Methods and compositions for neuroprotection

The present invention relates to compositions and methods for treating neurodegeneration and neurodegenerative diseases associated with axonal degeneration. Neurodegeneration and neurodegenerative diseases associated with axonal degeneration are treated with therapies comprising SARM1 inhibitors such as SARM1 antisense oligonucleotides.

1. 11. An antisense oligonucleotide comprising a sequence having at least 95% identity to a sequence selected from a group consisting of SEQ ID NO: 4-10, 12-14, 18-21, 23-26, and 38.
2. 22. The antisense oligonucleotide of claim 1, comprising a sequence selected from the group consisting of SEQ ID NO: 4-10, 12-14, 18-21, 23-26, and 38.
3. 33. The antisense oligonucleotide of claim 2, wherein the antisense oligonucleotide comprises one or more modifications.
4. 44. The antisense oligonucleotide of claim 3, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
5. 55. An antisense oligonucleotide comprising a sequence having at least 95% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39, wherein the antisense oligonucleotide comprises one or more modifications, the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof and the antisense oligonucleotide comprises internucleotide linkages of the pattern RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond.
6. 66. An antisense oligonucleotide comprising a sequence selected from the group consisting of SEQ ID NO: 2410-2412, wherein the antisense oligonucleotide comprises internucleotide linkages of the pattern RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond.

CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 62/940,437, filed Nov. 26, 2019, which is herein incorporated by reference in its entirety.


SEQUENCE LISTING
The instant application contains a Sequence Listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created Nov. 23, 2020 is named 2012800-0042_SL.txt, and is 652,394 bytes in size.
BACKGROUND
Axonal degeneration is a hallmark of several neurological disorders including peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases (Gerdts et al., Science, 2015, 348:453-457, hereby incorporated by reference in its entirety). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. Costs associated with these diseases currently exceed several hundred billion dollars annually in the Unites States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is rapidly increasing as demographics change.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the insight that, following axonal damage, Sterile Alpha and TIR motif-containing 1 (SARM1) serves as the central executioner in the axonal degeneration pathway. The present invention provides, among other things, the recognition that antisense oligonucleotides that inhibit SARM1 are particularly beneficial for preventing axonal degeneration.
In one aspect, the present disclosure provides antisense oligonucleotides comprising a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-2412.
In some embodiments, an antisense oligonucleotide comprises one or more modifications. In some embodiments, one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
In another aspect, the present disclosure comprises pharmaceutical compositions comprising antisense oligonucleotides of the present disclosure. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier.
In another aspect, the present disclosure comprises methods for treating and/or preventing axonal degeneration in a subject, comprising: administering to the subject an antisense oligonucleotide is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1).
In another aspect, the present disclosure comprises methods comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1.
In some embodiments, a target nucleic acid encoding SARM1 is a SARM1 mRNA.
In some embodiments, an antisense oligonucleotide comprises a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-2412.
In some embodiments, an antisense oligonucleotide comprises one or more modifications. In some embodiments, one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
In some embodiments, administering an antisense oligonucleotide decreases levels of SARM1 mRNA in the subject. In some embodiments, administering an antisense oligonucleotide decreases levels of SARM1 protein in the subject.
In some embodiments, a neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS. In some embodiments, a chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder. In some embodiments, a chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies. In some embodiments, a systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa. In some embodiments, a pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes. In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system. In some embodiments, an acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy. In some embodiments, a mechanical injury comprises a compression or entrapment injury or a pressure injury. In some embodiments, a compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone. In some embodiments, a pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure. In some embodiments, a chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin. In some embodiments, an epothilone is ixabepilone. In some embodiments, a taxane is paclitaxel or docetaxel. In some embodiments, a vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine. In some embodiments, a proteasome inhibitor is bortezomib. In some embodiments, a platinum-based drug is cisplatin, oxaliplatin, or carboplatin. In some embodiments, an auristatin is conjugated monomethyl auristatin E.
In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS. In some embodiments, a chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
In some embodiments, a chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder. In some embodiments, an optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide. In some embodiments, a traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE). In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS. In some embodiments, an acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis. In some embodiments, an ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy. In some embodiments, a traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer. In some embodiments, a viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia). In some embodiments, a neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
In some embodiments, a subject is a human. In some embodiments, a subject is a patient with one or more risk factors for developing a condition involving axonal degeneration. In some embodiments, one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof. In some embodiments, one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof. In some embodiments, engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing. In some embodiments, one or more biomarkers of neurodegeneration comprise: concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; constitutive NAD+ levels in neurons and/or axons of the subject; constitutive cADPR levels in neurons and/or axons of the subject; levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.



BRIEF DESCRIPTION OF THE DRAWING
The foregoing and other features and advantages of the present invention will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings. It should be understood that the present invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.
FIG. 1 shows a map of antisense oligonucleotides complementary to human SARM1 mRNA.
FIG. 2 shows a graph illustrating average fold-change in SARM1 gene expression in cells after transfection with SARM1 antisense oligonucleotides.
FIG. 3 shows a graph illustrating average fold-change in SARM1 gene expression in cells after transfection with SARM1 antisense oligonucleotides.
FIG. 4 shows a graph illustrating relative SARM1 mRNA expression in human induced pluripotent stem cells (IPSC)-derived motor neurons following transfection with antisense oligonucleotides targeting the SARM1 transcript.
FIG. 5 shows a graph illustrating relative SARM1 mRNA expression in human induced pluripotent stem cells (IPSC)-derived motor neurons following delivery by free uptake (i.e. in the absence of a lipid carrier) with antisense oligonucleotides targeting the SARM1 transcript.
FIG. 6 shows a graph illustrating relative SARM1 mRNA expression in human induced pluripotent stem cells (IPSC)-derived motor neurons 2 days and 6 days following delivery by free uptake (i.e. in the absence of a lipid carrier) with antisense oligonucleotides targeting the SARM1 transcript.
FIG. 7 shows a graph illustrating that SARM1 antisense oligonucleotides prevent axonal degeneration following axotomy in human iPSC-derived motor neurons treated using free uptake delivery.



DEFINITIONS
Binding: It will be understood that the term “binding”, as used herein, typically refers to an association (e.g., a non-covalent or covalent association) between or among two or more entities. “Direct” binding involves physical contact between entities or moieties; indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts-including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and/or in a biological system or cell).
Biological Sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; other body fluids, secretions, and/or excretions; and/or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
Biomarker: The term “biomarker” is used herein to refer to a to an entity, event, or characteristic whose presence, level, degree, type, and/or form, correlates with a particular biological event or state of interest, so that it is considered to be a “marker” of that event or state. To give but a few examples, in some embodiments, a biomarker may be or comprise a marker for a particular disease state, or for likelihood that a particular disease, disorder or condition may develop, occur, or reoccur. In some embodiments, a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof. Thus, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest. A biomarker may be or comprise an entity of any chemical class, and may be or comprise a combination of entities. For example, in some embodiments, a biomarker may be or comprise a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an inorganic agent (e.g., a metal or ion), or a combination thereof. In some embodiments, a biomarker is a cell surface marker. In some embodiments, a biomarker is intracellular. In some embodiments, a biomarker is detected outside of cells (e.g., is secreted or is otherwise generated or present outside of cells, e.g., in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc. In some embodiments, a biomarker may be or comprise a genetic or epigenetic signature. In some embodiments, a biomarker may be or comprise a gene expression signature.
In some embodiments, a biomarker may be or comprise a marker for neurodegeneration, or for likelihood that a neurodegenerative disease, disorder or condition may develop, occur, or reoccur. In some embodiments, a biomarker may be or comprise a marker of neurodegeneration a therapeutic outcome, or likelihood thereof. Thus, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, and in some embodiments, a biomarker is diagnostic, of a neurodegenerative disease, disorder or condition. In some embodiments changes in biomarker levels can be detected via cerebral spinal fluid (CSF), plasma and/or serum. In some embodiments a biomarker can be a detectable signal produced by medical imaging techniques including, but not limited to, magnetic resonance imaging (MRI), positron emission-tomography (PET), and/or computed tomography (CT). In some embodiments, a biomarker can be a detectable change in electrophysiological properties.
In some embodiments, neurodegeneration may be assessed, for example, by detecting an increase and/or decrease in the concentration of neurofilament light chain protein (NF-L) and/or neurofilament heavy chain protein (NF-H) contained in bodily fluids from a subject including, but not limited to, cerebral spinal fluid, blood, serum and/or plasma. In some embodiments, the incidence and/or progression of neurodegeneration can be assessed via positron emission tomography (PET) with a synaptic vesicle glycoprotein 2a (SV2A) ligand. In some embodiments, a detectable change in constitutive NAD+ and/or cADPR levels in neurons can be used to assess neurodegeneration.
In some embodiments, a detectable change in one or more neurodegeneration associated proteins in a subject, relative to a healthy reference population can be used as a biomarker of neurodegeneration. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, and/or total-tau. In some embodiments, an increase in cytokines and/or chemokines, including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and/or Il6, can be used as a biomarker of neurodegeneration.
Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.
Combination: The terms “combination therapy” or “in combination with”, as used herein, refer to those situations in which two or more different pharmaceutical agents for the treatment of disease are administered in overlapping regimens so that the subject is simultaneously exposed to at least two agents. In some embodiments, the different agents are administered simultaneously. In some embodiments, the administration of one agent overlaps the administration of at least one other agent. In some embodiments, the different agents are administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen) such that the agents have simultaneous biologically activity within a subject. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form—e.g., gas, gel, liquid, solid, etc.
Domain: The term “domain” as used herein refers to a section or portion of an entity. In some embodiments, a “domain” is associated with a particular structural and/or functional feature of the entity so that, when the domain is physically separated from the rest of its parent entity, it substantially or entirely retains the particular structural and/or functional feature. Alternatively or additionally, a domain may be or include a portion of an entity that, when separated from that (parent) entity and linked with a different (recipient) entity, substantially retains and/or imparts on the recipient entity one or more structural and/or functional features that characterized it in the parent entity. In some embodiments, a domain is a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a section of a polypeptide; in some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, aa-helix character, ββ-sheet character, coiled-coil character, random coil character, etc.), and/or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).
Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.
Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).
Excipient: as used herein, refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
Inhibitory agent: As used herein, the term “inhibitory agent” refers to an entity, condition, or event whose presence, level, or degree correlates with decreased level or activity of a target. In some embodiments, an inhibitory agent may act directly (in which case it exerts its influence directly upon its target, for example, by binding to the target); in some embodiments, an inhibitory agent may act indirectly (in which case it exerts its influence by interacting with and/or otherwise altering a regulator of the target, so that level and/or activity of the target is reduced). In some embodiments, an inhibitory agent is one whose presence or level correlates with a target level or activity that is reduced relative to a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known inhibitory agent, or absence of the inhibitory agent in question, etc.).
Neurodegeneration: As used herein, the term “neurodegeneration” refers to a reduction in one or more features, structures, function, or characteristics of a neuron or neuronal tissue. In some embodiments, neurodegeneration is observed as a pathological reduction in an organism. Those skilled in the art will appreciate that neurodegeneration is associated with certain diseases, disorders and conditions, including those that affect humans. In some embodiments, neurodegeneration may be transient (e.g., as sometimes occurs in association with certain infections and/or chemical or mechanical disruptions); in some embodiments, neurodegeneration may be chronic and/or progressive (e.g., as is often associated with certain diseases, disorders or conditions such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington disease, or Alzheimer's disease). In some embodiments, neurodegeneration may be assessed, for example, by detecting in a subject an increase in a biomarker associated with neurodegeneration. In some embodiments, neurodegeneration may be assessed, for example, by detecting in a subject a decrease in a biomarker associated with neurodegeneration. Alternatively or additionally, in some embodiments, neurodegeneration may be assessed by magnetic resonance imaging (MRI), biomarkers contained in cerebral spinal fluid, or other biomarkers observed in subjects. In some embodiments, neurodegeneration is defined as a score below 24 on the mini-mental state examination. In some embodiments, neurodegeneration refers to loss of synapses. In some embodiments, neurodegeneration refers to a reduction in neural tissue relating to a traumatic injury (e.g. exposure to an external force which disrupts the integrity of the neural tissue). In some embodiments, neurodegeneration refers to a reduction in peripheral neural tissue. In some embodiments, neurodegeneration refers to a reduction in central nervous tissue.
Nucleic acid: As used herein, in its broadest sense, refers to any compound and/or substance that is or can be incorporated into an oligonucleotide chain. In some embodiments, a nucleic acid is a compound and/or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester linkage. As will be clear from context, in some embodiments, “nucleic acid” refers to an individual nucleic acid residue (e.g., a nucleotide and/or nucleoside); in some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising individual nucleic acid residues. In some embodiments, a “nucleic acid” is or comprises RNA; in some embodiments, a “nucleic acid” is or comprises DNA. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural nucleic acid residues. In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleic acid analogs. In some embodiments, a nucleic acid analog differs from a nucleic acid in that it does not utilize a phosphodiester backbone. For example, in some embodiments, a nucleic acid is, comprises, or consists of one or more “peptide nucleic acids”, which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone, and are considered within the scope of the present invention. Alternatively or additionally, in some embodiments, a nucleic acid has one or more phosphorothioate and/or 5′-N-phosphoramidite linkages rather than phosphodiester bonds. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxy guanosine, and deoxycytidine). In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a nucleic acid comprises one or more modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose) as compared with those in natural nucleic acids. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or protein. In some embodiments, a nucleic acid includes one or more introns. In some embodiments, nucleic acids are prepared by one or more of isolation from a natural source, enzymatic synthesis by polymerization based on a complementary template (in vivo or in vitro), reproduction in a recombinant cell or system, and chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues long. In some embodiments, a nucleic acid is partly or wholly single stranded; in some embodiments, a nucleic acid is partly or wholly double stranded. In some embodiments a nucleic acid has a nucleotide sequence comprising at least one element that encodes, or is the complement of a sequence that encodes, a polypeptide. In some embodiments, a nucleic acid has enzymatic activity. In some embodiments, a nucleic acid comprises a small interfering RNA (siRNA), a short hairpin RNA (shRNA), an antisense oligonucleotide, a microRNA, a gapmer, or an aptamer.
Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
Patient: As used herein, the term “patient” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient displays one or more symptoms of a disorder or condition. In some embodiments, a patient has been diagnosed with one or more disorders or conditions. In some embodiments, the patient is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.
Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
Specific: The term “specific”, when used herein with reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity. In some embodiments, a binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and/or increased stability to its target entity as compared with the competing alternative target(s).
Subject: As used herein, the term “subject” refers to an organism, typically a mammal (e.g., a human, in some embodiments including prenatal human forms). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and/or therapy is and/or has been administered.
Therapeutic agent: As used herein, the phrase “therapeutic agent” in general refers to any agent that elicits a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject to prevent the risk of developing pathology associated with or resulting from a medical procedure and/or treatment.
DETAILED DESCRIPTION
Axonal Degeneration and SARM1
The present invention may be used to treat a subject who is suffering from or susceptible to axonal degeneration. Axonal degeneration is a major pathological feature of neurological diseases such as, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, inherited neuropathy, traumatic brain injury, and/or glaucoma. Damaged or unhealthy axons are eliminated via an intrinsic self-destruction program known as Wallerian degeneration, which is distinct from traditional cellular death pathways like apoptosis (Gerdts, J., et al., Neuron, 2016, 89, 449-460; Whitmore, A. et al., Cell Death Differ., 2003, 10, 260-261, each of which is hereby incorporated by reference in its entirety). During Wallerian degeneration, a nerve undergoes selective breakdown of the axon segment distal to an injury, whereas the proximal axon segment and cell body remain intact. Axonal degeneration following an injury is characterized by the sequential depletion of NMNAT2, NAD+ and ATP, followed by neurofilament proteolysis and axonal fragmentation occurring approximately 8 to 24 hours after the original injury (Gerdts, J., et al., Neuron, 2016, 89, 449-460, hereby incorporated by reference in its entirety).
It has recently been discovered that knocking-down or eliminating the expression of SARM1 leads to long-lasting protection of sensory neurons against injury-induced axonal degeneration (Gerdts et al., J. Neurosci, 2013, 33, 13569-13580, which is hereby incorporated by reference in its entirety). Following axonal damage, SARM1 serves as the central executioner in the axonal degeneration pathway. Activated SARM1 is a highly effective NADase that depletes local axonal NAD+ reserves within minutes to a few hours after activation, leading to a local bioenergetic crisis, followed by rapid axonal degeneration. Activation of SARM1 via axonal injury or forced dimerization of SARM1-TIR domains promotes rapid and catastrophic depletion of NAD+, followed soon after by axonal degeneration, which highlights the central role of NAD+ homeostasis in axonal integrity (Gerdts, J., et al., Science, 2015, 348, 453-457). SARM1 is required for this injury-induced NAD+ depletion both in vitro and in vivo and SARM1 activation triggers axon degeneration locally via NAD+ destruction (Gerdts et al., et al., Science, 2015, 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238, each of which is hereby incorporated by reference in its entirety).
The protein sequence of wild-type human SARM1 is as follows:







(SEQ ID NO: 1)


MVLTLLLSAYKLCRFFAMSGPRPGAERLAVPGPDGGGGTGPWWAAGGRGP


 


REVSPGAGTEVQDALERALPELQQALSALKQAGGARAVGAGLAEVFQLVE


 


EAWLLPAVGREVAQGLCDAIRLDGGLDLLLRLLQAPELETRVQAARLLEQ


 


ILVAENRDRVARIGLGVILNLAKEREPVELARSVAGILEHMFKHSEETCQ


 


RLVAAGGLDAVLYWCRRTDPALLRHCALALGNCALHGGQAVQRRMVEKRA


 


AEWLFPLAFSKEDELLRLHACLAVAVLATNKEVEREVERSGTLALVEPLV


 


ASLDPGRFARCLVDASDTSQGRGPDDLQRLVPLLDSNRLEAQCIGAFYLC


 


AEAAIKSLQGKTKVFSDIGAIQSLKRLVSYSTNGTKSALAKRALRLLGEE


 


VPRPILPSVPSWKEAEVQTWLQQIGFSKYCESFREQQVDGDLLLRLTEEE


 


LQTDLGMKSGITRKRFFRELTELKTFANYSTCDRSNLADWLGSLDPRFRQ


 


YTYGLVSCGLDRSLLHRVSEQQLLEDCGIHLGVHRARILTAAREMLHSPL


 


PCTGGKPSGDTPDVFISYRRNSGSQLASLLKVHLQLHGFSVFIDVEKLEA


 


GKFEDKLIQSVMGARNFVLVLSPGALDKCMQDHDCKDWVHKEIVTALSCG


 


KNIVPIIDGFEWPEPQVLPEDMQAVLTFNGIKWSHEYQEATIEKIIRFLQ


 


GRSSRDSSAGSDTSLEGAAPMGPT.






Genetic loss-of-function studies indicate that SARM1 serves as the central executioner of the axonal degeneration pathway following an injury. Genetic deletion or knockout of SARM1 allows for preservation of axons for 14 or more days after nerve transection (Osterloh, J. M., et al., Science, 2012, 337, 481-484; Gerdts, J., et al. J. Neurosci., 2013, 33, 13569-13580, each of which is hereby incorporated by reference in its entirety) and also improves functional outcomes in mice after traumatic brain injury (Henninger, N. et al., Brain, 139, 2016, 1094-1105, which is hereby incorporated by reference in its entirety). In addition to the direct role SARM1 plays in axonal injury, SARM1 is also required for the axonal degeneration observed in chemotherapy-induced peripheral neuropathy (CIPN). Loss of SARM1 prevents CIPN, inhibiting both the axonal degeneration and the heightened pain sensitivity that develops after chemotherapeutic vincristine treatment (Geisler et al, Brain, 2016, 139, 3092-3108, which is hereby incorporated by reference in its entirety).
SARM1 Antisense Oligonucleotides
In some embodiments, the present disclosure provides antisense oligonucleotides. In some embodiments, an antisense oligonucleotide is an RNase H-dependent oligonucleotide, wherein the antisense oligonucleotide induces the degradation of mRNA. In some embodiments, an antisense oligonucleotide is a steric-blocker oligonucleotide, wherein the antisense oligonucleotide physically prevents or inhibits the progression of splicing or translational machinery. Antisense oligonucleotides of the present disclosure are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity. In some embodiments, antisense activity comprises degradation of a target nucleic acid by RNase H. In some embodiments, antisense activity comprises an antisense oligonucleotide physically preventing or inhibiting the progression of splicing or translational machinery.
In some embodiments, antisense oligonucleotides specifically hybridize to one or more target nucleic acids. In some embodiments, a target nucleic acid comprises a full-length mRNA. In some embodiments, a target nucleic acid comprises a region of an mRNA. In some embodiments, antisense oligonucleotides of the present invention hybridize to the same target nucleic acid. In some embodiments, antisense oligonucleotides of the present invention hybridize to different target nucleic acids. In some embodiments, a specifically hybridizing antisense oligonucleotide has a nucleobase sequence comprising a region having sufficient complementarity to a target nucleic acid to allow hybridization and result in antisense activity and insufficient complementarity to any non-target so as to avoid non-specific hybridization to any non-target nucleic acid sequences under conditions in which specific hybridization is desired (e.g., under physiological conditions for in vivo or therapeutic uses, and under conditions in which assays are performed in the case of in vitro assays).
In some embodiments, the present disclosure provides antisense oligonucleotides that are fully complementary to a target nucleic acid over the entire length of the antisense oligonucleotide. In some embodiments, an antisense oligonucleotide is 99% complementary to a target nucleic acid over the entire length of the antisense oligonucleotide. In some embodiments, an antisense oligonucleotide is 95% complementary to a target nucleic acid over the entire length of the antisense oligonucleotide. In some embodiments, an antisense oligonucleotide is 90% complementary to a target nucleic acid over the entire length of the antisense oligonucleotide. In some embodiments, an antisense oligonucleotide is 85% complementary to a target nucleic acid over the entire length of the antisense oligonucleotide. In some embodiments, an antisense oligonucleotide is 80% complementary to a target nucleic acid over the entire length of the antisense oligonucleotide. In some embodiments, an antisense oligonucleotide is between 80% and 99% complementary to a target nucleic acid over the entire length of the antisense oligonucleotide. In some embodiments, an antisense oligonucleotide comprises a region that is fully complementary to a target nucleic acid and is at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide. In some embodiments, the region of full complementarity is from 6 to 14 nucleobases in length.
In some embodiments, an antisense oligonucleotide comprises a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-26. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-2081.
In some embodiments, an antisense oligonucleotide comprises a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-2412.
In some embodiments, an antisense oligonucleotide comprises a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549. In some embodiments, an antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549. In some embodiments, an antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549.
In some embodiments, a target nucleic acid is an endogenous RNA molecule. In some embodiments, a target nucleic acid is an exogenous RNA molecule. In some embodiments, a target nucleic acid is a pre-mRNA. In some embodiments, a target nucleic acid is a mature mRNA. In some embodiments, a target nucleic acid is a SARM1 transcript.
In some embodiments, an antisense oligonucleotide of the present disclosure is complementary to a region of a SARM1 mRNA. In some embodiments, an antisense oligonucleotide is complementary to a region of a 5′ untranslated region (UTR) of a SARM1 mRNA. In some embodiments, an antisense oligonucleotide is complementary to a coding region of a SARM1 mRNA. In some embodiments, an antisense oligonucleotide is complementary to a region of a 3′ UTR of a SARM1 mRNA. In some embodiments, an antisense oligonucleotide of the present invention is complementary to a region of a SARM1 mRNA as illustrated in FIG. 1 and Table 1. Table 1 includes exemplary SARM1 antisense oligonucleotide sequences, region of complementarity in SAMR1 mRNA (5′ UTR, coding region (CDS), or 3′ UTR), oligonucleotide starting position (starting position from 5′ end of SARM1 mRNA) and code letter corresponding to antisense oligonucleotide in FIG. 1.







TABLE 1







Antisense oligonucleotide sequences,


region of complementarity and starting position












Antisense





SEQ
Oligonucleotide

Oligo



ID NO:
Sequence (5′-3′)
Region
Start
Code














3
GGCCTCCTCCACCAGTTGGA
CDS
626
B


 


4
GCAGGCTCTTGATGGCAGCC
CDS
1395
E


 


5
GCCATCCACCTGCTGCTCCC
CDS
1640
H


 


6
TCCCCACTGGGTTTGCCACC
CDS
1999
L


 


7
ACTTGCCTGCTTCCAGCTTC
CDS
2127
M


 


8
CTTGTCCAGTGCTCCAGGTG
CDS
2204
N


 


9
GCACAGCCTGCATGTCCTCA
CDS
2346
O


 


10
CCCAGGTTGTCTCAGCCCAG
3′UTR
2596
Q


 


11
TCCCTTCCCTCTCCAGATAC
3′UTR
2688
R


 


12
TGCAGAACCACCCCCACCCC
3′UTR
2814
S


 


13
GCCCAGGCCCTTGCTCAGAA
3′UTR
2932
T


 


14
GGCACTCATCCCTGGCTGGC
3′UTR
2958
U


 


15
CCCCATGCCCAGACCCAGGC
3′UTR
3231
W


 


16
GCCTCTTTCCACAGAGCTGC
3′UTR
3420
X


 


17
TCTCAGCCACCAGGATCTGC
CDS
786
D


 


18
GAGCTCCCTAAAGAACCTCT
CDS
1730
J


 


19
CCAGGTTGTCTCAGCCCAGG
3′UTR
2595
P


 


20
GGTGCAGCAGGGAGCGGTCC
CDS
1869
K


 


21
GCAGCGTCAGGACCATGGGC
5′UTR
336
A


 


22
ACCAGGCGTTTCAGGCTCTG
CDS
1453
F


 


23
CACCTCCTCGCCCAGCAGGC
CDS
1523
G


 


24
GTCTGGAGTTCCTCCTCCGT
CDS
1678
I


 


25
CCCTCGCCCTGGATGTGGCA
3′UTR
3124
V


 


26
GGCCTGCACACGCGTCTCCA
CDS
752
C


 


38
AGGTTGTCTCAGCCCAGGGA
3′UTR
2593
Y


 


