Compositions and methods for targeting astrocytes to treat neurological disorders

Abstract

Provided herein are methods and compositions for prevention of, reduction of risk of, amelioration of, and / or treatment of neurological disorders, particularly neurological disorders characterized by neurodegeneration and / or neuroinflammation. In particular aspects, methods and / or compositions include means for transgenically overexpressing NFIA, SOX9, A2M, and / or MEGF10 in one or more populations of cells, such as astrocytes.

Description

COMPOSITIONS AND METHODS FOR TARGETING ASTROCYTES TO TREAT NEUROLOGICAL DISORDERSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application Serial No. 63 / 609,136 filed December 12, 2023, the contents of which are hereby incorporated by reference in their entirety.STATEMENT OF GOVERNMENT SUPPORT

[0002] The invention was made with government support under NS071153 and AG071687 awarded by the National Institutes of Health. The government has certain rights in the invention.SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted in ST26 format and is hereby incorporated by reference in its entirety. Said ST26 copy, created on December 10, 2024, is named SeqLst_BAYMP0404WO.xml and is 150,736 bytes in size.BACKGROUNDI. Technical Field

[0004] This disclosure relates to the field of neurological disease, aging biology, neurology, genetics, medicine, and therapeutic treatment methods.IL Background

[0005] Diseases characterized by neurodegeneration and / or neuroinflammation present a major burden that impacts all aspects of health care systems, and have far reaching consequences on the family members and care takers of individuals with said diseases. Over 6 million Americans are suffering from Alzheimer’s Disease (AD), making it a major health burden that impacts all aspects of the US healthcare system. Currently, there are no effective therapies that can reverse the cognitive deficits or slow the eventual progression of AD.

[0006] Despite advances in uncovering the mechanisms that underlie neuroinflammation and neurodegenerative diseases, therapies that prevent neuronal loss or restore neuronal function remain elusive. Targeting of disease-defining markers in conditions such as Alzheimer disease (AD; e.g., amyloid-P (AP) and / or tau) or Parkinson disease (e.g., a-synuclein) have been met with limited success. At the cellular level, AD manifests as a neurodegenerative disease, where the buildup Amyloid beta (AP) plaques in key brain areas associated with memory and executive tasks results in the death of vital neuronal populations that are essential for cognitive function. Oneconsequence of this neuronal loss is the accumulation of reactive astrocytes in regions that are populated with plaques. Astrocytes perform essential tasks for normal brain function and contribute to various neurological disorders, however, their role in AD remains enigmatic.BRIEF SUMMARY

[0007] There is a pressing need to develop effective therapies that can slow the progression, treat, and / or reverse the symptoms associated with neurological disorders, such as those characterized by neurodegeneration and / or neuroinflammation.

[0008] As disclosed herein, discoveries have been made that address certain needs outlined above, and provided herein are at least compositions, methods, and kits for treatment of diseases associated with neurological disorders, in particular neurological disorders associated with the accumulation of potentially toxic molecules that can form plaques (for example but not limited to, Ap, tau, alpha-synuclein, mutant huntingtin, etc.).

[0009] In some aspects, provided herein are engineered polynucleotide sequences comprising one or more transgenes operably linked to a promoter, such as a heterologous promoter, wherein the transgenes encode one or more modulators of astrocyte function (e.g., a modulator of phagocytic function, lysosomal function, etc.). In some aspects, a transgene comprises a sequence encoding Nuclear Factor 1A (NFIA), SRY-box transcription factor 9 (SOX9), alpha-2 - macroglobulin (A2M), and / or multiple endothelial growth factor like domains 10 (MEGF10). In some aspects, a polynucleotide comprises more than one, e.g., 1, 2, 3, 4, 5, or more, transgenes operably linked to one or more promoters. In some aspects, more than one transgenes are separated by one or more sequences encoding an internal transcriptional start site, translational split site, and / or a cleavage element, such as a 2A element.

[0010] In some aspects, a transgene comprises a sequence encoding NFIA. In some aspects, a NFIA transgene comprises a sequence that is, or is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to one or more of SEQ ID NOs: 1-5. In some aspects, a transgene comprises a sequence according to one or more of SEQ ID NOs: 1-5. In some aspects, a transgene comprises a sequence encoding a human NFIA transcript. In some aspects, a transgene comprises a sequence encoding human NFIA transcript variant 1 (tvl), NFIA transcript variant 2 (tv2), NFIA transcript variant 3 (tv3), or NFIA transcript variant 4 (tv4). In some aspects, a transgene comprises a sequence encoding human NFIA tv2. In some aspects, a transgene encodes a polypeptide comprising a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to one or more of SEQ ID NOs: 6-10. In some aspects, the transgene encodes a polypeptideaccording to one or more of SEQ ID NOs: 6-10. In some aspects, the transgene encodes a human polypeptide.

