RPL29P26


pseudogene 26


ribosomal protein L29
RPL29P9


pseudogene 9


ribosomal protein L3
RPL3


ribosomal protein L30
RPL30


ribosomal protein L31
RPL31


ribosomal protein L32
RPL32


ribosomal protein L34
RPL34


ribosomal protein L35
RPL35


ribosomal protein L35a
RPL35A


ribosomal protein L36
RPL36


ribosomal protein L37a
RPL37A


ribosomal protein L38
RPL38


ribosomal protein L4
RPL4


ribosomal protein L5
RPL5


ribosomal protein L6
RPL6


ribosomal protein L7
RPL7


ribosomal protein L7a
RPL7A


ribosomal protein L8
RPL8


ribosomal protein L9
RPL9


ribosomal protein, large, PO
RPLP0


ribosomal protein, large, P0
RPLP0P2


pseudogene 2


ribosomal protein, large, PO
RPLP0P3


pseudogene 3


ribosomal protein, large, PO
RPLP0P6


pseudogene 6


ribosomal protein, large, P1
RPLP1


ribosomal protein, large, P2
RPLP2


ribophorin I
RPN1


ribophorin II
RPN2


ribonuclease P/MRP 30 kDa
RPP30


subunit


regulation of nuclear pre-
RPRD1B


mRNA domain containing 1B


ribosomal protein S10
RPS10


ribosomal protein S10
RPS10P11


pseudogene 11


ribosomal protein S10
RPS10P13


pseudogene 13


ribosomal protein S10
RPS10P22


pseudogene 22


ribosomal protein S10
RPS10P4


pseudogene 4


ribosomal protein S10
RPS10P7


pseudogene 7


ribosomal protein S11
RPS11


ribosomal protein S12
RPS12


ribosomal protein S13
RPS13


ribosomal protein S14
RPS14


ribosomal protein S15
RPS15


ribosomal protein S15a
RPS15A


ribosomal protein S16
RPS16


ribosomal protein S16
RPS16P1


pseudogene 1


ribosomal protein S16
RPS16P10


pseudogene 10


ribosomal protein S17
RPS17


ribosomal protein S18
RPS18


ribosomal protein S18
RPS18P12


pseudogene 12


ribosomal protein S18
RPS18P5


pseudogene 5


ribosomal protein S19
RPS19


ribosomal protein S2
RPS2


ribosomal protein S20
RPS20


ribosomal protein S21
RPS21


ribosomal protein S23
RPS23


ribosomal protein S24
RPS24


ribosomal protein S25
RPS25


ribosomal protein S26
RPS26


ribosomal protein S27
RPS27


ribosomal protein S27a
RPS27A


ribosomal protein S27a
RPS27AP11


pseudogene 11


ribosomal protein S27a
RPS27AP12


pseudogene 12


ribosomal protein S27a
RPS27AP16


pseudogene 16


ribosomal protein S27-like
RPS27L


ribosomal protein S28
RPS28


ribosomal protein S29
RPS29


ribosomal protein S2
RPS2P11


pseudogene 11


ribosomal protein S2
RPS2P12


pseudogene 12


ribosomal protein S2
RPS2P17


pseudogene 17


ribosomal protein S2
RPS2P20


pseudogene 20


ribosomal protein S2
RPS2P5


pseudogene 5


ribosomal protein S2
RPS2P51


pseudogene 51


ribosomal protein S2
RPS2P55


pseudogene 55


ribosomal protein S2
RPS2P8


pseudogene 8


ribosomal protein S3
RPS3


ribosomal protein S3A
RPS3A


ribosomal protein S3
RPS3P3


pseudogene 3


ribosomal protein S4, X-linked
RPS4X


ribosomal protein S4X
RPS4XP13


pseudogene 13


ribosomal protein S4X
RPS4XP6


pseudogene 6


ribosomal protein S4, Y-linked 1
RPS4Y1


ribosomal protein S4, Y-linked 2
RPS4Y2


ribosomal protein S5
RPS5


ribosomal protein S6
RPS6


ribosomal protein S6 kinase,
RPS6KA1


90 kDa, polypeptide 1


ribosomal protein S6 kinase,
RPS6KA3


90 kDa, polypeptide 3


ribosomal protein S6 kinase,
RPS6KA4


90 kDa, polypeptide 4


ribosomal protein S6 kinase,
RPS6KA5


90 kDa, polypeptide 5


ribosomal protein S6 kinase,
RPS6KA6


90 kDa, polypeptide 6


ribosomal protein S7
RPS7


ribosomal protein S8
RPS8


ribosomal protein S9
RPS9


ribosomal protein SA
RPSA


ribosomal protein SA
RPSAP12


pseudogene 12


ribosomal protein SA
RPSAP15


pseudogene 15


ribosomal protein SA
RPSAP18


pseudogene 18


ribosomal protein SA
RPSAP19


pseudogene 19


ribosomal protein SA
RPSAP29


pseudogene 29


ribosomal protein SA
RPSAP58


pseudogene 58


ribosomal protein SA
RPSAP61


pseudogene 61


ribosomal protein SA
RPSAP8


pseudogene 8


ribosomal protein SA
RPSAP9


pseudogene 9


repetin
RPTN


regulatory associated protein
RPTOR


of MTOR, complex 1


RCD1 required for cell
RQCD1


differentiation1 homolog


(S. pombe)


Ras-related GTP binding A
RRAGA


Ras-related GTP binding B
RRAGB


Ras-related GTP binding C
RRAGC


Ras-related GTP binding D
RRAGD


related RAS viral (r-ras)
RRAS


oncogene homolog


related RAS viral (r-ras)
RRAS2


oncogene homolog 2


ras responsive element
RREB1


binding protein 1


ribonucleotide reductase M1
RRM1


ribonucleotide reductase M2
RRM2


ribosomal RNA processing 12
RRP12


homolog (S. cerevisiae)


ribosomal RNA processing 1B
RRP1B


ribosomal RNA processing 9,
RRP9


small subunit (SSU)


processome component,


homolog (yeast)


RRS1 ribosome biogenesis
RRS1


regulator homolog (S.


cerevisiae)


ribosomal L1 domain
RSL1D1


containing 1


ring finger and SPRY domain
RSPRY1


containing 1


Ras suppressor protein 1
RSU1


RNA 3′-terminal phosphate
RTCA


cyclase


RNA 2′,3′-cyclic phosphate
RTCB


and 5′-OH ligase


regulator of telomere
RTEL1


elongation helicase 1


rhotekin
RTKN


retrotransposon-like 1
RTL1


reticulon 2
RTN2


reticulon 3
RTN3


reticulon 4
RTN4


reticulon 4 receptor
RTN4R


RUN and FYVE domain
RUFY1


containing 1


RUN and SH3 domain
RUSC2


containing 2


RuvB-like AAA ATPase 1
RUVBL1


RuvB-like AAA ATPase 2
RUVBL2


ryanodine receptor 1
RYR1


(skeletal)


ryanodine receptor 2 (cardiac)
RYR2


S100 calcium binding protein A10
S100A10


S100 calcium binding protein A11
S100A11


S100 calcium binding protein A11
S100A11P1


pseudogene 1


S100 calcium binding protein A13
S100A13


S100 calcium binding protein A14
S100A14


S100 calcium binding protein A16
S100A16


S100 calcium binding protein A4
S100A4


S100 calcium binding protein A6
S100A6


S100 calcium binding protein A7
S100A7


S100 calcium binding protein A7A
S100A7A


S100 calcium binding protein A8
S100A8


S100 calcium binding protein A9
S100A9


S100 calcium binding protein P
S100P


S100P binding protein
S100PBP


serum amyloid A1
SAA1


serum amyloid A2
SAA2


serum amyloid A4, constitutive
SAA4


SAC1 suppressor of actin
SACM1L


mutations 1-like (yeast)


sacsin molecular chaperone
SACS


SUMO1 activating enzyme
SAE1


subunit 1


S-antigen; retina and pineal
SAG


gland (arrestin)


spalt-like transcription factor 1
SALL1


sterile alpha motif domain
SAMD4A


containing 4A


sterile alpha motif domain
SAMD9


containing 9


sterile alpha motif domain
SAMD9L


containing 9-like


SAM domain and HD domain 1
SAMHD1


SAMM50 sorting and
SAMM50


assembly machinery


component


Sin3A-associated protein,
SAP18


18 kDa


Sin3A-associated protein,
SAP30


30 kDa


secretion associated, Ras
SAR1A


related GTPase 1A


secretion associated, Ras
SAR1B


related GTPase 1B


seryl-tRNA synthetase
SARS


squamous cell carcinoma
SART3


antigen recognized by T cells 3


spindle assembly 6 homolog
SASS6


(C. elegans)


spermidine/spermine N1-
SAT2


acetyltransferase family


member 2


SATB homeobox 1
SATB1


Shwachman-Bodian-Diamond
SBDS


syndrome


SET binding factor 1
SBF1


suprabasin
SBSN


secretory carrier membrane
SCAMP1


protein 1


secretory carrier membrane
SCAMP2


protein 2


secretory carrier membrane
SCAMP3


protein 3


secretory carrier membrane
SCAMP4


protein 4


scavenger receptor class B,
SCARB1


member 1


scavenger receptor class B,
SCARB2


member 2


saccharopine dehydrogenase
SCCPDH


(putative)


sciellin
SCEL


sec1 family domain containing 1
SCFD1


single-chain Fv fragment
SCFV


secretoglobin, family 2A,
SCGB2A1


member 1


secretoglobin, family 3A,
SCGB3A1


member 1


scinderin
SCIN


sodium channel, voltage
SCN10A


gated, type X alpha subunit


sodium channel, voltage
SCN11A


gated, type XI alpha subunit


sodium channel, voltage
SCN5A


gated, type V alpha subunit


short coiled-coil protein
SCOC


serine carboxypeptidase 1
SCPEP1


scribbled planar cell polarity
SCRIB


protein


secernin 1
SCRN1


secernin 2
SCRN2


scratch family zinc finger 1
SCRT1


SCY1-like 1 (S. cerevisiae)
SCYL1


SCY1-like 2 (S. cerevisiae)
SCYL2


syndecan 1
SDC1


syndecan 2
SDC2


syndecan 4
SDC4


syndecan binding protein
SDCBP


(syntenin)


syndecan binding protein
SDCBP2


(syntenin) 2


stromal cell-derived factor 2-
SDF2L1


like 1


stromal cell derived factor 4
SDF4


succinate dehydrogenase
SDHA


complex, subunit A,


flavoprotein (Fp)


sidekick cell adhesion
SDK2


molecule 2


serum deprivation response
SDPR


SEC11 homolog A
SEC11A


(S. cerevisiae)