39
CAGGTTGTCTCAGCCCAGGG
3′UTR
2594
Z









In some embodiments, an antisense oligonucleotide of the present disclosure comprises an oligonucleotide consisting of 8 to 30 linked nucleosides and having a nucleobase sequence comprising a complementary region comprising at least 8 contiguous nucleobases complementary to a target region of equal length of a SARM1 transcript.
In some embodiments, an antisense oligonucleotide comprises RNA. In some embodiments, an antisense oligonucleotide comprises DNA. In some embodiments, an antisense oligonucleotide comprises both RNA and DNA. In some embodiments, an antisense oligonucleotide is between 5 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 90 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 80 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 70 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 60 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 50 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 40 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 30 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 25 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 20 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 15 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 5 and 10 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 10 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 15 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 20 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 25 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 30 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 40 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 50 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 60 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 70 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is between 90 and 100 nucleotides in length. In some embodiments, an antisense oligonucleotide is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, an antisense oligonucleotide is 20 nucleotides in length.
In some embodiments, an antisense oligonucleotide comprises one or more modifications. In some embodiments, one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof. In some embodiments, any antisense oligonucleotide described herein comprises internucleotide linkages of the following pattern (5′ to 3′): RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond. In some embodiments, an antisense oligonucleotide comprises SEQ ID NO: 2410. In some embodiments, an antisense oligonucleotide comprises SEQ ID NO: 2411. In some embodiments, an antisense oligonucleotide comprises SEQ ID NO: 2412.
Methods of Treating Neurodegeneration
Methods described herein include treating and/or preventing axonal degeneration in a subject. In some embodiments, methods described herein include administering to the subject an SARM1 antisense agent. In some embodiments, methods described herein include administering to the subject an SARM1 antisense agent. Methods described herein include administering to a subject at risk of developing a neurodegenerative disease or disorder an SARM1 antisense agent. In some embodiments, an SARM1 antisense agent is an SARM1 antisense oligonucleotide.
Diseases, Disorders, and Conditions
In some embodiments, the present disclosure provides methods for treating subjects suffering from one or more diseases, disorders, or conditions. In some embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1.
In some embodiments, a neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the PNS. In some embodiments, an acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy. In some embodiments, a mechanical injury comprises a compression or entrapment injury or a pressure injury. In some embodiments, a compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone. In some embodiments, a pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure. In some embodiments, a chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin. In some embodiments, an epothilone is ixabepilone. In some embodiments, a taxane is paclitaxel or docetaxel. In some embodiments, a vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine. In some embodiments, a proteasome inhibitor is bortezomib. In some embodiments, a platinum-based drug is cisplatin, oxaliplatin, or carboplatin. In some embodiments, an auristatin is conjugated monomethyl auristatin E.
In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS. In some embodiments, a chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
In some embodiments, a chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
In some embodiments, a systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
In some embodiments, a pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS. In some embodiments, an acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
In some embodiments, an ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
In some embodiments, a traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
In some embodiments, a viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
In some embodiments, a chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
In some embodiments, a chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
In some embodiments, an optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
In some embodiments, a traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
In some embodiments, a neurodegenerative disease or disorder comprises a disease associated with neurodegeneration. In some embodiments, a neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
In some embodiments, a subject is a human. In some embodiments, a subject is at risk of developing a condition characterized by axonal degeneration. In some embodiments, a subject is a patient with one or more risk factors for developing a condition involving axonal degeneration. In some embodiments, one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
In some embodiments, one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
In some embodiments, a subject has a condition characterized by axonal degeneration. In some embodiments, a subject has been diagnosed with a condition characterized by axonal degeneration.
In some embodiments, engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
In some embodiments, one or more biomarkers of neurodegeneration comprises: concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; constitutive NAD+ levels in neurons and/or axons of the subject; constitutive cADPR levels in neurons and/or axons of the subject; levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
In some embodiments, a therapy provided herein is characterized such that, when administered to a population of subjects, the therapy reduces one or more symptoms or features of neurodegeneration. For example, in some embodiments, a relevant symptom or feature may be selected from the group consisting of extent, rate, and/or timing of neuronal disruption.
Subjects
In some embodiments, a composition as described herein is administered to subjects suffering from or susceptible to a disease, disorder or condition as described herein; in some embodiments, such a disease, disorder or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein.
In some embodiments, a subject to whom a composition is administered as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.
In some embodiments, provided methods comprise administering a composition to a patient in need thereof. In some such embodiments, the patient is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.
In some embodiments, provided methods comprise administering a composition as described herein to a patient population of in need thereof. In some embodiments, the population is drawn from individuals who engage in activities where the potential for traumatic neuronal injury is high. In some embodiments, the population is drawn from athletes who engage in contact sports or other high-risk activities.
In some embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the subject is identified as being at risk of axonal degeneration, e.g., based on the subject's genotype, a diagnosis of a condition associated with axonal degeneration, and/or exposure to an agent and/or a condition that induces axonal degeneration.
In some embodiments, the patient is at risk of developing a neurodegenerative disorder. In some embodiments the patient is elderly. In some embodiments, the patient is known to have a genetic risk factor for neurodegeneration. In some embodiments, the patient has a family history of neurodegenerative disease. In some embodiments, the patient expresses one or more copies of a known genetic risk factor for neurodegeneration (Lill et al., Semin Neurol, 2011, 31:531-541, hereby incorporated by reference in its entirety). In some embodiments, the patient is drawn from a population with a high incidence of neurodegeneration. For example, in some embodiments, the patient has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the patient has one or more copies of the Apolipoprotein E 4 (ApoE4) allele.
In some embodiments, the patient has one or more copies of a disease-causing mutation in APP, PSEN1, or PSEN2. In some embodiments, the patient has one or more copies of a disease-associated polymorphism in or near the following genes: ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, MS4A4E, MS4A6A, and PICALM.
In some embodiments, the patient has one or more copies of a disease-causing mutation in EIF4G1, LRRK2, PARK2, PARK7, PINK1, SNCA, or VPS35. In some embodiments, the patient has one or more copies of a disease-associated polymorphism in or near the following genes: ACMSD/TMEM163, BST1, CCDC62/HIP1R, FAM47E/STBD1, GAK/DGKQ, GBA, GPNMB, QWA_8p22/FGF20, HLA-II, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SETD1A/STX1B, SNCA, SREBF1/RAI1, STK29, and SYT11/RAB25.
In some embodiments, the patient has one or more copies of a disease-causing mutation in C9ORF72, CHMP2B, GRN, MAPT, or VCP. In some embodiments, the patient has one or more copies of a disease-associated polymorphism in or near the TMEM106B gene.
In some embodiments, the patient has one or more copies of a disease-causing mutation in ANG, ALS2, C9ORF72, FIG. 4, FUS, OPTN, SETX, SOD1, SPG11, TARDBP, UBQLN2, VAPB, or VCP. In some embodiments, the patient has one or more copies of a disease-associated polymorphism in or near the following genes: GWA_9p21.2, UNC13A and ATXN2.
In some embodiments, subjects to which a composition as described herein is administered may be or comprise subjects suffering from or susceptible to a neurodegenerative disease, disorder or condition. In some embodiments, a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury. In some embodiments, a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and/or explosive force, a penetrating injury in to the brain cavity or innervated region of the body. In some embodiments, a traumatic neuronal injury is a force which causes the axons to deform, stretch, crush or sheer.
In some embodiments, the subject engages in an activity identified as a risk factor for neuronal degeneration, e.g., a subject that engages in contact sports or occupations with a high chance for traumatic neuronal injury.
For example, the subject may be a patient who is receiving, or is prescribed, a chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), auristatins (e.g., Auristatin E) and platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).
In some embodiments, provided methods comprise administering a composition as described herein to a patient or patient population based on the presence or absence of one or more biomarkers. In some embodiments, provided methods further comprise monitoring the level of a biomarker in a patient or patient population and adjusting the dosing regimen accordingly.
Dosing
Those of skill in the art will appreciate that, in some embodiments, the exact amount of a particular SARM1 antisense agent included in and/or delivered by administration of a pharmaceutical composition or regimen as described herein may be selected by a medical practitioner and may be different for different subjects, for example, upon consideration of one or more of species, age, and general condition of the subject, and/or identity of the particular SARM1 antisense agent, its mode of administration, and the like. Alternatively, in some embodiments, the amount of an SARM1 antisense agent included in and/or delivered by administration of a pharmaceutical composition or regimen as described herein may be standardized across a relevant patient population (e.g., all patients, all patients of a particular age or stage of disease or expressing a particular biomarker, etc.).
A provided SARM1 antisense agent or composition of the present disclosure is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of a provided SARM1 antisense agent or composition of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the clinical condition of the individual patient; the cause of the disorder; the activity of the specific SARM1 antisense agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, delivery site of the agent, route of administration, and rate of degradation of the specific SARM1 antisense agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific SARM1 antisense agent employed, and like factors well known in the medical arts. In some embodiments, the effective amount of the SARM1 antisense agent to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit SARM1 activity, inflammatory activity, necroptosis or immune activity as required to prevent or treat the undesired disease or disorder, such as for example, neurodegeneration or traumatic neural injury.
In some embodiments, compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intradermal, intraocular, intravitreal, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered via intrathecal, intraventricular, intracerebroventricular, intracisternal, intraparenchymal or intravitreal injection.
In some embodiments, pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
The daily dose is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. This dosage regimen may be adjusted to provide the optimal therapeutic response. In some embodiments, compositions of the present disclosure can be delivered four times a week, three times a week, twice a week, once a week, every ten days, every two weeks, every three weeks, or more preferably every four weeks, once a month, every six weeks, every eight weeks, every other month, every three months, every four months, every six months, every eight months, every nine months or annually.
Compositions of the present disclosure may be administered in combination with other therapeutic agents. Those additional agents may be administered separately from a provided SARM1 antisense agent or composition thereof, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a provided SARM1 antisense agent in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another, normally within five hours from one another.
It should also be understood that a specific dosage and treatment regimen for any particular patient may depend upon a variety of factors, including the activity of the specific SARM1 antisense agent employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. In some embodiments, the amount of an SARM1 antisense agent of the present disclosure in the composition will also depend upon the particular SARM1 antisense agent in the composition.
In some embodiments, SARM1 antisense agents as described herein may be utilized in combination with one or more other therapies to treat a relevant disease, disorder, or condition. In some embodiments, dosing of an SARM1 antisense agent is altered when utilized in combination therapy as compared with when administered as monotherapy; alternatively or additionally, in some embodiments, a therapy that is administered in combination with an SARM1 antisense agent as described herein is administered according to a regimen or protocol that differs from its regimen or protocol when administered alone or in combination with one or more therapies other than an SARM1 antisense agent of the present disclosure. In some embodiments, compositions which comprise an additional therapeutic agent, that additional therapeutic agent and a provided SARM1 antisense agent may act synergistically. In some embodiments, one or both therapies utilized in a combination regimen are administered at a lower level or less frequently than when they are utilized individually as monotherapies.
In some embodiments, the present disclosure relates to a method of treating, preventing, and/or ameliorating a neurodegenerative disease, disorder or condition comprising i) providing a) a subject diagnosed with, at risk for, or exhibiting symptoms of, a neurodegenerative disease, disorder or condition and b) a combination comprising a SARM1 antisense oligonucleotide and a SARM1 inhibitor. In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 antisense oligonucleotide and a SARM1 inhibitor; and ii) administering said combination to said subject under conditions such that said neurodegenerative disease, disorder or condition is reduced. In some embodiments, a SARM1 antisense oligonucleotide and a SARM1 inhibitor act synergistically in treating, preventing, and/or ameliorating a neurodegenerative disease, disorder or condition. In some embodiments, a SARM1 inhibitor is a small molecule.
In some embodiments, the present disclosure relates to a method of treating, preventing, and/or ameliorating a neurodegenerative disease, disorder or condition comprising i) providing a) a subject diagnosed with, at risk for, or exhibiting symptoms of, a neurodegenerative disease, disorder or condition and b) a combination comprising a SARM1 antisense oligonucleotide and NAD+ or a NAD+ precursor (e.g., NR, NRH, NA, NaR, NAM, NMN, NaMN, TRP, vitamin B3, or NAAD); and ii) administering said combination to said subject under conditions such that said neurodegenerative disease, disorder or condition is reduced. In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 antisense oligonucleotide and NAD+ or a NAD+ precursor (e.g., NR, NRH, NA, NaR, NAM, NMN, NaMN, TRP, vitamin B3, or NAAD). In some embodiments, a SARM1 antisense oligonucleotide and NAD+ or a NAD+ precursor (e.g., NR, NRH, NA, NaR, NAM, NMN, NaMN, TRP, vitamin B3, or NAAD) act synergistically in treating, preventing, and/or ameliorating a neurodegenerative disease, disorder or condition.
In some embodiments, the present disclosure relates to a method of treating, preventing, and/or ameliorating a neurodegenerative disease, disorder or condition comprising i) providing a) a subject diagnosed with, at risk for, or exhibiting symptoms of, a neurodegenerative disease, disorder or condition and b) a combination comprising a SARM1 antisense oligonucleotide and any biologic agent known in the art (e.g., but not limited to, an antibody, aptamer, trophic factor, or antisense oligonucleotide against a target other than SARM1); and ii) administering said combination to said subject under conditions such that said neurodegenerative disease, disorder or condition is reduced.
In some embodiments, an SARM1 antisense agent and/or compositions comprising a SARM1 agent described herein are administered with a chemotherapeutic agent including, but not limited to, alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, topoisomerase inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids and derivatives. In some embodiments, an SARM1 antisense agent and/or compositions described herein are administered in combination with PARP inhibitors.
Pharmaceutical Compositions
In some embodiments, the present invention provides pharmaceutical compositions comprising one or more antisense agents. In some embodiments, pharmaceutical compositions comprise a suitable pharmaceutically acceptable diluent or carrier. In some embodiments, pharmaceutical compositions comprise a sterile saline solution and one or more antisense agents. In some embodiments, pharmaceutical compositions consist of a sterile saline solution and one or more antisense agents. In some embodiments, a sterile saline is pharmaceutical grade saline. In some embodiments, pharmaceutical compositions comprise sterile water and one or more antisense agents. In some embodiments, pharmaceutical compositions consist of sterile water and one or more antisense agents. In some embodiments, a sterile saline is pharmaceutical grade water. In some embodiments, pharmaceutical compositions comprise phosphate-buffered saline (PBS) and one or more antisense agents. In some embodiments, pharmaceutical compositions consist of sterile phosphate-buffered saline (PBS) and one or more antisense agents. In some embodiments, a sterile saline is pharmaceutical grade PBS.
In some embodiments, antisense agents may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
Pharmaceutical compositions comprising antisense agents as disclosed herein encompass any pharmaceutically acceptable salts, esters, or salts of such esters. In some embodiments, pharmaceutical compositions comprising antisense agents comprise one or more oligonucleotides which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense agents, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.
A prodrug can include the incorporation of additional nucleosides at one or both ends of an oligomeric compound which are cleaved by endogenous nucleases within the body, to form the active antisense oligomeric agent.
Lipid moieties have been used in nucleic acid therapies in a variety of methods. In certain such methods, a nucleic acid is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In some methods, DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid. In some embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue. In some embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to CNS tissue. In some embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to PNS tissue.
In some embodiments, pharmaceutical compositions provided herein comprise one or more modified oligonucleotides and one or more excipients. In certain such embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
In some embodiments, a pharmaceutical composition provided herein comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In some embodiments, certain organic solvents such as dimethylsulfoxide are used.
In some embodiments, a pharmaceutical composition provided herein comprises one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents of the present invention to specific tissues or cell types. For example, in some embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody.
In some embodiments, a pharmaceutical composition provided herein comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In some embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
In some embodiments, a pharmaceutical composition provided herein is prepared for oral administration. In some embodiments, pharmaceutical compositions are prepared for buccal administration. In some embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In some embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In some embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions. In some embodiments, a pharmaceutical composition is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
In some embodiments, a pharmaceutical composition provided herein comprises an oligonucleotide in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
In some embodiments, one or more modified oligonucleotides provided herein are formulated as a prodrug. In some embodiments, upon in vivo administration, a prodrug is chemically converted to a biologically, pharmaceutically or therapeutically more active form of an oligonucleotide. In some embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In some instances, a prodrug may have improved solubility compared to the corresponding active form. In some embodiments, prodrugs are less water soluble than the corresponding active form. In some instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In some embodiments, a prodrug is an ester. In certain such embodiments, the ester is metabolically hydrolyzed to carboxylic acid upon administration. In certain instances, the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is cleaved upon administration to form the corresponding active form.
In some embodiments, the present invention provides compositions and methods for reducing the amount or activity of a target nucleic acid in a cell. In some embodiments, the cell is in an animal. In some embodiments, an animal is a mammal. In some embodiments, an animal is a rodent. In some embodiments, an animal is a primate. In some embodiments, an animal is a non-human primate. In some embodiments, an animal is a human.
In some embodiments, the present invention provides methods of administering a pharmaceutical composition comprising an oligomeric agent of the present invention to an animal. Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intracerebroventricular, intraperitoneal, intranasal, intraocular, intratumoral, intracisternal and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In some embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical compositions may be injected directly in the area of desired effect (e.g., into the eyes, ears).
In some embodiments, a pharmaceutical composition is administered to an animal having at least one symptom associated with a neurodegenerative disease or disorder. In some embodiments, such administration results in amelioration of at least one symptom. In some embodiments, administration of a pharmaceutical composition to an animal results in a decrease of SARM1 mRNA in a cell of the animal. In some embodiments, such administration results in a decrease in SARM1 protein.
Exemplary Embodiments


    
    
        1. An antisense oligonucleotide comprising a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26.
        2. The antisense oligonucleotide of embodiment 1, comprising a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26.
        3. The antisense oligonucleotide of embodiment 1 or embodiment 2, comprising a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26.
        4. The antisense oligonucleotide of any one of embodiments 1-3, comprising a sequence selected from a group consisting of SEQ ID NO: 3-26.
        5. An antisense oligonucleotide comprising a sequence selected from a group consisting of SEQ ID NO: 3-2081.
        6. The antisense oligonucleotide of any one of embodiments 1-5, wherein the antisense oligonucleotide comprises one or more modifications.
        7. The antisense oligonucleotide of embodiment 6, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        8. A pharmaceutical composition comprising an antisense oligonucleotide of any one of the previous embodiments.
        9. The pharmaceutical composition of embodiment 8, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        10. A method for treating and/or preventing axonal degeneration in a subject, comprising: administering to the subject an antisense oligonucleotide is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1).
        11. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1.
        12. The method of embodiment 10 or embodiment 11, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        13. The method of any one of embodiments 10-12, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26.
        14. The method of any one of embodiments 10-13, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26.
        15. The method of any one of embodiments 10-14, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-26.
        16. The method of any one of embodiments 10-15, wherein the antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-26.
        17. The method of any one of embodiments 10-12, wherein the antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-2081.
        18. The method of any one of embodiments 10-17, wherein the antisense oligonucleotide comprises one or more modifications.
        19. The method of embodiment 18, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        20. The method of any one of embodiments 10-19, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        21. The method of any one of embodiments 10-19, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        22. The method of any one of embodiments 11-21, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        23. The method of any of embodiments 11-21, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        24. The method of embodiment 23, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        25. The method of embodiment 23, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        26. The method of embodiment 24, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        27. The method of embodiment 24, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        28. The method of embodiment 24, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        29. The method of any one of embodiments 11-22, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        30. The method of embodiment 29, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        31. The method of embodiment 30, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        32. The method of embodiment 31, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        33. The method of embodiment 31, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        34. The method of embodiment 30, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        35. The method of embodiment 34, wherein the epothilone is ixabepilone.
        36. The method of embodiment 34, wherein the taxane is paclitaxel or docetaxel.
        37. The method of embodiment 34, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        38. The method of embodiment 34, wherein the proteasome inhibitor is bortezomib.
        39. The method of embodiment 34, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        40. The method of embodiment 34, wherein the auristatin is conjugated monomethyl auristatin E.
        41. The method of any one of embodiments 11-22, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        42. The method of embodiment 41, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        43. The method of embodiment 41, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        44. The method of embodiment 43, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        45. The method of embodiment 43, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        46. The method of embodiment 43, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        47. The method of any one of embodiments 11-22, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        48. The method of embodiment 47, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        49. The method of embodiment 48, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        50. The method of embodiment 48, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        51. The method of embodiment 48, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        52. The method of any one of embodiments 11-22, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        53. The method of any one of embodiments 10-52, wherein the subject is a human.
        54. The method of any one of embodiments 10-53, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        55. The method of embodiments 54, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        56. The method of embodiment 55, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        57. The method of embodiment 55, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        58. The method of embodiment 55, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        59. An antisense oligonucleotide comprising a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        60. The antisense oligonucleotide of embodiment 59, comprising a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        61. The antisense oligonucleotide of embodiment 59 or embodiment 60, comprising a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        62. The antisense oligonucleotide of any one of embodiments 59-61, comprising a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        63. An antisense oligonucleotide comprising a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549.
        64. The antisense oligonucleotide of embodiment 63, comprising a sequence having at least 85% identity to a sequence selected from a group consisting of 8, 9, 13, 22, 38, and 549.
        65. The antisense oligonucleotide of embodiment 63 or embodiment 64, comprising a sequence having at least 90% identity to a sequence selected from a group consisting of 8, 9, 13, 22, 38, and 549.
        66. The antisense oligonucleotide of any one of embodiments 63-65, comprising a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549.
        67. An antisense oligonucleotide comprising a sequence selected from a group consisting of SEQ ID NO: 3-2412.
        68. The antisense oligonucleotide of any one of embodiments 59-66, wherein the antisense oligonucleotide comprises one or more modifications.
        69. The antisense oligonucleotide of embodiment 68, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        70. A pharmaceutical composition comprising an antisense oligonucleotide of any one of the previous embodiments.
        71. A pharmaceutical composition comprising an antisense oligonucleotide of any one of embodiments 59-70.
        72. The pharmaceutical composition of embodiment 70 or 71, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        73. A method for treating and/or preventing axonal degeneration in a subject, comprising: administering to the subject an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1).
        74. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1.
        75. The method of embodiment 73 or embodiment 74, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        76. The method of any one of embodiments 73-75, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        77. The method of any one of embodiments 73-76, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        78. The method of any one of embodiments 73-77, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        79. The method of any one of embodiments 73-78, wherein the antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-21, 23-26, 38 and 39.
        80. The method of any one of embodiments 73-75, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity to a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549.
        81. The method of any one of embodiments 73-75, and 80, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549.
        82. The method of any one of embodiments 73-75, and 80-81, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549.
        83. The method of any one of embodiments 73-75, and 80-82, wherein the antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 8, 9, 13, 22, 38, and 549.
        84. The method of any one of embodiments 73-75, wherein the antisense oligonucleotide comprises a sequence selected from a group consisting of SEQ ID NO: 3-2412.
        85. The method of any one of embodiments 73-84, wherein the antisense oligonucleotide comprises one or more modifications.
        86. The method of embodiment 85, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        87. The method of any one of embodiments 73-86, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        88. The method of any one of embodiments 73-86, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        89. The method of any one of embodiments 74-88, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        90. The method of any of embodiments 74-88, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        91. The method of embodiment 90, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        92. The method of embodiment 90, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        93. The method of embodiment 91, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        94. The method of embodiment 91, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        95. The method of embodiment 91, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        96. The method of any one of embodiments 74-89, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        97. The method of embodiment 96, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        98. The method of embodiment 97, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        99. The method of embodiment 98, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        100. The method of embodiment 98, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        101. The method of embodiment 97, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        102. The method of embodiment 101, wherein the epothilone is ixabepilone.
        103. The method of embodiment 101, wherein the taxane is paclitaxel or docetaxel.
        104. The method of embodiment 101, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        105. The method of embodiment 101, wherein the proteasome inhibitor is bortezomib.
        106. The method of embodiment 101, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        107. The method of embodiment 101, wherein the auristatin is conjugated monomethyl auristatin E.
        108. The method of any one of embodiments 74-89, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        109. The method of embodiment 108, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        110. The method of embodiment 108, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        111. The method of embodiment 110, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        112. The method of embodiment 110, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        113. The method of embodiment 110, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        114. The method of any one of embodiments 74-89, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        115. The method of embodiment 114, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        116. The method of embodiment 115, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        117. The method of embodiment 115, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        118. The method of embodiment 115, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        119. The method of any one of embodiments 74-89, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        120. The method of any one of embodiments 73-119, wherein the subject is a human.
        121. The method of any one of embodiments 73-120, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        122. The method of embodiment 121, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        123. The method of embodiment 122, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        124. The method of embodiment 122, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        125. The method of embodiment 122, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
            levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        
        
        126. An antisense oligonucleotide selected from Table 3, for use in the manufacture of a medicament.
        127. An antisense oligonucleotide selected from Table 3, for use in treatment of a disease, disorder or injury.
        128. The antisense oligonucleotide of embodiment 127, wherein the disease, disorder or injury comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies, other peripheral neuropathies, diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, polyarteritis nodosa, chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, diabetes, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, a mitochondrial disorder, carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture, a dislocated bone, pressure involving superficial nerves, pressure from a tumor, increased intraocular pressure, injury from a chemical agent or chemotherapy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, spinal cord injury, an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, exposure to cyanide, a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury, chronic traumatic encephalopathy (CTE), diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, mitochondrial disorders, cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy, a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, damage from a force which causes axons to deform, stretch, crush or sheer, enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        129. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 8.
        130. The antisense oligonucleotide of embodiment 129, comprising a sequence having at least 85% identity to SEQ ID NO: 8.
        131. The antisense oligonucleotide of embodiment 129 or embodiment 130, comprising a sequence having at least 90% identity to SEQ ID NO: 8.
        132. The antisense oligonucleotide of any one of embodiments 129-131, comprising SEQ ID NO: 8.
        133. The antisense oligonucleotide of any one of embodiments 129-132, wherein the antisense oligonucleotide comprises one or more modifications.
        134. The antisense oligonucleotide of embodiment 133, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        135. A pharmaceutical composition comprising an antisense oligonucleotide of any one of embodiments 129-134.
        136. The pharmaceutical composition of embodiment 135, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        137. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 9.
        138. The antisense oligonucleotide of embodiment 137, comprising a sequence having at least 85% identity to SEQ ID NO: 9.
        139. The antisense oligonucleotide of embodiment 137 or embodiment 138, comprising a sequence having at least 90% identity to SEQ ID NO: 9.
        140. The antisense oligonucleotide of any one of embodiments 137-139, comprising SEQ ID NO: 9.
        141. The antisense oligonucleotide of any one of embodiments 137-140, wherein the antisense oligonucleotide comprises one or more modifications.
        142. The antisense oligonucleotide of embodiment 141, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        143. A pharmaceutical composition comprising an antisense oligonucleotide of any one of embodiments 137-142.
        144. The pharmaceutical composition of embodiment 143, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        145. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 13.
        146. The antisense oligonucleotide of embodiment 145, comprising a sequence having at least 85% identity to SEQ ID NO: 13.
        147. The antisense oligonucleotide of embodiment 145 or embodiment 146, comprising a sequence having at least 90% identity to SEQ ID NO: 13.
        148. The antisense oligonucleotide of any one of embodiments 145-147, comprising SEQ ID NO: 13.
        149. The antisense oligonucleotide of any one of embodiments 145-148, wherein the antisense oligonucleotide comprises one or more modifications.
        150. The antisense oligonucleotide of embodiment 149, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        151. A pharmaceutical composition comprising an antisense oligonucleotide of any one of embodiments 145-150.
        152. The pharmaceutical composition of embodiment 151, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        153. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 22.
        154. The antisense oligonucleotide of embodiment 153, comprising a sequence having at least 85% identity to SEQ ID NO: 22.
        155. The antisense oligonucleotide of embodiment 153 or embodiment 154, comprising a sequence having at least 90% identity to SEQ ID NO: 22.
        156. The antisense oligonucleotide of any one of embodiments 153-155, comprising SEQ ID NO: 22.
        157. The antisense oligonucleotide of any one of embodiments 153-156, wherein the antisense oligonucleotide comprises one or more modifications.
        158. The antisense oligonucleotide of embodiment 157, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        159. A pharmaceutical composition comprising an antisense oligonucleotide of any one of embodiments 153-158.
        160. The pharmaceutical composition of embodiment 159, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        161. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 38.
        162. The antisense oligonucleotide of embodiment 161, comprising a sequence having at least 85% identity to SEQ ID NO: 38.
        163. The antisense oligonucleotide of embodiment 161 or embodiment 162, comprising a sequence having at least 90% identity to SEQ ID NO: 38.
        164. The antisense oligonucleotide of any one of embodiments 161-163, comprising SEQ ID NO: 38.
        165. The antisense oligonucleotide of any one of embodiments 161-164, wherein the antisense oligonucleotide comprises one or more modifications.
        166. The antisense oligonucleotide of embodiment 165, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        167. A pharmaceutical composition comprising an antisense oligonucleotide of any one of embodiments 161-166.
        168. The pharmaceutical composition of embodiment 167, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        169. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 549.
        170. The antisense oligonucleotide of embodiment 169, comprising a sequence having at least 85% identity to SEQ ID NO: 549.
        171. The antisense oligonucleotide of embodiment 169 or embodiment 170, comprising a sequence having at least 90% identity to SEQ ID NO: 549.
        172. The antisense oligonucleotide of any one of embodiments 169-171, comprising SEQ ID NO: 549.
        173. The antisense oligonucleotide of any one of embodiments 169-172, wherein the antisense oligonucleotide comprises one or more modifications.
        174. The antisense oligonucleotide of embodiment 173, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        175. A pharmaceutical composition comprising an antisense oligonucleotide of any one of embodiments 169-174.
        176. The pharmaceutical composition of embodiment 175, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        177. A method for treating and/or preventing axonal degeneration in a subject, comprising: administering to the subject an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1), wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 8.
        178. The method of embodiment 177, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 8.
        179. The method of embodiment 177 or embodiment 178, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 8.
        180. The method of any one of embodiments 177-179, wherein the antisense oligonucleotide comprises SEQ ID NO: 8.
        181. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 8.
        182. The method of embodiment 181, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 8.
        183. The method of embodiment 181 or embodiment 182, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 8.
        184. The method of any one of embodiments 181-183, wherein the antisense oligonucleotide comprises SEQ ID NO: 8.
        185. The method of any one of embodiments 177-184, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        186. The method of any one of embodiments 177-185, wherein the antisense oligonucleotide comprises one or more modifications.
        187. The method of embodiment 186, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        188. The method of any one of embodiments 177-187, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        189. The method of any one of embodiments 177-187, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        190. The method of any one of embodiments 181-189, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        191. The method of any of embodiments 181-189, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        192. The method of embodiment 191, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        193. The method of embodiment 191, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        194. The method of embodiment 192, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        195. The method of embodiment 192, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        196. The method of embodiment 192, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        197. The method of any one of embodiments 181-190, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        198. The method of embodiment 197, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        199. The method of embodiment 198, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        200. The method of embodiment 199, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        201. The method of embodiment 199, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        202. The method of embodiment 198, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        203. The method of embodiment 202, wherein the epothilone is ixabepilone.
        204. The method of embodiment 202, wherein the taxane is paclitaxel or docetaxel.
        205. The method of embodiment 202, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        206. The method of embodiment 202, wherein the proteasome inhibitor is bortezomib.
        207. The method of embodiment 202, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        208. The method of embodiment 202, wherein the auristatin is conjugated monomethyl auristatin E.
        209. The method of any one of embodiments 181-190, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        210. The method of embodiment 209, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        211. The method of embodiment 209, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        212. The method of embodiment 211, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        213. The method of embodiment 211, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        214. The method of embodiment 211, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        215. The method of any one of embodiments 181-190, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        216. The method of embodiment 215, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        217. The method of embodiment 216, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        218. The method of embodiment 216, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        219. The method of embodiment 216, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        220. The method of any one of embodiments 181-190, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        221. The method of any one of embodiments 177-220, wherein the subject is a human.
        222. The method of any one of embodiments 177-221, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        223. The method of embodiments 222, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        224. The method of embodiment 223, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        225. The method of embodiment 223, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        226. The method of embodiment 223, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        227. A method for treating and/or preventing axonal degeneration in a subject, comprising:
        
            administering to the subject an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1), wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 9.
        
        
        228. The method of embodiment 227, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 9.
        229. The method of embodiment 227 or embodiment 228, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 9.
        230. The method of any one of embodiments 227-229, wherein the antisense oligonucleotide comprises SEQ ID NO: 9.
        231. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 9.
        232. The method of embodiment 231, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 9.
        233. The method of embodiment 231 or embodiment 232, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 9.
        234. The method of any one of embodiments 231-233, wherein the antisense oligonucleotide comprises SEQ ID NO: 9.
        235. The method of any one of embodiments 227-234, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        236. The method of any one of embodiments 227-235, wherein the antisense oligonucleotide comprises one or more modifications.
        237. The method of embodiment 236, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        238. The method of any one of embodiments 227-237, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        239. The method of any one of embodiments 227-237, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        240. The method of any one of embodiments 231-239, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        241. The method of any of embodiments 231-239, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        242. The method of embodiment 241, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        243. The method of embodiment 241, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        244. The method of embodiment 242, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        245. The method of embodiment 242, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        246. The method of embodiment 242, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        247. The method of any one of embodiments 231-240, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        248. The method of embodiment 247, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        249. The method of embodiment 248, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        250. The method of embodiment 249, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        251. The method of embodiment 249, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        252. The method of embodiment 248, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        253. The method of embodiment 252, wherein the epothilone is ixabepilone.
        254. The method of embodiment 252, wherein the taxane is paclitaxel or docetaxel.
        255. The method of embodiment 252, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        256. The method of embodiment 252, wherein the proteasome inhibitor is bortezomib.
        257. The method of embodiment 252, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        258. The method of embodiment 252, wherein the auristatin is conjugated monomethyl auristatin E.
        259. The method of any one of embodiments 231-240, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        260. The method of embodiment 259, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        261. The method of embodiment 259, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        262. The method of embodiment 261, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        263. The method of embodiment 261, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        264. The method of embodiment 261, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        265. The method of any one of embodiments 231-240, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        266. The method of embodiment 215, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        267. The method of embodiment 266, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        268. The method of embodiment 266, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        269. The method of embodiment 266, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        270. The method of any one of embodiments 231-240, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        271. The method of any one of embodiments 227-270, wherein the subject is a human.
        272. The method of any one of embodiments 227-271, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        273. The method of embodiments 272, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        274. The method of embodiment 273, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a
        275. The method of embodiment 273, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        276. The method of embodiment 273, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        277. A method for treating and/or preventing axonal degeneration in a subject, comprising: administering to the subject an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1), wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 13.
        278. The method of embodiment 277, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 13.
        279. The method of embodiment 277 or embodiment 278, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 13.
        280. The method of any one of embodiments 277-279, wherein the antisense oligonucleotide comprises SEQ ID NO: 13.
        281. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 13.
        282. The method of embodiment 281, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 13.
        283. The method of embodiment 281 or embodiment 282, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 13.
        284. The method of any one of embodiments 281-283, wherein the antisense oligonucleotide comprises SEQ ID NO: 13.
        285. The method of any one of embodiments 277-284, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        286. The method of any one of embodiments 277-285, wherein the antisense oligonucleotide comprises one or more modifications.
        287. The method of embodiment 286, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        288. The method of any one of embodiments 277-287, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        289. The method of any one of embodiments 277-287, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        290. The method of any one of embodiments 281-289, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        291. The method of any of embodiments 281-289, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        292. The method of embodiment 291, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        293. The method of embodiment 291, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        294. The method of embodiment 292, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        295. The method of embodiment 292, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        296. The method of embodiment 292, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        297. The method of any one of embodiments 281-290, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        298. The method of embodiment 297, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        299. The method of embodiment 298, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        300. The method of embodiment 298, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        301. The method of embodiment 298, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        302. The method of embodiment 298, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        303. The method of embodiment 302, wherein the epothilone is ixabepilone.
        304. The method of embodiment 302, wherein the taxane is paclitaxel or docetaxel.
        305. The method of embodiment 302, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        306. The method of embodiment 302, wherein the proteasome inhibitor is bortezomib.
        307. The method of embodiment 302, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        308. The method of embodiment 302, wherein the auristatin is conjugated monomethyl auristatin E.
        309. The method of any one of embodiments 281-290, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        310. The method of embodiment 309, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        311. The method of embodiment 309, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        312. The method of embodiment 311, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        313. The method of embodiment 311, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        314. The method of embodiment 311, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        315. The method of any one of embodiments 281-290, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        316. The method of embodiment 315, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        317. The method of embodiment 316, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        318. The method of embodiment 316, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        319. The method of embodiment 316, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        320. The method of any one of embodiments 281-290, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        321. The method of any one of embodiments 277-320, wherein the subject is a human.
        322. The method of any one of embodiments 277-321, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        323. The method of embodiments 322, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        324. The method of embodiment 323, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        325. The method of embodiment 323, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        326. The method of embodiment 323, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        327. A method for treating and/or preventing axonal degeneration in a subject, comprising:
        
            administering to the subject an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1), wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 22.
        