[0011] In some aspects, a transgene comprises a sequence encoding SOX9. In some aspects, a SOX9 transgene is a human SOX9. In some aspects, a transgene comprises a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein, identical to one or more of SEQ ID NOs: 11-12. In some aspects, a transgene comprises a sequence according to one or more of SEQ ID NOs: 11-12. In some aspects, a transgene encodes a polypeptide comprising a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to SEQ ID NOs: 13-14. In some aspects, a transgene encodes a polypeptide according to one or more of SEQ ID NOs: 13-14.

[0012] In some aspects, a transgene comprises a sequence encoding A2M. In some aspects, a transgene comprises a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to one or more of SEQ ID NOs: 15-18. In some aspects, a transgene comprises a sequence according to one or more of SEQ ID NOs: 15-18. In some aspects, a transgene encodes a polypeptide comprising a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to one or more of SEQ ID NO: 19-22. In some aspects, a transgene encodes a polypeptide according to one or more of SEQ ID NOs: 19-22.

[0013] In some aspects, a transgene comprises a sequence encoding MEGF10. In some aspects, a transgene comprises a sequence a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to one or more of SEQ ID NOs: 23-25. In some aspects, a transgene comprises a sequence according to one or more of SEQ ID NOs: 23-25. In some aspects, a transgene encodes a polypeptide comprising a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to one or more of SEQ ID NO: 26- 28. In some aspects, a transgene encodes a polypeptide according to one or more of SEQ ID NO: 26-28.

[0014] In some aspects, a polynucleotide encoding a transgene further comprises a 5' untranslated region (UTR), a 3' UTR, one or more synthetic introns, one or more polyadenylation sites, a sequence encoding one or more fluorophores, a sequence encoding one or more inhibitory oligonucleotides, and / or a sequence encoding one or more tags. In some aspects, a promoter comprises a glial cell specific promoter. In some aspects, a promoter comprises an astrocyte specific promoter. In some aspects, a promoter comprises a glial fibrillary acidic protein (GFAP) promoter (pGFAP). In some aspects, a promoter comprises a sequence that is, or is at least 60%,65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to SEQ ID NO: 42. In some aspects, a promoter comprises a sequence according to SEQ ID NO: 42. In some aspects, a 3' UTR comprises a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to one or more of SEQ ID NOs: 63-64. In some aspects, a 3' UTR comprises a sequence according to one or more of SEQ ID NOs: 63-64. In some aspects, a synthetic intron comprises a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to SEQ ID NO: 43. In some aspects, a synthetic intron comprises a sequence according to SEQ ID NO: 43. In some aspects, an inhibitory oligonucleotide comprises a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to SEQ ID NO: 46. In some aspects, an inhibitory oligonucleotide comprises a sequence according to SEQ ID NO: 46.

[0015] In some aspects, a polynucleotide provided herein comprises at least one adeno- associated virus (AAV) inverted terminal repeat sequence (ITR) and / or at least one long-terminal repeat (LTR) sequence, and wherein the AAV ITR comprises an AAV 3' ITR and / or an AAV 5' ITR. In some aspects, an AAV 3' ITR and / or AAV 5' ITR comprises a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to SEQ ID NOs: 39 and / or 40. In some aspects, an AAV 3' ITR and / or AAV 5' ITR comprises a sequence according to SEQ ID NOs: 39 and / or 40. In some aspects, a LTR sequence comprises a sequence that is, or is at least 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to SEQ ID NO: 41.

[0016] In some aspects, a polynucleotide provided herein comprises or consists of a sequence that is, or is at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical, or any range derivable therein, to any one or more of SEQ ID NOs: 29-38. In some aspects, a polynucleotide sequence comprises any one or more of SEQ ID NOs: 29-38.