SEC13 homolog
SEC13


(S. cerevisiae)


SEC14-like 4 (S. cerevisiae)
SEC14L4


SEC16 homolog A
SEC16A


(S. cerevisiae)


SEC22 vesicle trafficking
SEC22B


protein homolog B


(S. cerevisiae)


(gene/pseudogene)


Sec23 homolog A
SEC23A


(S. cerevisiae)


Sec23 homolog B
SEC23B


(S. cerevisiae)


SEC23 interacting protein
SEC23IP


SEC24 family member A
SEC24A


SEC24 family member B
SEC24B


SEC24 family member C
SEC24C


SEC24 family member D
SEC24D


SEC31 homolog A
SEC31A


(S. cerevisiae)


Sec61 beta subunit
SEC61B


secreted and transmembrane 1
SECTM1


SEH1-like (S. cerevisiae)
SEH1L


selenium binding protein 1
SELENBP1


selectin L
SELL


selectin P (granule membrane
SELP


protein 140 kDa, antigen


CD62)


selectin P ligand
SELPLG


sema domain,
SEMA3C


immunoglobulin domain (Ig),


short basic domain, secreted,


(semaphorin) 3C


sema domain,
SEMA3F


immunoglobulin domain (Ig),


short basic domain, secreted,


(semaphorin) 3F


sema domain,
SEMA3G


immunoglobulin domain (Ig),


short basic domain, secreted,


(semaphorin) 3G


sema domain,
SEMA4C


immunoglobulin domain (Ig),


transmembrane domain (TM)


and short cytoplasmic


domain, (semaphorin) 4C


sema domain, seven
SEMA5A


thrombospondin repeats (type


1 and type 1-like),


transmembrane domain (TM)


and short cytoplasmic


domain, (semaphorin) 5A


semenogelin I
SEMG1


semenogelin II
SEMG2


selenoprotein P, plasma, 1
SEPP1


septin 1
SEPT1


septin 10
SEPT10


septin 11
SEPT11


septin 2
SEPT2


septin 5
SEPT5


septin 6
SEPT6


septin 7
SEPT7


septin 8
SEPT8


septin 9
SEPT9


SERPINE1 mRNA binding
SERBP1


protein 1


serine incorporator 1
SERINC1


serine incorporator 2
SERINC2


serine incorporator 3
SERINC3


serine incorporator 5
SERINC5


serpin peptidase inhibitor,
SERPINA1


clade A (alpha-1


antiproteinase, antitrypsin),


member 1


serpin peptidase inhibitor,
SERPINA3


clade A (alpha-1


antiproteinase, antitrypsin),


member 3


serpin peptidase inhibitor,
SERPINA4


clade A (alpha-1


antiproteinase, antitrypsin),


member 4


serpin peptidase inhibitor,
SERPINA5


clade A (alpha-1


antiproteinase, antitrypsin),


member 5


serpin peptidase inhibitor,
SERPINA7


clade A (alpha-1


antiproteinase, antitrypsin),


member 7


serpin peptidase inhibitor,
SERPINB1


clade B (ovalbumin), member 1


serpin peptidase inhibitor,
SERPINB12


clade B (ovalbumin), member 12


serpin peptidase inhibitor,
SERPINB13


clade B (ovalbumin), member 13


serpin peptidase inhibitor,
SERPINB3


clade B (ovalbumin), member 3


serpin peptidase inhibitor,
SERPINB4


clade B (ovalbumin), member 4


serpin peptidase inhibitor,
SERPINB5


clade B (ovalbumin), member 5


serpin peptidase inhibitor,
SERPINB6


clade B (ovalbumin), member 6


serpin peptidase inhibitor,
SERPINB9


clade B (ovalbumin), member 9


serpin peptidase inhibitor,
SERPINC1


clade C (antithrombin),


member 1


serpin peptidase inhibitor,
SERPIND1


clade D (heparin cofactor),


member 1


serpin peptidase inhibitor,
SERPINE1


clade E (nexin, plasminogen


activator inhibitor type 1),


member 1


serpin peptidase inhibitor,
SERPINE2


clade E (nexin, plasminogen


activator inhibitor type 1),


member 2


serpin peptidase inhibitor,
SERPINF1


clade F (alpha-2 antiplasmin,


pigment epithelium derived


factor), member 1


serpin peptidase inhibitor,
SERPINF2


clade F (alpha-2 antiplasmin,


pigment epithelium derived


factor), member 2


serpin peptidase inhibitor,
SERPING1


clade G (C1 inhibitor),


member 1


serpin peptidase inhibitor,
SERPINH1


clade H (heat shock protein


47), member 1, (collagen


binding protein 1)


SEC14 and spectrin domains 1
SESTD1


SET nuclear proto-oncogene
SET


SET domain containing 4
SETD4


splicing factor 3a, subunit 1,
SF3A1


120 kDa


splicing factor 3a, subunit 2,
SF3A2


66 kDa


splicing factor 3a, subunit 3,
SF3A3


60 kDa


splicing factor 3b, subunit 1,
SF3B1


155 kDa


splicing factor 3b, subunit 2,
SF3B2


145 kDa


splicing factor 3b, subunit 3,
SF3B3


130 kDa


splicing factor 3b, subunit 4,
SF3B4


49 kDa


splicing factor 3b, subunit 6,
SF3B6


14 kDa


Sfi1 homolog, spindle
SFI1


assembly associated (yeast)


Scm-like with four mbt
SFMBT1


domains 1


stratifin
SFN


splicing factor
SFPQ


proline/glutamine-rich


secreted frizzled-related
SFRP1


protein 1


secreted frizzled-related
SFRP4


protein 4


SFT2 domain containing 2
SFT2D2


sideroflexin 1
SFXN1


sphingosine-1-phosphate
SGPL1


lyase 1


small glutamine-rich
SGTA


tetratricopeptide repeat


(TPR)-containing, alpha


SH2B adaptor protein 1
SH2B1


SH2 domain containing 1A
SH2D1A


SH3 domain binding
SH3BGRL


glutamate-rich protein like


SH3 domain binding
SH3BGRL3


glutamate-rich protein like 3


SH3-domain binding protein 4
SH3BP4


SH3-domain GRB2-like 1
SH3GL1


SH3-domain GRB2-like
SH3GLB1


endophilin B1


SH3-domain kinase binding
SH3KBP1


protein 1


SH3 and multiple ankyrin
SHANK3


repeat domains 3


sex hormone-binding globulin
SHBG


SHC (Src homology 2 domain
SHC1


containing) transforming


protein 1


SHC (Src homology 2 domain
SHC2


containing) transforming


protein 2


shisa family member 2
SHISA2


serine
SHMT1


hydroxymethyltransferase 1


(soluble)


serine
SHMT2


hydroxymethyltransferase 2


(mitochondrial)


soc-2 suppressor of clear
SHOC2


homolog (C. elegans)


sedoheptulokinase
SHPK


shroom family member 1
SHROOM1


shroom family member 2
SHROOM2


shroom family member 3
SHROOM3


sucrase-isomaltase (alpha-
SI


glucosidase)


sialic acid acetylesterase
SIAE


single immunoglobulin and
SIGIRR


toll-interleukin 1 receptor


(TIR) domain


sialic acid binding Ig-like lectin
SIGLEC1


1, sialoadhesin


signal-induced proliferation-
SIPA1L1


associated 1 like 1


signal-regulatory protein alpha
SIRPA


signal-regulatory protein beta 1
SIRPB1


signaling threshold regulating
SIT1


transmembrane adaptor 1


src kinase associated
SKAP1


phosphoprotein 1


src kinase associated
SKAP2


phosphoprotein 2


superkiller viralicidic activity 2-
SKIV2L


like (S. cerevisiae)


superkiller viralicidic activity 2-
SKIV2L2


like 2 (S. cerevisiae)


SKI family transcriptional
SKOR2


corepressor 2


S-phase kinase-associated
SKP1


protein 1


Src-like-adaptor 2
SLA2


SLAIN motif family, member 1
SLAIN1


signaling lymphocytic
SLAMF1


activation molecule family


member 1


SLAM family member 6
SLAMF6


solute carrier family 10,
SLC10A3


member 3


solute carrier family 12
SLC12A1


(sodium/potassium/chloride


transporter), member 1


solute carrier family 12
SLC12A2


(sodium/potassium/chloride


transporter), member 2


solute carrier family 12
SLC12A3


(sodium/chloride transporter),


member 3


solute carrier family 12
SLC12A4


(potassium/chloride


transporter), member 4


solute carrier family 12
SLC12A5


(potassium/chloride


transporter), member 5


solute carrier family 12
SLC12A6


(potassium/chloride


transporter), member 6


solute carrier family 12
SLC12A7


(potassium/chloride


transporter), member 7


solute carrier family 12,
SLC12A9


member 9


solute carrier family 13
SLC13A2


(sodium-dependent


dicarboxylate transporter),


member 2


solute carrier family 13
SLC13A3


(sodium-dependent


dicarboxylate transporter),


member 3


solute carrier family 15
SLC15A2


(oligopeptide transporter),


member 2


solute carrier family 16
SLC16A1


(monocarboxylate


transporter), member 1


solute carrier family 16
SLC16A10


(aromatic amino acid


transporter), member 10


solute carrier family 16
SLC16A3


(monocarboxylate


transporter), member 3


solute carrier family 16,
SLC16A6


member 6


solute carrier family 19 (folate
SLC19A1


transporter), member 1


solute carrier family 19
SLC19A2


(thiamine transporter),


member 2


solute carrier family 1
SLC1A1


(neuronal/epithelial high


affinity glutamate transporter,


system Xag), member 1


solute carrier family 1 (glial
SLC1A3


high affinity glutamate


transporter), member 3


solute carrier family 1
SLC1A4


(glutamate/neutral amino acid


transporter), member 4


solute carrier family 1 (neutral
SLC1A5


amino acid transporter),


member 5


solute carrier family 20
SLC20A1


(phosphate transporter),


member 1


solute carrier family 20
SLC20A2


(phosphate transporter),


member 2


solute carrier family 22
SLC22A11


(organic anion/urate


transporter), member 11


solute carrier family 22
SLC22A12


(organic anion/urate


transporter), member 12


solute carrier family 22
SLC22A13


(organic anion/urate


transporter), member 13


solute carrier family 22
SLC22A16


(organic cation/carnitine


transporter), member 16


solute carrier family 22
SLC22A2


(organic cation transporter),


member 2


solute carrier family 22
SLC22A5


(organic cation/carnitine


transporter), member 5


solute carrier family 22
SLC22A6


(organic anion transporter),


member 6


solute carrier family 22
SLC22A8


(organic anion transporter),


member 8


solute carrier family 23
SLC23A1


(ascorbic acid transporter),


member 1


solute carrier family 23
SLC23A2


(ascorbic acid transporter),


member 2


solute carrier family 25
SLC25A1


(mitochondrial carrier; citrate


transporter), member 1


solute carrier family 25
SLC25A10


(mitochondrial carrier;