        
        328. The method of embodiment 327, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 22.
        329. The method of embodiment 327 or embodiment 328, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 22.
        330. The method of any one of embodiments 327-329, wherein the antisense oligonucleotide comprises SEQ ID NO: 22.
        331. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 22.
        332. The method of embodiment 331, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 22.
        333. The method of embodiment 331 or embodiment 332, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 22.
        334. The method of any one of embodiments 331-333, wherein the antisense oligonucleotide comprises SEQ ID NO: 22.
        335. The method of any one of embodiments 327-334, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        336. The method of any one of embodiments 327-335, wherein the antisense oligonucleotide comprises one or more modifications.
        337. The method of embodiment 336, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        338. The method of any one of embodiments 327-337, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        339. The method of any one of embodiments 327-337, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        340. The method of any one of embodiments 331-339, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        341. The method of any of embodiments 331-339, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        342. The method of embodiment 341, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        343. The method of embodiment 341, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        344. The method of embodiment 342, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        345. The method of embodiment 342, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        346. The method of embodiment 342, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        347. The method of any one of embodiments 331-340, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        348. The method of embodiment 347, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        349. The method of embodiment 348, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        350. The method of embodiment 348, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        351. The method of embodiment 348, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        352. The method of embodiment 348, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        353. The method of embodiment 352, wherein the epothilone is ixabepilone.
        354. The method of embodiment 352, wherein the taxane is paclitaxel or docetaxel.
        355. The method of embodiment 352, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        356. The method of embodiment 352, wherein the proteasome inhibitor is bortezomib.
        357. The method of embodiment 352, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        358. The method of embodiment 352, wherein the auristatin is conjugated monomethyl auristatin E.
        359. The method of any one of embodiments 331-340, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        360. The method of embodiment 359, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        361. The method of embodiment 359, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        362. The method of embodiment 361, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        363. The method of embodiment 361, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        364. The method of embodiment 361, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        365. The method of any one of embodiments 331-340, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        366. The method of embodiment 365, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        367. The method of embodiment 366, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        368. The method of embodiment 366, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        369. The method of embodiment 366, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        370. The method of any one of embodiments 331-340, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        371. The method of any one of embodiments 327-370, wherein the subject is a human.
        372. The method of any one of embodiments 327-371, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        373. The method of embodiments 372, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        374. The method of embodiment 373, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        375. The method of embodiment 373, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        376. The method of embodiment 373, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        377. A method for treating and/or preventing axonal degeneration in a subject, comprising: administering to the subject an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1), wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 38.
        378. The method of embodiment 377, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 38.
        379. The method of embodiment 377 or embodiment 378, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 38.
        380. The method of any one of embodiments 377-379, wherein the antisense oligonucleotide comprises SEQ ID NO: 38.
        381. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 38.
        382. The method of embodiment 381, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 38.
        383. The method of embodiment 381 or embodiment 382, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 38.
        384. The method of any one of embodiments 381-383, wherein the antisense oligonucleotide comprises SEQ ID NO: 38.
        385. The method of any one of embodiments 377-384, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        386. The method of any one of embodiments 377-385, wherein the antisense oligonucleotide comprises one or more modifications.
        387. The method of embodiment 386, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        388. The method of any one of embodiments 377-387, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        389. The method of any one of embodiments 377-387, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        390. The method of any one of embodiments 381-389, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        391. The method of any of embodiments 381-389, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        392. The method of embodiment 391, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        393. The method of embodiment 391, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        394. The method of embodiment 392, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        395. The method of embodiment 392, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        396. The method of embodiment 392, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        397. The method of any one of embodiments 381-390, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        398. The method of embodiment 397, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        399. The method of embodiment 398, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        400. The method of embodiment 398, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        401. The method of embodiment 398, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        402. The method of embodiment 398, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        403. The method of embodiment 402, wherein the epothilone is ixabepilone.
        404. The method of embodiment 402, wherein the taxane is paclitaxel or docetaxel.
        405. The method of embodiment 402, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        406. The method of embodiment 402, wherein the proteasome inhibitor is bortezomib.
        407. The method of embodiment 402, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        408. The method of embodiment 402, wherein the auristatin is conjugated monomethyl auristatin E.
        409. The method of any one of embodiments 381-390, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        410. The method of embodiment 409, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        411. The method of embodiment 409, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        412. The method of embodiment 411, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        413. The method of embodiment 411, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        414. The method of embodiment 411, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        415. The method of any one of embodiments 381-390, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        416. The method of embodiment 415, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        417. The method of embodiment 416, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        418. The method of embodiment 416, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        419. The method of embodiment 416, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        420. The method of any one of embodiments 381-390, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        421. The method of any one of embodiments 377-420, wherein the subject is a human.
        422. The method of any one of embodiments 377-421, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        423. The method of embodiments 422, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        424. The method of embodiment 423, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        425. The method of embodiment 423, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        426. The method of embodiment 423, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        427. A method for treating and/or preventing axonal degeneration in a subject, comprising:
        
            administering to the subject an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1), wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 549.
        
        
        428. The method of embodiment 427, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 549.
        429. The method of embodiment 427 or embodiment 428, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 549.
        430. The method of any one of embodiments 427-429, wherein the antisense oligonucleotide comprises SEQ ID NO: 549.
        431. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity SEQ ID NO: 549.
        432. The method of embodiment 431, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 549.
        433. The method of embodiment 431 or embodiment 432, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 549.
        434. The method of any one of embodiments 431-433, wherein the antisense oligonucleotide comprises SEQ ID NO: 549.
        435. The method of any one of embodiments 427-434, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        436. The method of any one of embodiments 427-425, wherein the antisense oligonucleotide comprises one or more modifications.
        437. The method of embodiment 436, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        438. The method of any one of embodiments 427-437, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        439. The method of any one of embodiments 427-437, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        440. The method of any one of embodiments 431-439, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        441. The method of any of embodiments 431-439, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        442. The method of embodiment 441, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        443. The method of embodiment 441, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        444. The method of embodiment 442, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        445. The method of embodiment 442, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        446. The method of embodiment 442, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        447. The method of any one of embodiments 431-440, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        448. The method of embodiment 447, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        449. The method of embodiment 448, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        450. The method of embodiment 448, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        451. The method of embodiment 448, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        452. The method of embodiment 448, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        453. The method of embodiment 452, wherein the epothilone is ixabepilone.
        454. The method of embodiment 452, wherein the taxane is paclitaxel or docetaxel.
        455. The method of embodiment 452, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        456. The method of embodiment 452, wherein the proteasome inhibitor is bortezomib.
        457. The method of embodiment 452, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        458. The method of embodiment 452, wherein the auristatin is conjugated monomethyl auristatin E.
        459. The method of any one of embodiments 431-440, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        460. The method of embodiment 459, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        461. The method of embodiment 459, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        462. The method of embodiment 461, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        463. The method of embodiment 461, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        464. The method of embodiment 461, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        465. The method of any one of embodiments 431-440, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        466. The method of embodiment 465, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        467. The method of embodiment 465, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        468. The method of embodiment 465, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        469. The method of embodiment 465, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        470. The method of any one of embodiments 431-440, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        471. The method of any one of embodiments 427-470, wherein the subject is a human.
        472. The method of any one of embodiments 427-471, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        473. The method of embodiments 472, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        474. The method of embodiment 473, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        475. The method of embodiment 473, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        476. The method of embodiment 473, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        477. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 2410.
        478. The antisense oligonucleotide of embodiment 477, comprising a sequence having at least 85% identity to SEQ ID NO: 2410.
        479. The antisense oligonucleotide of embodiment 477 or embodiment 478, comprising a sequence having at least 90% identity to SEQ ID NO: 2410.
        480. The antisense oligonucleotide of any one of embodiments 477-479, comprising SEQ ID NO: 2410.
        481. The antisense oligonucleotide of any one of embodiments 477-480, wherein the antisense oligonucleotide comprises one or more modifications.
        482. The antisense oligonucleotide of embodiment 481, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        483. A pharmaceutical composition comprising an antisense oligonucleotide of any one embodiments 477-482.
        484. The pharmaceutical composition of embodiment 483, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        485. A method for treating and/or preventing axonal degeneration in a subject, comprising:
        
            administering to the subject an antisense oligonucleotide is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1).
        
        
        486. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1.
        487. The method of embodiment 485 or embodiment 486, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        488. The method of any one of embodiments 485-487, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity to SEQ ID NO: 2410.
        489. The method of any one of embodiments 485-488, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 2410.
        490. The method of any one of embodiments 485-489, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 2410.
        491. The method of any one of embodiments 485-490, wherein the antisense oligonucleotide comprises SEQ ID NO: 2410.
        492. The method of any one of embodiments 485-491, wherein the antisense oligonucleotide comprises one or more modifications.
        493. The method of embodiment 492, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        494. The method of any one of embodiments 485-493, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        495. The method of any one of embodiments 485-493, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        496. The method of any one of embodiments 486-495, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        497. The method of any of embodiments 486-495, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        498. The method of embodiment 497, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        499. The method of embodiment 497, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        500. The method of embodiment 498, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        501. The method of embodiment 498, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        502. The method of embodiment 498, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        503. The method of any one of embodiments 486-496, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        504. The method of embodiment 503, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        505. The method of embodiment 504, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        506. The method of embodiment 505, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        507. The method of embodiment 505, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        508. The method of embodiment 504, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        509. The method of embodiment 508, wherein the epothilone is ixabepilone.
        510. The method of embodiment 508, wherein the taxane is paclitaxel or docetaxel.
        511. The method of embodiment 508, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        512. The method of embodiment 508, wherein the proteasome inhibitor is bortezomib.
        513. The method of embodiment 508, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        514. The method of embodiment 508, wherein the auristatin is conjugated monomethyl auristatin E.
        515. The method of any one of embodiments 486-496, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        516. The method of embodiment 515, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        517. The method of embodiment 515, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        518. The method of embodiment 517, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        519. The method of embodiment 517, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        520. The method of embodiment 517, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        521. The method of any one of embodiments 486-496, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        522. The method of embodiment 521, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        523. The method of embodiment 522, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        524. The method of embodiment 522, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        525. The method of embodiment 522, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        526. The method of any one of embodiments 486-496, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        527. The method of any one of embodiments 485-526, wherein the subject is a human.
        528. The method of any one of embodiments 485-527, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        529. The method of embodiments 528, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        530. The method of embodiment 529, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        531. The method of embodiment 529, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        532. The method of embodiment 529, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        533. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 2411.
        534. The antisense oligonucleotide of embodiment 533, comprising a sequence having at least 85% identity to SEQ ID NO: 2411.
        535. The antisense oligonucleotide of embodiment 533 or embodiment 534, comprising a sequence having at least 90% identity to SEQ ID NO: 2411.
        536. The antisense oligonucleotide of any one of embodiments 533-535, comprising SEQ ID NO: 2411.
        537. The antisense oligonucleotide of any one of embodiments 533-536, wherein the antisense oligonucleotide comprises one or more modifications.
        538. The antisense oligonucleotide of embodiment 537, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        539. A pharmaceutical composition comprising an antisense oligonucleotide of any one embodiments 533-538.
        540. The pharmaceutical composition of embodiment 539, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        541. A method for treating and/or preventing axonal degeneration in a subject, comprising:
        
            administering to the subject an antisense oligonucleotide is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1).
        
        
        542. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1.
        543. The method of embodiment 541 or embodiment 542, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        544. The method of any one of embodiments 541-543, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity to SEQ ID NO: 2411.
        545. The method of any one of embodiments 541-544, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 2411.
        546. The method of any one of embodiments 541-545, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 2411.
        547. The method of any one of embodiments 541-546, wherein the antisense oligonucleotide comprises SEQ ID NO: 2411.
        548. The method of any one of embodiments 541-547, wherein the antisense oligonucleotide comprises one or more modifications.
        549. The method of embodiment 548, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        550. The method of any one of embodiments 541-549, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        551. The method of any one of embodiments 541-549, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        552. The method of any one of embodiments 542-551, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        553. The method of any of embodiments 542-551, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        554. The method of embodiment 553, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        555. The method of embodiment 553, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        556. The method of embodiment 554, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        557. The method of embodiment 554, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        558. The method of embodiment 554, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        559. The method of any one of embodiments 542-552, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        560. The method of embodiment 559, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        561. The method of embodiment 560, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        562. The method of embodiment 561, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        563. The method of embodiment 561, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        564. The method of embodiment 560, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        565. The method of embodiment 564, wherein the epothilone is ixabepilone.
        566. The method of embodiment 564, wherein the taxane is paclitaxel or docetaxel.
        567. The method of embodiment 564, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        568. The method of embodiment 564, wherein the proteasome inhibitor is bortezomib.
        569. The method of embodiment 564, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        570. The method of embodiment 564, wherein the auristatin is conjugated monomethyl auristatin E.
        571. The method of any one of embodiments 542-552, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
    
    


572. The method of embodiment 571, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.

    
    
        573. The method of embodiment 571, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        574. The method of embodiment 573, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        575. The method of embodiment 573, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        576. The method of embodiment 573, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        577. The method of any one of embodiments 542-552, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        578. The method of embodiment 577, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        579. The method of embodiment 578, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        580. The method of embodiment 578, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        581. The method of embodiment 578, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        581. The method of any one of embodiments 542-552, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        582. The method of any one of embodiments 541-581, wherein the subject is a human.
        583. The method of any one of embodiments 541-582, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        584. The method of embodiments 583, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        585. The method of embodiment 584, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        586. The method of embodiment 584, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        587. The method of embodiment 584, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        588. An antisense oligonucleotide comprising a sequence having at least 80% identity to SEQ ID NO: 2412.
        589. The antisense oligonucleotide of embodiment 588, comprising a sequence having at least 85% identity to SEQ ID NO: 2412.
        590. The antisense oligonucleotide of embodiment 588 or embodiment 589, comprising a sequence having at least 90% identity to SEQ ID NO: 2412.
        591. The antisense oligonucleotide of any one of embodiments 588-590, comprising SEQ ID NO: 2412.
        592. The antisense oligonucleotide of any one of embodiments 588-591, wherein the antisense oligonucleotide comprises one or more modifications.
        593. The antisense oligonucleotide of embodiment 592, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        594. A pharmaceutical composition comprising an antisense oligonucleotide of any one embodiments 588-593.
        595. The pharmaceutical composition of embodiment 594, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
        596. A method for treating and/or preventing axonal degeneration in a subject, comprising:
        
            administering to the subject an antisense oligonucleotide is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1).
        
        
        597. A method comprising administering to a subject at risk of developing a neurodegenerative disease or disorder an antisense oligonucleotide that is complementary to a target region of a nucleic acid encoding SARM1.
        598. The method of embodiment 596 or embodiment 597, wherein the target nucleic acid encoding SARM1 is a SARM1 mRNA.
        599. The method of any one of embodiments 596-598, wherein the antisense oligonucleotide comprises a sequence having at least 80% identity to SEQ ID NO: 2412.
        600. The method of any one of embodiments 596-599, wherein the antisense oligonucleotide comprises a sequence having at least 85% identity to SEQ ID NO: 2412.
        601. The method of any one of embodiments 596-600, wherein the antisense oligonucleotide comprises a sequence having at least 90% identity to SEQ ID NO: 2412.
        602. The method of any one of embodiments 596-601, wherein the antisense oligonucleotide comprises SEQ ID NO: 2412.
        603. The method of any one of embodiments 596-602, wherein the antisense oligonucleotide comprises one or more modifications.
        604. The method of embodiment 603, wherein the one or more modifications comprise methylphosphonothioate internucleotide linkages, phosphorothioate internucleotide linkages, methylphosphonate internucleotide linkages, phosphoramidate internucleotide linkages, a 3′ end cap, a 3′ hair-pin loop structure, or a combination thereof.
        605. The method of any one of embodiments 596-604, wherein administering the antisense oligonucleotide decreases levels of SARM1 mRNA in the subject.
        606. The method of any one of embodiments 596-604, wherein administering the antisense oligonucleotide decreases levels of SARM1 protein in the subject.
        607. The method of any one of embodiments 597-606, wherein the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.
        608. The method of any of embodiments 597-606, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
        609. The method of embodiment 608, wherein the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.
        610. The method of embodiment 608, wherein the chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.
        611. The method of embodiment 609, wherein the systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.
        612. The method of embodiment 609, wherein the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.
        613. The method of embodiment 609, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
        614. The method of any one of embodiments 597-607, the neurodegenerative disease or disorder comprises an acute disease or disorder of the peripheral nervous system.
        615. The method of embodiment 614, wherein the acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy.
        616. The method of embodiment 615, wherein the mechanical injury comprises a compression or entrapment injury or a pressure injury.
        617. The method of embodiment 616, wherein the compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone.
        618. The method of embodiment 616, wherein the pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure.
        619. The method of embodiment 615, wherein the chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin.
        620. The method of embodiment 619, wherein the epothilone is ixabepilone.
        621. The method of embodiment 619, wherein the taxane is paclitaxel or docetaxel.
        622. The method of embodiment 619, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
        623. The method of embodiment 619, wherein the proteasome inhibitor is bortezomib.
        624. The method of embodiment 619, wherein the platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
        625. The method of embodiment 619, wherein the auristatin is conjugated monomethyl auristatin E.
        626. The method of any one of embodiments 597-607, wherein the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.
        627. The method of embodiment 626, wherein the chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury.
        628. The method of embodiment 626, wherein the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.
        629. The method of embodiment 628, wherein the optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.
        630. The method of embodiment 628, wherein the traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).
        631. The method of embodiment 628, wherein the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.
        632. The method of any one of embodiments 597-607, wherein the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
        633. The method of embodiment 632, wherein the acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
        634. The method of embodiment 633, wherein the ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
        635. The method of embodiment 633, wherein the traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.
        636. The method of embodiment 633, wherein the viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).
        637. The method of any one of embodiments 597-6070, wherein the neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.
        638. The method of any one of embodiments 596-637, wherein the subject is a human.
        639. The method of any one of embodiments 596-638, wherein the subject is a patient with one or more risk factors for developing a condition involving axonal degeneration.
        640. The method of embodiments 639, wherein the one or more risk factors for developing a condition involving axonal degeneration comprise age, one or more genetic risk factors for neurodegeneration, family history, engaging in one or more high-risk activities, one or more biomarkers of neurodegeneration, or a combination thereof.
        641. The method of embodiment 640, wherein the one or more genetic risk factors for neurodegeneration comprise one or more copies of a known genetic risk factor, a hexanucleotide repeat expansion in chromosome 9 open reading frame 72, one or more copies of the ApoE4 allele, or a combination thereof.
        642. The method of embodiment 640, wherein engaging in one or more high-risk activities comprises participating in an activity comprising American football, basketball, boxing, diving, field hockey, football, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, cheerleading, fencing, track and field, gymnastics, handball, horseback riding, skating, skiing, skateboarding, softball, squash, ultimate Frisbee, volleyball, or windsurfing.
        643. The method of embodiment 640, wherein the one or more biomarkers of neurodegeneration comprises:
        
            concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject;
            constitutive NAD+ levels in neurons and/or axons of the subject;
            constitutive cADPR levels in neurons and/or axons of the subject;
            levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and
        
        
        levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.
        644. The antisense oligonucleotide, pharmaceutical composition, or method of any one of embodiments 1-643, wherein the antisense oligonucleotide is complementary to a target region of a nucleic acid encoding Sterile Alpha and TIR motif-containing 1 (SARM1).
        645. The antisense oligonucleotide, pharmaceutical composition, or method of any one of embodiments 1-644, wherein the antisense oligonucleotide comprises internucleotide linkages of the pattern RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond.
    
    


EXAMPLES
The present teachings, including descriptions provided in the Examples, are not intended to limit the scope of any claim. Unless specifically presented in the past tense, inclusion in the Examples is not intended to imply that the experiments were actually performed. The following non-limiting examples are provided to further illustrate the present teachings. Those of skill in the art, in light of the present disclosure, will appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present teachings.
Example 1: Antisense Modulation of SARM1 Transcript in Human Neuroblastoma Cell Line
This Example illustrates an in vitro assay used to characterize oligonucleotides. Antisense oligonucleotides complementary to different regions the SARM1 transcript were synthesized and tested for their ability to inhibit the SARM1 transcript in vitro in a human neuroblastoma cell line.
Human Neuroblastoma Cell Line
The human neuroblastoma cell line SH-SY5Y (ATCC-CRL-2266) was cultured in DMEM medium (Sigma-Aldrich) supplemented with 10% fetal bovine serum (Gibco) and 1 mM penicillin-streptomycin (Sigma). Cultures were plated at a density of 100,000 cells/well in a 24-well tissue culture plate coated with poly-D-Lysine (0.1 mg/ml; Sigma) and laminin (3 mg/mL; Invitrogen). Cells were allowed to adhere to the plates in a humidified tissue culture incubator (5% CO2). Cells were transfected at 70% confluence with an antisense oligonucleotide comprising sequences selected from SEQ ID NO: 3-26 at a final concentration of 10-500 nM using Lipofectamine RNAiMAX diluted in Opti-MEM (ThermoFisher). The antisense oligonucleotides contained non-complementary 5-mer sequences 5′ and 3′ of nucleotide sequences selected from SEQ ID NO: 3-26 and internucleotide linkages of the following pattern (5′ to 3′): RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond. SARM1 siRNA (20 nM, Dharmacon) was used a positive control. All conditions were run in triplicate. Transfected cells were incubated for 24 to 72 hours and then harvested for RNA analysis. SARM1 transcript levels were evaluated using quantitative PCR carried out using TaqMan Real-Time PCR system (Thermo Fisher). SARM1 RNA levels were normalized to GAPDH (deltaCt) and plate-matched control transfected samples (delta-delta Ct), generating fold-change over control quantitation (2-(delta-deltaCt).
Results
The average fold-change over the control transfected cells is plotted in FIG. 2 and a summary over the overall percent knockdown of SARM1 transcript is listed in Table 2.







TABLE 2







Percent knockdown of SARM1 transcript











Average Percent



SEQ ID NO:
Knockdown







 3
31



 4
46



 5
 0



 6
 0



 7
16



 8
12



 9
23



10
34



11
26



12
11



13
40



14
50



15
27



16
60



17
53



18
59



19
69



20
43



21
35



22
31



23
 8



24
24



25
34



26
35










Specifically, SEQ ID NO:5 targeted the 5′UTR region, SEQ ID NOs: 4, 17, 18, 20 and 26 targeted the coding region and SEQ ID NOs: 13, 14, 16 and 19 targeted the 3′UTR. Surprisingly, some antisense oligonucleotide (ASO) sequences targeting different regions of the SARM1 transcript produced a robust knockdown of SARM1 expression compared to control, while other ASO sequences had little or no effect. Together, these results confirm that measurable knockdown of the SARM1 transcript can be produced by antisense targeting particular regions of the SARM1 mRNA sequence.
Example 2: Antisense Modulation of SARM1 Transcript in Human Neuroblastoma Cell Line
This Example illustrates an in vitro assay used to characterize oligonucleotides. Antisense oligonucleotides complementary to different regions the SARM1 transcript were synthesized and tested for their ability to inhibit the SARM1 transcript in vitro in a human neuroblastoma cell line.
Human Neuroblastoma Cell Line
The human neuroblastoma cell line SH-SY5Y (ATCC-CRL-2266) was cultured in DMEM medium (Sigma-Aldrich) supplemented with 10% fetal bovine serum (Gibco) and 1 mM penicillin-streptomycin (Sigma). Cultures were plated at a density of 100,000 cells/well in a 24-well tissue culture plate coated with poly-D-Lysine (0.1 mg/ml; Sigma) and laminin (3 mg/ml; Invitrogen). Cells were allowed to adhere to the plates in a humidified tissue culture incubator (5% CO2). Cells were transfected at 70% confluence with an antisense oligonucleotide selected from SEQ ID NO: 3-26 at a final concentration of 10-500 nM using Lipofectamine RNAiMAX diluted in Opti-MEM (ThermoFisher). The antisense oligonucleotides contained internucleotide linkages of the following pattern (5′ to 3′): RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond. SARM1 siRNA (20 nM, Dharmacon) was used a positive control. All conditions were run in triplicate. Transfected cells were incubated for 24 to 72 hours and then harvested for RNA analysis. SARM1 transcript levels were evaluated using quantitative PCR carried out using TaqMan Real-Time PCR system (Thermo Fisher). SARM1 RNA levels were normalized to GAPDH (deltaCt) and plate-matched control transfected samples (delta-delta Ct), generating fold-change over control quantitation (2-(delta-deltaCt).
Results
The average fold-change over the control transfected cells is plotted in FIG. 3. Specifically, SEQ ID NO:5 targeted the 5′UTR region, SEQ ID NOs: 4, 17, 18, 20 and 26 targeted the coding region and SEQ ID NOs: 13, 14, 16 and 19 targeted the 3′UTR. Surprisingly, some antisense oligonucleotide (ASO) sequences targeting different regions of the SARM1 transcript produced a robust knockdown of SARM1 expression compared to control, while other ASO sequences had little or no effect. Together, these results confirm that measurable knockdown of the SARM1 transcript can be produced by antisense targeting particular regions of the SARM1 mRNA sequence.
Example 3: Antisense Modulation of SARM1 Transcript in Human Motor Neurons
This Example illustrates robust concentration-dependent knockdown of SARM1 gene expression levels in vitro in human induced pluripotent stem cells (IPSC)-derived motor neurons following transfection with antisense oligonucleotides targeting the SARM1 transcript.
Human iPSC-derived motor neurons (Cellular Dynamics-R1049) were cultured and maintained according to the manufacturer's instructions for 14 days using iCell Complete Maintenance Medium plus DAPT (Cellular Dynamics). Motor neuron dispersed cultures were created by seeding 80,000 cells/well in a 24-well tissue culture plate coated with poly-D-Lysine (0.1 mg/ml; Sigma) and laminin (3 mg/ml; Invitrogen). Cells were transfected with 0.1, 0.3, 1, 3 or 10 nM of antisense oligonucleotides comprising SEQ ID NO: 9, 13, 22 or 38 using Lipofectamine RNAiMAX diluted in Opti-MEM (ThermoFisher). The antisense oligonucleotides contained internucleotide linkages of the following pattern (5′ to 3′): RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond. After 24 hours, a three-quarter medium change was performed to wash and remove the transfection solutions. At 48 hours, the cells were harvested and lysed for TaqMan RT-PCR analysis of SARM1 gene expression levels and normalized to Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) gene expression levels. Results are shown in FIG. 4 and data (n=3) are expressed as mean±SEM and normalized to control-treated cells. FIG. 4 illustrates that for all four antisense oligonucleotides, as concentration increased, SARM1 expression in IPSC-derived motor neurons decreased.
Example 4: Antisense Modulation of SARM1 Transcript in Human Motor Neurons after Free Uptake Delivery
This Example illustrates robust concentration-dependent knockdown of SARM1 gene expression levels in vitro in human induced pluripotent stem cells (IPSC)-derived motor neurons following delivery by free uptake (i.e. in the absence of a lipid carrier) with antisense oligonucleotides targeting the SARM1 transcript.
Human iPSC-derived motor neurons (Cellular Dynamics-R1049) were cultured and maintained according to the manufacturer's instructions for 14 days using iCell Complete Maintenance Medium plus DAPT (Cellular Dynamics). Motor neuron cultures were created by seeding 10,000 cells/well in a 96-well tissue culture plate coated with poly-D-Lysine (0.1 mg/ml; Sigma) and laminin (3 mg/ml; Invitrogen). Cells were allowed to adhere to the plates in a humidified tissue culture incubator (5% CO2) and then tissue culture wells were filled with 1 ml of cell culture media. Antisense oligonucleotides comprising SEQ ID NO: 9, 13 or 38 were diluted in Opti-MEM (ThermoFisher) at a concentration range of 1.25 to 10 UM and added to the cell culture media. The antisense oligonucleotides contained internucleotide linkages of the following pattern (5′ to 3′): RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, RO is an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond. After 9 days, cells were harvested and lysed for TaqMan RT-PCR analysis of SARM1 gene expression levels and normalized to Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) gene expression levels. Results are shown in FIG. 5 and data (n=2) are expressed as mean±SEM and normalized to control-treated cells. FIG. 5 illustrates that for all three antisense oligonucleotides, as concentration increased, SARM1 expression in IPSC-derived motor neurons decreased.
Example 5: Time-Dependent Antisense Modulation of SARM1 Transcript in Human Motor Neurons After Free Uptake Delivery
This Example illustrates time-dependent knockdown of SARM1 gene expression levels in vitro in human induced pluripotent stem cells (IPSC)-derived motor neurons following free uptake (no lipid carrier) delivery with antisense oligonucleotides targeting the SARM1 transcript.
Human iPSC-derived motor neurons (Cellular Dynamics-R1049) were cultured and maintained according to the manufacturer's instructions for 14 days using iCell Complete Maintenance Medium plus DAPT (Cellular Dynamics). Motor neuron cultures were created by seeding 80,000 cells/well as a spot in the center of each well of a 24-well tissue culture plate coated with poly-D-Lysine (0.1 mg/ml; Sigma) and laminin (3 mg/ml; Invitrogen). Cells were allowed to adhere to the plates in a humidified tissue culture incubator (5% CO2) and then tissue culture wells were filled with 1 ml of cell culture media. Antisense oligonucleotides comprising SEQ ID NO: 8, 9, 13, 22 or 38 were diluted in Opti-MEM (ThermoFisher) to a concentration of 10 UM and added to the cell culture media for free uptake delivery. The antisense oligonucleotides contained internucleotide linkages of the following pattern (5′ to 3′): RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, Rois an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond. After 2- or 6-days, cells were harvested and lysed for TaqMan RT-PCR analysis of SARM1 gene expression levels and normalized to Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) gene expression levels. Results are shown in FIG. 6 and data (n=3) expressed as mean±SEM and normalized to control-treated cells. FIG. 6 illustrates that for motor neurons treated with any of the five antisense oligonucleotides, SARM1 expression decreased at both time-points relative to the untreated control.
Example 6: SARM1 Antisense Prevents Axonal Degeneration Following Axotomy in Human iPSC-Derived Motor Neurons
This Example illustrates that treatment with SARM1 antisense oligonucleotides prevented axonal degeneration following axotomy. Specifically, an in vitro axon degeneration assay was used to test the efficacy of oligonucleotides complementary to different regions the SARM1 transcript to prevent axonal degeneration in a human induced pluripotent stem cell (iPSC)-derived motor neuron drop culture.
Human Motor Neuron Drop Culture
Human iPSC-derived motor neurons (Cellular Dynamics-R1049) were cultured and maintained according to the manufacturer's instructions for 14 days using iCell Complete Maintenance Medium plus DAPT (Cellular Dynamics). Motor neuron drop cultures were created by seeding 10,000 cells/well as a spot in the center of each well of a 24-well tissue culture plate coated with poly-D-Lysine (0.1 mg/mL; Sigma) and laminin (3 mg/mL; Invitrogen). Cells were allowed to adhere to the plates in a humidified tissue culture incubator (5% CO2) and then tissue culture wells were filled with 1 ml of cell culture media. Antisense oligonucleotides comprising SEQ ID NO: 9, 22, 38 or 39 were diluted in Opti-MEM (ThermoFisher) to a 5 μM concentration and added to the cell culture media for free uptake delivery. The antisense oligonucleotides contained internucleotide linkages of the following pattern (5′ to 3′): RSRORSRORSDSDSDSDSDSDSDSDSDSDSRORSRORS, wherein RS is an RNA (2′-MOE) phosphorothioate bond, Rois an RNA (2′-MOE) phosphodiester bond and DS is a DNA phosophorothioate bond. 10 days post-transfection, the axonal degeneration assay was performed.
Axon Degeneration Assay
Axonal degeneration was stimulated by manual axonal transection using a scalpel blade. After 16 hours, motor neuron cultures were fixed in 1% PFA plus sucrose and kept in the refrigerator prior to imaging. Cells were immuno-stained for beta-3 Tubulin (Clone TuJ1, R&D systems), images of motor neuron axons and cell bodies were collected using the 20× water immersion lens of a Phenix automated confocal microscope (PerkinElmer) and quantitation of axons was performed using in-house developed scripts (Acapella, PerkinElmer). The degeneration index reflects the integrity of the axon such that a higher value indicates a greater level of axonal fragmentation and a lower value indicates a lower level of axonal fragmentation. As shown in FIG. 7, ASOs that knock-down SARM1 expression reduced axonal degeneration in this assay. The data in FIG. 7 is expressed as mean±SEM (n=3-4). The dashed line labeled ‘Cut’ denotes mean level of degeneration observed in control-cut axons and dashed line labeled ‘Non-Cut’ denotes mean level of degeneration observed in intact control axons.
EXEMPLARY SEQUENCES
Wild-Type Human SARM1 Protein Sequence












MVLTLLLSAYKLCRFFAMSGPRPGAERLAVPGPDGGGGTGPWWAAGGRGPREVSPGAGTEVQDALERALPELQQAL


SALKQAGGARAVGAGLAEVFQLVEEAWLLPAVGREVAQGLCDAIRLDGGLDLLLRLLQAPELETRVQAARLLEQILVAE


NRDRVARIGLGVILNLAKEREPVELARSVAGILEHMFKHSEETCQRLVAAGGLDAVLYWCRRTDPALLRHCALALGNCA


LHGGQAVQRRMVEKRAAEWLFPLAFSKEDELLRLHACLAVAVLATNKEVEREVERSGTLALVEPLVASLDPGRFARCLV


DASDTSQGRGPDDLQRLVPLLDSNRLEAQCIGAFYLCAEAAIKSLOGKTKVFSDIGAIQSLKRLVSYSTNGTKSALAKRAL


RLLGEEVPRPILPSVPSWKEAEVQTWLQQIGFSKYCESFREQQVDGDLLLRLTEEELQTDLGMKSGITRKRFFRELTELKT


FANYSTCDRSNLADWLGSLDPRFRQYTYGLVSCGLDRSLLHRVSEQQLLEDCGIHLGVHRARILTAAREMLHSPLPCTG


GKPSGDTPDVFISYRRNSGSQLASLLKVHLQLHGFSVFIDVEKLEAGKFEDKLIQSVMGARNFVLVLSPGALDKCMQDH


DCKDWVHKEIVTALSCGKNIVPIIDGFEWPEPQVLPEDMQAVLTFNGIKWSHEYQEATIEKIIRFLOGRSSRDSSAGSDT


SLEGAAPMGPT (SEQ ID NO: 1).