[0017] In some aspects, a polynucleotide sequence is comprised or is not comprised in a retroviral capsid. In some aspects, a polynucleotide sequence or a polynucleotide sequence comprised in a retroviral capsid may be comprised in a composition. In some aspects, provided herein are AAV particles comprising a polynucleotide sequence of the disclosure comprised within an AAV capsid. In some aspects, an AAV particle comprises or does not comprise an AAV1, AAV2, AAV4, AAV5, AAV8, and / or AAV9 capsid. In some aspects, an AAV particle comprises an AAV2 / 1, AAV2 / 2, AAV2 / 3, AAV2 / 4, AAV2 / 5, AAV2 / 6, AAV2 / 8, or AAV2 / 9 pseudotype.In some aspects, an AAV particle comprises or does not comprise an AAV2 / 9 pseudotype. In some aspects, an AAV particle is not AAV1, AAV2, AAV4, AAV5, AAV8, AAV9, AAV2 / 1, AAV2 / 2, AAV2 / 3, AAV2 / 4, AAV2 / 5, AAV2 / 6, AAV2 / 8, AAV2 / 9, or a combination thereof. In some aspects, an AAV particle is capable of retrograde infection. In some aspects, an AAV particle is not capable of retrograde infection. In some aspects, an AAV particle is comprised within a composition comprising a pharmaceutically acceptable excipient. In some aspects, provided herein are lentiviral particles comprising a polynucleotide of the disclosure comprised within a lentiviral capsid. In some aspects, a viral particle is not a lentivirus. In some aspects, a lentiviral particle is comprised within a composition comprising a pharmaceutically acceptable excipient.

[0018] In some aspects, provided herein is a cell (including single cells or populations of cells) transfected and / or transduced with a polynucleotide sequence, composition, lentiviral particle, and / or AAV particle of the disclosure. In some aspects, a cell comprises a neuron and / or neuroglial cell. In some aspects, a cell is not a neuron. In some aspects, a neuroglial cell comprises an astrocyte, an oligodendrocyte, and / or a microglial cell. In some aspects, a cell is not an oligodendrocyte, or microglia. In some aspects, a cell comprises, consists essentially of, or consists of an astrocyte. In some aspects, a cell is a human cell. In some aspects, a cell (including a population of cells) are included in a composition. In some aspects, a polynucleotide sequence, composition, lentiviral particle, AAV particle, and / or cell of the disclosure are included in a composition comprising a pharmaceutically acceptable excipient. It is specifically contemplated that the cell is a human cell or a mammalian cell, which may or may not be in a human or mammal.

[0019] Also provided herein are methods of modulating (e.g., improving or maintaining) astrocyte functionality (e.g., in regard to maintaining / promoting brain health, taking up and / or clearing plaques, etc.) in a subject comprising contacting the astrocyte with a polynucleotide sequence, composition, lentiviral particle, AAV particle, and / or cell of the present disclosure. In some aspects, methods of modulating astrocyte functionality comprise transgenically overexpressing and / or activating NFIA, SOX9, A2M, and / or MEGF10 in the astrocyte. In some aspects, modulating astrocyte functionality comprises increasing astrocyte phagocytic activity, increasing astrocyte modulation of synaptic function, increasing astrocyte synaptogenesis, increasing astrocyte sensing and response to neurotransmission, increasing astrocyte uptake of plaques, increasing astrocyte clearance of plaques, increasing astrocyte calcium activity, and / or increasing astrocyte morphological complexity.

[0020] Also provided herein are methods of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof, the method comprising administering a polynucleotide sequence, lentiviral particle, AAV particle, composition, and / or cell of the disclosure to the subject. In some aspects, methodscomprise administering an AAV particle and / or lentiviral particle to the subject. In some aspects, a neurological disorder comprises a neurodevelopmental disorder. In some aspects, a neurological disorder comprises a neurodegenerative disorder. In some aspects, a neurological disorder can be characterized by loss of synapses, by aberrant synapse pruning, and / or by undesirable accumulation of molecules. In some aspects, a neurological disorder is characterized by an undesirable accumulation of molecules. In some aspects, an undesirable molecule that can accumulate comprises amyloid beta (AP), mutant huntingtin, tau protein, and / or alpha-synuclein. In some aspects, an undesirable molecule is not tau protein, or alpha-synuclein. In some aspects, methods provided herein comprise suppressing onset of undesirable accumulation of molecules in the subject. In some aspects, methods provided herein comprise suppressing plaque formation in the subject. In some aspects, methods provided herein comprise significantly reducing and / or eliminating undesirable accumulation of molecules in the subject. In some aspects, methods provided herein comprise significantly reducing and / or eliminating undesirable accumulation of molecules in the subject by or by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein or any value therebetween, relative to a control (e.g., another subject that has not been administered compositions / methods described herein, the same subject prior to being administered compositions / method methods described herein, etc.).