dicarboxylate transporter),


member 10


solute carrier family 25
SLC25A11


(mitochondrial carrier;


oxoglutarate carrier),


member 11


solute carrier family 25
SLC25A13


(aspartate/glutamate carrier),


member 13


solute carrier family 25
SLC25A3


(mitochondrial carrier;


phosphate carrier), member 3


solute carrier family 25
SLC25A31


(mitochondrial carrier;


adenine nucleotide


translocator), member 31


solute carrier family 25
SLC25A4


(mitochondrial carrier;


adenine nucleotide


translocator), member 4


solute carrier family 25
SLC25A5


(mitochondrial carrier;


adenine nucleotide


translocator), member 5


solute carrier family 25
SLC25A6


(mitochondrial carrier;


adenine nucleotide


translocator), member 6


solute carrier family 26 (anion
SLC26A11


exchanger), member 11


solute carrier family 26 (anion
SLC26A2


exchanger), member 2


solute carrier family 26 (anion
SLC26A4


exchanger), member 4


solute carrier family 26 (anion
SLC26A6


exchanger), member 6


solute carrier family 26 (anion
SLC26A9


exchanger), member 9


solute carrier family 27 (fatty
SLC27A2


acid transporter), member 2


solute carrier family 29
SLC29A1


(equilibrative nucleoside


transporter), member 1


solute carrier family 29
SLC29A2


(equilibrative nucleoside


transporter), member 2


solute carrier family 2
SLC2A1


(facilitated glucose


transporter), member 1


solute carrier family 2
SLC2A12


(facilitated glucose


transporter), member 12


solute carrier family 2
SLC2A14


(facilitated glucose


transporter), member 14


solute carrier family 2
SLC2A3


(facilitated glucose


transporter), member 3


solute carrier family 2
SLC2A5


(facilitated glucose/fructose


transporter), member 5


solute carrier family 30 (zinc
SLC30A1


transporter), member 1


solute carrier family 34 (type II
SLC34A1


sodium/phosphate


cotransporter), member 1


solute carrier family 34 (type II
SLC34A2


sodium/phosphate


cotransporter), member 2


solute carrier family 35
SLC35B2


(adenosine 3′-phospho 5′-


phosphosulfate transporter),


member B2


solute carrier family 35 (UDP-
SLC35D2


GlcNAc/UDP-glucose


transporter), member D2


solute carrier family 35,
SLC35D3


member D3


solute carrier family 35,
SLC35F6


member F6


solute carrier family 36
SLC36A2


(proton/amino acid


symporter), member 2


solute carrier family 37
SLC37A2


(glucose-6-phosphate


transporter), member 2


solute carrier family 38,
SLC38A1


member 1


solute carrier family 38,
SLC38A2


member 2


solute carrier family 38,
SLC38A3


member 3


solute carrier family 38,
SLC38A5


member 5


solute carrier family 39 (zinc
SLC39A1


transporter), member 1


solute carrier family 39 (zinc
SLC39A10


transporter), member 10


solute carrier family 39 (zinc
SLC39A14


transporter), member 14


solute carrier family 39 (zinc
SLC39A4


transporter), member 4


solute carrier family 39 (zinc
SLC39A5


transporter), member 5


solute carrier family 39 (zinc
SLC39A6


transporter), member 6


solute carrier family 39,
SLC39A9


member 9


solute carrier family 3 (amino
SLC3A1


acid transporter heavy chain),


member 1


solute carrier family 3 (amino
SLC3A2


acid transporter heavy chain),


member 2


solute carrier family 43,
SLC43A3


member 3


solute carrier family 44
SLC44A1


(choline transporter), member 1


solute carrier family 44
SLC44A2


(choline transporter), member 2


solute carrier family 44,
SLC44A4


member 4


solute carrier family 45,
SLC45A2


member 2


solute carrier family 46 (folate
SLC46A1


transporter), member 1


solute carrier family 46,
SLC46A3


member 3


solute carrier family 4 (anion
SLC4A1


exchanger), member 1 (Diego


blood group)


solute carrier family 4, sodium
SLC4A11


borate transporter, member 11


solute carrier family 4 (anion
SLC4A2


exchanger), member 2


solute carrier family 4 (sodium
SLC4A4


bicarbonate cotransporter),


member 4


solute carrier family 4, sodium
SLC4A7


bicarbonate cotransporter,


member 7


solute carrier family 4, sodium
SLC4A8


bicarbonate cotransporter,


member 8


solute carrier family 5
SLC5A1


(sodium/glucose


cotransporter), member 1


solute carrier family 5
SLC5A10


(sodium/sugar cotransporter),


member 10


solute carrier family 5
SLC5A12


(sodium/monocarboxylate


cotransporter), member 12


solute carrier family 5
SLC5A2


(sodium/glucose


cotransporter), member 2


solute carrier family 5
SLC5A3


(sodium/myo-inositol


cotransporter), member 3


solute carrier family 5
SLC5A5


(sodium/iodide cotransporter),


member 5


solute carrier family 5
SLC5A6


(sodium/multivitamin and


iodide cotransporter), member


6


solute carrier family 5
SLC5A8


(sodium/monocarboxylate


cotransporter), member 8


solute carrier family 5
SLC5A9


(sodium/sugar cotransporter),


member 9


solute carrier family 6
SLC6A13


(neurotransmitter transporter),


member 13


solute carrier family 6 (amino
SLC6A14


acid transporter), member 14


solute carrier family 6 (neutral
SLC6A15


amino acid transporter),


member 15


solute carrier family 6 (neutral
SLC6A17


amino acid transporter),


member 17


solute carrier family 6 (neutral
SLC6A19


amino acid transporter),


member 19


solute carrier family 6
SLC6A4


(neurotransmitter transporter),


member 4


solute carrier family 6
SLC6A6


(neurotransmitter transporter),


member 6


solute carrier family 6
SLC6A8


(neurotransmitter transporter),


member 8


solute carrier family 6
SLC6A9


(neurotransmitter transporter,


glycine), member 9


solute carrier family 7
SLC7A1


(cationic amino acid


transporter, y+ system),


member 1


solute carrier family 7 (neutral
SLC7A10


amino acid transporter light


chain, asc system), member


10


solute carrier family 7 (anionic
SLC7A11


amino acid transporter light


chain, xc− system), member


11


solute carrier family 7
SLC7A2


(cationic amino acid


transporter, y+ system),


member 2


solute carrier family 7 (amino
SLC7A5


acid transporter light chain, L


system), member 5


solute carrier family 7 (amino
SLC7A8


acid transporter light chain, L


system), member 8


solute carrier family 8
SLC8A1


(sodium/calcium exchanger),


member 1


solute carrier family 9,
SLC9A1


subfamily A (NHE1, cation


proton antiporter 1), member 1


solute carrier family 9,
SLC9A3


subfamily A (NHE3, cation


proton antiporter 3), member 3


solute carrier family 9,
SLC9A3R1


subfamily A (NHE3, cation


proton antiporter 3), member


3 regulator 1


solute carrier family 9,
SLC9A3R2


subfamily A (NHE3, cation


proton antiporter 3), member


3 regulator 2


solute carrier family 9,
SLC9A9


subfamily A (NHE9, cation


proton antiporter 9), member 9


solute carrier family 9,
SLC9C1


subfamily C (Na+-transporting


carboxylic acid


decarboxylase), member 1


solute carrier organic anion
SLCO3A1


transporter family, member


3A1


solute carrier organic anion
SLCO4A1


transporter family, member


4A1


solute carrier organic anion
SLCO4C1


transporter family, member


4C1


schlafen family member 11
SLFN11


schlafen family member 5
SLFN5


slit homolog 2 (Drosophila)
SLIT2


STE20-like kinase
SLK


secretory leukocyte peptidase
SLPI


inhibitor


SAFB-like, transcription
SLTM


modulator


SMAD family member 2
SMAD2


SMAD family member 5
SMAD5


SWI/SNF related, matrix
SMARCA4


associated, actin dependent


regulator of chromatin,


subfamily a, member 4


SWI/SNF related, matrix
SMARCA5


associated, actin dependent


regulator of chromatin,


subfamily a, member 5


SWI/SNF related, matrix
SMARCB1


associated, actin dependent


regulator of chromatin,


subfamily b, member 1


SWI/SNF related, matrix
SMARCC1


associated, actin dependent


regulator of chromatin,


subfamily c, member 1


SWI/SNF related, matrix
SMARCC2


associated, actin dependent


regulator of chromatin,


subfamily c, member 2


SWI/SNF related, matrix
SMARCD1


associated, actin dependent


regulator of chromatin,


subfamily d, member 1


SWI/SNF related, matrix
SMARCD2


associated, actin dependent


regulator of chromatin,


subfamily d, member 2


SWI/SNF related, matrix
SMARCE1


associated, actin dependent


regulator of chromatin,


subfamily e, member 1


structural maintenance of
SMC1A


chromosomes 1A


structural maintenance of
SMC2


chromosomes 2


structural maintenance of
SMC3


chromosomes 3


structural maintenance of
SMC4


chromosomes 4


structural maintenance of
SMC5


chromosomes 5


structural maintenance of
SMCHD1


chromosomes flexible hinge


domain containing 1


small integral membrane
SMIM22


protein 22


small integral membrane
SMIM24


protein 24


survival of motor neuron 1,
SMN1


telomeric


survival of motor neuron 2,
SMN2


centromeric


smoothened, frizzled class
SMO


receptor


sphingomyelin
SMPDL3B


phosphodiesterase, acid-like


3B


spermine synthase
SMS


smoothelin
SMTN


smu-1 suppressor of mec-8
SMU1


and unc-52 homolog


(C. elegans)