 


Wild-type human SARM1 cDNA sequence (corresponding to mRNA sequence) (NCBI


Accession Number: NM_15077.4) The target sequences of exemplary ASOs are denoted


in bold capital letters and in the case where the sequences overlap it is denoted


by underline. In the one instance where there is an overlap in ASO targeting, the


sequence is denoted in both bold and underlined capital letters.








1
atctcccagctcagccgagcccgtgcccaggccacgctttgttccagccgccgcctcctc


 


61
taccctacggcgtccggagccatccctcgcctgctcgctctctcctttcgcccactccct


 


121
gcatctgggcctgcatcacctttgccaaccgctcccccgatcctgccgacactcctcccc


 


181
caaacttctgaccggcacccttgcctggtacccttctctccattcctccccctccatctt


 


241
ctttccccgacccctctcgggtccctcttttcccaaaacccgggtctctccgcgtggccc


 


301
cgcctccaggccggggatgtcccccgcggccccgcGCCCATGGTCCTGACGCTGCttctc


 


361
tccgcctacaagctgtgtcgcttcttcgccatgtcgggcccacggccgggcgccgagcgg


 


421
ctggcggtgcctgggccagatgggggcggtggcacgggcccatggtgggctgcgggtggc


 


481
cgcgggccccgcgaagtgtcgccgggggcaggcaccgaggtgcaggacgccctggagcgc


 


541
gcgctgccggagctgcagcaggccttgtccgcgctgaagcaggcgggcggcgcgcgggcc


 


601
gtgggcgccggcctggccgaggtctTCCAACTGGTGGAGGAGGCCtggctgctgccggcc


 


661
gtgggccgcgaggtagcccagggtctgtgcgacgccatccgcctcgatggcggcctcgac


 


721
ctgctgttgcggctgctgcaggcgccggagtTGGAGACGCGTGTGCAGGCCgcgcgcctg


 


781
ctggaGCAGATCCTGGTGGCTGAGAaccgagaccgcgtggcgcgcattgggctgggcgtg


 


841
atcctgaacctggcgaaggaacgcgaacccgtagagctggcgcggagcgtggcaggcatc


 


901
ttggagcacatgttcaagcattcggaggagacatgccagaggctggtggcggccggcggc


 


961
ctggacgcggtgctgtattggtgccgccgcacggaccccgcgctgctgcgccactgcgcg


 


1021
ctggcgctgggcaactgcgcgctgcacgggggccaggcggtgcagcgacgcatggtagag


 


1081
aagcgcgcagccgagtggctcttcccgctcgccttctccaaggaggacgagctgcttcgg


 


1141
ctgcacgcctgcctcgcagtagcggtgttggcgactaacaaggaggtggagcgcgaggtg


 


1201
gagcgctcgggcacgctggcgctcgtggagccgcttgtggcctcgctggaccctggccgc


 


1261
ttcgcccgctgtctggtggacgccagcgacacaagccagggccgcgggcccgacgacctg


 


1321
cagcgcctcgtgccgttgctcgactctaaccgcttggaggcgcagtgcatcggggctttc


 


1381
tacctctgcgccgaGGCTGCCATCAAGAGCCTGCaaggcaagaccaaggtgttcagcgac


 


1441
atcggcgccatcCAGAGCCTGAAACGCCTGGTttcctactctaccaatggcactaagtcg


 


1501
gcgctggccaagcgcgcgctgcGCCTGCTGGGCGAGGAGGTGccacggcccatcctgccc


 


1561
tccgtgcccagctggaaggaggccgaggttcagacgtggctgcagcagatcggtttctcc


 


1621
aagtactgcgagagcttccGGGAGCAGCAGGTGGATGGCgacctgcttctgcggctcACG


 


1681
GAGGAGGAACTCCAGACcgacctgggcatgaaatcgggcatcacccgcaAGAGGTTCTTT


 


1741
AGGGAGCTCacggagctcaagaccttcgccaactattctacgtgcgaccgcagcaacctg


 


1801
gcggactggctgggcagcctggacccgcgcttccgccagtacacctacggcctggtcagc


 


1861
tgcggcctGGACCGCTCCCTGCTGCACCgcgtgtctgagcagcagctgctggaagactgc


 


1921
ggcatccacctgggcgtgcaccgcgcccgcatcctcacggcggccagagaaatgctacac


 


1981
tccccgctgccctgtactGGTGGCAAACCCAGTGGGGAcactccagatgtcttcatcagc


 


2041
taccgccggaactcaggttcccagctggccagtctcctgaaggtgcacctgcagctgcat


 


2101
ggcttcagtgtcttcattgatgtggaGAAGCTGGAAGCAGGCAAGTtcgaggacaaactc


 


2161
atccagagtgtcatgggtgcccgcaactttgtgttggtgctatCACCTGGAGCACTGGAC


 


2221
AAGtgcatgcaagaccatgactgcaaggattgggtgcataaggagattgtgactgcttta


 


2281
agctgcggcaagaacattgtgcccatcattgatggcttcgagtggcctgagccccaggtc


 


2341
ctgccTGAGGACATGCAGGCTGTGCttactttcaacggtatcaagtggtcccacgaatac


 


2401
caggaggccaccattgagaagatcatccgcttcctgcagggccgctcctcccgggactca


 


2461
tctgcaggctctgacaccagtttggagggtgctgcacccatgggtccaacctaaccagtc


 


2521
cccagttccccagccctgctgtgacttccatttccatcgtcctttctgaaggaacagctc


 


2581
ctgaaaccagtcTCCCTGGGCTGAGACAACCTGGGctcttcttaggaaatggctctccct


 


2641
ccccctgtcccccaccctcatggcccacctccaacccactttcctcaGTATCTGGAGAGG


 


2701
GAAGGGAagtcaggcttgggcacgggaggttagaactcccccaggccctgccattgggtt


 


2761
gtctgtctccgtcatggggagggtccctgctcagttctggagacactggagttGGGGTGG


 


2821
GGGTGGTTCTGCAttcccttctcctgctgatagcagtcagcttgaggaggatgacggaag


 


2881
gcagcctcagacaggaattaaggcaatgcccaggcgggcctgggcactgtaTTCTGAGCA


 


2941
AGGGCCTGGGCccaggaGCCAGCCAGGGATGAGTGCCatcatggctctccactcagactg


 


3001
tgcctggcccctgcacttacaacttcctgccgctctgtggccttgccctgtaatcactca


 


3061
gtgcccttagctagcctgactaagtcccagatcccctacagcttccttcggtgtggtatc


 


3121
tttTGCCACATCCAGGGCGAGGGttgaggcaaaccagccctccctctgacttccttgtca


 


3181
ctgcagccagctttgctgcacttgctggtgcacaggagcctcctgtttggGCCTGGGTCT


 


3241
GGGCATGGGGaggccgtgcctcaaagcccaccctaccccatgccttggtgctgtgcctca


 


3301
ggctccttcctggtctggcccagctggcttccccagcccctcagccatccagggctaccc


 


3361
actgcttactcagggaccaggcagcccccatggcagtaaaagcagcctagacagaacctG


 


3421
CAGCTCTGTGGAAAGAGgcaaagtcctgaaaaggcaaagggttgtcacttagggcagctt


 


3481
ctccaactttaacatgcatccaagtcacctgggaatgttgttaaaatcaggagatctggg


 


3541
gtggggcctaggactctgcatttcttacagattcccaggtgagctgatgctggtggttaa


 


3601
gggtagcaaatctctaaagcacgaagccctcacaaatctttgccatttcccaaacactcc


 


3661
gctccatggtctccagtcatcagagcaactctacctggtattatcatccccattttacag


 


3721
ataatgacactgaggctcagaaaggttgaggataagcccactttcctgtcattagtggca


 


3781
gccccagatccagacctaggcctcctggcacccagtccactggcagtggaattgctttcc


 


3841
tgagaatcattctgaggctgggctattgcttctcccttgcttcaaagaatctagcagcgg


 


3901
gggataggattttgcaacaaaaagctgacccagaggccatacagagcaggaatatcccat


 


3961
tgccccctcctccactgggttcagagggtaagaaagcaccctccaataaacccaggctcc


 


4021
aggccgtgggggctgctgaaggctctttccccgcaagggccaggtgttgacaccttaaag


 


4081
ctggctgcgcccccagccccactcttggctgtgctggccaggtgactcctagttcttggc


 


4141
cacatcatcagaaagtcaaaggtctcactccaggtttggggctccttccttccactcccc


 


4201
tccctgccagagtctgtcttggccagtgccagcctcgatgctttggttttgaccccacct


 


4261
gatcctcctttcctcatgcagcacaagtgctcaccggggccagagccagggcatggatat


 


4321
gacaagcagggcagcctggacactgccctcacaggacagcgccaataacaatacagtgtc


 


4381
tgagtatctccaggggatgatttctggctctttgtctccaatcagtcccactccctcctg


 


4441
aggtccccaagggcagtattcagagaggtttcctgcgttttatttctatttggtataccc


 


4501
tccactgttgtccactgccctgtgtggccttctggttgacctctgcccgatcttctgtct


 


4561
ctctgagggaatcagagtccagcatccagccccagctggaacagctgaagtcacaagcct


 


4621
cctctaagccaaggccagtgtgttcagaggtgactgccacccatactaggacaaacacag


 


4681
ctcagatcaccaggtcaagcacctaggcctggcttctcctgagacagaggactcagaagt


 


4741
ggcctttcctccaaagcctgctcagacacaggtctgtagggccagggtgttctgcttggc


 


4801
tgggctgcagctgctacccctcggttggggctgagtcagccagatcctccccctacttct


 


4861
ccccaagggccaagaactgctcagggacattaaaggtcaaaagtccagccacactcattc


 


4921
atcctttccccaggcccatgaagagaggcatctcattgtagaatgtatgaggaagtggga


 


4981
agtatctcagagaatcagctaagtttcctaacttgtccatccaaatgtgatcaccacgat


 


5041
tcaacaatttggggcattgctgatctagccgttcctagtggggcttgctcaaggttgcac


 


5101
agcgagtcagtagaagccctggctggccccacttggtaccaatccaccaggcagctcagg


 


5161
gctcctgcccagcccagcagcttctgttgtctaacgtatggcaggcagactgggagcagg


 


5221
aaaacagagggccccaaagcccaaggcaccagaaggtttgtttcagtttgctgaagctga


 


5281
tttgtaatgattggcactcttcagccaggggagtgggtaggccatagccaaggatcgatt


 


5341
ccccaaccacagcaaaggcaacactcttcctccagagatcaccaagcccctcttacctcc


 


5401
ctccctccttcccaaggctggcactaaccaggtaccacattcattgttaaggaatggctg


 


5461
atgactgctacacgtgttgggaacctggttggggctgtgcagtttgggctggaaggagag


 


5521
atgccagccctcgtgctgcctctggtccctgaagtgtcacctctctcaggacctctcctc


 


5581
tggcctgtggggttataagtgatggatagcagaaagggagaactgactcctgtcccaaat


 


5641
agctcctctgccacctgtcctgcagtgggcctgtgtgggttatgattctagatcctagac


 


5701
agaggctgggtcagctgtggatggggtggtgccttggtctctcttgactacctcgtccaa


 


5761
agagagcactgcccttagacaagagttgcttgtcctgctgtgggctgggcttccagctgc


 


5821
agacctccagttgcttggtgttcactttgctcctcttgccctctgtcttctggtccaggc


 


5881
agatcaggggctctggggaaactgctggaactcgaggtgaggatcagccttttccagcat


 


5941
cctgtgagagaccagagagagagtttggatttcatgtggggaaccctcaaggcctgtctg


 


6001
gagaagtgacacaggatttactggggtgggctggtccaggtagctctcctgaacctcctc


 


6061
cttccccaagctgagaagctgagagctggaggacaatatccagggacatggctctggaaa


 


6121
ataacttttttttttttaagagacagggtcttgctctgttgtccaggctggagggcagtg


 


6181
acataatcatagctcactgtacccttgaactcctgggctcaagtgatcctcctgcctcag


 


6241
cctccttagtagctgggactaccagtgcataccaccatgcctgggtgattttttaaattt


 


6301
tttatacagacaaggtcttgctatgttgcccaggctgatcttgaattcccgggctcaagt


 


6361
ggtcctcctgcctcagcctcccacaggatcgggattacaggcaagagcctccacgcccgg


 


6421
ccatgaaatataattcttaatatcatacaggaaaaagtcagcgggtcaagctagcctgtg


 


6481
gcccagccacaactagctgacaaagcttcctggccttccctttaacacagttctgctgcc


 


6541
atagttccatctataaaatgggaatggagggaaataggggaactgggagagagaacacag


 


6601
ccttgccaagcagcaatgttagcctgatccttcctccacctagctcgccatctcgccctt


 


6661
ggaaaatggctcctggaggattaggcagccatctgcaaggagaggggcaacctgggacaa


 


6721
gacacccagagggtaaggattccaggaatgaagctgccatttctggttgggaggagaaga


 


6781
ggaaacttttaagagaaagggctccattatgagcatgggttcagggccctgcattaccca


 


6841
atcagaacagccgggatgagcaggaggccagctcccaggaggaaggggaaccccttcata


 


6901
aagttcagagtggctgggtagagtgagttgaagatgccggaggccgtcagcatggccagg


 


6961
ctattcacacaggccacagcagaaaagagagcacctgtgaagaaataaataccatactct


 


7021
ggagtccgaaagggccatattccaactctggcaccaccacctcacagctgtgtgaccggg


 


7081
agtagtcacttaacctatgtctccccttcctcaccagtaaatcctgctacatcatgtact


 


7141
gtgacaaggattcagtaaggtcatatgtggacagtagctggcacagaggggctactaaac


 


7201
aaatggctgctattaaatccacattaaaagtacatgtgatctgacagaacccagcacata


 


7261
aaagaaaaaaaaagtacatgtgatattgtctgatgaaagcttgatggaaatggctttttt


 


7321
ctggtttatcctctttggaatcatctcctgtttgggattaactgctggtctgatcagttc


 


7381
caatattcatagcggtgtcaccactgaatagcttcttatcctttgggttcctgttcctcc


 


7441
ttctgctaaataaggataatacctatttcctagattgtgagcaacattaagttcacatgg


 


7501
aaatcacccatcactgggcctggtcccctggaagtagctagttagtaagggctgttcttt


 


7561
tctcctgtttctcttgacatctctgggcacagagaaagtgctgggaaaaaaagtttaggt


 


7621
gaatgaatgaagacacatggattctggggacaccagaacccacagtgggctctgtatggc


 


7681
accagagtctctgtcatcatcagatcctcattccaggacagatggaaaaagatgaatgtt


 


7741
tccagactggggcataaagacccagaggctggagaagctgttctttatagatataccagg


 


7801
agaacccacagtttacaaaatgtgcaacaacccaacagaagttgagattaaattctgtca


 


7861
catctagaggggtctgtgatgtcatcaaaagcaaaccacccacatcacagatgaagaaac


 


7921
aggcctgtggcagggctcggactaaaacccagatcctgagaccagctgcttttaaacaca


 


4981
gacgtaggtttgcatcctagctccaccatttactgagtaaccttgggtgagccaatgtaa


 


8041
ccccctgggtctctgtttctttatctgtcaactgtggaaaatgaaacccatgtcacaagg


 


8101
ttgttcacttctgggcttgtacacgctgaccccagagaaacagggaactctggcatcacc


 


8161
acacccatcttacagacggaaaagctgaggtctgcagagagtaaatcctctgctctggtt


 


8221
atctagaaagaacataattgtgctctgctgactgcaaatcccaactctgcggtttgaaaa


 


8281
tccaaggtggcatgatcctctgcccattgtgggcaatttcacagaaatgtgtttgttttg


 


8341
gccacttacttctccagggtgagaggggggaaggcaagctgttcccccagccatggctgc


 


8401
ccatcagcccgtttcgggcagcactggacatgaggaaccagacacaggtgggttctgaca


 


8461
ctcaccctgctctgtctctctcaccagcttggagagtttagcccggatgacaggtgtgat


 


8521
gactaatgacaggaaaagcaacccatatcctgtggagaaacaaacactcatcaggaaaat


 


8581
ggggctggggagaggggcgtccaagggaaaggcagcagagctcctatccataccccacgt


 


8641
ggggcttaggttagacccaggaagaacttccttgatggtgagggtgggaagacagtagtc


 


8701
aaggaggaatggagactgcccttgtctgggcttggccacctgctagctctcatgaatgaa


 


8761
tgctaattcccattgattgctttcttgtctgaacctcttgtggtcacagcaggcatcacc


 


8821
cacccacttggcacttagtagggatatggcagggcacagaaaacaagcatgggctttgga


 


8881
gtcagccctgagttcaaaacctgatgccattacatattatctgtgtggcctggggtactt


 


8941
accctctctgatcctgactccctgtatgaggaagataataaggccttcatcacaggatgg


 


9001
ttctgaggcataggaggctgaataatggtgcccaatggcatcagattcatagccctggaa


 


9061
cctgtaaatactaccttatttggaaaatgagtctatgcaggtgtgcagttaagcctcctg


 


9121
agagagcagagttatcctggattaggttgggccctaaatgccgtcacacatatctttata


 


9181
agaggaaagcagacggagatttggcaccgacagaattgagaaggcacaaagaggaggaga


 


9241
gtcaatgtgagcacagaggcagagactggtgatggccgccccaagccaaggaatgccagc


 


9301
agccccagaagctggaagaaatgagaaacacgttctctcctggaggcttgcaagggagca


 


9361
ctgcctgctgactgcttccattcagcccggtggtactgactttggacttctggcctccag


 


9421
aactgtgagagaatatgtttctgttgtgttaagcccccaagtttgtggtatgtcattaca


 


9481
gcaatctcagggaaccaatacatgaggtaaaaaggtaacatctatgaagagcatggcata


 


9541
gggacacagcaaatgggagttccttttccctttgcattcagttacttacaggcttcctgt


 


9601
tttcttcataaccatttctctccctgtgcgactgctgactcctcagcaaaactgcaaact


 


9661
cctacaggacagtggatcctccaaagaaggtatacgatgaggcatccagggaccctagca


 


9721
gtgtcaggcccctcaaatcccactctgttgagacctccccccgacccagagcaatgacag


 


9781
catctttatcatctctgcatcccccagggccatcagcaggagggaaaggttcccttctgc


 


9841
ttaattgtcagacaagcagttgagttaagaaatctgtgattattgtattgttgactatac


 


9901
acagcacattttagggctctatcaaaataaatctgtccctttaaaaaaagttaactaaag


 


9961
ccgggcacggtggctcatgcctgtaatcccaacactttgggaggctgaggcaggcggatc


 


10021
cttgagctcaggagttagagacctggactgggcaaaatggtgaggaccccatctctataa


 


10081
aaaatacaaaaattagcaaggtgtggtaatgtgcaccagtggtcccagctactagagagg


 


10141
ccaaggtgggaggatcatctgggcccgggggatgaggctgcagtgagccatgatcgtgcc


 


10201
actgcactctagcctgggtaacaaagcgagaccctgtctctaaatacatcaatcaaataa


 


10261
aaattttaaaaagttaa (SEQ ID NO: 2)










Table 3-SARM1 antisense oligonucleotide sequences








Antisense Oligonucleotide Sequence
SEQ ID NO:





GGCCTCCTCCACCAGTTGGA
3


 


GCAGGCTCTTGATGGCAGCC
4


 


GCCATCCACCTGCTGCTCCC
5


 


TCCCCACTGGGTTTGCCACC
6


 


ACTTGCCTGCTTCCAGCTTC
7


 


CTTGTCCAGTGCTCCAGGTG
8


 


GCACAGCCTGCATGTCCTCA
9


 


CCCAGGTTGTCTCAGCCCAG
10


 


TCCCTTCCCTCTCCAGATAC
11


 


TGCAGAACCACCCCCACCCC
12


 


GCCCAGGCCCTTGCTCAGAA
13


 


GGCACTCATCCCTGGCTGGC
14


 


CCCCATGCCCAGACCCAGGC
15


 


GCCTCTTTCCACAGAGCTGC
16


 


TCTCAGCCACCAGGATCTGC
17


 


GAGCTCCCTAAAGAACCTCT
18


 


CCAGGTTGTCTCAGCCCAGG
19


 


GGTGCAGCAGGGAGCGGTCC
20


 


GCAGCGTCAGGACCATGGGC
21


 


ACCAGGCGTTTCAGGCTCTG
22


 


CACCTCCTCGCCCAGCAGGC
23


 


GTCTGGAGTTCCTCCTCCGT
24


 


CCCTCGCCCTGGATGTGGCA
25


 


GGCCTGCACACGCGTCTCCA
26


 


ACTTGTCCAGTGCTCCAGGT
27


 


AGCACAGCCTGCATGTCCTC
28


 


GCCCAGGTTGTCTCAGCCCA
29


 


GCACTCATCCCTGGCTGGCT
30


 


ATGCCCAGACCCAGGCCCAA
31


 


AGGCTCTTGATGGCAGCCTC
32


 


TTCTCAGCCACCAGGATCTG
33


 


GGTTCTCAGCCACCAGGATC
34


 


GTGAGCTCCCTAAAGAACCT
35


 


TTGTCCAGTGCTCCAGGTGA
36


 


GGTTGTCTCAGCCCAGGGAG
37


 


AGGTTGTCTCAGCCCAGGGA
38


 


CAGGTTGTCTCAGCCCAGGG
39


 


CACTCATCCCTGGCTGGCTC
40


 


TGGCACTCATCCCTGGCTGG
41


 


AGCTCCCTAAAGAACCTCTT
42


 


CTCCCTAAAGAACCTCTTGC
43


 


GCTCCCTAAAGAACCTCTTG
44


 


TGAGCTCCCTAAAGAACCTC
45


 


GTGCAGCAGGGAGCGGTCCA
46


 


CCAGGCGTTTCAGGCTCTGG
47


 


CAGGCGTTTCAGGCTCTGGA
48


 


CGGTTCTCAGCCACCAGGAT
49


 


AGGCGTTTCAGGCTCTGGAT
50


 


AACCAGGCGTTTCAGGCTCT
51


 


CCATCCACCTGCTGCTCCCG
52


 


TGGCACCTCCTCGCCCAGCA
53


 


GGTCGCCATCCACCTGCTGC
54


 


GTCGCCATCCACCTGCTGCT
55


 


CGCCATCCACCTGCTGCTCC
56


 


ATCCACCTGCTGCTCCCGGA
57


 


TCGCCATCCACCTGCTGCTC
58


 


CATCCACCTGCTGCTCCCGG
59


 


GTGGCACCTCCTCGCCCAGC
60


 


GGTCGGTCTGGAGTTCCTCC
61


 


GTCGGTCTGGAGTTCCTCCT
62


 


ACCCTCGCCCTGGATGTGGC
63


 


GAGTTCCTCCTCCGTGAGCC
64


 


GGTCTGGAGTTCCTCCTCCG
65


 


CGGTCTGGAGTTCCTCCTCC
66


 


GGAGTTCCTCCTCCGTGAGC
67


 


TGCAGCAGGGAGCGGTCCAG
68


 


AGCAGCGTCAGGACCATGGG
69


 


GAACCTCTTGCGGGTGATGC
70


 


AAACCAGGCGTTTCAGGCTC
71


 


GAAACCAGGCGTTTCAGGCT
72


 


AGAACCTCTTGCGGGTGATG
73


 


AAGAACCTCTTGCGGGTGAT
74


 


CCCTAAAGAACCTCTTGCGG
75


 


TCCCTAAAGAACCTCTTGCG
76


 


CCTAAAGAACCTCTTGCGGG
77


 


CTAAAGAACCTCTTGCGGGT
78


 


TAAAGAACCTCTTGCGGGTG
79


 


GCCCACGGCCGGCAGCAGCC
80


 


GCGGTGCAGCAGGGAGCGGT
81


 


CCACGGCCGGCAGCAGCCAG
82


 


CACGGCCGGCAGCAGCCAGG
83


 


CGGTGCAGCAGGGAGCGGTC
84


 


CACGCGGTGCAGCAGGGAGC
85


 


AGCGTCAGGACCATGGGCGC
86


 


GACACGCGGTGCAGCAGGGA
87


 


GCCCCGATGCACTGCGCCTC
88


 


CCCCGATGCACTGCGCCTCC
89


 


GCCCGTGCCACCGCCCCCAT
90


 


TTCCTCCTCCGTGAGCCGCA
91


 


TCCTCCTCCGTGAGCCGCAG
92


 


AGCCCCGATGCACTGCGCCT
93


 


CCTCCTCCGTGAGCCGCAGA
94


 


CCCACGGCCGGCAGCAGCCA
95


 


ACGGCCGGCAGCAGCCAGGC
96


 


CAGCGTCAGGACCATGGGCG
97


 


ACACGCGGTGCAGCAGGGAG
98


 


TAGGTGTACTGGCGGAAGCG
99


 


GGGTCCAGGCTGCCCAGCCA
100


 


GTCCAGGCTGCCCAGCCAGT
101


 


GGTCCAGGCTGCCCAGCCAG
102


 


GTCCAGGCTGCCCTGCTTGT
103


 


TCCAGGCTGCCCTGCTTGTC
104


 


CCATGGGTGCAGCACCCTCC
105


 


GGTCTTGCCTTGCAGGCTCT
106


 


CCTGTCTGAGGCTGCCTTCC
107


 


AGGCCTCCTCCACCAGTTGG
108


 


ACTGAGCAGGGACCCTCCCC
109


 


CCCCACTGGGTTTGCCACCA
110


 


CAGCCTGCATGTCCTCAGGC
111


 


TCCTGTCTGAGGCTGCCTTC
112


 


TGGTCTTGCCTTGCAGGCTC
113


 


GTCTTGCCTTGCAGGCTCTT
114


 


CAGGCTGCCCTGCTTGTCAT
115


 


GGGTACCAGGCAAGGGTGCC
116


 


GCATGTCCTCAGGCAGGACC
117


 


CAGGAGGCTCCTGTGCACCA
118


 


GCACAGACCCTGGGCTACCT
119


 


ACAGGAGGCTCCTGTGCACC
120


 


TTCCTGTCTGAGGCTGCCTT
121


 


TTGGTCTTGCCTTGCAGGCT
122


 


CTTGGTCTTGCCTTGCAGGC
123


 


AGGAGGCTCCTGTGCACCAG
124


 


GCACTTGTCCAGTGCTCCAG
125


 


GCTCCTGTGCACCAGCAAGT
126


 


CCCACTGGGTTTGCCACCAG
127


 


GAGGTGGGCCATGAGGGTGG
128


 


GGAGGTGGGCCATGAGGGTG
129


 


TGGAGGTGGGCCATGAGGGT
130


 


CCACTGGGTTTGCCACCAGT
131


 


TGCACTTGTCCAGTGCTCCA
132


 


CCTTGGTCTTGCCTTGCAGG
133


 


GATGGCACTCATCCCTGGCT
134


 


GCCCAGACCCAGGCCCAAAC
135


 


CAGGCTCTTGATGGCAGCCT
136


 


GGCTCCTGTGCACCAGCAAG
137


 


AGGCTCCTGTGCACCAGCAA
138


 


ACAGCCTGCATGTCCTCAGG
139


 


TGCCCAGACCCAGGCCCAAA
140


 


GCATGCACTTGTCCAGTGCT
141


 


CATGTCCTCAGGCAGGACCT
142


 


ATGCACTTGTCCAGTGCTCC
143


 


CCCAGGCCCTTGCTCAGAAT
144


 


GGCCAGACCAGGAAGGAGCC
145


 


CACAGACCCTGGGCTACCTC
146


 


CTGGTGTCAGAGCCTGCAGA
147


 


AGGGTACCAGGCAAGGGTGC
148


 


GGCCCAAACAGGAGGCTCCT
149


 


AGAGCCTGCAGATGAGTCCC
150


 


ATGGCACTCATCCCTGGCTG
151


 


TCTTGCCTTGCAGGCTCTTG
152


 


AACTGAGCAGGGACCCTCCC
153


 


CCTTGCAGGCTCTTGATGGC
154


 


GCCTTGCAGGCTCTTGATGG
155


 


TCCTGTGCACCAGCAAGTGC
156


 


TGCAGGCTCTTGATGGCAGC
157


 


GCCATGATGGCACTCATCCC
158


 


GCCAGACCAGGAAGGAGCCT
159


 


CTTGCCTTGCAGGCTCTTGA
160


 


GTGCACCAGCAAGTGCAGCA
161


 


TCCACAGAGCTGCAGGTTCT
162


 


ACTGGTGTCAGAGCCTGCAG
163


 


TGATGGCACTCATCCCTGGC
164


 


CACAGCCTGCATGTCCTCAG
165


 


GGGCCAGACCAGGAAGGAGC
166


 


TGCATGTCCTCAGGCAGGAC
167


 


CCTGTGCACCAGCAAGTGCA
168


 


GCCTGGGTTTATTGGAGGGT
169


 


CCTCTTTCCACAGAGCTGCA
170


 


GGGTGCAGCACCCTCCAAAC
171


 


GGTTTGCCACCAGTACAGGG
172


 


GGGTTTGCCACCAGTACAGG
173


 


GCCAGCACAGCCAAGAGTGG
174


 


GGCCAGCACAGCCAAGAGTG
175


 


TGGCCAGCACAGCCAAGAGT
176


 


AGGCCCAAACAGGAGGCTCC
177


 


GAACTTGCCTGCTTCCAGCT
178


 


GGGCACCCATGACACTCTGG
179


 


AAGCACAGCCTGCATGTCCT
180


 


GCAGCACCCTCCAAACTGGT
181


 


GGTGCAGCACCCTCCAAACT
182


 


CCCTCTGAACCCAGTGGAGG
183


 


TGTGCACCAGCAAGTGCAGC
184


 


CTTTCCACAGAGCTGCAGGT
185


 


GGTGTCAGAGCCTGCAGATG
186


 


TGGTGTCAGAGCCTGCAGAT
187


 


CCAGGCCCAAACAGGAGGCT
188


 


AGTGTAGCATTTCTCTGGCC
189


 


ACAGAGCTGCAGGTTCTGTC
190


 


CATGCACTTGTCCAGTGCTC
191


 


TTCCACAGAGCTGCAGGTTC
192


 


GAACTGAGCAGGGACCCTCC
193


 


CTGGGTTTGCCACCAGTACA
194


 


CACTGGGTTTGCCACCAGTA
195


 


GTGCAGCAAAGCTGGCTGCA
196


 


AACTTGCCTGCTTCCAGCTT
197


 


TTGCCTTGCAGGCTCTTGAT
198


 


GCACCCTCCAAACTGGTGTC
199


 


CCACAGAGCTGCAGGTTCTG
200


 


GCCTGAGGCACAGCACCAAG
201


 


GCCCAAACAGGAGGCTCCTG
202


 


CAGAGCCTGCAGATGAGTCC
203


 


CCATGATGGCACTCATCCCT
204


 