[0021] In some aspects, a neurological disorder is or is not Alzheimer’s disease, Huntington disease, Parkinson’s disease, frontal -temporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Pick disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, corticobasal syndrome, Richardson syndrome, pure akinesia with gait freezing, cerebellar ataxia, vanishing white matter (VWM) disease, autism spectrum disorders (ASDs), down syndrome, hyperekplexia, epilepsy, other developmental neurological disorders (e.g., applicable rare but impactful neurological diseases, e.g., applicable diseases described by the National Institute of Neurological Disorders and Stroke), and / or aging-related cognitive decline, or some combination therof. In some aspects, a neurological disorder comprises Alzheimer’s disease. In some aspects, a neurological disorder comprises Huntington disease. In some aspects, a neurological disorder comprises Parkinson’sdisease. In some aspects, a neurological disorder comprises frontal-temporal dementia (FTD). In some aspects, a neurological disorder comprises aging-related cognitive decline.

[0022] In some aspects, administering comprises injecting into the central nervous system. In some aspects, administering comprises injecting into the peripheral nervous system. In some aspects, administering does not comprise injecting into the peripheral nervous system. In some aspects, administering comprises injecting into the cerebral spinal fluid (CSF). In some aspects, administering comprises intracranial injection. In some aspects, administering comprises intracranial injection into the hippocampus and / or cortex. In some aspects, administering occurs prior to and / or after an onset of symptoms of the neurological disorder in the subject. In some aspects, administering occurs prior to the onset of symptoms of the neurological disorder in the subject. In some aspects, administering occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or greater than 12 months, or any range derivable therein, prior to the onset of symptoms of the neurological disorder in the subject. In some aspects, administering occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years, or greater than 12 years, or any range derivable therein, prior to the onset of symptoms of the neurological disorder in the subject. In some aspects, administering occurs after the onset of symptoms of the neurological disorder in the subject. In some aspects, administering occurs within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or any range derivable therein, after the onset of symptoms of the neurological disorder in the subject. In some aspects, administering occurs within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years, or any range derivable therein, after the onset of symptoms of the neurological disorder in the subject. In some aspects, administering occurs multiple times.

[0023] In some aspects, methods described herein comprise suppressing onset of Ap plaque formation in a subject. In some aspects, methods described herein comprise suppressing the rate of Ap plaque formation in the subject. In some aspects, methods described herein comprise significantly reducing and / or eliminating Ap plaques in the subject. In some aspects, methods provided herein comprise significantly reducing and / or eliminating Ap plaques in the subject by or by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%,37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%,54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein or any value therebetween, relative to a control (e.g., another subject that has not been administered compositions / methods described herein, the same subject prior to being administered compositions / method methods described herein, etc.). In some aspects, methodscomprise suppressing and / or reversing progression of benchmarks of Alzheimer’s Disease pathogenesis in the subject.

[0024] In some aspects, methods provided herein comprise preserving and / or restoring neuronal integrity in the subject. In some aspects, methods provided herein comprise significantly preserving and / or restoring neuronal integrity in the subject by or by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein or any value therebetween, relative to a control (e.g., another subject that has not been administered compositions / methods described herein, the same subject prior to being administered compositions / method methods described herein, etc.). In some aspects, methods provided herein comprise suppressing and / or reversing progression of benchmarks of disorder pathogenesis in the subject. In some aspects, methods comprise restoring cognitive deficits in the subject. In some aspects, methods comprise restoring cognitive function levels of the subject to match cognitive function levels equivalent to those demonstrated prior to onset of and / or onset of symptoms of the neurological disorder.

[0025] Also provided herein are methods of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Alzheimer's Disease prior to, during, and / or after an undesirable accumulation of Ap plaques, the methods comprising administering a polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of the disclosure to the subject. In some aspects, methods comprise administering a lentiviral particle and / or AAV particle to the subject. In some aspects, administering comprises intracranial injection. In some aspects, administering occurs prior to and / or after an onset of symptoms of Alzheimer’s Disease. In some aspects, administering occurs more than once. In some aspects, administering increases astrocyte uptake and / or clearance of Ap plaques. In some aspects, methods provided herein comprise preserving neuronal integrity in a subject that has, is expected to have, or is expected to develop, Alzheimer’s Disease.

[0026] Also provided herein are methods of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Huntington disease prior to, during, and / or after an undesirable accumulation of mutant huntingtin, the methods comprising administering a polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of the disclosure to the subject. In some aspects, methods comprise administering a lentiviral particle and / or AAV particle to the subject. In some aspects, administering comprises intracranialinjection. In some aspects, administering occurs prior to and / or after an onset of symptoms of Huntington disease. In some aspects, administering occurs more than once. In some aspects, administering increases astrocyte uptake and / or clearance of mutant huntingtin. In some aspects, methods provided herein comprise preserving neuronal integrity in a subject that has, is expected to have, or is expected to develop, Huntington disease.