SMAD specific E3 ubiquitin
SMURF1


protein ligase 1


synaptosomal-associated
SNAP23


protein, 23 kDa


synaptosomal-associated
SNAP25


protein, 25 kDa


synaptosomal-associated
SNAP29


protein, 29 kDa


synuclein, alpha (non A4
SNCA


component of amyloid


precursor)


synuclein, beta
SNOB


synuclein, gamma (breast
SNCG


cancer-specific protein 1)


staphylococcal nuclease and
SND1


tudor domain containing 1


SNF8, ESCRT-II complex
SNF8


subunit


small nucleolar RNA, H/ACA
SNORA27


box 27


small nuclear
SNRNP200


ribonucleoprotein 200 kDa


(U5)


small nuclear
SNRNP40


ribonucleoprotein 40 kDa (U5)


small nuclear
SNRNP70


ribonucleoprotein 70 kDa (U1)


small nuclear
SNRPA


ribonucleoprotein polypeptide


A


small nuclear
SNRPA1


ribonucleoprotein polypeptide


A′


small nuclear
SNRPB


ribonucleoprotein


polypeptides B and B1


small nuclear
SNRPB2


ribonucleoprotein polypeptide


B


small nuclear
SNRPD1


ribonucleoprotein D1


polypeptide 16 kDa


small nuclear
SNRPD2


ribonucleoprotein D2


polypeptide 16.5 kDa


small nuclear
SNRPD3


ribonucleoprotein D3


polypeptide 18 kDa


small nuclear
SNRPE


ribonucleoprotein polypeptide


E


small nuclear
SNRPF


ribonucleoprotein polypeptide


F


small nuclear
SNRPG


ribonucleoprotein polypeptide


G


small nuclear
SNRPN


ribonucleoprotein polypeptide


N


syntrophin, alpha 1
SNTA1


syntrophin, beta 1
SNTB1


(dystrophin-associated protein


A1, 59 kDa, basic component


1)


syntrophin, beta 2
SNTB2


(dystrophin-associated protein


A1, 59 kDa, basic component


2)


sorting nexin 1
SNX1


sorting nexin 12
SNX12


sorting nexin 17
SNX17


sorting nexin 18
SNX18


sorting nexin 2
SNX2


sorting nexin 25
SNX25


sorting nexin family member
SNX27


27


sorting nexin 3
SNX3


sorting nexin 33
SNX33


sorting nexin 4
SNX4


sorting nexin 5
SNX5


sorting nexin 6
SNX6


sorting nexin 9
SNX9


superoxide dismutase 1,
SOD1


soluble


superoxide dismutase 3,
SOD3


extracellular


suppressor of glucose,
SOGA1


autophagy associated 1


SON DNA binding protein
SON


sorbin and SH3 domain
SORBS1


containing 1


sorbin and SH3 domain
SORBS3


containing 3


sortilin-related VPS10 domain
SORCS2


containing receptor 2


sorbitol dehydrogenase
SORD


sortilin-related receptor,
SORL1


L(DLR class) A repeats


containing


sortilin 1
SORT1


SRY (sex determining region
SOX1


Y)-box 1


SRY (sex determining region
SOX18


Y)-box 18


sperm acrosome associated 1
SPACA1


sperm associated antigen 1
SPAG1


sperm associated antigen 5
SPAG5


sperm associated antigen 9
SPAG9


secreted protein, acidic,
SPARC


cysteine-rich (osteonectin)


spastin
SPAST


spermatogenesis associated
SPATA21


21


spermatogenesis associated
SPATA5


5


spermatogenesis associated
SPATA5L1


5-like 1


spermatogenesis associated
SPATA7


7


signal peptidase complex
SPCS2


subunit 2 homolog


(S. cerevisiae)


signal peptidase complex
SPCS3


subunit 3 homolog


(S. cerevisiae)


sperm antigen with calponin
SPECC1


homology and coiled-coil


domains 1


sperm antigen with calponin
SPECC1L


homology and coiled-coil


domains 1-like


sperm flagellar 2
SPEF2


spen family transcriptional
SPEN


repressor


spastic paraplegia 11
SPG11


(autosomal recessive)


spastic paraplegia 20 (Troyer
SPG20


syndrome)


spastic paraplegia 21
SPG21


(autosomal recessive, Mast


syndrome)


scaffolding protein involved in
SPIDR


DNA repair


serine peptidase inhibitor,
SPINK1


Kazal type 1


serine peptidase inhibitor,
SPINK5


Kazal type 5


serine peptidase inhibitor,
SPINT1


Kunitz type 1


serine peptidase inhibitor,
SPINT2


Kunitz type, 2


spire-type actin nucleation
SPIRE1


factor 1


sialophorin
SPN


spinster homolog 1
SPNS1


(Drosophila)


sparc/osteonectin, cwcv and
SPOCK1


kazal-like domains


proteoglycan (testican) 1


spondin 1, extracellular matrix
SPON1


protein


spondin 2, extracellular matrix
SPON2


protein


secreted phosphoprotein 1
SPP1


secreted phosphoprotein 2,
SPP2


24 kDa


signal peptide peptidase like
SPPL2A


2A


sepiapterin reductase (7,8-
SPR


dihydrobiopterin:NADP+


oxidoreductase)


small proline-rich protein 3
SPRR3


sprouty homolog 1, antagonist
SPRY1


of FGF signaling (Drosophila)


sprouty homolog 4
SPRY4


(Drosophila)


SPRY domain containing 7
SPRYD7


spectrin, alpha, non-
SPTAN1


erythrocytic 1


spectrin, beta, erythrocytic
SPTB


spectrin, beta, non-
SPTBN1


erythrocytic 1


spectrin, beta, non-
SPTBN2


erythrocytic 2


spectrin, beta, non-
SPTBN4


erythrocytic 4


spectrin, beta, non-
SPTBN5


erythrocytic 5


serine palmitoyltransferase,
SPTLC1


long chain base subunit 1


sequestosome 1
SQSTM1


steroid receptor RNA activator
SRA1


1


SRC proto-oncogene, non-
SRC


receptor tyrosine kinase


splicing regulatory
SREK1


glutamine/lysine-rich protein 1


SLIT-ROBO Rho GTPase
SRGAP1


activating protein 1


SLIT-ROBO Rho GTPase
SRGAP2


activating protein 2


serglycin
SRGN


sorcin
SRI


spermidine synthase
SRM


signal recognition particle
SRP14


14 kDa (homologous Alu RNA


binding protein)


signal recognition particle
SRP54


54 kDa


signal recognition particle
SRP68


68 kDa


signal recognition particle
SRP72


72 kDa


signal recognition particle
SRP9


9 kDa


SRSF protein kinase 1
SRPK1


SRSF protein kinase 2
SRPK2


signal recognition particle
SRPR


receptor (docking protein)


signal recognition particle
SRPRB


receptor, B subunit


sushi-repeat containing
SRPX


protein, X-linked


sushi-repeat containing
SRPX2


protein, X-linked 2


serine/arginine repetitive
SRRM2


matrix 2


serrate, RNA effector
SRRT


molecule


serine/arginine-rich splicing
SRSF1


factor 1


serine/arginine-rich splicing
SRSF10


factor 10


serine/arginine-rich splicing
SRSF2


factor 2


serine/arginine-rich splicing
SRSF3


factor 3


serine/arginine-rich splicing
SRSF4


factor 4


serine/arginine-rich splicing
SRSF5


factor 5


serine/arginine-rich splicing
SRSF6


factor 6


serine/arginine-rich splicing
SRSF7


factor 7


serine/arginine-rich splicing
SRSF9


factor 9


Sjogren syndrome antigen B
SSB


(autoantigen La)


single-stranded DNA binding
SSBP1


protein 1, mitochondrial


SCO-spondin
SSPO


signal sequence receptor,
SSR1


alpha


signal sequence receptor,
SSR3


gamma (translocon-


associated protein gamma)


signal sequence receptor,
SSR4


delta


structure specific recognition
SSRP1


protein 1


suppression of tumorigenicity
ST13


13 (colon carcinoma) (Hsp70


interacting protein)


suppression of tumorigenicity
ST13P4


13 (colon carcinoma) (Hsp70


interacting protein)


pseudogene 4


suppression of tumorigenicity
ST13P5


13 (colon carcinoma) (Hsp70


interacting protein)


pseudogene 5


suppression of tumorigenicity
ST14


14 (colon carcinoma)


ST3 beta-galactoside alpha-
ST3GAL1


2,3-sialyltransferase 1


ST3 beta-galactoside alpha-
ST3GAL6


2,3-sialyltransferase 6


ST6 (alpha-N-acetyl-
ST6GALNAC6


neuraminyl-2,3-beta-


galactosyl-1,3)-N-


acetylgalactosaminide alpha-


2,6-sialyltransferase 6


stromal antigen 2
STAG2


stromal antigen 3
STAG3


signal transducing adaptor
STAM


molecule (SH3 domain and


ITAM motif) 1


signal transducing adaptor
STAM2


molecule (SH3 domain and


ITAM motif) 2


STAM binding protein
STAMBP


StAR-related lipid transfer
STARD9


(START) domain containing 9


signal transducer and
STAT1


activator of transcription 1,


91 kDa


signal transducer and
STAT2


activator of transcription 2,


113 kDa


signal transducer and
STAT3


activator of transcription 3


(acute-phase response factor)


signal transducer and
STAT5A


activator of transcription 5A


signal transducer and
STAT6


activator of transcription 6,


interleukin-4 induced


staufen double-stranded RNA
STAU1


binding protein 1


staufen double-stranded RNA
STAU2


binding protein 2


stanniocalcin 1
STC1


stanniocalcin 2
STC2


STEAP family member 3,
STEAP3


metalloreductase


STEAP family member 4
STEAP4


stromal interaction molecule 1
STIM1


stress-induced
STIP1


phosphoprotein 1


serine/threonine kinase 10
STK10


serine/threonine kinase 11
STK11


serine/threonine kinase 17b
STK17B


serine/threonine kinase 24
STK24


serine/threonine kinase 25
STK25


serine/threonine protein
STK26


kinase 26


serine/threonine kinase 38
STK38


serine/threonine kinase 38
STK38L


like


serine threonine kinase 39
STK39


serine/threonine kinase 4
STK4


stathmin 1
STMN1


stomatin
STOM


stomatin (EPB72)-like 2
STOML2


stomatin (EPB72)-like 3
STOML3


stonin 2
STON2


stimulated by retinoic acid 6
STRA6


serine/threonine kinase
STRAP


receptor associated protein


spermatid perinuclear RNA
STRBP


binding protein


striatin interacting protein 1
STRIP1


striatin, calmodulin binding
STRN3


protein 3


STT3A, subunit of the
STT3A


oligosaccharyltransferase


complex (catalytic)