CTCCTGTGCACCAGCAAGTG
205


 


GAAGAGCCCAGGTTGTCTCA
206


 


CTTGCAGGCTCTTGATGGCA
207


 


GGCACCCATGACACTCTGGA
208


 


GTCAGAGCCTGCAGATGAGT
209


 


TCAGGACTTTGCCTCTTTCC
210


 


ACAGACTCTGGCAGGGAGGG
211


 


ACTGGGTTTGCCACCAGTAC
212


 


GGAAGTCACAGCAGGGCTGG
213


 


TGCCTTGCAGGCTCTTGATG
214


 


CCAGCACAGCCAAGAGTGGG
215


 


GGACTTTGCCTCTTTCCACA
216


 


GCTGCTTTTACTGCCATGGG
217


 


AGTGCAGCAAAGCTGGCTGC
218


 


GTGTCAGAGCCTGCAGATGA
219


 


CAGGACTTTGCCTCTTTCCA
220


 


GGCACAGCACCAAGGCATGG
221


 


GGGAATGCAGAACCACCCCC
222


 


CCAGGCCCTTGCTCAGAATA
223


 


CTGAGGCACAGCACCAAGGC
224


 


AACAGGAGGCTCCTGTGCAC
225


 


AGAAGAGCCCAGGTTGTCTC
226


 


TTTCCACAGAGCTGCAGGTT
227


 


TGCCTTTTCAGGACTTTGCC
228


 


AGCCATGATGGCACTCATCC
229


 


TCTTTCCACAGAGCTGCAGG
230


 


AGCACCCTCCAAACTGGTGT
231


 


AAGAGCCCAGGTTGTCTCAG
232


 


CAGGCCCAAACAGGAGGCTC
233


 


CCTCCACCAGTTGGAAGACC
234


 


ACCCAGGCCCAAACAGGAGG
235


 


CCTCTGAACCCAGTGGAGGA
236


 


AGGACTTTGCCTCTTTCCAC
237


 


TCCCTCTCCAGATACTGAGG
238


 


TGGGTTTGCCACCAGTACAG
239


 


CAGAATACAGTGCCCAGGCC
240


 


TAAGCACAGCCTGCATGTCC
241


 


CCTGAGGCACAGCACCAAGG
242


 


CCTTTTCAGGACTTTGCCTC
243


 


AGCCTGGGTTTATTGGAGGG
244


 


CTGTGCACCAGCAAGTGCAG
245


 


GAGGCACAGCACCAAGGCAT
246


 


CCAGACCCAGGCCCAAACAG
247


 


GGCCAAGACAGACTCTGGCA
248


 


GTGCAGCACCCTCCAAACTG
249


 


CCCTCTCCAGATACTGAGGA
250


 


GCCTGGGCATTGCCTTAATT
251


 


TGAGGCACAGCACCAAGGCA
252


 


CTCTTTCCACAGAGCTGCAG
253


 


GTAAGCACAGCCTGCATGTC
254


 


CTCCTTATGCACCCAATCCT
255


 


AATGCAGAACCACCCCCACC
256


 


GCCCAGCCTCAGAATGATTC
257


 


TTGCAGGCTCTTGATGGCAG
258


 


GCCCCAAACCTGGAGTGAGA
259


 


GAGTGGAAGGAAGGAGCCCC
260


 


GAGTGTAGCATTTCTCTGGC
261


 


TCAGAGCCTGCAGATGAGTC
262


 


TCTCCTTATGCACCCAATCC
263


 


GGAATGCAGAACCACCCCCA
264


 


AGTGGAAGGAAGGAGCCCCA
265


 


CCCAATCCTTGCAGTCATGG
266


 


ATGATGGCACTCATCCCTGG
267


 


TGCAGCACCCTCCAAACTGG
268


 


GACCCAGGCCCAAACAGGAG
269


 


AGACCCAGGCCCAAACAGGA
270


 


GTCTCCAGAACTGAGCAGGG
271


 


TGGTTAGGTTGGACCCATGG
272


 


GAAGGGTACCAGGCAAGGGT
273


 


CAGACCCAGGCCCAAACAGG
274


 


GCACCCATGACACTCTGGAT
275


 


ACTTTGCCTCTTTCCACAGA
276


 


GACTTTGCCTCTTTCCACAG
277


 


AGCCCCAAACCTGGAGTGAG
278


 


CACCCAATCCTTGCAGTCAT
279


 


CTCCACCAGTTGGAAGACCT
280


 


CACCCTCCAAACTGGTGTCA
281


 


AGAACTGAGCAGGGACCCTC
282


 


TGGCCAAGACAGACTCTGGC
283


 


GGAGTGGAAGGAAGGAGCCC
284


 


CTGAACCCAGTGGAGGAGGG
285


 


CCCTCCAAACTGGTGTCAGA
286


 


AGGCACAGCACCAAGGCATG
287


 


CTTTGCCTCTTTCCACAGAG
288


 


GCCCTTGCTCAGAATACAGT
289


 


CTGGTTAGGTTGGACCCATG
290


 


TGGAAGTCACAGCAGGGCTG
291


 


AGCCCAGCCTCAGAATGATT
292


 


AGTAAGCACAGCCTGCATGT
293


 


TCCACCAGTTGGAAGACCTC
294


 


TCCTCCACCAGTTGGAAGAC
295


 


CAGCACCCTCCAAACTGGTG
296


 


TGGCAAAGGTGATGCAGGCC
297


 


GTGCCATTGGTAGAGTAGGA
298


 


TCCTTATGCACCCAATCCTT
299


 


GAGCCATGATGGCACTCATC
300


 


CAGAACTGAGCAGGGACCCT
301


 


GGAAGGAGCCCCAAACCTGG
302


 


GTGATTACAGGGCAAGGCCA
303


 


TCAGAATACAGTGCCCAGGC
304


 


GGCATTGCCTTAATTCCTGT
305


 


TGCACCAGCAAGTGCAGCAA
306


 


TTCCCTCTCCAGATACTGAG
307


 


TTCAGGACTTTGCCTCTTTC
308


 


GCAAGTGCAGCAAAGCTGGC
309


 


TCCAGAACTGAGCAGGGACC
310


 


CATGATGGCACTCATCCCTG
311


 


ACCCTCCAAACTGGTGTCAG
312


 


CCAAACTGGTGTCAGAGCCT
313


 


AGGGAATGCAGAACCACCCC
314


 


GGCCCTTGCTCAGAATACAG
315


 


AGGCCCTTGCTCAGAATACA
316


 


CAGGCCCTTGCTCAGAATAC
317


 


AAACAGGAGGCTCCTGTGCA
318


 


GGAGTGTAGCATTTCTCTGG
319


 


GGGAGTGTAGCATTTCTCTG
320


 


GAATGCAGAACCACCCCCAC
321


 


TGTCAGAGCCTGCAGATGAG
322


 


TCTGAACCCAGTGGAGGAGG
323


 


AGACAGACTCTGGCAGGGAG
324


 


GCCAAGACAGACTCTGGCAG
325


 


GCTCAGAATACAGTGCCCAG
326


 


GGGAGTGGAAGGAAGGAGCC
327


 


TAGCCCAGCCTCAGAATGAT
328


 


ATAGCCCAGCCTCAGAATGA
329


 


TCCAAACTGGTGTCAGAGCC
330


 


ACCCAATCCTTGCAGTCATG
331


 


CCCAGCCTCAGAATGATTCT
332


 


CCTTAATTCCTGTCTGAGGC
333


 


GCCTTAATTCCTGTCTGAGG
334


 


AGTGATTACAGGGCAAGGCC
335


 


CCTGGGCATTGCCTTAATTC
336


 


TTGCCTTTTCAGGACTTTGC
337


 


CTTATGCACCCAATCCTTGC
338


 


AGTGCCATTGGTAGAGTAGG
339


 


CCAAACAGGAGGCTCCTGTG
340


 


AAACTGGTGTCAGAGCCTGC
341


 


TCTCCAGAACTGAGCAGGGA
342


 


AGACAACCCAATGGCAGGGC
343


 


GAAGGAGCCCCAAACCTGGA
344


 


GTGGAAGGAAGGAGCCCCAA
345


 


GCATTGCCTTAATTCCTGTC
346


 


CTCTGAACCCAGTGGAGGAG
347


 


AGAGCCATGATGGCACTCAT
348


 


GATTACAGGGCAAGGCCACA
349


 


GCACTGAGTGATTACAGGGC
350


 


CCTTATGCACCCAATCCTTG
351


 


TTTCAGGACTTTGCCTCTTT
352


 


CTTAGTGCCATTGGTAGAGT
353


 


AAGAAGAGCCCAGGTTGTCT
354


 


TTATGCACCCAATCCTTGCA
355


 


CTGGCCAAGACAGACTCTGG
356


 


TTGCTCAGAATACAGTGCCC
357


 


TATGCACCCAATCCTTGCAG
358


 


TGTCTCCAGAACTGAGCAGG
359


 


CCAGCAAGTGCAGCAAAGCT
360


 


CTCCAGAACTGAGCAGGGAC
361


 


AAGGAGCCCCAAACCTGGAG
362


 


AGGAAGGAGCCCCAAACCTG
363


 


ACAATCTCCTTATGCACCCA
364


 


CACAATCTCCTTATGCACCC
365


 


AGAAGGGTACCAGGCAAGGG
366


 


CCAAGACAGACTCTGGCAGG
367


 


CTCAGAATACAGTGCCCAGG
368


 


ATCTCCTTATGCACCCAATC
369


 


GCACCAGCAAGTGCAGCAAA
370


 


CTCCAAACTGGTGTCAGAGC
371


 


CAAGTGCAGCAAAGCTGGCT
372


 


AAGGAAGTCAGAGGGAGGGC
373


 


CTTAATTCCTGTCTGAGGCT
374


 


TGATTACAGGGCAAGGCCAC
375


 


GCTTTAGAGATTTGCTACCC
376


 


CCAGCTTCTCCACATCAATG
377


 


CCAGCCTCAGAATGATTCTC
378


 


CCTCCAAACTGGTGTCAGAG
379


 


GGCACTGAGTGATTACAGGG
380


 


GGGCACTGAGTGATTACAGG
381


 


TTGGCAAAGGTGATGCAGGC
382


 


AAGACAGACTCTGGCAGGGA
383


 


ACCAGCAAGTGCAGCAAAGC
384


 


GCCCTGGATGTGGCAAAAGA
385


 


GAGTGATTACAGGGCAAGGC
386


 


GACTTAGTGCCATTGGTAGA
387


 


CAAGACAGACTCTGGCAGGG
388


 


ACCCATGACACTCTGGATGA
389


 


GAGAAGGGTACCAGGCAAGG
390


 


CACCCATGACACTCTGGATG
391


 


CATTGCCTTAATTCCTGTCT
392


 


CTTGCTCAGAATACAGTGCC
393


 


CCTTGCTCAGAATACAGTGC
394


 


CCCATGACACTCTGGATGAG
395


 


ACTGGCCAAGACAGACTCTG
396


 


AAGTGCAGCAAAGCTGGCTG
397


 


CAGACAACCCAATGGCAGGG
398


 


AAGGAAGGAGCCCCAAACCT
399


 


GCCTCAGAATGATTCTCAGG
400


 


CCCTTGCTCAGAATACAGTG
401


 


CAAACTGGTGTCAGAGCCTG
402


 


GTTGGCAAAGGTGATGCAGG
403


 


GGTTGGCAAAGGTGATGCAG
404


 


TAAGAAGAGCCCAGGTTGTC
405


 


TCACAATCTCCTTATGCACC
406


 


CCTCTCCAGATACTGAGGAA
407


 


AGCAAGTGCAGCAAAGCTGG
408


 


TTAGTGCCATTGGTAGAGTA
409


 


ACTTAGTGCCATTGGTAGAG
410


 


TAGTGCCATTGGTAGAGTAG
411


 


GAAGGAAGGAGCCCCAAACC
412


 


GGTAGAGTAGGAAACCAGGC
413


 


CACTGAGTGATTACAGGGCA
414


 


GAGAGAAGGGTACCAGGCAA
415


 


CAATCTCCTTATGCACCCAA
416


 


GCTGTTCCTTCAGAAAGGAC
417


 


GTCACAATCTCCTTATGCAC
418


 


TTTGCCTTTTCAGGACTTTG
419


 


ACACTCTGGATGAGTTTGTC
420


 


AGCTGTTCCTTCAGAAAGGA
421


 


CTTTAGAGATTTGCTACCCT
422


 


CAGCTTCTCCACATCAATGA
423


 


GACACTCTGGATGAGTTTGT
424


 


AAGTAAGCACAGCCTGCATG
425


 


CAGCCTCAGAATGATTCTCA
426


 


GGAAGGAAGGAGCCCCAAAC
427


 


AGGGCACTGAGTGATTACAG
428


 


TGCCATTGGTAGAGTAGGAA
429


 


CAAGGAAGTCAGAGGGAGGG
430


 


AGAGAAGGGTACCAGGCAAG
431


 


ACAGACAACCCAATGGCAGG
432


 


AAGGGAATGCAGAACCACCC
433


 


AATCTCCTTATGCACCCAAT
434


 


GCAGGAAGTTGTAAGTGCAG
435


 


AGGAAGTTGTAAGTGCAGGG
436


 


AGCCTCAGAATGATTCTCAG
437


 


TTTAGAGATTTGCTACCCTT
438


 


TGCTTTAGAGATTTGCTACC
439


 


GAGACAGACAACCCAATGGC
440


 


GACAGACAACCCAATGGCAG
441


 


AGACAGACAACCCAATGGCA
442


 


AAAGTAAGCACAGCCTGCAT
443


 


CATGACACTCTGGATGAGTT
444


 


TGAGTGATTACAGGGCAAGG
445


 


GCCATTGGTAGAGTAGGAAA
446


 


CAGGAAGTTGTAAGTGCAGG
447


 


ACTGAGTGATTACAGGGCAA
448


 


GGTAGCTGATGAAGACATCT
449


 


GAAGGGAATGCAGAACCACC
450


 


GCTTCTCCACATCAATGAAG
451


 


AGCTTCTCCACATCAATGAA
452


 


ATGACACTCTGGATGAGTTT
453


 


TGACACTCTGGATGAGTTTG
454


 


TGGTAGAGTAGGAAACCAGG
455


 


TTTTGGGAAAAGAGGGACCC
456


 


GTTTTGGGAAAAGAGGGACC
457


 


CTCTCCAGATACTGAGGAAA
458


 


CTCCAGATACTGAGGAAAGT
459


 


GCTTAAAGCAGTCACAATCT
460


 


GTAGCTGATGAAGACATCTG
461


 


GGTTTTGGGAAAAGAGGGAC
462


 


TTGAAAGTAAGCACAGCCTG
463


 


CCAGATACTGAGGAAAGTGG
464


 


TTGGTAGAGTAGGAAACCAG
465


 


CCTGGATGTGGCAAAAGATA
466


 


GGATGTGGCAAAAGATACCA
467


 


TAGCTGATGAAGACATCTGG
468


 


ATTGGTAGAGTAGGAAACCA
469


 


CATTGGTAGAGTAGGAAACC
470


 


CCATTGGTAGAGTAGGAAAC
471


 


TCTCCACATCAATGAAGACA
472


 


TCTCCAGATACTGAGGAAAG
473


 


AGCTTAAAGCAGTCACAATC
474


 


CAGCTTAAAGCAGTCACAAT
475


 


TCCAGATACTGAGGAAAGTG
476


 


CAGATACTGAGGAAAGTGGG
477


 


TGGATGTGGCAAAAGATACC
478


 


TCCACATCAATGAAGACACT
479


 


CTCCACATCAATGAAGACAC
480


 


TTCTCCACATCAATGAAGAC
481


 


TGTGGCAAAAGATACCACAC
482


 


GATGTGGCAAAAGATACCAC
483


 


ATGTGGCAAAAGATACCACA
484


 


TCTTTGAAGCAAGGGAGAAG
485


 


CCACATCAATGAAGACACTG
486


 


CACATCAATGAAGACACTGA
487


 


ACATCAATGAAGACACTGAA
488


 


AGCCATCAATGATGGGCACA
489


 


GATGGGCACAATGTTCTTGC
490


 


GCCATCAATGATGGGCACAA
491


 


ATGATGGGCACAATGTTCTT
492


 


TGATGGGCACAATGTTCTTG
493


 


CCATCAATGATGGGCACAAT
494


 


AATGATGGGCACAATGTTCT
495


 


CAATGATGGGCACAATGTTC
496


 


TCAATGATGGGCACAATGTT
497


 


ATCAATGATGGGCACAATGT
498


 


CATCAATGATGGGCACAATG
499


 


ATGGGCACAATGTTCTTGCC
500


 


CTCAATGGTGGCCTCCTGGT
501


 


ATGGTGGCCTCCTGGTATTC
502


 


TCAATGGTGGCCTCCTGGTA
503


 


CACCTTCAGGAGACTGGCCA
504


 


TGCACCTTCAGGAGACTGGC
505


 


GTGCACCTTCAGGAGACTGG
506


 


GAAGCCATCAATGATGGGCA
507


 


ACATCTGGAGTGTCCCCACT
508


 


CCTTGCAGTCATGGTCTTGC
509


 


GACATCTGGAGTGTCCCCAC
510


 


CATCTGGAGTGTCCCCACTG
511


 


AGACATCTGGAGTGTCCCCA
512


 


GCAGTCATGGTCTTGCATGC
513


 


TCCTTGCAGTCATGGTCTTG
514


 


AAGACATCTGGAGTGTCCCC
515


 


GCTGAACACCTTGGTCTTGC
516


 


CTGAACACCTTGGTCTTGCC
517


 


ATGATCTTCTCAATGGTGGC
518


 


GATGATCTTCTCAATGGTGG
519


 


GGATGATCTTCTCAATGGTG
520


 


GCAGCTTAAAGCAGTCACAA
521


 


TCTGGAGTGTCCCCACTGGG
522


 


ATCTGGAGTGTCCCCACTGG
523


 


CAATGGTGGCCTCCTGGTAT
524


 


AATGGTGGCCTCCTGGTATT
525


 


CTGATGAAGACATCTGGAGT
526


 


ATCCTTGCAGTCATGGTCTT
527


 


GAACACCTTGGTCTTGCCTT
528


 


TGAACACCTTGGTCTTGCCT
529


 


AATCCTTGCAGTCATGGTCT
530


 


AACACCTTGGTCTTGCCTTG
531


 


GAAGACATCTGGAGTGTCCC
532


 


TCAGACACTGTATTGTTATT
533


 


CAGACACTGTATTGTTATTG
534


 


GACACTGAAGCCATGCAGCT
535


 


ACACTGAAGCCATGCAGCTG
536


 


AGACACTGAAGCCATGCAGC
537


 


CTCTGGATGAGTTTGTCCTC
538


 


CTGGAGTGTCCCCACTGGGT
539


 


GGAGTGTCCCCACTGGGTTT
540


 


TGGAGTGTCCCCACTGGGTT
541


 


GAGTGTCCCCACTGGGTTTG
542


 


CACCTTGGTCTTGCCTTGCA
543


 


ACACCTTGGTCTTGCCTTGC
544


 


TTGACTTTCTGATGATGTGG
545


 


ACTCTGGATGAGTTTGTCCT
546


 


CACTCTGGATGAGTTTGTCC
547


 


GCAGGTTCTGTCTAGGCTGC
548


 


GCTGCAGGTTCTGTCTAGGC
549


 


CAGGTTCTGTCTAGGCTGCT
550


 


CTGCAGGTTCTGTCTAGGCT
551


 


TGCAGGTTCTGTCTAGGCTG
552


 


AACCCAATGGCAGGGCCTGG
553


 


CAACCCAATGGCAGGGCCTG
554


 


GTGTCTCCAGAACTGAGCAG
555


 


GGGCTGCCTGGTCCCTGAGT
556


 


GGCTGCCTGGTCCCTGAGTA
557


 


GCCTGACTTCCCTTCCCTCT
558


 


GTCCTGTGAGGGCAGTGTCC
559


 


ACTCATCCCTGGCTGGCTCC
560


 


GTGAGGGCAGTGTCCAGGCT
561


 


GTGGGTAGCCCTGGATGGCT
562


 


GTATGGCCTCTGGGTCAGCT
563


 


AGTGGGTTGGAGGTGGGCCA
564


 


GTGGGTTGGAGGTGGGCCAT
565


 


TGTGAGGGCAGTGTCCAGGC
566


 


GGGTAGCCCTGGATGGCTGA
567


 


CCCCAACTCCAGTGTCTCCA
568


 


GTTGTCTCAGCCCAGGGAGA
569


 


CTGTCCTGTGAGGGCAGTGT
570


 


CCCAGATGCAGGGAGTGGGC
571


 


TGTCCTGTGAGGGCAGTGTC
572


 


CCTGTGAGGGCAGTGTCCAG
573


 


ATGGCCTCTGGGTCAGCTTT
574


 


GCTGCCTGGTCCCTGAGTAA
575


 


TGCAGGCCCAGATGCAGGGA
576


 


GGGTTGGAGGTGGGCCATGA
577


 


GGCTGCCCTGCTTGTCATAT
578


 


TGGGTAGCCCTGGATGGCTG
579


 


CTGTGAGGGCAGTGTCCAGG
580


 


AAGCCTGACTTCCCTTCCCT
581


 


GGTGATGCAGGCCCAGATGC
582


 


TATGGCCTCTGGGTCAGCTT
583


 


TGTCCAGTGCTCCAGGTGAT
584


 


GCTGCCCTGCTTGTCATATC
585


 


AAGTGGGTTGGAGGTGGGCC
586


 


GTAGCCCTGGATGGCTGAGG
587


 


ATGCAGGCCCAGATGCAGGG
588


 


GTCCAGTGCTCCAGGTGATA
589


 


CAAGCCTGACTTCCCTTCCC
590


 


CCAAGCCTGACTTCCCTTCC
591


 


TGCCTGGTCCCTGAGTAAGC
592


 


GCCTGGAGCCTGGGTTTATT
593


 


AGGCCCAGATGCAGGGAGTG
594


 


GTGCTCCAGGTGATAGCACC
595


 


TGGGTTGGAGGTGGGCCATG
596


 


GGTTCTGTCTAGGCTGCTTT
597


 


AGGTTCTGTCTAGGCTGCTT
598


 


CTGCCCTGCTTGTCATATCC
599


 


AAGCAGTGGGTAGCCCTGGA
600


 


GTGATGCAGGCCCAGATGCA
601


 


TTGTCTCAGCCCAGGGAGAC
602


 


CCCAACTCCAGTGTCTCCAG
603


 


GTTGGAGGTGGGCCATGAGG
604


 


GGTTGGAGGTGGGCCATGAG
605


 


CAGAGCTGCAGGTTCTGTCT
606


 


GATGCAGGCCCAGATGCAGG
607


 


GCTTGTCATATCCATGCCCT
608


 


GCCCTGCTTGTCATATCCAT
609


 


GGCTGGCACTGGCCAAGACA
610


 


TGCCCTGCTTGTCATATCCA
611


 


AGCTGCAGGTTCTGTCTAGG
612


 


TTGGAGGTGGGCCATGAGGG
613


 


AGAATACAGTGCCCAGGCCC
614


 


AGGCTGGCACTGGCCAAGAC
615


 


GTTTCAGGAGCTGTTCCTTC
616


 


CTGCCTGGTCCCTGAGTAAG
617


 


TGCTCCAGGTGATAGCACCA
618


 


CCCTTTGCCTTTTCAGGACT
619


 


GCAGCCAGCTTTAAGGTGTC
620


 


GGCAAAGGTGATGCAGGCCC
621


 


GTTCTGTCTAGGCTGCTTTT
622


 


GAGCTGCAGGTTCTGTCTAG
623


 


AGAGCTGCAGGTTCTGTCTA
624


 


GTCAGGCTAGCTAAGGGCAC
625


 


CCAACTCCAGTGTCTCCAGA
626


 


AGGTGATGCAGGCCCAGATG
627


 


TGCTTGTCATATCCATGCCC
628


 


AGTCAGGCTAGCTAAGGGCA
629


 


GCTGGCACTGGCCAAGACAG
630


 


AGTGCTCCAGGTGATAGCAC
631


 


TCAGGAGCTGTTCCTTCAGA
632


 


TCTAGGCTGCTTTTACTGCC
633


 


TGATGCAGGCCCAGATGCAG
634


 


ACAACCCAATGGCAGGGCCT
635


 


ACCCTTTGCCTTTTCAGGAC
636


 


ACCCTCTGAACCCAGTGGAG
637


 


GCAAAGGTGATGCAGGCCCA
638


 


GACTGGTTAGGTTGGACCCA
639


 


GTCTAGGCTGCTTTTACTGC
640


 


ACAGTCTGAGTGGAGAGCCA
641


 


CACAGTCTGAGTGGAGAGCC
642


 


GACAACCCAATGGCAGGGCC
643


 


AGGAAGTCAGAGGGAGGGCT
644


 


TCAGGCTAGCTAAGGGCACT
645


 


CCTGGAGCCTGGGTTTATTG
646


 


TCTTACCCTCTGAACCCAGT
647


 


GCACTTGTGCTGCATGAGGA
648


 


GGGTTTATTGGAGGGTGCTT
649


 


TTCAGGAGCTGTTCCTTCAG
650


 


TACCCTCTGAACCCAGTGGA
651


 


GGAGAGCCATGATGGCACTC
652


 


CTGCTTGTCATATCCATGCC
653


 


CCTGCTTGTCATATCCATGC
654


 


CAGTCTGAGTGGAGAGCCAT
655


 


ATCTGGGACTTAGTCAGGCT
656


 


TAGTCAGGCTAGCTAAGGGC
657


 


GTGGAGAGCCATGATGGCAC
658


 


GTCTGAGTGGAGAGCCATGA
659


 


GAGTGGAGAGCCATGATGGC
660


 


TGGGTTTATTGGAGGGTGCT
661


 


CTGGGTTTATTGGAGGGTGC
662


 


GTGAGCACTTGTGCTGCATG
663


 


AAGGTGATGCAGGCCCAGAT
664


 


GCTAGCTAAGGGCACTGAGT
665


 


GGCACAGTCTGAGTGGAGAG
666


 


AGGCACAGTCTGAGTGGAGA
667


 


AGTGGAGAGCCATGATGGCA
668


 


CCCTGCTTGTCATATCCATG
669


 


CTGGAGCCTGGGTTTATTGG
670


 


GGCACTGGCCAAGACAGACT
671


 


CAGGCACAGTCTGAGTGGAG
672


 


TTACCCTCTGAACCCAGTGG
673


 


AGCACTTGTGCTGCATGAGG
674


 


GATCTGGGACTTAGTCAGGC
675


 


GAGCCTGGGTTTATTGGAGG
676


 


GGAGCCTGGGTTTATTGGAG
677


 


CAGCCAGCTTTAAGGTGTCA
678


 


CCTGGGTTTATTGGAGGGTG
679


 


ATGGAAGTCACAGCAGGGCT
680


 


CTCCAGTGTCTCCAGAACTG
681


 


GGCTAGCTAAGGGCACTGAG
682


 


AGGCTAGCTAAGGGCACTGA
683


 


GGAGAGAAGGGTACCAGGCA
684


 


TGGAGCCTGGGTTTATTGGA
685


 


GAGAGCCATGATGGCACTCA
686


 


CTTACCCTCTGAACCCAGTG
687


 


GCAAAGCTGGCTGCAGTGAC
688


 


CAGGCTAGCTAAGGGCACTG
689


 


AGTCTGAGTGGAGAGCCATG
690


 


CTGGCACTGGCCAAGACAGA
691


 


CTGTCTAGGCTGCTTTTACT
692


 


TGGAGAGCCATGATGGCACT
693


 


AGCAAAGCTGGCTGCAGTGA
694


 


GCACTGGCCAAGACAGACTC
695


 


AACCCTTTGCCTTTTCAGGA
696


 


CAGCAAAGCTGGCTGCAGTG
697


 


CAACCCTTTGCCTTTTCAGG
698


 


TCTGTCTAGGCTGCTTTTAC
699


 


GAGCACTTGTGCTGCATGAG
700


 


GGGCAATGGGATATTCCTGC
701


 


GGTTTATTGGAGGGTGCTTT
702


 


TTCTGTCTAGGCTGCTTTTA
703


 


TGAGCACTTGTGCTGCATGA
704


 


GTGACAACCCTTTGCCTTTT
705


 


TTCTTACCCTCTGAACCCAG
706


 


TGGAGAGAAGGGTACCAGGC
707


 


AGTGTCTCCAGAACTGAGCA
708


 


CAGTGTCTCCAGAACTGAGC
709


 


AAAGGTGATGCAGGCCCAGA
710


 


TGGCACTGGCCAAGACAGAC
711


 


GGCAATGGGATATTCCTGCT
712


 


CAAAGGTGATGCAGGCCCAG
713


 


GACAACCCTTTGCCTTTTCA
714


 


GTTGCAAAATCCTATCCCCC
715


 


CAGGAGCTGTTCCTTCAGAA
716


 


TCCTAAGAAGAGCCCAGGTT
717


 


TTCCTAAGAAGAGCCCAGGT
718


 


CCAGTGTCTCCAGAACTGAG
719


 


CCCAAACCTGGAGTGAGACC
720


 


GTTTATTGGAGGGTGCTTTC
721


 


CCTGGAGTGAGACCTTTGAC
722


 


GAGGGAGAGCCATTTCCTAA
723


 


TCTGAGTGGAGAGCCATGAT
724


 


GCAATGGGATATTCCTGCTC
725


 


TGTCTAGGCTGCTTTTACTG
726


 


ACAACCCTTTGCCTTTTCAG
727


 


GACTTTCTGATGATGTGGCC
728


 


CACTGGCCAAGACAGACTCT
729


 


TGACAACCCTTTGCCTTTTC
730


 


CAACTCCAGTGTCTCCAGAA
731


 


GCCAGCTTTAAGGTGTCAAC
732


 


CAAAGCTGGCTGCAGTGACA
733


 


AGCCAGCTTTAAGGTGTCAA
734


 


GCCATTTCCTAAGAAGAGCC
735


 


CCTAAGAAGAGCCCAGGTTG
736


 


TTATTGGAGGGTGCTTTCTT
737


 


TGAGTGGAGAGCCATGATGG
738


 


CCAAACCTGGAGTGAGACCT
739


 


CCATTTCCTAAGAAGAGCCC
740


 


CTGGAGTGAGACCTTTGACT
741


 


GCTGCAGTGACAAGGAAGTC
742


 


AAGCTGGCTGCAGTGACAAG
743


 


CTGAGTGGAGAGCCATGATG
744


 


TTTCCTAAGAAGAGCCCAGG
745


 


GGCAAAGATTTGTGAGGGCT
746


 


CACTTGTGCTGCATGAGGAA
747


 


CCTGGAGATACTCAGACACT
748


 


TGTTGCAAAATCCTATCCCC
749


 


TGGAGTGAGACCTTTGACTT
750


 


AGTGAGACCTTTGACTTTCT
751


 


AACCTGGAGTGAGACCTTTG
752


 


GCTGCATGAGGAAAGGAGGA
753


 


GTGAGACCTTTGACTTTCTG
754


 


CATTTCCTAAGAAGAGCCCA
755


 


AAAGCTGGCTGCAGTGACAA
756


 


TGACTTTCTGATGATGTGGC
757


 


AGCCATTTCCTAAGAAGAGC
758


 


CAAACCTGGAGTGAGACCTT
759


 


TGGCAAAGATTTGTGAGGGC
760


 


TGTGCTGCATGAGGAAAGGA
761


 


ATTTCCTAAGAAGAGCCCAG
762


 


CTGCAGTGACAAGGAAGTCA
763


 


GCAAAGATTTGTGAGGGCTT
764


 


GCAGTGACAAGGAAGTCAGA
765


 


GTGCTTTAGAGATTTGCTAC
766


 


AAACCTGGAGTGAGACCTTT
767


 


GGAATGGAGAGAAGGGTACC
768


 


TGAGACCTTTGACTTTCTGA
769


 


TGGAGATACTCAGACACTGT
770


 


TTGTGCTGCATGAGGAAAGG
771


 