STT3B, subunit of the
STT3B


oligosaccharyltransferase


complex (catalytic)


STIP1 homology and U-box
STUB1


containing protein 1, E3


ubiquitin protein ligase


syntaxin 10
STX10


syntaxin 11
STX11


syntaxin 12
STX12


syntaxin 16
STX16


syntaxin 1A (brain)
STX1A


syntaxin 1B
STX1B


syntaxin 2
STX2


syntaxin 3
STX3


syntaxin 4
STX4


syntaxin 6
STX6


syntaxin 7
STX7


syntaxin 8
STX8


syntaxin binding protein 1
STXBP1


syntaxin binding protein 2
STXBP2


syntaxin binding protein 3
STXBP3


syntaxin binding protein 4
STXBP4


syntaxin binding protein 5
STXBP5


(tomosyn)


syntaxin binding protein 6
STXBP6


(amisyn)


SUB1 homolog (S. cerevisiae)
SUB1


succinate-CoA ligase, ADP-
SUCLA2


forming, beta subunit


succinate-CoA ligase, GDP-
SUCLG2


forming, beta subunit


succinate receptor 1
SUCNR1


SGT1, suppressor of G2 allele
SUGT1


of SKP1 (S. cerevisiae)


sulfatase 2
SULF2


sulfotransferase family,
SULT1A1


cytosolic, 1A, phenol-


preferring, member 1


small ubiquitin-like modifier 2
SUMO2


small ubiquitin-like modifier 3
SUMO3


small ubiquitin-like modifier 4
SUMO4


suppressor of Ty 16 homolog
SUPT16H


(S. cerevisiae)


suppressor of Ty 20 homolog
SUPT20H


(S. cerevisiae)


suppressor of Ty 5 homolog
SUPT5H


(S. cerevisiae)


surfeit 4
SURF4


sushi domain containing 1
SUSD1


sushi domain containing 2
SUSD2


sushi domain containing 3
SUSD3


sushi, von Willebrand factor
SVEP1


type A, EGF and pentraxin


domain containing 1


small VCP/p97-interacting
SVIP


protein


SWAP switching B-cell
SWAP70


complex 70 kDa subunit


synaptonemal complex
SYCP2


protein 2


spleen tyrosine kinase
SYK


symplekin
SYMPK


synapsin II
SYN2


synaptotagmin binding,
SYNCRIP


cytoplasmic RNA interacting


protein


spectrin repeat containing,
SYNE1


nuclear envelope 1


spectrin repeat containing,
SYNE2


nuclear envelope 2


synaptogyrin 1
SYNGR1


synaptogyrin 2
SYNGR2


synaptojanin 2
SYNJ2


synergin, gamma
SYNRG


synaptophysin-like 1
SYPL1


synaptotagmin I
SYT1


synaptotagmin V
SYT5


synaptotagmin IX
SYT9


synaptotagmin-like 1
SYTL1


synaptotagmin-like 2
SYTL2


synaptotagmin-like 4
SYTL4


synaptotagmin-like 5
SYTL5


seizure threshold 2 homolog
SZT2


(mouse)


trace amine associated
TAAR2


receptor 2


transforming, acidic coiled-coil
TACC2


containing protein 2


tumor-associated calcium
TACSTD2


signal transducer 2


TAF10 RNA polymerase II,
TAF10


TATA box binding protein


(TBP)-associated factor,


30 kDa


transgelin
TAGLN


transgelin 2
TAGLN2


transaldolase 1
TALDO1


tetratricopeptide repeat,
TANC1


ankyrin repeat and coiled-coil


containing 1


TAO kinase 1
TAOK1


TAO kinase 2
TAOK2


TAO kinase 3
TAOK3


transporter 1, ATP-binding
TAP1


cassette, sub-family B


(MDR/TAP)


TAP binding protein (tapasin)
TAPBP


TAR (HIV-1) RNA binding
TARBP1


protein 1


TAR DNA binding protein
TARDBP


threonyl-tRNA synthetase
TARS


threonyl-tRNA synthetase-like 2
TARSL2


taste receptor, type 2,
TAS2R60


member 60


Taxi (human T-cell leukemia
TAX1BP1


virus type 1) binding protein 1


Taxi (human T-cell leukemia
TAX1BP3


virus type I) binding protein 3


TBC1 (tre-2/USP6, BUB2,
TBC1D1


cdc16) domain family,


member 1


TBC1 domain family, member
TBC1D10A


10A


TBC1 domain family, member
TBC1D10B


10B


TBC1 domain family, member
TBC1D15


15


TBC1 domain family, member
TBC1D2


2


TBC1 domain family, member
TBC1D21


21


TBC1 domain family, member
TBC1D24


24


TBC1 domain family, member
TBC1D32


32


tubulin folding cofactor A
TBCA


tubulin folding cofactor B
TBCB


tubulin folding cofactor D
TBCD


tubulin folding cofactor E
TBCE


TANK-binding kinase 1
TBK1


transducin (beta)-like 1 X-
TBL1XR1


linked receptor 1


thromboxane A2 receptor
TBXA2R


thromboxane A synthase 1
TBXAS1


(platelet)


tandem C2 domains, nuclear
TC2N


TRPM8 channel-associated
TCAF1


factor 1


transcription elongation factor
TCEA1


A (SII), 1


transcription elongation factor
TCEB1


B (SIII), polypeptide 1 (15 kDa,


elongin C)


transcription elongation factor
TCEB2


B (SIII), polypeptide 2 (18 kDa,


elongin B)


T-cell, immune regulator 1,
TCIRG1


ATPase, H + transporting,


lysosomal VO subunit A3


transcobalamin I (vitamin B12
TCN1


binding protein, R binder


family)


Treacher Collins-
TCOF1


Franceschetti syndrome 1


t-complex 1
TCP1


tyrosyl-DNA
TDP2


phosphodiesterase 2


tudor domain containing 9
TDRD9


tec protein tyrosine kinase
TEC


tectorin alpha
TECTA


tektin 3
TEKT3


telomere maintenance 2
TELO2


teneurin transmembrane
TENM3


protein 3


teneurin transmembrane
TENM4


protein 4


telomerase-associated protein
TEP1


1


telomeric repeat binding factor
TERF1


(NIMA-interacting) 1


telomeric repeat binding factor
TERF1P2


(NIMA-interacting) 1


pseudogene 2


telomeric repeat binding factor
TERF1P3


(NIMA-interacting) 1


pseudogene 3


telomeric repeat binding factor
TERF1P5


(NIMA-interacting) 1


pseudogene 5


telomeric repeat binding factor
TERF2IP


2, interacting protein


testin LIM domain protein
TES


tescalcin
TESC


testis-specific kinase 1
TESK1


testis expressed 10
TEX10


transferrin
TF


TRK-fused gene
TFG


tissue factor pathway inhibitor
TFPI


(lipoprotein-associated


coagulation inhibitor)


transferrin receptor
TFRC


transforming growth factor,
TGFB1


beta 1


transforming growth factor,
TGFB2


beta 2


transforming growth factor,
TGFBI


beta-induced, 68kDa


transforming growth factor,
TGFBR2


beta receptor II (70/80 kDa)


transforming growth factor,
TGFBR3


beta receptor III


transforming growth factor,
TGFBRAP1


beta receptor associated


protein 1


transglutaminase 1
TGM1


transglutaminase 2
TGM2


transglutaminase 3
TGM3


transglutaminase 4
TGM4


trans-golgi network protein 2
TGOLN2


thyroid adenoma associated
THADA


THAP domain containing 11
THAP11


thrombospondin 1
THBS1


thrombospondin 2
THBS2


thrombospondin 4
THBS4


thymocyte selection
THEMIS


associated


thymocyte selection
THEMIS2


associated family member 2


threonine synthase-like 1
THNSL1


(S. cerevisiae)


threonine synthase-like 2
THNSL2


(S. cerevisiae)


THO complex 1
THOC1


THO complex 2
THOC2


THO complex 5
THOC5


THO complex 6
THOC6


THO complex 7
THOC7


thimet oligopeptidase 1
THOP1


thyroid hormone receptor
THRAP3


associated protein 3


thrombospondin, type I,
THSD1


domain containing 1


thrombospondin, type I,
THSD4


domain containing 4


thrombospondin, type I,
THSD7A


domain containing 7A


Thy-1 cell surface antigen
THY1


thymocyte nuclear protein 1
THYN1


TIA1 cytotoxic granule-
TIAL1


associated RNA binding


protein-like 1


T-cell lymphoma invasion and
TIAM2


metastasis 2


tigger transposable element
TIGD4


derived 4


translocase of inner
TIMM50


mitochondrial membrane 50


homolog (S. cerevisiae)


TIMP metallopeptidase
TIMP1


inhibitor 1


TIMP metallopeptidase
TIMP2


inhibitor 2


TIMP metallopeptidase
TIMP3


inhibitor 3


tubulointerstitial nephritis
TINAGL1


antigen-like 1


TOR signaling pathway
TIPRL


regulator


tight junction protein 1
TJP1


tight junction protein 2
TJP2


triokinase/FMN cyclase
TKFC


transketolase
TKT


talin 1
TLN1


talin 2
TLN2


toll-like receptor 2
TLR2


transmembrane 7 superfamily
TM7SF3


member 3


transmembrane 9 superfamily
TM9SF2


member 2


transmembrane 9 superfamily
TM9SF3


member 3


transmembrane 9 superfamily
TM9SF4


protein member 4


transmembrane BAX inhibitor
TMBIM1


motif containing 1


transmembrane BAX inhibitor
TMBIM6


motif containing 6


transmembrane channel-like 6
TMC6


transmembrane channel-like 7
TMC7


transmembrane channel-like 8
TMC8


transmembrane and coiled-
TMCO1


coil domains 1


transmembrane emp24
TMED1


protein transport domain


containing 1


transmembrane emp24-like
TMED10


trafficking protein 10 (yeast)


transmembrane emp24
TMED2


domain trafficking protein 2


transmembrane emp24
TMED4


protein transport domain


containing 4


transmembrane emp24
TMED5


protein transport domain


containing 5


transmembrane emp24
TMED7


protein transport domain


containing 7


TMED7-TICAM2 readthrough
TMED7-TICAM2


transmembrane emp24
TMED8


protein transport domain


containing 8


transmembrane emp24
TMED9


protein transport domain


containing 9


transmembrane protein 100
TMEM100


transmembrane protein 104
TMEM104


transmembrane protein 109
TMEM109


transmembrane protein 117
TMEM117


transmembrane protein 165
TMEM165


TMEM189-UBE2V1
TMEM189-UBE2V1


readthrough


transmembrane protein 192
TMEM192


transmembrane protein 2
TMEM2


transmembrane protein 200A
TMEM200A


transmembrane protein 237
TMEM237


transmembrane protein 256
TMEM256


transmembrane protein 27
TMEM27


transmembrane protein 30A
TMEM30A


transmembrane protein 30B
TMEM30B


transmembrane protein 33
TMEM33


transmembrane protein 38A
TMEM38A


transmembrane protein 40
TMEM40


transmembrane protein 43
TMEM43


transmembrane protein 45B
TMEM45B


transmembrane protein 47
TMEM47


transmembrane protein 50A
TMEM50A


transmembrane protein 51
TMEM51


transmembrane protein 52B
TMEM52B


transmembrane protein 55A
TMEM55A


transmembrane protein 55B
TMEM55B


transmembrane protein 59
TMEM59


transmembrane protein 63A
TMEM63A


transmembrane protein 63B
TMEM63B


transmembrane protein 87A
TMEM87A


transmembrane protein 87B
TMEM87B


transmembrane protein 9
TMEM9


TATA element modulatory
TMF1


factor 1


tropomodulin 2 (neuronal)
TMOD2


tropomodulin 3 (ubiquitous)
TMOD3


thymopoietin
TMPO


transmembrane protease,
TMPRSS11B


serine 11B


transmembrane protease,
TMPRSS11D


serine 11D


transmembrane protease,
TMPRSS2


serine 2


transmembrane protease,
TMPRSS4


serine 4


thioredoxin-related
TMX1


transmembrane protein 1


thioredoxin-related
TMX2


transmembrane protein 2


tenascin C
TNC


tumor necrosis factor, alpha-
TNFAIP2


induced protein 2


tumor necrosis factor, alpha-
TNFAIP3


induced protein 3


tumor necrosis factor, alpha-
TNFAIP8


induced protein 8


tumor necrosis factor receptor
TNFRSF10A


superfamily, member 10a


tumor necrosis factor receptor
TNFRSF10B


superfamily, member 10b


tumor necrosis factor receptor
TNFRSF10D


superfamily, member 10d,


decoy with truncated death


domain


tumor necrosis factor receptor
TNFRSF11A, RANK


superfamily, member 11a,


RANK


tumor necrosis factor receptor
TNFRSF11B


superfamily, member 11b


tumor necrosis factor receptor
TNFRSF12A


superfamily, member 12A


tumor necrosis factor receptor
TNFRSF1A


superfamily, member 1A


tumor necrosis factor receptor
TNFRSF21


superfamily, member 21


tumor necrosis factor receptor
TNFRSF8


superfamily, member 8


tumor necrosis factor (ligand)
TNFSF10,TRAIL


superfamily, member 10,


tumor necrosis factor-related


apoptosis-inducing ligand


(TRAIL)


tumor necrosis factor (ligand)
TNFSF12


superfamily, member 12


tumor necrosis factor (ligand)
TNFSF13


superfamily, member 13


tumor necrosis factor (ligand)
TNFSF18


superfamily, member 18


TRAF2 and NCK interacting
TNIK


kinase


TNFAIP3 interacting protein 1
TNIP1


tankyrase 1 binding protein 1,
TNKS1BP1


182 kDa


troponin I type 2 (skeletal,
TNNI2


fast)


transportin 1
TNPO1


transportin 2
TNPO2


transportin 3
TNPO3


tensin 3
TNS3


tensin 4
TNS4


target of EGR1, member 1
TOE1


(nuclear)


toll interacting protein
TOLLIP


target of myb1 (chicken)
TOM1


target of myb1 (chicken)-like 1
TOM1L1


target of myb1-like 2 (chicken)
TOM1L2


Mitochondrial import receptor
TOM20


subunit TOM20


translocase of outer
TOMM22


mitochondrial membrane 22


homolog (yeast)


translocase of outer
TOMM34


mitochondrial membrane 34


translocase of outer
TOMM40


mitochondrial membrane 40


homolog (yeast)


translocase of outer
TOMM70A


mitochondrial membrane 70


homolog A (S. cerevisiae)


topoisomerase (DNA) I
TOP1


topoisomerase (DNA) II alpha
TOP2A


170 kDa


topoisomerase (DNA) II beta
TOP2B


180 kDa


torsin family 1, member A
TOR1A


(torsin A)


torsin family 1, member B
TOR1B


(torsin B)


torsin family 3, member A
TOR3A


torsin family 4, member A
TOR4A


TP53 regulating kinase
TP53RK


trophoblast glycoprotein
TPBG


trophoblast glycoprotein-like
TPBGL


two pore segment channel 1
TPCN1


tumor protein D52
TPD52


tumor protein D52-like 2
TPD52L2


triosephosphate isomerase 1
TPI1


triosephosphate isomerase 1
TPI1P1


pseudogene 1


tropomyosin 1 (alpha)
TPM1


tropomyosin 2 (beta)
TPM2


tropomyosin 3
TPM3


tropomyosin 4
TPM4


thiopurine S-
TPMT


methyltransferase


tripeptidyl peptidase I
TPP1


tripeptidyl peptidase II
TPP2


tubulin polymerization
TPPP


promoting protein


tumor protein p63 regulated 1-
TPRG1L


like


taperin
TPRN


tyrosylprotein sulfotransferase 2
TPST2


tumor protein, translationally-
TPT1


controlled 1


transformer 2 alpha homolog
TRA2A


(Drosophila)


transformer 2 beta homolog
TRA2B


(Drosophila)


TNFRSF1A-associated via
TRADD


death domain


TNF receptor-associated
TRAF1


factor 1


TNF receptor-associated
TRAF4


factor 4


trafficking protein, kinesin
TRAK1


binding 1


tetratricopeptide repeat and
TRANK1


ankyrin repeat containing 1


TNF receptor-associated
TRAP1


protein 1


trafficking protein particle
TRAPPC10


complex 10


trafficking protein particle
TRAPPC11


complex 11


trafficking protein particle
TRAPPC12


complex 12


trafficking protein particle
TRAPPC13


complex 13


trafficking protein particle
TRAPPC3


complex 3


trafficking protein particle
TRAPPC4


complex 4


trafficking protein particle
TRAPPC5


complex 5


trafficking protein particle
TRAPPC8


complex 8


trafficking protein particle
TRAPPC9


complex 9


T cell receptor associated
TRAT1


transmembrane adaptor 1


trehalase (brush-border
TREH


membrane glycoprotein)


triggering receptor expressed
TREM1


on myeloid cells 1


triggering receptor expressed
TREML1


on myeloid cells-like 1


triggering receptor expressed
TREML2


on myeloid cells-like 2


triggering receptor expressed
TREML5P


on myeloid cells-like 5,


pseudogene


thyrotropin-releasing hormone
TRHDE


degrading enzyme


tripartite motif containing 16
TRIM16


tripartite motif containing 21
TRIM21


tripartite motif containing 23
TRIM23


tripartite motif containing 25
TRIM25


tripartite motif containing 26
TRIM26


tripartite motif containing 28
TRIM28


tripartite motif containing 32
TRIM32


tripartite motif containing 38
TRIM38


tripartite motif containing 40
TRIM40


tripartite motif containing 41
TRIM41


tripartite motif containing 56
TRIM56


tripartite motif containing 58
TRIM58


tripartite motif containing 65
TRIM65


tripartite motif containing 69
TRIM69


trio Rho guanine nucleotide
TRIO


exchange factor


TRIO and F-actin binding
TRIOBP


protein


thyroid hormone receptor
TRIP10


interactor 10


thyroid hormone receptor
TRIP11


interactor 11


thyroid hormone receptor
TRIP12


interactor 12


thyroid hormone receptor
TRIP13


interactor 13


thyroid hormone receptor
TRIP6


interactor 6


tRNA methyltransferase 10
TRMT10A


homolog A (S. cerevisiae)


tRNA methyltransferase 11-2
TRMT112


homolog (S. cerevisiae)


tRNA methyltransferase 1
TRMT1L


homolog (S. cerevisiae)-like


tRNA methyltransferase 2
TRMT2A


homolog A (S. cerevisiae)


tRNA methyltransferase 61A
TRMT61A


TROVE domain family,
TROVE2


member 2


transient receptor potential
TRPC6


cation channel, subfamily C,


member 6


transient receptor potential
TRPM4


cation channel, subfamily M,


member 4


transient receptor potential
TRPV4


cation channel, subfamily V,


member 4


transformation/transcription
TRRAP


domain-associated protein


TruB pseudouridine (psi)
TRUB1


synthase family member 1


tuberous sclerosis 2
TSC2


tumor susceptibility 101
TSG101


thyroid stimulating hormone
TSHR


receptor


teashirt zinc finger homeobox 1
TSHZ1


translin
TSN


translin-associated factor X
TSNAX


translin-associated factor X
TSNAXIP1


interacting protein 1


tetraspanin 1
TSPAN1


tetraspanin 10
TSPAN10


tetraspanin 14
TSPAN14


tetraspanin 15
TSPAN15


tetraspanin 3
TSPAN3


tetraspanin 33
TSPAN33


tetraspanin 4
TSPAN4


tetraspanin 6
TSPAN6


tetraspanin 8
TSPAN8


tetraspanin 9
TSPAN9


translocator protein (18 kDa)
TSPO


TSPY-like 4
TSPYL4


TSR1, 20S rRNA
TSR1


accumulation, homolog


(S. cerevisiae)