TTGTTGCAAAATCCTATCCC
772


 


ACTTGTGCTGCATGAGGAAA
773


 


GGAGATACTCAGACACTGTA
774


 


GGAGACAGACAACCCAATGG
775


 


CTGCTAGATTCTTTGAAGCA
776


 


CTTGTGCTGCATGAGGAAAG
777


 


TGAGGAAAGGAGGATCAGGT
778


 


TGCAGTGACAAGGAAGTCAG
779


 


GTGGCAAAAGATACCACACC
780


 


GCATGAGGAAAGGAGGATCA
781


 


GAGCCATTTCCTAAGAAGAG
782


 


AGAGCCATTTCCTAAGAAGA
783


 


GGAGAAGGGAATGCAGAACC
784


 


TCTCAGGAAAGCAATTCCAC
785


 


CAAAGATTTGTGAGGGCTTC
786


 


CTGCATGAGGAAAGGAGGAT
787


 


AATGGAGAGAAGGGTACCAG
788


 


AAATGGAAGTCACAGCAGGG
789


 


GATACTGAGGAAAGTGGGTT
790


 


TGCATGAGGAAAGGAGGATC
791


 


AGATACTGAGGAAAGTGGGT
792


 


GAGATACTCAGACACTGTAT
793


 


ATGGCAAAGATTTGTGAGGG
794


 


ATTCTCAGGAAAGCAATTCC
795


 


AGGAATGGAGAGAAGGGTAC
796


 


GATTCTTTGAAGCAAGGGAG
797


 


AGATTCTTTGAAGCAAGGGA
798


 


GAAATGGAAGTCACAGCAGG
799


 


GGAAATGGAAGTCACAGCAG
800


 


TTTGTTGCAAAATCCTATCC
801


 


ATGAGGAAAGGAGGATCAGG
802


 


TGGAAATGGAAGTCACAGCA
803


 


AGATACTCAGACACTGTATT
804


 


GCTAGATTCTTTGAAGCAAG
805


 


TGCTAGATTCTTTGAAGCAA
806


 


AGGAGAAGGGAATGCAGAAC
807


 


ATGGAAATGGAAGTCACAGC
808


 


CATGAGGAAAGGAGGATCAG
809


 


TAGATTCTTTGAAGCAAGGG
810


 


TTCTTTGAAGCAAGGGAGAA
811


 


GATTCTCAGGAAAGCAATTC
812


 


CTAGATTCTTTGAAGCAAGG
813


 


GAATGATTCTCAGGAAAGCA
814


 


TTTTGTTGCAAAATCCTATC
815


 


TGATTCTCAGGAAAGCAATT
816


 


AGAATGATTCTCAGGAAAGC
817


 


ATGATTCTCAGGAAAGCAAT
818


 


AATGGCAAAGATTTGTGAGG
819


 


GATGGAAATGGAAGTCACAG
820


 


AATGATTCTCAGGAAAGCAA
821


 


AAATGGCAAAGATTTGTGAG
822


 


CTCAAGCTGACTGCTATCAG
823


 


TCCTCAAGCTGACTGCTATC
824


 


CCTCAAGCTGACTGCTATCA
825


 


AGACACTGTATTGTTATTGG
826


 


ATGGGATATTCCTGCTCTGT
827


 


GATAGCACCAACACAAAGTT
828


 


GCCCCCATCTGGCCCAGGCA
829


 


AAGAGCCTTCAGCAGCCCCC
830


 


GCTGTCCTGTGAGGGCAGTG
831


 


AGTGGGTAGCCCTGGATGGC
832


 


TGTATGGCCTCTGGGTCAGC
833


 


GCCTGGTCCCTGAGTAAGCA
834


 


TGTCTCAGCCCAGGGAGACT
835


 


GGAGGGTGCTTTCTTACCCT
836


 


AGGGTGCTTTCTTACCCTCT
837


 


GGGTGCTTTCTTACCCTCTG
838


 


GAGGGTGCTTTCTTACCCTC
839


 


CCTCTGGGTCAGCTTTTTGT
840


 


AGTAAGCAGTGGGTAGCCCT
841


 


GGTTTCAGGAGCTGTTCCTT
842


 


GTAAGCAGTGGGTAGCCCTG
843


 


GAGTAAGCAGTGGGTAGCCC
844


 


GGTGCTTTCTTACCCTCTGA
845


 


TCCCTGAGTAAGCAGTGGGT
846


 


GTCCCTGAGTAAGCAGTGGG
847


 


GGTCCCTGAGTAAGCAGTGG
848


 


GGGACTTAGTCAGGCTAGCT
849


 


TAAGCAGTGGGTAGCCCTGG
850


 


GGTGAGCACTTGTGCTGCAT
851


 


CCTGGTCCCTGAGTAAGCAG
852


 


CTGGTCCCTGAGTAAGCAGT
853


 


GGGACTGGTTAGGTTGGACC
854


 


GGAGGGAGAGCCATTTCCTA
855


 


CCCTGAGTAAGCAGTGGGTA
856


 


TGGGACTTAGTCAGGCTAGC
857


 


GCTCCAGGTGATAGCACCAA
858


 


GGAAAGAGCCTTCAGCAGCC
859


 


TGGTCCCTGAGTAAGCAGTG
860


 


TGAGTAAGCAGTGGGTAGCC
861


 


TCTGGGACTTAGTCAGGCTA
862


 


GGACTTAGTCAGGCTAGCTA
863


 


GGGAAAGAGCCTTCAGCAGC
864


 


GTGCTTTCTTACCCTCTGAA
865


 


CTGGGACTTAGTCAGGCTAG
866


 


CTGAGTAAGCAGTGGGTAGC
867


 


AGTGACAACCCTTTGCCTTT
868


 


CCTGAGTAAGCAGTGGGTAG
869


 


AGAACTAGGAGTCACCTGGC
870


 


CTCCAGGTGATAGCACCAAC
871


 


ACTTTCTGATGATGTGGCCA
872


 


TCCAGGTGATAGCACCAACA
873


 


TTAGTCAGGCTAGCTAAGGG
874


 


ATTGGAGGGTGCTTTCTTAC
875


 


GTGGCCAAGAACTAGGAGTC
876


 


TGCTTTCTTACCCTCTGAAC
877


 


AAGTGACAACCCTTTGCCTT
878


 


CTTAGTCAGGCTAGCTAAGG
879


 


TATTGGAGGGTGCTTTCTTA
880


 


TAAGTGACAACCCTTTGCCT
881


 


CAATGGGATATTCCTGCTCT
882


 


GACTTAGTCAGGCTAGCTAA
883


 


TGTGGCCAAGAACTAGGAGT
884


 


GCTGCTAGATTCTTTGAAGC
885


 


CTTTCTGATGATGTGGCCAA
886


 


CCAGCTTTAAGGTGTCAACA
887


 


ACTTAGTCAGGCTAGCTAAG
888


 


AATGGGATATTCCTGCTCTG
889


 


TTCTGATGATGTGGCCAAGA
890


 


AGCTTTAAGGTGTCAACACC
891


 


GTGCTGCATGAGGAAAGGAG
892


 


GATGTGGCCAAGAACTAGGA
893


 


TTTCTGATGATGTGGCCAAG
894


 


GAGACCTTTGACTTTCTGAT
895


 


GACCTTTGACTTTCTGATGA
896


 


ATGTGGCCAAGAACTAGGAG
897


 


GACACTGTATTGTTATTGGC
898


 


AGACCTTTGACTTTCTGATG
899


 


CAGCTTTAAGGTGTCAACAC
900


 


ACCTTTGACTTTCTGATGAT
901


 


TAGCACCAACACAAAGTTGC
902


 


GGTGATAGCACCAACACAAA
903


 


TGATAGCACCAACACAAAGT
904


 


GTGATAGCACCAACACAAAG
905


 


CTTTTTGTTGCAAAATCCTA
906


 


ATAGCACCAACACAAAGTTG
907


 


TCAAGCTGACTGCTATCAGC
908


 


TCCATGCCCTGGCTCTGGCC
909


 


CTCAGCCCAGGGAGACTGGT
910


 


GTCTCAGCCCAGGGAGACTG
911


 


GGTGTCAACACCTGGCCCTT
912


 


TCAGCCCAGGGAGACTGGTT
913


 


TCTCAGCCCAGGGAGACTGG
914


 


TGTCATATCCATGCCCTGGC
915


 


CAGCCCAGGGAGACTGGTTT
916


 


TCCTCCTCAAGCTGACTGCT
917


 


AAAGAGCCTTCAGCAGCCCC
918


 


CTGGTTTCAGGAGCTGTTCC
919


 


AAGTCAGAGGGAGGGCTGGT
920


 


GAAAGAGCCTTCAGCAGCCC
921


 


CCTCCTCAAGCTGACTGCTA
922


 


CTGGGTCAGCTTTTTGTTGC
923


 


TTGTCATATCCATGCCCTGG
924


 


TCTGGGTCAGCTTTTTGTTG
925


 


GCCCTAAGTGACAACCCTTT
926


 


TGGGATATTCCTGCTCTGTA
927


 


CTCCTCAAGCTGACTGCTAT
928


 


GCCAAGAACTAGGAGTCACC
929


 


CTAAGTGACAACCCTTTGCC
930


 


CCTAAGTGACAACCCTTTGC
931


 


GCTTTAAGGTGTCAACACCT
932


 


GGCCAAGAACTAGGAGTCAC
933


 


CCCTAAGTGACAACCCTTTG
934


 


TGGCCAAGAACTAGGAGTCA
935


 


CCAAGAACTAGGAGTCACCT
936


 


GCAGGAGAAGGGAATGCAGA
937


 


AAGAACTAGGAGTCACCTGG
938


 


TTTAAGGTGTCAACACCTGG
939


 


TGATGTGGCCAAGAACTAGG
940


 


TCTGATGATGTGGCCAAGAA
941


 


CTTTAAGGTGTCAACACCTG
942


 


GCTTTTTGTTGCAAAATCCT
943


 


TGATGATGTGGCCAAGAACT
944


 


CTGATGATGTGGCCAAGAAC
945


 


CAAGAACTAGGAGTCACCTG
946


 


GATGATGTGGCCAAGAACTA
947


 


ATGATGTGGCCAAGAACTAG
948


 


TTAATGTCCCTGAGCAGTTC
949


 


CCAGAAGGCCACACAGGGCA
950


 


TCCTTCCAGCCCAAACTGCA
951


 


TAATGTCCCTGAGCAGTTCT
952


 


TAGAGGAGGCTTGTGACTTC
953


 


TTTAATGTCCCTGAGCAGTT
954


 


TTAGAGGAGGCTTGTGACTT
955


 


GTCCCAGGTTGCCCCTCTCC
956


 


CCTCCTGGGAGCTGGCCTCC
957


 


CTGCTCCCAGTCTGCCTGCC
958


 


GTCTTGTCCCAGGTTGCCCC
959


 


TGTCCCAGGTTGCCCCTCTC
960


 


GCTCCCAGTCTGCCTGCCAT
961


 


TGCTCCCAGTCTGCCTGCCA
962


 


GGTTCCCCTTCCTCCTGGGA
963


 


CTCCTGGGAGCTGGCCTCCT
964


 


TCCTCCTGGGAGCTGGCCTC
965


 


CTGGGCTGGGCAGGAGCCCT
966


 


GGAGCCCTGAGCTGCCTGGT
967


 


CCCTCTGGGTGTCTTGTCCC
968


 


TTCCTGCTCCCAGTCTGCCT
969


 


TTGTCCCAGGTTGCCCCTCT
970


 


CTTGTCCCAGGTTGCCCCTC
971


 


TCTTGTCCCAGGTTGCCCCT
972


 


GCTGGGCAGGAGCCCTGAGC
973


 


AGCAGTTTCCCCAGAGCCCC
974


 


GCCCTCTGTTTTCCTGCTCC
975


 


GGGCCCTCTGTTTTCCTGCT
976


 


TTCCTCCTGGGAGCTGGCCT
977


 


GGTTGCCCCTCTCCTTGCAG
978


 


AGGTTGCCCCTCTCCTTGCA
979


 


CAGGTTGCCCCTCTCCTTGC
980


 


GGCTGGGCCACAGGCTAGCT
981


 


CTGTGGGTTCTGGTGTCCCC
982


 


GGCCCTCTGTTTTCCTGCTC
983


 


TGGGCTGGGCAGGAGCCCTG
984


 


TTTCCTGCTCCCAGTCTGCC
985


 


CTGGACCAGCCCACCCCAGT
986


 


CCCAGAGCCCCTGATCTGCC
987


 


CCCCAGAGCCCCTGATCTGC
988


 


CCTGGACCAGCCCACCCCAG
989


 


CCAGGTTGCCCCTCTCCTTG
990


 


GCCCCTGATCTGCCTGGACC
991


 


GTGTCTTGTCCCAGGTTGCC
992


 


GTTGCCCCTCTCCTTGCAGA
993


 


TGTCTTGTCCCAGGTTGCCC
994


 


GCAGCTGGAAGCCCAGCCCA
995


 


ATCCATGCCCTGGCTCTGGC
996


 


CCTCTGGGTGTCTTGTCCCA
997


 


GCCCAGCCCACAGCAGGACA
998


 


GGCCTTGAGGGTTCCCCACA
999


 


CCAGCAGTTTCCCCAGAGCC
1000


 


GAGCCCTGAGCTGCCTGGTG
1001


 


GTGTTCTCTCTCCCAGTTCC
1002


 


CCCTGAGCAGTTCTTGGCCC
1003


 


ACCCTCTGGGTGTCTTGTCC
1004


 


TACCTGGACCAGCCCACCCC
1005


 


GGTGTCTTGTCCCAGGTTGC
1006


 


AGTTTCCCCAGAGCCCCTGA
1007


 


GGCACCACCCCATCCACAGC
1008


 


AGCCCAGCCCACAGCAGGAC
1009


 


TCCTCCAGCTCTCAGCTTCT
1010


 


AGGAGCCCTGAGCTGCCTGG
1011


 


GCCTCTCTTCATGGGCCTGG
1012


 


TGGCTGGGCCACAGGCTAGC
1013


 


CTGGGTGTCTTGTCCCAGGT
1014


 


GTTTCCCCAGAGCCCCTGAT
1015


 


AGGCTGTGTTCTCTCTCCCA
1016


 


ACCTTCTGGTGCCTTGGGCT
1017


 


GCTACCTGGACCAGCCCACC
1018


 


TGCAGCTGGAAGCCCAGCCC
1019


 


TTCCCCAGAGCCCCTGATCT
1020


 


GCTATGGCCTACCCACTCCC
1021


 


AGCCCACTGTGGGTTCTGGT
1022


 


CCTTCTGGTGCCTTGGGCTT
1023


 


GCCTCTGGGTCTTTATGCCC
1024


 


CTCTCTCCCAGTTCCCCTAT
1025


 


CTCCCAGTCTGCCTGCCATA
1026


 


TGGACCAGCCCACCCCAGTA
1027


 


ATGGCCTACCCACTCCCCTG
1028


 


CCCTGGCCCTACAGACCTGT
1029


 


TCCCCAGAGCCCCTGATCTG
1030


 


GCCCACTGTGGGTTCTGGTG
1031


 


GAGCCCCTGATCTGCCTGGA
1032


 


CTACCTGGACCAGCCCACCC
1033


 


GCTAGTTGTGGCTGGGCCAC
1034


 


ACTGTGGGTTCTGGTGTCCC
1035


 


CAGCCCCAACCAGGTTCCCA
1036


 


TCCAGCAGTTTCCCCAGAGC
1037


 


CCTGAGCAGTTCTTGGCCCT
1038


 


GGCTATGGCCTACCCACTCC
1039


 


TATGGCCTACCCACTCCCCT
1040


 


CTATGGCCTACCCACTCCCC
1041


 


TCCACAGCTGACCCAGCCTC
1042


 


GTCCCTGAGCAGTTCTTGGC
1043


 


AGCTAGTTGTGGCTGGGCCA
1044


 


CAGCTAGTTGTGGCTGGGCC
1045


 


TCCCTGAGCAGTTCTTGGCC
1046


 


CCTCTGGGTCTTTATGCCCC
1047


 


CAGGAGCCCTGAGCTGCCTG
1048


 


TTTTCCTGCTCCCAGTCTGC
1049


 


ACAGCCCCAACCAGGTTCCC
1050


 


GAGGGCTGGCATCTCTCCTT
1051


 


CCCTGAGCTGCCTGGTGGAT
1052


 


CTGCAGCTGGAAGCCCAGCC
1053


 


GGGTGTCTTGTCCCAGGTTG
1054


 


TGGGTGTCTTGTCCCAGGTT
1055


 


AGCCCCTGATCTGCCTGGAC
1056


 


CCCCATCCACAGCTGACCCA
1057


 


GGGTCTTTATGCCCCAGTCT
1058


 


TTTCCCCAGAGCCCCTGATC
1059


 


GCCAGGCCTAGGTGCTTGAC
1060


 


CCCACTGTGGGTTCTGGTGT
1061


 


TCCCAGTCTGCCTGCCATAC
1062


 


CCCCTGATCTGCCTGGACCA
1063


 


TCTGGGTGTCTTGTCCCAGG
1064


 


TCCTGCTCTGTATGGCCTCT
1065


 


GCCTTGAGGGTTCCCCACAT
1066


 


GTCAGTTCTCCCTTTCTGCT
1067


 


GGGCTGGTTTGCCTCAACCC
1068


 


AGAGCCCCTGATCTGCCTGG
1069


 


GAGTTCCAGCAGTTTCCCCA
1070


 


GGTCTGCAGCTGGAAGCCCA
1071


 


TCTCTCCCAGTTCCCCTATT
1072


 


AGCCAGGCCTAGGTGCTTGA
1073


 


GTACCTGGTTAGTGCCAGCC
1074


 


AGGCCCACTGCAGGACAGGT
1075


 


GACAGGCCTTGAGGGTTCCC
1076


 


GATCTGGCTGACTCAGCCCC
1077


 


GGTTAGTGCCAGCCTTGGGA
1078


 


GCCTAGGTGCTTGACCTGGT
1079


 


GTTTTCCTGCTCCCAGTCTG
1080


 


TGTTTTCCTGCTCCCAGTCT
1081


 


CTGTTTTCCTGCTCCCAGTC
1082


 


TCTGTTTTCCTGCTCCCAGT
1083


 


AGCAGTTCTTGGCCCTTGGG
1084


 


CACCCTGGCCCTACAGACCT
1085


 


ACCCACACAGGCCCACTGCA
1086


 


GAGCTACCTGGACCAGCCCA
1087


 


ATTGTCCTCCAGCTCTCAGC
1088


 


GGCCCTACAGACCTGTGTCT
1089


 


GCCACAGGCTAGCTTGACCC
1090


 


GGCTGGTTTGCCTCAACCCT
1091


 


CTCTGGGTGTCTTGTCCCAG
1092


 


ACAGCTTCTCCAGCCTCTGG
1093


 


TCCAGAGCCATGTCCCTGGA
1094


 


ATGCCTCTCTTCATGGGCCT
1095


 


TCCTTGGCTATGGCCTACCC
1096


 


GGCCCACTGCAGGACAGGTG
1097


 


CCAGGCCTAGGTGCTTGACC
1098


 


CTGGTGCCTTGGGCTTTGGG
1099


 


ACCTGGTTAGTGCCAGCCTT
1100


 


TGCCTCTCTTCATGGGCCTG
1101


 


AAGCTGCTGGGCTGGGCAGG
1102


 


GCCACTTCTGAGTCCTCTGT
1103


 


GGACCAGCCCACCCCAGTAA
1104


 


GCTCTCTTTTCTGCTGTGGC
1105


 


TCCCCTGGCTGAAGAGTGCC
1106


 


AGTTGTGGCTGGGCCACAGG
1107


 


TCCTCTTCTCCTCCCAACCA
1108


 


AAGCCCAGCCCACAGCAGGA
1109


 


GAAGCCCAGCCCACAGCAGG
1110


 


TGCCCCTCTCCTTGCAGATG
1111


 


AGTTCCAGCAGTTTCCCCAG
1112


 


GCACAGCCCCAACCAGGTTC
1113


 


GACCCAGCCTCTGTCTAGGA
1114


 


GGTACCTGGTTAGTGCCAGC
1115


 


GGATCTGGCTGACTCAGCCC
1116


 


CTCCAGCCTCTGGGTCTTTA
1117


 


GGCCTTGGCTTAGAGGAGGC
1118


 


AGCTACCTGGACCAGCCCAC
1119


 


AGAGCTACCTGGACCAGCCC
1120


 


TCAGCTAGTTGTGGCTGGGC
1121


 


GGGTTCTGGTGTCCCCAGAA
1122


 


GGCCTAGGTGCTTGACCTGG
1123


 


CCCAGCCTCTGTCTAGGATC
1124


 


CCTTGGCTATGGCCTACCCA
1125


 


GCTGGTTTGCCTCAACCCTC
1126


 


CTGCACAGCCCCAACCAGGT
1127


 


GGCCACAGGCTAGCTTGACC
1128


 


CTGCAGCCCAGCCAAGCAGA
1129


 


CAGGCCAGAGGAGAGGTCCT
1130


 


TTCCTGCTCTGTATGGCCTC
1131


 


AGGCACCACCCCATCCACAG
1132


 


TCTGGTGCCTTGGGCTTTGG
1133


 


CCCCTGGCTGAAGAGTGCCA
1134


 


ACCCTGGCCCTACAGACCTG
1135


 


CCACACAGGCCCACTGCAGG
1136


 


CTTCTGGTGCCTTGGGCTTT
1137


 


TACCTGGTTAGTGCCAGCCT
1138


 


CAGAGCCCACTGTGGGTTCT
1139


 


GAGCAGTTCTTGGCCCTTGG
1140


 


AGTCAGTTCTCCCTTTCTGC
1141


 


CACTGTGGGTTCTGGTGTCC
1142


 


CTGGGTCTTTATGCCCCAGT
1143


 


GGCCAGAGGAGAGGTCCTGA
1144


 


TCTCTTTTCTGCTGTGGCCT
1145


 


CTCTCTTTTCTGCTGTGGCC
1146


 


AGCCTCTGGGTCTTTATGCC
1147


 


TGTGTTCTCTCTCCCAGTTC
1148


 


GGCCACTTCTGAGTCCTCTG
1149


 


GTCATATCCATGCCCTGGCT
1150


 


GTTTCCTCTTCTCCTCCCAA
1151


 


CACAGCCCCAACCAGGTTCC
1152


 


GGTGCTCTCTTTTCTGCTGT
1153


 


TGGTTAGTGCCAGCCTTGGG
1154


 


GCCTAATCCTCCAGGAGCCA
1155


 


TCCCAGCACTTTCTCTGTGC
1156


 


CTCTGGGTCTTTATGCCCCA
1157


 


ACCAAGGCACCACCCCATCC
1158


 


TGGGTCTTTATGCCCCAGTC
1159


 


CCTGCTCTGTATGGCCTCTG
1160


 


TATCCATGCCCTGGCTCTGG
1161


 


GGAGTCAGTTCTCCCTTTCT
1162


 


TACCCTCTGGGTGTCTTGTC
1163


 


GTATGGGTGGCAGTCACCTC
1164


 


GAAGCTGCTGGGCTGGGCAG
1165


 


AGAAGCTGCTGGGCTGGGCA
1166


 


GTTCTCCCTTTCTGCTATCC
1167


 


AAGGCTGTGTTCTCTCTCCC
1168


 


GTCCCTGGATATTGTCCTCC
1169


 


GCCCCAACCAGGTTCCCAAC
1170


 


GTCAGCTAGTTGTGGCTGGG
1171


 


TCTTTTCTGCTGTGGCCTGT
1172


 


GTCTCAGGAGAAGCCAGGCC
1173


 


GAGCTGCCTGGTGGATTGGT
1174


 


ACCCCACAGGCCAGAGGAGA
1175


 


TGCTCTGTATGGCCTCTGGG
1176


 


GTCACTTCTCCAGACAGGCC
1177


 


CCTCTTCTCCTCCCAACCAG
1178


 


GTCCTAGTATGGGTGGCAGT
1179


 


CAGGCCTAGGTGCTTGACCT
1180


 


CCAGAGCCATGTCCCTGGAT
1181


 


CTGAGCAGTTCTTGGCCCTT
1182


 


CCTGGCCCTACAGACCTGTG
1183


 


GGCTGCCTAATCCTCCAGGA
1184


 


AGCCCCAACCAGGTTCCCAA
1185


 


CTCCCCTGGCTGAAGAGTGC
1186


 


ACCCAGCCTCTGTCTAGGAT
1187


 


GGGCCACAGGCTAGCTTGAC
1188


 


GTGTTGCCTTTGCTGTGGTT
1189


 


GAAGCCAGGCCTAGGTGCTT
1190


 


CTGGCCCTACAGACCTGTGT
1191


 


CTAGTTGTGGCTGGGCCACA
1192


 


CCCCACAGGCCAGAGGAGAG
1193


 


CAGGCCCACTGCAGGACAGG
1194


 


GTGGTACCTGGTTAGTGCCA
1195


 


AGAAGCCAGGCCTAGGTGCT
1196


 


GCCAGCCTTGGGAAGGAGGG
1197


 


AAGTTTCCTCTTCTCCTCCC
1198


 


TGACCCAGCCTCTGTCTAGG
1199


 


GTCTTTATGCCCCAGTCTGG
1200


 


GGTCTTTATGCCCCAGTCTG
1201


 


TGGCCCTACAGACCTGTGTC
1202


 


GGGCAGTGCTCTCTTTGGAC
1203


 


GGTGCCATACAGAGCCCACT
1204


 


TCCAGACAGGCCTTGAGGGT
1205


 


AACCTTCTGGTGCCTTGGGC
1206


 


CCTGAGCTGCCTGGTGGATT
1207


 


AGGCCAGAGGAGAGGTCCTG
1208


 


TGGCTATGGCCTACCCACTC
1209


 


TCTGGTGCCATACAGAGCCC
1210


 


TGCACAGCCCCAACCAGGTT
1211


 


TCTGGCTGACTCAGCCCCAA
1212


 


TCACTCTACCCAGCCACTCT
1213


 


ACAGGCCAGAGGAGAGGTCC
1214


 


CTGCTCTGTATGGCCTCTGG
1215


 


CCAGCCTCTGTCTAGGATCT
1216


 


GGACCTCAGGAGGGAGTGGG
1217


 


AGAGCCCACTGTGGGTTCTG
1218


 


AGGGCAGTGCTCTCTTTGGA
1219


 


TGCCTAATCCTCCAGGAGCC
1220


 


ACAGAGCCCACTGTGGGTTC
1221


 


AGGGCTGGTTTGCCTCAACC
1222


 


CCACTGCAGGACAGGTGGCA
1223


 


GAGAAGCCAGGCCTAGGTGC
1224


 


TACCCACTCCCCTGGCTGAA
1225


 


TTTTCCAGAGCCATGTCCCT
1226


 


TTCCAGCAGTTTCCCCAGAG
1227


 


TCCAGCCTCTGGGTCTTTAT
1228


 


GACAGGAGTCAGTTCTCCCT
1229


 


TGGGCCACAGGCTAGCTTGA
1230


 


ATGGGTGGCAGTCACCTCTG
1231


 


CATATCCATGCCCTGGCTCT
1232


 


GGAGGGCTGGTTTGCCTCAA
1233


 


GCCCTACAGACCTGTGTCTG
1234


 


GTTGCCTTTGCTGTGGTTGG
1235


 


ATTCCTGCTCTGTATGGCCT
1236


 


CCCACAGGCCAGAGGAGAGG
1237


 


AGACAGGCCTTGAGGGTTCC
1238


 


CTGGTGCCATACAGAGCCCA
1239


 


GGGCAGAGGATCATGCCACC
1240


 


TCTGGGTCTTTATGCCCCAG
1241


 


TTACCCTCTGGGTGTCTTGT
1242


 


GTCTAAGGGCAGTGCTCTCT
1243


 


TCATATCCATGCCCTGGCTC
1244


 


AGGCCTAGGTGCTTGACCTG
1245


 


AGTATGGGTGGCAGTCACCT
1246


 


TCTGAGTCCTCTGTCTCAGG
1247


 


AGACCTGTGTCTGAGCAGGC
1248


 


CCTCAGGAGGGAGTGGGACT
1249


 


TATGGGTGGCAGTCACCTCT
1250


 


GCAGTCATCAGCCATTCCTT
1251


 


CACAGGCCCACTGCAGGACA
1252


 


AGCAGTCATCAGCCATTCCT
1253


 


AACCCACACAGGCCCACTGC
1254


 


CTCTTTTCTGCTGTGGCCTG
1255


 


GCAGAACACCCTGGCCCTAC
1256


 


AGGAGTCAGTTCTCCCTTTC
1257


 


TCACTTCTCCAGACAGGCCT
1258


 


CTTCAGGGACCAGAGGCAGC
1259


 


TTCTGGTGCCTTGGGCTTTG
1260


 


GGTTCTGGTGTCCCCAGAAT
1261


 


TGTGGTACCTGGTTAGTGCC
1262


 


GACCAAGGCACCACCCCATC
1263


 


TGGCTGCCTAATCCTCCAGG
1264


 


TCTGGTGTCCCCAGAATCCA
1265


 


TGTCAACACCTGGCCCTTGC
1266


 


GCTGCCTGGTGGATTGGTAC
1267


 


GAGACCAAGGCACCACCCCA
1268


 


CAGGTGCTCTCTTTTCTGCT
1269


 


CTGGCTGACTCAGCCCCAAC
1270


 


GCAAGGCTGTGTTCTCTCTC
1271


 


AAGCCAGGCCTAGGTGCTTG
1272


 


ACTGCACAGCCCCAACCAGG
1273


 


CCAGACAGGCCTTGAGGGTT
1274


 


AGCAGAACACCCTGGCCCTA
1275


 


TTGGCTATGGCCTACCCACT
1276


 


CTTGGCTATGGCCTACCCAC
1277


 


GGCAGAGGATCATGCCACCT
1278


 


ATCCTTGGCTATGGCCTACC
1279


 


GCCAGAGGAGAGGTCCTGAG
1280


 


TGTCCCTGAGCAGTTCTTGG
1281


 


TAGTTGTGGCTGGGCCACAG
1282


 


TCCTAGTATGGGTGGCAGTC
1283


 


ACACAGGCCCACTGCAGGAC
1284


 


AGCTGCCTGGTGGATTGGTA
1285


 


CTCCAGACAGGCCTTGAGGG
1286


 


CTTTTCTGCTGTGGCCTGTG
1287


 


GGGTGGCAGTCACCTCTGAA
1288


 


TTGCCTTTGCTGTGGTTGGG
1289


 


ACAGGAGTCAGTTCTCCCTT
1290


 


GACCTCAGGAGGGAGTGGGA
1291


 


CCTTGAGGGTTCCCCACATG
1292


 


GGCCAGGAAGCTTTGTCAGC
1293


 


GCCTGTGTGAATAGCCTGGC
1294


 


GCTGGACTCTGATTCCCTCA
1295


 


GTGCTGGGTTCTGTCAGATC
1296


 


TCAGTTCTCCCTTTCTGCTA
1297


 


CAGCCTCTGGGTCTTTATGC
1298


 


CTCTTCTCCTCCCAACCAGA
1299


 


AGGATCTGGCTGACTCAGCC
1300


 


AGGAGAAGCCAGGCCTAGGT
1301


 


GTGCCAGCCTTGGGAAGGAG
1302


 


AGTGCCAGCCTTGGGAAGGA
1303


 


ACAGGCCCACTGCAGGACAG
1304


 


CTCTGGTGCCATACAGAGCC
1305


 


TCAGGGACCAGAGGCAGCAC
1306


 


CAGGAGTCAGTTCTCCCTTT
1307


 


TCCCTGGATATTGTCCTCCA
1308


 


ACTCTACCCAGCCACTCTGA
1309


 


TGAGCAGTTCTTGGCCCTTG
1310


 


TTCTGGTGTCCCCAGAATCC
1311


 


GGGCTGGATGCTGGACTCTG
1312


 


GCAACTGGAGGTCTGCAGCT
1313


 


CTGCCTAATCCTCCAGGAGC
1314


 