tumor suppressing
TSSC1


subtransferable candidate 1


thiosulfate sulfurtransferase
TST


(rhodanese)


tissue specific transplantation
TSTA3


antigen P35B


tau tubulin kinase 2
TTBK2


tetratricopeptide repeat
TTC17


domain 17


tetratricopeptide repeat
TTC21B


domain 21B


tetratricopeptide repeat
TTC27


domain 27


tetratricopeptide repeat
TTC37


domain 37


tetratricopeptide repeat
TTC38


domain 38


tetratricopeptide repeat
TTC39A


domain 39A


tetratricopeptide repeat
TTC7A


domain 7A


tetratricopeptide repeat
TTC7B


domain 7B


TELO2 interacting protein 1
TTI1


TELO2 interacting protein 2
TTI2


tubulin tyrosine ligase-like
TTLL12


family member 12


tubulin tyrosine ligase-like
TTLL3


family member 3


titin
TTN


transthyretin
TTR


tweety family member 2
TTYH2


tweety family member 3
TTYH3


tubulin, alpha 1a
TUBA1A


tubulin, alpha 1b
TUBA1B


tubulin, alpha 1c
TUBA1C


tubulin, alpha 3c
TUBA3C


tubulin, alpha 3d
TUBA3D


tubulin, alpha 3e
TUBA3E


tubulin, alpha 4a
TUBA4A


tubulin, alpha 4b
TUBA4B


tubulin, alpha 8
TUBA8


tubulin, alpha-like 3
TUBAL3


tubulin, alpha pseudogene 2
TUBAP2


tubulin, beta class I
TUBB


tubulin, beta 1 class VI
TUBB1


tubulin, beta 2A class Ila
TUBB2A


tubulin, beta 2B class IIb
TUBB2B


tubulin, beta 3 class III
TUBB3


tubulin, beta 4A class IVa
TUBB4A


tubulin, beta 4B class IVb
TUBB4B


tubulin, beta 6 class V
TUBB6


tubulin, beta 7, pseudogene
TUBB7P


tubulin, beta 8 class VIII
TUBB8


tubulin, beta pseudogene 1
TUBBP1


tubulin, beta pseudogene 2
TUBBP2


tubulin, beta class I
TUBBP6


pseudogene 6


tubulin, gamma 1
TUBG1


tubulin, gamma complex
TUBGCP2


associated protein 2


tubulin, gamma complex
TUBGCP3


associated protein 3


tubulin, gamma complex
TUBGCP4


associated protein 4


Tu translation elongation
TUFM


factor, mitochondrial


twinfilin actin binding protein 1
TWF1


twinfilin actin binding protein 2
TWF2


taxilin alpha
TXLNA


thioredoxin
TXN


thioredoxin domain containing 16
TXNDC16


thioredoxin domain containing 17
TXNDC17


thioredoxin domain containing 5
TXNDC5


(endoplasmic reticulum)


thioredoxin domain containing 8
TXNDC8


(spermatozoa)


thioredoxin-like 1
TXNL1


thioredoxin reductase 1
TXNRD1


tyrosine kinase 2
TYK2


thymidine phosphorylase
TYMP


tyrosinase-related protein 1
TYRP1


tRNA-yW synthesizing protein 5
TYW5


U2 small nuclear RNA
U2AF1


auxiliary factor 1


U2 small nuclear RNA
U2AF1L4


auxiliary factor 1-like 4


U2 small nuclear RNA
U2AF2


auxiliary factor 2


U2 snRNP-associated SURP
U2SURP


domain containing


uveal autoantigen with coiled-
UACA


coil domains and ankyrin


repeats


UDP-N-acetylglucosamine
UAP1


pyrophosphorylase 1


UDP-N-acetylglucosamine
UAP1L1


pyrophosphorylase 1 like 1


ubiquitin-like modifier
UBA1


activating enzyme 1


ubiquitin-like modifier
UBA2


activating enzyme 2


ubiquitin-like modifier
UBA5


activating enzyme 5


ubiquitin A-52 residue
UBA52


ribosomal protein fusion


product 1


ubiquitin-like modifier
UBA6


activating enzyme 6


ubiquitin-like modifier
UBA7


activating enzyme 7


UBA domain containing 1
UBAC1


UBA domain containing 2
UBAC2


ubiquitin associated protein 1
UBAP1


ubiquitin associated protein 2-
UBAP2L


like


ubiquitin associated and SH3
UBASH3B


domain containing B


ubiquitin B
UBB


ubiquitin C
UBC


ubiquitin-conjugating enzyme
UBE2D2


E2D 2


ubiquitin-conjugating enzyme
UBE2D3


E2D 3


ubiquitin-conjugating enzyme
UBE2G1


E2G 1


ubiquitin-conjugating enzyme
UBE2K


E2K


ubiquitin-conjugating enzyme
UBE2L3


E2L 3


ubiquitin-conjugating enzyme
UBE2M


E2M


ubiquitin-conjugating enzyme
UBE2N


E2N


ubiquitin-conjugating enzyme
UBE2NL


E2N-like (gene/pseudogene)


ubiquitin-conjugating enzyme
UBE2O


E2O


ubiquitin-conjugating enzyme
UBE2V1


E2 variant 1


ubiquitin-conjugating enzyme
UBE2V2


E2 variant 2


ubiquitin-conjugating enzyme
UBE2Z


E2Z


ubiquitin protein ligase E3A
UBE3A


ubiquitin protein ligase E3B
UBE3B


ubiquitin protein ligase E3C
UBE3C


ubiquitination factor E4A
UBE4A


ubiquitination factor E4B
UBE4B


ubiquitin-like 3
UBL3


ubiquilin 1
UBQLN1


ubiquilin 2
UBQLN2


ubiquilin 4
UBQLN4


ubiquitin protein ligase E3
UBR2


component n-recognin 2


ubiquitin protein ligase E3
UBR4


component n-recognin 4


ubiquitin domain containing 1
UBTD1


ubiquitin domain containing 2
UBTD2


UBX domain protein 1
UBXN1


UBX domain protein 6
UBXN6


ubiquitin carboxyl-terminal
UCHL1


esterase L1 (ubiquitin


thiolesterase)


ubiquitin carboxyl-terminal
UCHL3


esterase L3 (ubiquitin


thiolesterase)


ubiquitin carboxyl-terminal
UCHL5


hydrolase L5


uridine-cytidine kinase 2
UCK2


UEV and lactate/malate
UEVLD


dehyrogenase domains


ubiquitin-fold modifier
UFC1


conjugating enzyme 1


ubiquitin fusion degradation 1
UFD1L


like (yeast)


UFM1-specific ligase 1
UFL1


UDP-glucose ceramide
UGCG


glucosyltransferase


UDP-glucose 6-
UGDH


dehydrogenase


UDP-glucose glycoprotein
UGGT1


glucosyltransferase 1


UDP-glucose
UGP2


pyrophosphorylase 2


ubiquitin-like with PHD and
UHRF1


ring finger domains 1


unc-51 like kinase 3
ULK3


uromodulin
UMOD


uridine monophosphate
UMPS


synthetase


unc-119 homolog B
UNC119B


(C. elegans)


unc-13 homolog B
UNC13B


(C. elegans)


unc-13 homolog C
UNC13C


(C. elegans)


unc-13 homolog D
UNC13D


(C. elegans)


unc-45 homolog A
UNC45A


(C. elegans)


unc-5 homolog D
UNC5D


(C. elegans)


unc-80 homolog
UNC80


(C. elegans)


ureidopropionase, beta
UPB1


UPF1 regulator of nonsense
UPF1


transcripts homolog (yeast)


uroplakin 1A
UPK1A


uroplakin 1B
UPK1B


uroplakin 2
UPK2


uroplakin 3A
UPK3A


uroplakin 3B-like
UPK3BL


uridine phosphorylase 1
UPP1


ubiquinol-cytochrome c
UQCRC1


reductase core protein I


ubiquinol-cytochrome c
UQCRC2


reductase core protein II


URB1 ribosome biogenesis 1
URB1


homolog (S. cerevisiae)


uroporphyrinogen
UROD


decarboxylase


USO1 vesicle transport factor
USO1


ubiquitin specific peptidase 1
USP1


ubiquitin specific peptidase 11
USP11


ubiquitin specific peptidase 14
USP14


(tRNA-guanine


transglycosylase)


ubiquitin specific peptidase 15
USP15


ubiquitin specific peptidase 24
USP24


ubiquitin specific peptidase 39
USP39


ubiquitin specific peptidase 4
USP4


(proto-oncogene)


ubiquitin specific peptidase 46
USP46


ubiquitin specific peptidase 49
USP49


ubiquitin specific peptidase 5
USP5


(isopeptidase T)


USP6 N-terminal like
USP6NL


ubiquitin specific peptidase 7
USP7


(herpes virus-associated)


ubiquitin specific peptidase 9,
USP9X


X-linked


ubiquitin specific peptidase 9,
USP9Y


Y-linked


UTP14, U3 small nucleolar
UTP14A


ribonucleoprotein, homolog A


(yeast)