GCTGCCTAATCCTCCAGGAG
1315


 


CTGCCTGGTGGATTGGTACC
1316


 


TTTCCTCTTCTCCTCCCAAC
1317


 


TTCAGGGACCAGAGGCAGCA
1318


 


TCTTTATGCCCCAGTCTGGA
1319


 


CACTCTACCCAGCCACTCTG
1320


 


GTTCTGGTGTCCCCAGAATC
1321


 


GTGTCAACACCTGGCCCTTG
1322


 


TGGTGCCATACAGAGCCCAC
1323


 


CAAGGCTGTGTTCTCTCTCC
1324


 


GTGTCTGAGCAGGCTTTGGA
1325


 


CCTAGTATGGGTGGCAGTCA
1326


 


GGCTAGATCAGCAATGCCCC
1327


 


CACTCCCCTGGCTGAAGAGT
1328


 


GGAGAAGCCAGGCCTAGGTG
1329


 


CCTAGGTGCTTGACCTGGTG
1330


 


GCCAGGAAGCTTTGTCAGCT
1331


 


GTGCTCTCTTTTCTGCTGTG
1332


 


CCTGATCTGCCTGGACCAGA
1333


 


ACTGTGGGTTCTCCTGGTAT
1334


 


CTCCTTCCAGCCCAAACTGC
1335


 


CCCCAACCAGGTTCCCAACA
1336


 


CCTGTGTGAATAGCCTGGCC
1337


 


ACCTCAGGAGGGAGTGGGAC
1338


 


GAGTCAGTTCTCCCTTTCTG
1339


 


AGACCAAGGCACCACCCCAT
1340


 


TCTCCAGACAGGCCTTGAGG
1341


 


ATTTTCCAGAGCCATGTCCC
1342


 


CCAGCCTCTGGGTCTTTATG
1343


 


CACTTCTCCAGACAGGCCTT
1344


 


GTCTGAGCAGGCTTTGGAGG
1345


 


CCAGCCCAAACTGCACAGCC
1346


 


GTGGCCTGTGTGAATAGCCT
1347


 


GGTCTCTCACAGGATGCTGG
1348


 


TGTCAGCTAGTTGTGGCTGG
1349


 


TGCCAGCCTTGGGAAGGAGG
1350


 


GGTGCTTGACCTGGTGATCT
1351


 


CCTGGTGATCTGAGCTGTGT
1352


 


TGGCAAGGCTGTGTTCTCTC
1353


 


AGGTGCTCTCTTTTCTGCTG
1354


 


GACCAGCCCACCCCAGTAAA
1355


 


GAGGGCTGGTTTGCCTCAAC
1356


 


GTGTAGCAGTCATCAGCCAT
1357


 


GCCATACAGAGCCCACTGTG
1358


 


TGCCATACAGAGCCCACTGT
1359


 


GTGCCATACAGAGCCCACTG
1360


 


GGAATCCTTACCCTCTGGGT
1361


 


GATGGCTGCCTAATCCTCCA
1362


 


TACAGAGCCCACTGTGGGTT
1363


 


ACAGGTGCTCTCTTTTCTGC
1364


 


TTTCCCAGCACTTTCTCTGT
1365


 


CCAGCCTTGGGAAGGAGGGA
1366


 


GTTAGTGCCAGCCTTGGGAA
1367


 


CACAGGCCAGAGGAGAGGTC
1368


 


CTGGTGTCCCCAGAATCCAT
1369


 


GGAGGCTTGTGACTTCAGCT
1370


 


GGCTTGGTGATCTCTGGAGG
1371


 


GGGCTTGGTGATCTCTGGAG
1372


 


CAGCCCACCCCAGTAAATCC
1373


 


CCAGCCCACCCCAGTAAATC
1374


 


TGCTGGACTCTGATTCCCTC
1375


 


CCTGTGTCACTTCTCCAGAC
1376


 


ATCCTCCAGGAGCCATTTTC
1377


 


AAGCAGAACACCCTGGCCCT
1378


 


AACCCCACAGGCCAGAGGAG
1379


 


TGGTACCTGGTTAGTGCCAG
1380


 


TATTGTCCTCCAGCTCTCAG
1381


 


ATACAGAGCCCACTGTGGGT
1382


 


AACAGCTTCTCCAGCCTCTG
1383


 


TGCAGGACAGGTGGCAGAGG
1384


 


TGCTCTCTTTTCTGCTGTGG
1385


 


TGTCTAAGGGCAGTGCTCTC
1386


 


AAGGCCACTTCTGAGTCCTC
1387


 


TGAGCTGCCTGGTGGATTGG
1388


 


GGCTGGATGCTGGACTCTGA
1389


 


GGAGAGGTCCTGAGAGAGGT
1390


 


CTGGTCTCTCACAGGATGCT
1391


 


GCCAAGCAGAACACCCTGGC
1392


 


GATATTGTCCTCCAGCTCTC
1393


 


TATTCCTGCTCTGTATGGCC
1394


 


TGTCCCTGGATATTGTCCTC
1395


 


CTCAGGAGAAGCCAGGCCTA
1396


 


CCTAATCCTCCAGGAGCCAT
1397


 


ACCAGAAGGCCACACAGGGC
1398


 


CAGACAGGCCTTGAGGGTTC
1399


 


GGCCTGTGTGAATAGCCTGG
1400


 


GCAGATGGCTGCCTAATCCT
1401


 


AATCCTTACCCTCTGGGTGT
1402


 


ACTCCCCTGGCTGAAGAGTG
1403


 


TTGTCCTAGTATGGGTGGCA
1404


 


ACTGGCCTTGGCTTAGAGGA
1405


 


TGTCTCAGGAGAAGCCAGGC
1406


 


GGTTCAGGAGAGCTACCTGG
1407


 


TGCTTGGCAAGGCTGTGTTC
1408


 


ATATTGTCCTCCAGCTCTCA
1409


 


TGTCCTAGTATGGGTGGCAG
1410


 


GGGAGGATCTGGCTGACTCA
1411


 


AGATGGCTGCCTAATCCTCC
1412


 


CAGTTCTCCCTTTCTGCTAT
1413


 


GGCTTGTGACTTCAGCTGTT
1414


 


TCTGGTCTCTCACAGGATGC
1415


 


TGTCACTTCTCCAGACAGGC
1416


 


GCTAGATCAGCAATGCCCCA
1417


 


CTGTGGGTTCTCCTGGTATA
1418


 


TAGTATGGGTGGCAGTCACC
1419


 


GGTGGCAGTCACCTCTGAAC
1420


 


TGTTGCCTTTGCTGTGGTTG
1421


 


GCAGAGGATCATGCCACCTT
1422


 


GGAGGTTCAGGAGAGCTACC
1423


 


AGGCTTGTGACTTCAGCTGT
1424


 


TAGTGCCAGCCTTGGGAAGG
1425


 


GATTGGGTAATGCAGGGCCC
1426


 


CACTGGCCTTGGCTTAGAGG
1427


 


CCCTACAGACCTGTGTCTGA
1428


 


AGCAACTGGAGGTCTGCAGC
1429


 


GATCCTTGGCTATGGCCTAC
1430


 


TAGCAGTCATCAGCCATTCC
1431


 


CAGAGCCATGTCCCTGGATA
1432


 


ATGGCTGCCTAATCCTCCAG
1433


 


TGTGCTGGGTTCTGTCAGAT
1434


 


ATGTGCTGGGTTCTGTCAGA
1435


 


CTGGCCTTGGCTTAGAGGAG
1436


 


TGTGTCTGAGCAGGCTTTGG
1437


 


GTGAATAGCCTGGCCATGCT
1438


 


ACTTCTCCAGACAGGCCTTG
1439


 


CTTGAGGGTTCCCCACATGA
1440


 


ATCCTCCTCAAGCTGACTGC
1441


 


CAAGCAGAACACCCTGGCCC
1442


 


CCAAGCAGAACACCCTGGCC
1443


 


ACCAGCCCACCCCAGTAAAT
1444


 


AGAAGGCCACACAGGGCAGT
1445


 


GTCTCTCACAGGATGCTGGA
1446


 


TAACCCCACAGGCCAGAGGA
1447


 


GTAGCAGTCATCAGCCATTC
1448


 


GAGAGACCAAGGCACCACCC
1449


 


GACCTGGTGATCTGAGCTGT
1450


 


CAGGAGAAGCCAGGCCTAGG
1451


 


TTGGCAAGGCTGTGTTCTCT
1452


 


ATCTGAGCTGTGTTTGTCCT
1453


 


GAGGATCTGGCTGACTCAGC
1454


 


CACTTCAGGGACCAGAGGCA
1455


 


GTGTCCCCAGAATCCATGTG
1456


 


TCTAAGGGCAGTGCTCTCTT
1457


 


ATGGCAGCTTCATTCCTGGA
1458


 


CTTTCTCTGTGCCCAGAGAT
1459


 


GGGAGACTGGTTTCAGGAGC
1460


 


TTTGTCCTAGTATGGGTGGC
1461


 


TGCTGGGTTCTGTCAGATCA
1462


 


CCCTTTCTGCTATCCATCAC
1463


 


GCTTGGTGATCTCTGGAGGA
1464


 


TCAGGAGAGCTACCTGGACC
1465


 


CTGCTGTGGCCTGTGTGAAT
1466


 


TCACAGGTGCTCTCTTTTCT
1467


 


CAGACCTGTGTCTGAGCAGG
1468


 


TCCAGCCCAAACTGCACAGC
1469


 


GAGGTTCAGGAGAGCTACCT
1470


 


AGGTGCTTGACCTGGTGATC
1471


 


CCATACAGAGCCCACTGTGG
1472


 


GTGTTTGTCCTAGTATGGGT
1473


 


AAGGGCAGTGCTCTCTTTGG
1474


 


CATTGCTGCTTGGCAAGGCT
1475


 


TTTGTCAGCTAGTTGTGGCT
1476


 


CTTTGTCAGCTAGTTGTGGC
1477


 


GCTTTGTCAGCTAGTTGTGG
1478


 


GCCTCTGTCTAGGATCTAGA
1479


 


TGGATATTGTCCTCCAGCTC
1480


 


CCCTGGCTGAAGAGTGCCAA
1481


 


TGGGCAGAGGATCATGCCAC
1482


 


GTGTCACTTCTCCAGACAGG
1483


 


TCAACTCACTCTACCCAGCC
1484


 


AGGAGCCATTTTCCAAGGGC
1485


 


GCTTGTGACTTCAGCTGTTC
1486


 


TTGTCTAAGGGCAGTGCTCT
1487


 


CTTGTCTAAGGGCAGTGCTC
1488


 


TCTTGTCTAAGGGCAGTGCT
1489


 


CTCTTGTCTAAGGGCAGTGC
1490


 


CTAGGTGCTTGACCTGGTGA
1491


 


TGAGCTGTGTTTGTCCTAGT
1492


 


ATGCTGGACTCTGATTCCCT
1493


 


AGGAGGCTTGTGACTTCAGC
1494


 


GGCTTAGAGGAGGCTTGTGA
1495


 


ACACTTCAGGGACCAGAGGC
1496


 


TGTGGCCTGTGTGAATAGCC
1497


 


TCTGAGCAGGCTTTGGAGGA
1498


 


TTCTCCAGACAGGCCTTGAG
1499


 


CAGCCTCTGTCTAGGATCTA
1500


 


GCCCACAATGGGCAGAGGAT
1501


 


GTTCAGGAGAGCTACCTGGA
1502


 


GAGCCATGTCCCTGGATATT
1503


 


GATCTGAGCTGTGTTTGTCC
1504


 


CCAGCCAAGCAGAACACCCT
1505


 


CAGGAGAGCTACCTGGACCA
1506


 


CTGTGTGAATAGCCTGGCCA
1507


 


GGATTTGCAGTCAGCAGAGC
1508


 


CACACTGGCCTTGGCTTAGA
1509


 


GTTGGGATTTGCAGTCAGCA
1510


 


AGAGCCATGTCCCTGGATAT
1511


 


AACTGTGGGTTCTCCTGGTA
1512


 


TGCCCACAATGGGCAGAGGA
1513


 


ACTCTGGTGCCATACAGAGC
1514


 


GCTGACTGCTATCAGCAGGA
1515


 


CTCAGGAGGGAGTGGGACTG
1516


 


GTGTGGCTGGACTTTTGACC
1517


 


TCAGGAGAAGCCAGGCCTAG
1518


 


ACTTCAGGGACCAGAGGCAG
1519


 


TTGTCAGCTAGTTGTGGCTG
1520


 


CCCCAGAATCCATGTGTCTT
1521


 


CCCAACCAGGTTCCCAACAC
1522


 


TGGGTCAGCTTTTTGTTGCA
1523


 


ATGTCCCTGGATATTGTCCT
1524


 


ATGTGGTACCTGGTTAGTGC
1525


 


GTGGCAGTCACCTCTGAACA
1526


 


GAGCTGTGTTTGTCCTAGTA
1527


 


TCTTTTTCCATCTGTCCTGG
1528


 


TCATCCTCCTCAAGCTGACT
1529


 


GTTTGTCCTAGTATGGGTGG
1530


 


ACTGGTTTCAGGAGCTGTTC
1531


 


GATGCTGGACTCTGATTCCC
1532


 


CTTGTGACTTCAGCTGTTCC
1533


 


CATACAGAGCCCACTGTGGG
1534


 


GAATCCTTACCCTCTGGGTG
1535


 


CTTCTGTTGGGTTGTTGCAC
1536


 


ACTTCTGTTGGGTTGTTGCA
1537


 


CTAGTATGGGTGGCAGTCAC
1538


 


GGTGGAGGAAGGATCAGGCT
1539


 


TGCAGATGGCTGCCTAATCC
1540


 


CCCAAACTGCACAGCCCCAA
1541


 


TGTCTGAGCAGGCTTTGGAG
1542


 


GTGCTTGACCTGGTGATCTG
1543


 


TGGTCTCTCACAGGATGCTG
1544


 


GAGGATCATGCCACCTTGGA
1545


 


CTAAGGGCAGTGCTCTCTTT
1546


 


TCAGGAGGGAGTGGGACTGA
1547


 


ACACACTGGCCTTGGCTTAG
1548


 


ACCTGGTGATCTGAGCTGTG
1549


 


AGGAGAGCTACCTGGACCAG
1550


 


AGCCTCTGTCTAGGATCTAG
1551


 


TCATCCCCTGGAGATACTCA
1552


 


ACACTGGCCTTGGCTTAGAG
1553


 


TTGGCTTAGAGGAGGCTTGT
1554


 


CTGTGTCACTTCTCCAGACA
1555


 


GAATAGCCTGGCCATGCTGA
1556


 


CTGGACTCTGATTCCCTCAG
1557


 


ACATTGCTGCTTGGCAAGGC
1558


 


GGGTTCTCCTGGTATATCTA
1559


 


TTGCCCACAATGGGCAGAGG
1560


 


GGCTAACATTGCTGCTTGGC
1561


 


TGTGAATAGCCTGGCCATGC
1562


 


GAGGCTTGTGACTTCAGCTG
1563


 


GTGGCTGGACTTTTGACCTT
1564


 


TTAGTGCCAGCCTTGGGAAG
1565


 


AACTGCACAGCCCCAACCAG
1566


 


GAGGTCCTGAGAGAGGTGAC
1567


 


AGGTTCAGGAGAGCTACCTG
1568


 


TCTTCTCCTCCCAACCAGAA
1569


 


GCTGGATGCTGGACTCTGAT
1570


 


GGAGGATCTGGCTGACTCAG
1571


 


GGACTCTGATTCCCTCAGAG
1572


 


TGTAGCAGTCATCAGCCATT
1573


 


GCCCACAGCAGGACAAGCAA
1574


 


TTTGCAGTCAGCAGAGCACA
1575


 


GAGATACTTCCCACTTCCTC
1576


 


GACAGAGACTCTGGTGCCAT
1577


 


CAGATGGCTGCCTAATCCTC
1578


 


AGCTGACTGCTATCAGCAGG
1579


 


ACTTCCCACTTCCTCATACA
1580


 


TGGCCTGTGTGAATAGCCTG
1581


 


CTTTATGCCCCAGTCTGGAA
1582


 


CAGTCATCAGCCATTCCTTA
1583


 


AGGTCCTGAGAGAGGTGACA
1584


 


TGACAGAGACTCTGGTGCCA
1585


 


CATAACCCACACAGGCCCAC
1586


 


TGGAATCCTTACCCTCTGGG
1587


 


AGATACTTCCCACTTCCTCA
1588


 


AAAGTTTCCTCTTCTCCTCC
1589


 


TTGTGACTTCAGCTGTTCCA
1590


 


CTGGTGATCTGAGCTGTGTT
1591


 


TCCCCTGGAGATACTCAGAC
1592


 


GGCAGAGGAGCTATTTGGGA
1593


 


AGAGGTCCTGAGAGAGGTGA
1594


 


GAGAGGTCCTGAGAGAGGTG
1595


 


CCCCAGTAAATCCTGTGTCA
1596


 


CACAGGTGCTCTCTTTTCTG
1597


 


TGGCTTAGAGGAGGCTTGTG
1598


 


GAACACACTGGCCTTGGCTT
1599


 


TTCTGTTGGGTTGTTGCACA
1600


 


TGGACTCTGATTCCCTCAGA
1601


 


GGATGCTGGACTCTGATTCC
1602


 


GATTTGCAGTCAGCAGAGCA
1603


 


CTGTGGCCTGTGTGAATAGC
1604


 


ACAGACCTGTGTCTGAGCAG
1605


 


AATAGCCTGGCCATGCTGAC
1606


 


GATACTTCCCACTTCCTCAT
1607


 


CTAATCCTCCAGGAGCCATT
1608


 


CTACAGACCTGTGTCTGAGC
1609


 


GAGGAGGTTCAGGAGAGCTA
1610


 


TTGGGACAGGAGTCAGTTCT
1611


 


CATCTTTTTCCATCTGTCCT
1612


 


GGGCAGTGGACAACAGTGGA
1613


 


AGGAGAGGTCCTGAGAGAGG
1614


 


AGAGGATCATGCCACCTTGG
1615


 


TTTATGTGCTGGGTTCTGTC
1616


 


GGCAGTCACCTCTGAACACA
1617


 


CCAGGAGCCATTTTCCAAGG
1618


 


CCCACTTCCTCATACATTCT
1619


 


CTTCCCACTTCCTCATACAT
1620


 


AAACCTTCTGGTGCCTTGGG
1621


 


CCCCTGGAGATACTCAGACA
1622


 


TAGGTGCTTGACCTGGTGAT
1623


 


GCCCCAGTCTGGAAACATTC
1624


 


AGCTGTGTTTGTCCTAGTAT
1625


 


CCATGCTCATAATGGAGCCC
1626


 


CCCATGCTCATAATGGAGCC
1627


 


TCTGTTGGGTTGTTGCACAT
1628


 


TATTTTCCAGAGCCATGTCC
1629


 


AAACTGTGGGTTCTCCTGGT
1630


 


GTGTGAATAGCCTGGCCATG
1631


 


TGTGTGAATAGCCTGGCCAT
1632


 


GGATCATGCCACCTTGGATT
1633


 


ACCCCAGTAAATCCTGTGTC
1634


 


TGAACACACTGGCCTTGGCT
1635


 


ATCCCCTGGAGATACTCAGA
1636


 


ATCATCCCCTGGAGATACTC
1637


 


GCTTAGAGGAGGCTTGTGAC
1638


 


TGCTGTGGCCTGTGTGAATA
1639


 


CACCTCTGAACACACTGGCC
1640


 


CTGGGTTCTGTCAGATCACA
1641


 


AGGATCATGCCACCTTGGAT
1642


 


GGGTTCCCCACATGAAATCC
1643


 


AAGAGTGTTGCCTTTGCTGT
1644


 


TCTGTCTCAGGAGAAGCCAG
1645


 


AGCCAAGCAGAACACCCTGG
1646


 


CATCCTCCTCAAGCTGACTG
1647


 


CATCCCCTGGAGATACTCAG
1648


 


TCCCACTTCCTCATACATTC
1649


 


GTGGCAGAGGAGCTATTTGG
1650


 


CCAAGCAACTGGAGGTCTGC
1651


 


CCCAGAATCCATGTGTCTTC
1652


 


AGCTTTGTCAGCTAGTTGTG
1653


 


GCTCATAATGGAGCCCTTTC
1654


 


CCACACAGGGCAGTGGACAA
1655


 


CCTACAGACCTGTGTCTGAG
1656


 


AATCCTCCAGGAGCCATTTT
1657


 


ATTCCTGGAATCCTTACCCT
1658


 


GCTGTGTTTGTCCTAGTATG
1659


 


TTGACCTGGTGATCTGAGCT
1660


 


CTTGACCTGGTGATCTGAGC
1661


 


GCTTGACCTGGTGATCTGAG
1662


 


GTGATCTGAGCTGTGTTTGT
1663


 


TGAATAGCCTGGCCATGCTG
1664


 


ACTTATAACCCCACAGGCCA
1665


 


CACTTATAACCCCACAGGCC
1666


 


CTTGGCTTAGAGGAGGCTTG
1667


 


AGAGAGACCAAGGCACCACC
1668


 


ATATTCCTGCTCTGTATGGC
1669


 


CACCCCAGTAAATCCTGTGT
1670


 


ATTTGCAGTCAGCAGAGCAC
1671


 


GGAAGGCCAGGAAGCTTTGT
1672


 


AGCTTCATTCCTGGAATCCT
1673


 


GCTAACATTGCTGCTTGGCA
1674


 


CAGGAGGGAGTGGGACTGAT
1675


 


AAAGGCCACTTCTGAGTCCT
1676


 


CCCACAATGGGCAGAGGATC
1677


 


AGGAGGTTCAGGAGAGCTAC
1678


 


ATGACAGAGACTCTGGTGCC
1679


 


TACAGACCTGTGTCTGAGCA
1680


 


GCAGGCTTTGGAGGAAAGGC
1681


 


GTGACACTTCAGGGACCAGA
1682


 


GGGATATTCCTGCTCTGTAT
1683


 


GGGTCAGCTTTTTGTTGCAA
1684


 


TGATTGGGTAATGCAGGGCC
1685


 


CTTATAACCCCACAGGCCAG
1686


 


AGGGAAGGCCAGGAAGCTTT
1687


 


TGTGTCACTTCTCCAGACAG
1688


 


TGCTTGACCTGGTGATCTGA
1689


 


TCTTTTATGTGCTGGGTTCT
1690


 


GTGTCTTCATTCATTCACCT
1691


 


TCCAGGAGCCATTTTCCAAG
1692


 


GGCTTTGGAGGAAAGGCCAC
1693


 


GCAGAGGTCAACCAGAAGGC
1694


 


TGACCTGGTGATCTGAGCTG
1695


 


AGGGCAGTGGACAACAGTGG
1696


 


TTCAGGAGAGCTACCTGGAC
1697


 


CAGGAGCCATTTTCCAAGGG
1698


 


TGAGATACTTCCCACTTCCT
1699


 


CTGAGATACTTCCCACTTCC
1700


 


GGTCAACCAGAAGGCCACAC
1701


 


GAGTGTGGCTGGACTTTTGA
1702


 


TGGCAGAGGAGCTATTTGGG
1703


 


TACTTCCCACTTCCTCATAC
1704


 


AGAGCCAGAAATCATCCCCT
1705


 


TAAGGGCAGTGCTCTCTTTG
1706


 


TTCAACTCACTCTACCCAGC
1707


 


GAGGTCAACCAGAAGGCCAC
1708


 


GAGGAGGCTTGTGACTTCAG
1709


 


AGAGGAGGCTTGTGACTTCA
1710


 


GACCTTTAATGTCCCTGAGC
1711


 


TCTGCCTGGACCAGAAGACA
1712


 


GAAAGGCCACTTCTGAGTCC
1713


 


AGGCTTTGGAGGAAAGGCCA
1714


 


CAGGCTTTGGAGGAAAGGCC
1715


 


GGGAAGGCCAGGAAGCTTTG
1716


 


AATGGCAGCTTCATTCCTGG
1717


 


TGGCAGTCACCTCTGAACAC
1718


 


GGTGATCTGAGCTGTGTTTG
1719


 


TGGTGATCTGAGCTGTGTTT
1720


 


GAGGAGAGGTCCTGAGAGAG
1721


 


TTGAGGGTTCCCCACATGAA
1722


 


GACTCTGGTGCCATACAGAG
1723


 


AGACTCTGGTGCCATACAGA
1724


 


GAGACTCTGGTGCCATACAG
1725


 


AGAGACTCTGGTGCCATACA
1726


 


CAGAGACTCTGGTGCCATAC
1727


 


ACAGAGACTCTGGTGCCATA
1728


 


TTCCAGCCCAAACTGCACAG
1729


 


CAGAGGATCATGCCACCTTG
1730


 


TTATAACCCCACAGGCCAGA
1731


 


TAATCCTCCAGGAGCCATTT
1732


 


AGGTCAACCAGAAGGCCACA
1733


 


CCTGGCTGAAGAGTGCCAAT
1734


 


CTGTTGGGTTGTTGCACATT
1735


 


ACCTTTAATGTCCCTGAGCA
1736


 


GGAGGAAGAGTGTTGCCTTT
1737


 


AGGAGGGAGTGGGACTGATT
1738


 


CTGATCTGCCTGGACCAGAA
1739


 


TTGGGATTTGCAGTCAGCAG
1740


 


AAACTGCACAGCCCCAACCA
1741


 


CAAACTGCACAGCCCCAACC
1742


 


GAGCCAGAAATCATCCCCTG
1743


 


AACACACTGGCCTTGGCTTA
1744


 


GCTATTTGGGACAGGAGTCA
1745


 


AGAGGTCAACCAGAAGGCCA
1746


 


CAGAGGTCAACCAGAAGGCC
1747


 


TTCCCACTTCCTCATACATT
1748


 


GGTTCCCCACATGAAATCCA
1749


 


AAACTCTCTCTCTGGTCTCT
1750


 


GAAGGCCAGGAAGCTTTGTC
1751


 


TGTTTGTCCTAGTATGGGTG
1752


 


TGTGTTTGTCCTAGTATGGG
1753


 


TCTCTGAGATACTTCCCACT
1754


 


CAGCCAAGCAGAACACCCTG
1755


 


GGTTCTGTCAGATCACATGT
1756


 


ATTGCCCACAATGGGCAGAG
1757


 


TTTGGGACAGGAGTCAGTTC
1758


 


TGCCCCAGTCTGGAAACATT
1759


 


GCAGAGGAGCTATTTGGGAC
1760


 


GATCTGCCTGGACCAGAAGA
1761


 


CCTTTAATGTCCCTGAGCAG
1762


 


ATACTTCCCACTTCCTCATA
1763


 


CATGCTCATAATGGAGCCCT
1764


 


ACAGGGCAGTGGACAACAGT
1765


 


AAGGCCAGGAAGCTTTGTCA
1766


 


AGTGGACAACAGTGGAGGGT
1767


 


GTGCCCAGAGATGTCAAGAG
1768


 


GGGAGTGGGACTGATTGGAG
1769


 


AGGGAGTGGGACTGATTGGA
1770


 


GAGGGAGTGGGACTGATTGG
1771


 


GGAGGGAGTGGGACTGATTG
1772


 


AGGGAGACTGGTTTCAGGAG
1773


 


AGTGTGGCTGGACTTTTGAC
1774


 


TGGAGGAAGAGTGTTGCCTT
1775


 


ACTCTTGTCTAAGGGCAGTG
1776


 


AATGGGCAGAGGATCATGCC
1777


 


GCAGTCACCTCTGAACACAC
1778


 


GGTTCTCCTGGTATATCTAT
1779


 


GCAGTCAGCAGAGCACAATT
1780


 


GAGAGGTGACACTTCAGGGA
1781


 


CATGCCACCTTGGATTTTCA
1782


 


GTGGAGGAAGGATCAGGCTA
1783


 


GCTAGGTGGAGGAAGGATCA
1784


 


ACAACAGAAGCTGCTGGGCT
1785


 


CTGAGCAGGCTTTGGAGGAA
1786


 


TCCTCCCAACCAGAAATGGC
1787


 


TGCTCATAATGGAGCCCTTT
1788


 


CCATCTGTCCTGGAATGAGG
1789


 


CTTTAATGTCCCTGAGCAGT
1790


 


GCTATCAGCAGGAGAAGGGA
1791


 


TGGCTGGACTTTTGACCTTT
1792


 


TCTTCAACTCACTCTACCCA
1793


 


TCTCTGAATACTGCCCTTGG
1794


 


GCAACTCTTGTCTAAGGGCA
1795


 


ATCCAAACTCTCTCTCTGGT
1796


 


TGTGCCCAGAGATGTCAAGA
1797


 


TCACCTCTGAACACACTGGC
1798


 


AGCCATTTCCATCAAGCTTT
1799


 


GCAGTGGACAACAGTGGAGG
1800


 


GGCAGTGGACAACAGTGGAG
1801


 


CTCAACTTCTGTTGGGTTGT
1802


 


GATCATGCCACCTTGGATTT
1803


 


CTGTGTTTGTCCTAGTATGG
1804


 


GAGTTGGGATTTGCAGTCAG
1805


 


AGAGTTGGGATTTGCAGTCA
1806


 


TCTGATTCCCTCAGAGAGAC
1807


 


GGGTTCTGTCAGATCACATG
1808


 


TGGGTTCTGTCAGATCACAT
1809


 


GGAAAGGCCACTTCTGAGTC
1810


 


ATCTGCCTGGACCAGAAGAC
1811


 


TGATCTGAGCTGTGTTTGTC
1812


 


CTGACTGCTATCAGCAGGAG
1813


 


CAAACTCTCTCTCTGGTCTC
1814


 


CCTCCCAACCAGAAATGGCA
1815


 


CAGGGCAGTGGACAACAGTG
1816


 


AGCTATTTGGGACAGGAGTC
1817


 


TCACTTATAACCCCACAGGC
1818


 


ATGCTCATAATGGAGCCCTT
1819


 


CTGATTGGGTAATGCAGGGC
1820


 


TATGCCCCAGTCTGGAAACA
1821


 


AACTTCTGTTGGGTTGTTGC
1822


 


TGCAGTCAGCAGAGCACAAT
1823


 


GTTGGGTTGTTGCACATTTT
1824


 


GGCAGAGGTCAACCAGAAGG
1825


 


GGGCAGAGGTCAACCAGAAG
1826


 


GGCTGGACTTTTGACCTTTA
1827


 


CCCAGTAAATCCTGTGTCAC
1828


 


TGAGTGTGGCTGGACTTTTG
1829


 


AGACAGAGGGCAAGAGGAGC
1830


 


CTTAGAGGAGGCTTGTGACT
1831


 


TTCTTTTATGTGCTGGGTTC
1832


 


GTCATCAGCCATTCCTTAAC
1833


 


CACCAAGCAACTGGAGGTCT
1834


 


GAGCTATTTGGGACAGGAGT
1835


 


GTGGACAACAGTGGAGGGTA
1836


 


CATAATGGAGCCCTTTCTCT
1837


 


CTCATAATGGAGCCCTTTCT
1838


 


GACAACAGAAGCTGCTGGGC
1839


 


CCCACAGCAGGACAAGCAAC
1840


 


CTGATTCCCTCAGAGAGACA
1841


 


CTTTCTGCTATCCATCACTT
1842


 


CAACAGAAGCTGCTGGGCTG
1843


 


AAGCTTTGTCAGCTAGTTGT
1844


 


CAAGCAACTGGAGGTCTGCA
1845


 


TCAGGCTAACATTGCTGCTT
1846


 


AACCTCTCTGAATACTGCCC
1847


 


CCAGAATCCATGTGTCTTCA
1848


 


GATTCCCTCAGAGAGACAGA
1849


 


AGTCATCAGCCATTCCTTAA
1850


 


ACCCATGCTCATAATGGAGC
1851


 


CCCTGGAGATACTCAGACAC
1852


 


AGCTAGGTGGAGGAAGGATC
1853


 


TTCCATCTGTCCTGGAATGA
1854


 


TGGGTTGTTGCACATTTTGT
1855


 


TGTTGGGTTGTTGCACATTT
1856


 


TGATCTGCCTGGACCAGAAG
1857


 


TGACTGCTATCAGCAGGAGA
1858


 


CCACAATGGGCAGAGGATCA
1859


 


TCATAATGGAGCCCTTTCTC
1860


 


CTAGATCAGCAATGCCCCAA
1861


 


CCCAACCAGAAATGGCAGCT
1862


 


GGAGTGGGACTGATTGGAGA
1863


 


TCCATCTGTCCTGGAATGAG
1864


 


AGAGAGGTGACACTTCAGGG
1865


 


AGCAACTCTTGTCTAAGGGC
1866


 


AGGCTAACATTGCTGCTTGG
1867


 


TGTGTCTTCATTCATTCACC
1868


 


GTCACCTCTGAACACACTGG
1869


 


TTCTCTGAGATACTTCCCAC
1870


 


ATCATGCCACCTTGGATTTT
1871


 


CTGGATGCTGGACTCTGATT
1872


 


GAGCTAGGTGGAGGAAGGAT
1873


 


TCATTCCTGGAATCCTTACC
1874


 


TTATGCCCCAGTCTGGAAAC
1875


 


ATCAGGCTAACATTGCTGCT
1876


 


GTAAACTGTGGGTTCTCCTG
1877


 


TGTAAACTGTGGGTTCTCCT
1878


 


ATTTGGGACAGGAGTCAGTT
1879


 


GGAGCTATTTGGGACAGGAG
1880


 


AGGAGCTATTTGGGACAGGA
1881


 


GAGGAGCTATTTGGGACAGG
1882


 


ATCTTCAACTCACTCTACCC
1883


 


AAGGGAAGGCCAGGAAGCTT
1884


 


CTATGGCAGCAGAACTGTGT
1885


 


GGCATCTTCAACTCACTCTA
1886


 


CTTCAACTCACTCTACCCAG
1887


 


CAAGCTGACTGCTATCAGCA
1888


 


CTGGCTGAAGAGTGCCAATC
1889


 


AGGGTTCCCCACATGAAATC
1890


 


ACACAGGGCAGTGGACAACA
1891


 


CACACAGGGCAGTGGACAAC
1892


 


TTTATGCCCCAGTCTGGAAA
1893


 


TCCCAACCAGAAATGGCAGC
1894


 


ATAATGGAGCCCTTTCTCTT
1895


 


TTATTTTCCAGAGCCATGTC
1896


 


GGGTTGTTGCACATTTTGTA
1897


 


TTTTCCATCTGTCCTGGAAT
1898


 


GGATATTCCTGCTCTGTATG
1899


 


TGCTATCAGCAGGAGAAGGG
1900


 


GAGGGTTCCCCACATGAAAT
1901


 


AGGAAAGGCCACTTCTGAGT
1902


 


GGCTGTTCTGATTGGGTAAT
1903


 


TGGATGCTGGACTCTGATTC
1904


 


GATTCTCTGAGATACTTCCC
1905


 


TGAGGGTTCCCCACATGAAA
1906


 


CTGTCCTGGAATGAGGATCT
1907


 


TGCCCAGAGATGTCAAGAGA
1908


 


CACAGGGCAGTGGACAACAG
1909


 


ATTCTCTGAGATACTTCCCA
1910


 


GAATGTGGTACCTGGTTAGT
1911


 


AATCATCCCCTGGAGATACT
1912


 


GATCAGGCTAACATTGCTGC
1913


 


ACCAAGCAACTGGAGGTCTG
1914


 


AATTGCCCACAATGGGCAGA
1915


 


CAGTGGACAACAGTGGAGGG
1916


 


TAAACTGTGGGTTCTCCTGG
1917


 


ATGAGATGCCTCTCTTCATG
1918


 


TCAACTTCTGTTGGGTTGTT
1919


 


TTTCCATCTGTCCTGGAATG
1920


 


ATCTCAACTTCTGTTGGGTT
1921


 


ACACCAAGCAACTGGAGGTC
1922


 


TAATGGAGCCCTTTCTCTTA
1923


 


TCTCAACTTCTGTTGGGTTG
1924


 


GGCTGAAGAGTGCCAATCAT
1925


 


GCTGACTTTTTCCTGTATGA
1926


 


GCTGGAAAAGGCTGATCCTC
1927


 


TTGGAGGAAAGGCCACTTCT
1928


 


TCCATCACTTATAACCCCAC
1929


 


TCTGTCCTGGAATGAGGATC
1930


 


AACTCTTGTCTAAGGGCAGT
1931


 


GAATGAGTGTGGCTGGACTT
1932


 


GAGGAAGAGTGTTGCCTTTG
1933


 


ATCCATGTGTCTTCATTCAT
1934


 


CAGTCACCTCTGAACACACT
1935


 


CCACTTCCTCATACATTCTA
1936


 


CTGCTATCAGCAGGAGAAGG
1937


 


GATCTCTGGAGGAAGAGTGT
1938


 


GTGATCTCTGGAGGAAGAGT
1939


 


TATTTGGGACAGGAGTCAGT
1940


 


GTCCTGGAATGAGGATCTGA
1941


 


CCAGTAAATCCTGTGTCACT
1942


 


GCAGGACAAGCAACTCTTGT
1943


 


AAGCTGACTGCTATCAGCAG
1944


 


TGATTCCCTCAGAGAGACAG
1945


 


CCATCACTTATAACCCCACA
1946


 


CAATGGGCAGAGGATCATGC
1947


 


CATCTGTCCTGGAATGAGGA
1948


 


GAGAGAGGTGACACTTCAGG
1949


 


CTTGGTGATCTCTGGAGGAA
1950


 


CAGGCTAACATTGCTGCTTG
1951


 


GAAATGGCAGCTTCATTCCT
1952


 


TGGAGGAAAGGCCACTTCTG
1953


 


GGAAAAGGCTGATCCTCACC
1954


 


AGCAGGCTTTGGAGGAAAGG
1955


 


TGAATGAGTGTGGCTGGACT
1956


 


TCATCAGCCATTCCTTAACA
1957


 


ATCCATCACTTATAACCCCA
1958


 


AAAGAACAGCTTCTCCAGCC
1959


 


CAGAGGAGCTATTTGGGACA
1960


 


CCTCTGTCTAGGATCTAGAA
1961


 


CAATGAGATGCCTCTCTTCA
1962


 


GAAGCTTTGTCAGCTAGTTG
1963


 


GGTGATCTCTGGAGGAAGAG
1964


 


TTGTAAACTGTGGGTTCTCC
1965


 


AAGAGCCAGAAATCATCCCC
1966


 


TGTCTTCATTCATTCACCTA
1967


 


ATGGCAGCAGAACTGTGTTA
1968


 


TATGGCAGCAGAACTGTGTT
1969


 


AAAAGGCTGATCCTCACCTC
1970


 


GTTCTGTCAGATCACATGTA
1971


 


AATGAGTGTGGCTGGACTTT
1972


 


AGGATCAGGCTAACATTGCT
1973


 


TCTGATTGGGTAATGCAGGG
1974


 


CAGAAATCATCCCCTGGAGA
1975


 


GACTGCTATCAGCAGGAGAA
1976


 


GAGTGGGACTGATTGGAGAC
1977


 


GAAAAGGCTGATCCTCACCT
1978


 


CTTCATTCCTGGAATCCTTA
1979


 


ACAGAGGGCAAGAGGAGCAA
1980


 


CTTTGGAGGAAAGGCCACTT
1981


 


TCAAGAGAGACCAAGGCACC
1982


 


TGGTGATCTCTGGAGGAAGA
1983


 


TTGACCTTTAATGTCCCTGA
1984


 


GTGTTAAAGGGAAGGCCAGG
1985


 


ATCTCTGGAGGAAGAGTGTT
1986


 


ATGCCACCTTGGATTTTCAA
1987


 


TTTCTGCTATCCATCACTTA
1988


 


AGTGGGACTGATTGGAGACA
1989


 


AATGTGGTACCTGGTTAGTG
1990


 


TCCATCAAGCTTTCATCAGA
1991


 


TGACCTTTAATGTCCCTGAG
1992


 


GTTCTCCTGGTATATCTATA
1993


 


GAGGTAGTCAAGAGAGACCA
1994


 


ACAATGAGATGCCTCTCTTC
1995


 


CTCCCAACCAGAAATGGCAG
1996


 


GCATCTTCAACTCACTCTAC
1997


 


CTGAGAGAGGTGACACTTCA
1998


 


CAAGAGAGACCAAGGCACCA
1999


 


GGATCAGGCTAACATTGCTG
2000


 


AGTCACCTCTGAACACACTG
2001


 


ATGGAGCCCTTTCTCTTAAA
2002


 


AATGGAGCCCTTTCTCTTAA
2003


 


TGCTGGAAAAGGCTGATCCT
2004


 


CAACTTCTGTTGGGTTGTTG
2005


 


TTTGGAGGAAAGGCCACTTC
2006


 


ATCTGTCCTGGAATGAGGAT
2007


 


TTCTGCTATCCATCACTTAT
2008


 


GGTCAGCTTTTTGTTGCAAA
2009


 


AGAGGAGCTATTTGGGACAG
2010


 


GCCCAGAGATGTCAAGAGAA
2011


 


TTTTGACCTTTAATGTCCCT
2012


 


CTTTTGACCTTTAATGTCCC
2013


 


TGTCCTGGAATGAGGATCTG
2014


 


GTCAAGAGAGACCAAGGCAC
2015


 


TCAGCAGGAGAAGGGAATGC
2016


 


GCAATGCCCCAAATTGTTGA
2017


 


GTTCCCCACATGAAATCCAA
2018


 


GAGCAGGCTTTGGAGGAAAG
2019


 


CATCTTCAACTCACTCTACC
2020


 


TGGACAACAGTGGAGGGTAT
2021


 


AAATGGCAGCTTCATTCCTG
2022


 


GAGGGCAAGAGGAGCAAAGT
2023


 


CAGCAGGACAAGCAACTCTT
2024


 


TTGGGTTGTTGCACATTTTG
2025


 


ACTATGGCAGCAGAACTGTG
2026


 


AATGAGATGCCTCTCTTCAT
2027


 


GAAATTGCCCACAATGGGCA
2028


 


AAGAGAGACCAAGGCACCAC
2029


 


CAGCAGGAGAAGGGAATGCA
2030


 


CCAACCAGAAATGGCAGCTT
2031


 


TCTGTCAGATCACATGTACT
2032


 


TTTGACCTTTAATGTCCCTG
2033


 


CAACTCTTGTCTAAGGGCAG
2034


 


GATCAGCAATGCCCCAAATT
2035


 


CTGTGTTAAAGGGAAGGCCA
2036


 


CCTGAACCCATGCTCATAAT
2037


 


TTTCCATCAAGCTTTCATCA
2038


 


GCTGAAGAGTGCCAATCATT
2039


 


GGGCAAGAGGAGCAAAGTGA
2040


 


CCATCAAGCTTTCATCAGAC
2041


 


TATCCATCACTTATAACCCC
2042


 


AGATCAGCAATGCCCCAAAT
2043


 


AGGACAAGCAACTCTTGTCT
2044


 


GAATCCATGTGTCTTCATTC
2045


 


TTCCATCAAGCTTTCATCAG
2046


 


ATCACTTATAACCCCACAGG
2047


 


GATGGAACTATGGCAGCAGA
2048


 


GGACAACAGTGGAGGGTATA
2049


 


CTGTTCTGATTGGGTAATGC
2050


 


GCTGTTCTGATTGGGTAATG
2051


 


CCCAGTCTGGAAACATTCAT
2052


 


AATCCATGTGTCTTCATTCA
2053


 


ATTCCCTCAGAGAGACAGAA
2054


 


AGACAACAGAAGCTGCTGGG
2055


 


TTCATTCCTGGAATCCTTAC
2056


 


AATCTCAACTTCTGTTGGGT
2057


 


ATGAATGAGTGTGGCTGGAC
2058


 


GCCACCTTGGATTTTCAAAC
2059


 


CACAATGGGCAGAGGATCAT
2060


 


CAGAATCCATGTGTCTTCAT
2061


 


CCCTCAGAGAGACAGAAGAT
2062


 


GCTGATTCTCTGAGATACTT
2063


 


GAGCCCTTTCTCTTAAAAGT
2064


 


AGCAATGCCCCAAATTGTTG
2065


 


CTAACATTGCTGCTTGGCAA
2066


 


GGAGGAAGGATCAGGCTAAC
2067


 


ACTGTGTTAAAGGGAAGGCC
2068


 


GTTCTGATTGGGTAATGCAG
2069


 


CAGTCAGCAGAGCACAATTA
2070


 


AGCTGATTCTCTGAGATACT
2071


 


CTGGAAAAGGCTGATCCTCA
2072


 


TGTTAAAGGGAAGGCCAGGA
2073


 


AAATTGCCCACAATGGGCAG
2074


 


GAAATCATCCCCTGGAGATA
2075


 


CAGGACAAGCAACTCTTGTC
2076


 


AGCAGGAGAAGGGAATGCAG
2077


 


GGACAAGCAACTCTTGTCTA
2078


 


CTTAGCTGATTCTCTGAGAT
2079


 


GTCTTCATTCATTCACCTAA
2080


 


TGTTCTGATTGGGTAATGCA
2081


 


GGAACTATGGCAGCAGAACT
2082


 


TGAATGTGGTACCTGGTTAG
2083


 


TTTCTGTGAAATTGCCCACA
2084


 


TGAAATTGCCCACAATGGGC
2085


 


GAATCATAACCCACACAGGC
2086


 


AGCAGGACAAGCAACTCTTG
2087


 


GCTGGACTTTTGACCTTTAA
2088


 


TGCCACCTTGGATTTTCAAA
2089


 


TGAGAGAGGTGACACTTCAG
2090


 


GGAGCCCTTTCTCTTAAAAG
2091


 


AGGGCAAGAGGAGCAAAGTG
2092


 


CTGTCAGATCACATGTACTT
2093


 


TTCTGATTGGGTAATGCAGG
2094


 


ATGAATGTGGTACCTGGTTA
2095


 


AACACCAAGCAACTGGAGGT
2096


 


ACTTCCTCATACATTCTACA
2097


 


CACTTCCTCATACATTCTAC
2098


 


ATGCTGGAAAAGGCTGATCC
2099


 


AGATGGAACTATGGCAGCAG
2100


 


TGGAGGAAGGATCAGGCTAA
2101


 


TCCTGGAATGAGGATCTGAT
2102


 


AAACAAACCTTCTGGTGCCT
2103


 


ATTTCCATCAAGCTTTCATC
2104


 


AGTAAATCCTGTGTCACTTC
2105


 


AATCCAAACTCTCTCTCTGG
2106


 


GCCCTTTCTCTTAAAAGTTT
2107


 


AGAATCCATGTGTCTTCATT
2108


 


CATCACTTATAACCCCACAG
2109


 


TGGAGCCCTTTCTCTTAAAA
2110


 


GTGGGACTGATTGGAGACAA
2111


 


TGATTCTCTGAGATACTTCC
2112


 


TGATCTCTGGAGGAAGAGTG
2113


 


GCTATCCATCACTTATAACC
2114


 


CATTTCTGTGAAATTGCCCA
2115


 


AAATCATCCCCTGGAGATAC
2116


 


CAGTAAATCCTGTGTCACTT
2117


 


AGCCCTTTCTCTTAAAAGTT
2118


 


CAGAGGGCAAGAGGAGCAAA
2119


 


TGTGTTAAAGGGAAGGCCAG
2120


 


GAACCCATGCTCATAATGGA
2121


 


TTCTGTCAGATCACATGTAC
2122


 


TAGTCAAGAGAGACCAAGGC
2123


 


ACAATGGGCAGAGGATCATG
2124


 


ACAGGATGCTGGAAAAGGCT
2125


 


CTATCCATCACTTATAACCC
2126


 


AACTATGGCAGCAGAACTGT
2127


 


GAAACAAACCTTCTGGTGCC
2128


 


CATCAGCCATTCCTTAACAA
2129


 


GTGAAATTGCCCACAATGGG
2130


 


AGTCAGCAGAGCACAATTAT
2131


 


GAGGAAGGATCAGGCTAACA
2132


 


TAGATGGAACTATGGCAGCA
2133


 


CAACCAGAAATGGCAGCTTC
2134


 


ATTTCTGTGAAATTGCCCAC
2135


 


CTGACTTTTTCCTGTATGAT
2136


 


GGTTGTTGCACATTTTGTAA
2137


 


AAACCTCTCTGAATACTGCC
2138


 


GACAACAGTGGAGGGTATAC
2139


 


TCAGCAGAGCACAATTATGT
2140


 


GTCAGCAGAGCACAATTATG
2141


 


TTTGTAAACTGTGGGTTCTC
2142


 


CTATCAGCAGGAGAAGGGAA
2143


 


GTCAGATCACATGTACTTTT
2144


 


CACAGGATGCTGGAAAAGGC
2145


 


CCAGTCTGGAAACATTCATC
2146


 


CTCTGTCTAGGATCTAGAAT
2147


 


GTGAACACCAAGCAACTGGA
2148


 


ACTTTTGACCTTTAATGTCC
2149


 


AACCCATGCTCATAATGGAG
2150


 


GTAGTCAAGAGAGACCAAGG
2151


 


GGTAGTCAAGAGAGACCAAG
2152


 


AGGTAGTCAAGAGAGACCAA
2153


 


GAACACCAAGCAACTGGAGG
2154


 


CCTCAGAGAGACAGAAGATC
2155


 


TGGAACTATGGCAGCAGAAC
2156


 


TGAACCCATGCTCATAATGG
2157


 


AAGGATCAGGCTAACATTGC
2158


 


GCAGGAAACCTCTCTGAATA
2159


 


ATCAGCCATTCCTTAACAAT
2160


 


GATGATGACAGAGACTCTGG
2161


 


GGAAGGATCAGGCTAACATT
2162


 


TCAGCCATTCCTTAACAATG
2163


 


ATGCCCCAAATTGTTGAATC
2164


 


TCTGTCTAGGATCTAGAATC
2165


 


CAGCCATTCCTTAACAATGA
2166


 


TTCTGTGAAATTGCCCACAA
2167


 


ATTCTACAATGAGATGCCTC
2168


 


ATAGATGGAACTATGGCAGC
2169


 


AGGAAGGATCAGGCTAACAT
2170


 


GAGGAGCAAAGTGAACACCA
2171


 


AAGCAACTCTTGTCTAAGGG
2172


 


TAGCTGATTCTCTGAGATAC
2173


 


CTGTCTAGGATCTAGAATCA
2174


 


TTTTGTAAACTGTGGGTTCT
2175


 


CATTCTACAATGAGATGCCT
2176


 


CTGATTCTCTGAGATACTTC
2177


 


GGAAACTTAGCTGATTCTCT
2178


 


ATGGAACTATGGCAGCAGAA
2179


 


CCCCACATGAAATCCAAACT
2180


 


GAACTATGGCAGCAGAACTG
2181


 


CTGAACCCATGCTCATAATG
2182


 


TCTGTGAAATTGCCCACAAT
2183


 


TTAGCTGATTCTCTGAGATA
2184


 


GATGCTGGAAAAGGCTGATC
2185


 


AGTGAACACCAAGCAACTGG
2186


 


ATCAGCAGGAGAAGGGAATG
2187


 


AACTTAGCTGATTCTCTGAG
2188


 


TCCCCACATGAAATCCAAAC
2189


 


GCCACTCTGAACTTTATGAA
2190


 


GGACTTTTGACCTTTAATGT
2191


 


AAAGAGCCAGAAATCATCCC
2192


 


CCTTTCTCTTAAAAGTTTCC
2193


 


CCCTTTCTCTTAAAAGTTTC
2194


 


TTCCCCACATGAAATCCAAA
2195


 


TAATCTCAACTTCTGTTGGG
2196


 


ATTGGAGACAAAGAGCCAGA
2197


 


TATCAGCAGGAGAAGGGAAT
2198


 


GTCAGCTTTTTGTTGCAAAA
2199


 


ACAATGAATGTGGTACCTGG
2200


 


AGAGGAGCAAAGTGAACACC
2201


 


TCACATTTGGATGGACAAGT
2202


 


TGATCACATTTGGATGGACA
2203


 


GGATCTGATGATGACAGAGA
2204


 


GAGGATCTGATGATGACAGA
2205


 


CAGTCTGGAAACATTCATCT
2206


 


GGATCTAGAATCATAACCCA
2207


 


GAAATCCAAACTCTCTCTCT
2208


 


GAAACCTCTCTGAATACTGC
2209


 


CTGAAGAGTGCCAATCATTA
2210


 


CAAGCAACTCTTGTCTAAGG
2211


 


AAAAGCCATTTCCATCAAGC
2212


 


GACTTTTTCCTGTATGATAT
2213


 


TTCTCCTGGTATATCTATAA
2214


 


AGCTTTTTGTTGCAAAATCC
2215


 


GAAGAGTGCCAATCATTACA
2216


 


TGACTTTTTCCTGTATGATA
2217


 


GCTTTCATCAGACAATATCA
2218


 


ACATTCTACAATGAGATGCC
2219


 


TTTGGATGGACAAGTTAGGA
2220


 


TTCTCTTAAAAGTTTCCTCT
2221


 


GAGCAAAGTGAACACCAAGC
2222


 


AGCAAAGTGAACACCAAGCA
2223


 


CAATGCCCCAAATTGTTGAA
2224


 


TGGAGAAGTAAGTGGCCAAA
2225


 


ATTACAAATCAGCTTCAGCA
2226


 


CATTACAAATCAGCTTCAGC
2227


 


GTCTGGAAACATTCATCTTT
2228


 


GACTTTTGACCTTTAATGTC
2229


 


AGGAAACTTAGCTGATTCTC
2230


 


ACATTTTGTAAACTGTGGGT
2231


 


CACATTTGGATGGACAAGTT
2232


 


ATTTTGTAAACTGTGGGTTC
2233


 


AGGATCTAGAATCATAACCC
2234


 


CCCAGAGATGTCAAGAGAAA
2235


 


AGGATCTGATGATGACAGAG
2236


 


CATTTTGTAAACTGTGGGTT
2237


 


GCACATTTTGTAAACTGTGG
2238


 


GACAAGCAACTCTTGTCTAA
2239


 


ACTTTTTCCTGTATGATATT
2240


 


GCCAATCATTACAAATCAGC
2241


 


GAAGGATCAGGCTAACATTG
2242


 


TGAGGATCTGATGATGACAG
2243


 


TGATGATGACAGAGACTCTG
2244


 


AGGAAACCTCTCTGAATACT
2245


 


TTCCTCATACATTCTACAAT
2246


 


AGCTTTCATCAGACAATATC
2247


 


ATGAGGATCTGATGATGACA
2248


 


TGAAGAGTGCCAATCATTAC
2249


 


CTTTCTCTTAAAAGTTTCCT
2250


 


GGAAACCTCTCTGAATACTG
2251


 


TCTTCATTCATTCACCTAAA
2252


 


AAACTTAGCTGATTCTCTGA
2253


 


GAAACTTAGCTGATTCTCTG
2254


 


GATCACATTTGGATGGACAA
2255


 


AATGCCCCAAATTGTTGAAT
2256


 


ATTTGGATGGACAAGTTAGG
2257


 


TCCTCATACATTCTACAATG
2258


 


AGCCATTCCTTAACAATGAA
2259


 


CCTCATACATTCTACAATGA
2260


 


AACTGTGTTAAAGGGAAGGC
2261


 


GATCTAGAATCATAACCCAC
2262


 


AGGAGCAAAGTGAACACCAA
2263


 


GATCTGATGATGACAGAGAC
2264


 


GCCATTCCTTAACAATGAAT
2265


 


CAAAGAGCCAGAAATCATCC
2266


 


CAGGAAACCTCTCTGAATAC
2267


 


TTAATCTCAACTTCTGTTGG
2268


 


TTTCTCTTAAAAGTTTCCTC
2269


 


ACAAGCAACTCTTGTCTAAG
2270


 


ATAAAGAACAGCTTCTCCAG
2271


 


GGGAAAGGATGAATGAGTGT
2272


 


CTATAAAGAACAGCTTCTCC
2273


 


ACTGAAACAAACCTTCTGGT
2274


 


CTTTTTCCTGTATGATATTA
2275


 


CTTCATTCATTCACCTAAAC
2276


 


GGAGAAGTAAGTGGCCAAAA
2277


 


GTTGTTGCACATTTTGTAAA
2278


 


GTGCCAATCATTACAAATCA
2279


 


GCAAAGTGAACACCAAGCAA
2280


 


CACATTTTGTAAACTGTGGG
2281


 


ACTGATTGGAGACAAAGAGC
2282


 


TGGACTTTTGACCTTTAATG
2283


 


TCTCCTGGTATATCTATAAA
2284


 


TTACAAATCAGCTTCAGCAA
2285


 


GTTAGGAAACTTAGCTGATT
2286


 


ACATTTGGATGGACAAGTTA
2287


 


TTGGATGGACAAGTTAGGAA
2288


 


TAGGAAACTTAGCTGATTCT
2289


 


CAGCTTTTTGTTGCAAAATC
2290


 


TCAGCTTTTTGTTGCAAAAT
2291


 


AGTTAGGAAACTTAGCTGAT
2292


 


CCACATGAAATCCAAACTCT
2293


 


CTGAAACAAACCTTCTGGTG
2294


 


TATAAAGAACAGCTTCTCCA
2295


 


TCCTTAACAATGAATGTGGT
2296


 


CATTTGGATGGACAAGTTAG
2297


 


GAGATGATTCCAAAGAGGAT
2298


 


CCAATCATTACAAATCAGCT
2299


 


TTATAGATGGAACTATGGCA
2300


 


TTGCACATTTTGTAAACTGT
2301


 


GTTGCACATTTTGTAAACTG
2302


 


TGTTGCACATTTTGTAAACT
2303


 


AGAGTGCCAATCATTACAAA
2304


 


AAGAGTGCCAATCATTACAA
2305


 


AAGTGAACACCAAGCAACTG
2306


 


CAAGCTTTCATCAGACAATA
2307


 


TCATTACAAATCAGCTTCAG
2308


 


TATAGATGGAACTATGGCAG
2309


 


GAGTGCCAATCATTACAAAT
2310


 


AGTGCCAATCATTACAAATC
2311


 


CATCAGACAATATCACATGT
2312


 


ATCATTACAAATCAGCTTCA
2313


 


TGCACATTTTGTAAACTGTG
2314


 


ACATGTACTTTTAATGTGGA
2315


 


CACATGTACTTTTAATGTGG
2316


 


GAATGAGGATCTGATGATGA
2317


 


CTTTCATCAGACAATATCAC
2318


 


AACAATGAATGTGGTACCTG
2319


 


ACAAGTTAGGAAACTTAGCT
2320


 


CCAGAGATGTCAAGAGAAAC
2321


 


TTTATAGATGGAACTATGGC
2322


 


CAGACAATATCACATGTACT
2323


 


ATTTAATCTCAACTTCTGTT
2324


 


TTTAATCTCAACTTCTGTTG
2325


 


GGATGGACAAGTTAGGAAAC
2326


 


GAGAAGTAAGTGGCCAAAAC
2327


 


TTAGGAAACTTAGCTGATTC
2328


 


AGAAGTAAGTGGCCAAAACA
2329


 


TCCTGGTATATCTATAAAGA
2330


 


GAACTGTGTTAAAGGGAAGG
2331


 


TCCAAAGAGGATAAACCAGA
2332


 


TTTCATCAGACAATATCACA
2333


 


TAACAATGAATGTGGTACCT
2334


 


CAAGAGGAGCAAAGTGAACA
2335


 


AATGAGGATCTGATGATGAC
2336


 


TACATTCTACAATGAGATGC
2337


 


AAGCTTTCATCAGACAATAT
2338


 


AAGTTAGGAAACTTAGCTGA
2339


 


CAAGTTAGGAAACTTAGCTG
2340


 


CCTTAACAATGAATGTGGTA
2341


 


GACAAGTTAGGAAACTTAGC
2342


 


TGGATGGACAAGTTAGGAAA
2343


 


GGAAAGGATGAATGAGTGTG
2344


 


TTCATCAGACAATATCACAT
2345


 


AGATGATTCCAAAGAGGATA
2346


 


TTGTTGCACATTTTGTAAAC
2347


 


TCTATAAAGAACAGCTTCTC
2348


 


TCAGACAATATCACATGTAC
2349


 


ATCACATGTACTTTTAATGT
2350


 


AAAGTGAACACCAAGCAACT
2351


 


ACAAAGAGCCAGAAATCATC
2352


 


TGCCAATCATTACAAATCAG
2353


 


TCATCAGACAATATCACATG
2354


 


TAGGATCTAGAATCATAACC
2355


 


AAGAGGAGCAAAGTGAACAC
2356


 


TTCCAAAGAGGATAAACCAG
2357


 


ATCAGACAATATCACATGTA
2358


 


CTCATACATTCTACAATGAG
2359


 


TTCCTTAACAATGAATGTGG
2360


 


ATGTCAAGAGAAACAGGAGA
2361


 


GATGTCAAGAGAAACAGGAG
2362


 


AGATGTCAAGAGAAACAGGA
2363


 


GAGATGTCAAGAGAAACAGG
2364


 


ATTCCAAAGAGGATAAACCA
2365


 


GATTCCAAAGAGGATAAACC
2366


 


CAAAGTGAACACCAAGCAAC
2367


 


CCATTCCTTAACAATGAATG
2368


 


ATGGACAAGTTAGGAAACTT
2369


 


TTAACAATGAATGTGGTACC
2370


 


TCATACATTCTACAATGAGA
2371


 


ATCTATAAAGAACAGCTTCT
2372


 


GAAGTAAGTGGCCAAAACAA
2373


 


GCCAAAACAAACACATTTCT
2374


 


GGACAAGTTAGGAAACTTAG
2375


 


TGGACAAGTTAGGAAACTTA
2376


 


AATTTAATCTCAACTTCTGT
2377


 


CATTCCTTAACAATGAATGT
2378


 


GATCACATGTACTTTTAATG
2379


 


CAATCATTACAAATCAGCTT
2380


 


CAGAGATGTCAAGAGAAACA
2381


 


AATCATTACAAATCAGCTTC
2382


 


GATGATTCCAAAGAGGATAA
2383


 


CCAAAGAGGATAAACCAGAA
2384


 


CTAGGATCTAGAATCATAAC
2385


 


CATACATTCTACAATGAGAT
2386


 


CCTGGTATATCTATAAAGAA
2387


 


AGAGATGTCAAGAGAAACAG
2388


 


ATTCCTTAACAATGAATGTG
2389


 


TTTTATAGATGGAACTATGG
2390


 


TCCTGTATGATATTAAGAAT
2391


 


CTTAACAATGAATGTGGTAC
2392


 


TCAGCAAACTGAAACAAACC
2393


 


AGCAAACTGAAACAAACCTT
2394


 


TATCTATAAAGAACAGCTTC
2395


 


ATACATTCTACAATGAGATG
2396


 


AAGTAAGTGGCCAAAACAAA
2397


 


CATTTTATAGATGGAACTAT
2398


 


CAAACACATTTCTGTGAAAT
2399


 


GTATATCTATAAAGAACAGC
2400


 


CTTCAGCAAACTGAAACAAA
2401


 


ATTTTATAGATGGAACTATG
2402


 


TATATCTATAAAGAACAGCT
2403


 


CTGGTATATCTATAAAGAAC
2404


 


GGTATATCTATAAAGAACAG
2405


 


TGGTATATCTATAAAGAACA
2406


 


TTCAGCAAACTGAAACAAAC
2407


 


CTGTATGATATTAAGAATTA
2408


 


GATATTAAGAATTATATTTC
2409


 


GCACAGCCTGCATGTCCTCA
2410


 


GCCCAGGCCCTTGCTCAGAA
2411


 


AGGTTGTCTCAGCCCAGGGA
2412









EQUIVALENTS
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH for the natural 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) for natural uracil of RNA).
Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to, such nucleic acids having modified nucleobases. By way of further example and without limitation, an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any oligomeric compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligomeric compounds having other modified or naturally occurring bases, such as “ATmeCGAUCG,” wherein meC indicates a cytosine base comprising a methyl group at the 5-position.