UTP20, small subunit (SSU)
UTP20


processome component,


homolog (yeast)


utrophin
UTRN


urotensin 2
UTS2


UDP-glucuronate
UXS1


decarboxylase 1


Vac14 homolog
VAC14


(S. cerevisiae)


vesicle-associated membrane
VAMP1


protein 1 (synaptobrevin 1)


vesicle-associated membrane
VAMP2


protein 2 (synaptobrevin 2)


vesicle-associated membrane
VAMP3


protein 3


vesicle-associated membrane
VAMP5


protein 5


vesicle-associated membrane
VAMP7


protein 7


vesicle-associated membrane
VAMP8


protein 8


VANGL planar cell polarity
VANGL1


protein 1


VAMP (vesicle-associated
VAPA


membrane protein)-


associated protein A, 33 kDa


VAMP (vesicle-associated
VAPB


membrane protein)-


associated protein B and C


valyl-tRNA synthetase
VARS


vasorin
VASN


vasodilator-stimulated
VASP


phosphoprotein


vesicle amine transport 1
VAT1


vesicle amine transport 1-like
VAT1L


vav 1 guanine nucleotide
VAV1


exchange factor


von Hippel-Lindau binding
VBP1


protein 1


versican
VCAN


vinculin
VCL


valosin containing protein
VCP


valosin containing protein
VCPIP1


(p97)/p47 complex interacting


protein 1


voltage-dependent anion
VDAC1


channel 1


voltage-dependent anion
VDAC2


channel 2


voltage-dependent anion
VDAC3


channel 3


vascular endothelial growth
VEGFC


factor C


villin 1
VIL1


vimentin
VIM


vitelline membrane outer layer
VMO1


1 homolog (chicken)


vanin 1
VNN1


vacuolar protein sorting 11
VPS11


homolog (S. cerevisiae)


vacuolar protein sorting 13
VPS13C


homolog C (S. cerevisiae)


vacuolar protein sorting 13
VPS13D


homolog D (S. cerevisiae)


vacuolar protein sorting 16
VPS16


homolog (S. cerevisiae)


vacuolar protein sorting 18
VPS18


homolog (S. cerevisiae)


vacuolar protein sorting 25
VPS25


homolog (S. cerevisiae)


vacuolar protein sorting 26
VPS26A


homolog A (S. pombe)


vacuolar protein sorting 26
VPS26B


homolog B (S. pombe)


vacuolar protein sorting 28
VPS28


homolog (S. cerevisiae)


vacuolar protein sorting 29
VPS29


homolog (S. cerevisiae)


vacuolar protein sorting 33
VPS33A


homolog A (S. cerevisiae)


vacuolar protein sorting 33
VPS33B


homolog B (yeast)


vacuolar protein sorting 35
VPS35


homolog (S. cerevisiae)


vacuolar protein sorting 36
VPS36


homolog (S. cerevisiae)


vacuolar protein sorting 37
VPS37B


homolog B (S. cerevisiae)


vacuolar protein sorting 37
VPS37C


homolog C (S. cerevisiae)


vacuolar protein sorting 37
VPS37D


homolog D (S. cerevisiae)


vacuolar protein sorting 39
VPS39


homolog (S. cerevisiae)


vacuolar protein sorting 41
VPS41


homolog (S. cerevisiae)


vacuolar protein sorting 45
VPS45


homolog (S. cerevisiae)


vacuolar protein sorting 4
VPS4A


homolog A (S. cerevisiae)


vacuolar protein sorting 4
VPS4B


homolog B (S. cerevisiae)


vacuolar protein sorting 51
VPS51


homolog (S. cerevisiae)


vacuolar protein sorting 52
VPS52


homolog (S. cerevisiae)


vacuolar protein sorting 53
VPS53


homolog (S. cerevisiae)


vacuolar protein sorting 8
VPS8


homolog (S. cerevisiae)


vaccinia related kinase 1
VRK1


vaccinia related kinase 3
VRK3


visual system homeobox 2
VSX2


vesicle (multivesicular body)
VTA1


trafficking 1


vesicle transport through
VTI1A


interaction with t-SNAREs 1A


vesicle transport through
VTI1B


interaction with t-SNAREs 1B


vitronectin
VTN


von Willebrand factor A
VWA1


domain containing 1


von Willebrand factor A
VWA2


domain containing 2


von Willebrand factor A
VWA3B


domain containing 3B


von Willebrand factor
VWF


tryptophanyl-tRNA synthetase
WARS


Wiskott-Aldrich syndrome
WAS


WAS protein family, member 1
WASF1


WAS protein family, member 2
WASF2


WAS protein family, member 3
WASF3


Wiskott-Aldrich syndrome-like
WASL


WW domain binding protein 2
WBP2


WD repeat and FYVE domain
WDFY1


containing 1


WDFY family member 4
WDFY4


WD repeat domain 1
WDR1


WD repeat domain 11
WDR11


WD repeat domain 18
WDR18


WD repeat domain 26
WDR26


WD repeat domain 33
WDR33


WD repeat domain 37
WDR37


WD repeat domain 4
WDR4


WD repeat domain 44
WDR44


WD repeat domain 48
WDR48


WD repeat domain 49
WDR49


WD repeat domain 5
WDR5


WD repeat domain 61
WDR61


WD repeat domain 63
WDR63


WD repeat domain 7
WDR7


WD repeat domain 70
WDR70


WD repeat domain 77
WDR77


WD repeat domain 82
WDR82


WD repeat domain 92
WDR92


WD and tetratricopeptide
WDTC1


repeats 1


WEE1 G2 checkpoint kinase
WEE1


Wolf-Hirschhorn syndrome
WHSC1


candidate 1


WAS/WASL interacting
WIPF1


protein family, member 1


widely interspaced zinc finger
WIZ


motifs


wingless-type MMTV
WNT10B


integration site family,


member 10B


wingless-type MMTV
WNT5A


integration site family,


member 5A


wingless-type MMTV
WNT5B


integration site family,


member 5B


Werner helicase interacting
WRNIP1


protein 1


RAB6C-like
WTH3DI


WW domain containing E3
WWP1


ubiquitin protein ligase 1


WW domain containing E3
WWP2


ubiquitin protein ligase 2


XPA binding protein 2
XAB2


xanthine dehydrogenase
XDH


X-prolyl aminopeptidase
XPNPEP1


(aminopeptidase P) 1, soluble


X-prolyl aminopeptidase
XPNPEP2


(aminopeptidase P) 2,


membrane-bound


X-prolyl aminopeptidase 3,
XPNPEP3


mitochondrial


exportin 1
XPO1


exportin 4
XPO4


exportin 5
XPO5


exportin 6
XPO6


exportin 7
XPO7


exportin, tRNA
XPOT


xenotropic and polytropic
XPR1


retrovirus receptor 1


X-ray repair complementing
XRCC5


defective repair in Chinese


hamster cells 5 (double-


strand-break rejoining)


X-ray repair complementing
XRCC6


defective repair in Chinese


hamster cells 6


5′-3′ exoribonuclease 2
XRN2


xylulokinase homolog
XYLB


(H. influenzae)


tyrosyl-tRNA synthetase
YARS


Y box binding protein 1
YBX1


Y box binding protein 2
YBX2


Y box binding protein 3
YBX3


YES proto-oncogene 1, Src
YES1


family tyrosine kinase


Yip1 interacting factor
YIF1B


homolog B (S. cerevisiae)


Yip1 domain family, member 2
YIPF2


Yip1 domain family, member 6
YIPF6


YKT6 v-SNARE homolog
YKT6


(S. cerevisiae)


YTH domain containing 2
YTHDC2


tyrosine 3-
YWHAB


monooxygenase/tryptophan


5-monooxygenase activation


protein, beta


tyrosine 3-
YWHAE


monooxygenase/tryptophan


5-monooxygenase activation


protein, epsilon


tyrosine 3-
YWHAEP5


monooxygenase/tryptophan


5-monooxygenase activation


protein, epsilon pseudogene 5


tyrosine 3-
YWHAG


monooxygenase/tryptophan


5-monooxygenase activation


protein, gamma


tyrosine 3-
YWHAH


monooxygenase/tryptophan


5-monooxygenase activation


protein, eta


tyrosine 3-
YWHAQ


monooxygenase/tryptophan


5-monooxygenase activation


protein, theta


tyrosine 3-
YWHAZ


monooxygenase/tryptophan


5-monooxygenase activation


protein, zeta


zeta-chain (TOR) associated
ZAP70


protein kinase 70 kDa


zinc finger and BTB domain
ZBTB10


containing 10


zinc finger and BTB domain
ZBTB4


containing 4


zinc finger and BTB domain
ZBTB49


containing 49


zinc finger CCCH-type,
ZC3HAV1


antiviral 1


zinc finger CCCH-type,
ZC3HAV1L


antiviral 1-like


zinc finger, C4H2 domain
ZC4H2


containing


zinc finger, CCHC domain
ZCCHC11


containing 11


zinc finger, DHHC-type
ZDHHC1


containing 1


zinc finger, DHHC-type
ZDHHC13


containing 13


zinc finger, DHHC-type
ZDHHC18


containing 18


zinc finger, DHHC-type
ZDHHC20


containing 20


zinc finger, DHHC-type
ZDHHC5


containing 5


zinc finger, AN1-type domain
ZFAND5


5


zinc finger, C3H1-type
ZFC3H1


containing


zinc finger protein, FOG
ZFPM1


family member 1


zinc finger, FYVE domain
ZFYVE26


containing 26


zymogen granule protein 16B
ZG16B


zinc finger, GRF-type
ZGRF1


containing 1


zinc finger with KRAB and
ZKSCAN5


SCAN domains 5


zinc metallopeptidase STE24
ZMPSTE24


zinc finger, MYM-type 1
ZMYM1


zinc finger protein 114
ZNF114


zinc finger protein 134
ZNF134


zinc finger protein 169
ZNF169


zinc finger protein 185 (LIM
ZNF185


domain)


zinc finger protein 205
ZNF205


zinc finger protein 217
ZNF217


zinc finger protein 254
ZNF254


zinc finger protein 28
ZNF28


zinc finger protein 326
ZNF326


zinc finger protein 33A
ZNF33A


zinc finger protein 486
ZNF486


zinc finger protein 503
ZNF503


zinc finger protein 518A
ZNF518A


zinc finger protein 541
ZNF541


zinc finger protein 571
ZNF571


zinc finger protein 614
ZNF614


zinc finger protein 624
ZNF624


zinc finger protein 638
ZNF638


zinc finger protein 764
ZNF764


zinc finger protein 792
ZNF792


zinc finger protein 862
ZNF862


zinc finger, HIT-type
ZNHIT6


containing 6


zona pellucida glycoprotein 3
ZP3


(sperm receptor)


zw10 kinetochore protein
ZW10


zyxin
ZYX


zinc finger, ZZ-type with EF-
ZZEF1


hand domain 1