[0027] Also provided herein are methods of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Parkinson’s disease prior to, during, and / or after an undesirable accumulation of alpha-synuclein and / or tau protein, the methods comprising administering a polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of the disclosure to the subject. In some aspects, methods comprise administering a lentiviral particle and / or AAV particle to the subject. In some aspects, administering comprises intracranial injection. In some aspects, administering occurs prior to and / or after an onset of symptoms of Parkinson’s disease. In some aspects, administering occurs more than once. In some aspects, administering increases astrocyte uptake and / or clearance of alpha-synuclein and / or tau protein. In some aspects, administering increases astrocyte uptake and / or clearance of alpha- synuclein. In some aspects, administering increases astrocyte uptake and / or clearance of tau protein. In some aspects, methods provided herein comprise preserving neuronal integrity in a subject that has, is expected to have, or is expected to develop, Parkinson’s disease.

[0028] Also provided herein are methods of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing frontal-temporal dementia (FTD) prior to, during, and / or after an undesirable accumulation of tau protein, the methods comprising administering a polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of the disclosure to the subject. In some aspects, methods comprise administering a lentiviral particle and / or AAV particle to the subject. In some aspects, administering comprises intracranial injection. In some aspects, administering occurs prior to and / or after an onset of symptoms of frontal-temporal dementia. In some aspects, administering occurs more than once. In some aspects, administering increases astrocyte uptake and / or clearance of tau protein. In some aspects, methods provided herein comprise preserving neuronal integrity in a subject that has, is expected to have, or is expected to develop, FTD.

[0029] Also provided herein are methods of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof, the methods comprising administering a polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of the disclosure to the subject. In some aspects, methods comprise administering a lentiviral particle and / or AAV particle to the subject. In some aspects, administering comprises intracranial injection. In some aspects, administering occurs prior toand / or after an onset of symptoms of the neurological disorder. In some aspects, administering occurs more than once. In some aspects, administering increases astrocyte uptake and / or clearance of undesirable molecules and / or plaques. In some aspects, methods provided herein comprise preserving neuronal integrity in a subject that has, is expected to have, or is expected to develop, a neurological disorder.

[0030] Also provided herein are kits comprising means for performing methods of the disclosure and / or a polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of the disclosure.

[0031] Certain aspects of the present disclosure are characterized through the following enumerated aspects.

[0032] Aspect 1 is an engineered polynucleotide sequence comprising a transgene operably linked to a heterologous promoter, wherein the transgene encodes SRY-box transcription factor 9 (SOX9), Nuclear Factor 1 A (NFIA), alpha-2 -macroglobulin (A2M), and / or multiple endothelial growth factor like domains 10 (MEGF10).

[0033] Aspect 2 is the polynucleotide sequence of aspect 1, wherein the transgene comprises a sequence encoding NFIA.

[0034] Aspect 3 is the polynucleotide sequence of aspect 1 or 2, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 1-5.

[0035] Aspect 4 is the polynucleotide sequence of any one of aspects 1-3, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 1-5.

[0036] Aspect 5 is the polynucleotide sequence of any one of aspects 1-4, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 6-10.

[0037] Aspect 6 is the polynucleotide sequence of any one of aspects 1-5, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NOs: 6-10.

[0038] Aspect 7 is the polynucleotide sequence of any one of aspects 1-6, wherein the transgene comprises a sequence encoding SOX9.

[0039] Aspect 8 is the polynucleotide sequence of any one of aspects 1-8, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 11-12.

[0040] Aspect 9 is the polynucleotide sequence of any one of aspects 1-8, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 11-12.

[0041] Aspect 10 is the polynucleotide sequence of any one of aspects 1-9, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NOs: 13-14.

[0042] Aspect 11 is the polynucleotide sequence of any one of aspects 1-10, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NOs: 13-14.

[0043] Aspect 12 is the polynucleotide sequence of any one of aspects 1-11, wherein the transgene comprises a sequence encoding A2M.

[0044] Aspect 13 is the polynucleotide sequence of any one of aspects 1-12, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 15-18.

[0045] Aspect 14 is the polynucleotide sequence of any one of aspects 1-13, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 15-18.

[0046] Aspect 15 is the polynucleotide sequence of any one of aspects 1-14, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NO: 19-22.

[0047] Aspect 16 is the polynucleotide sequence of any one of aspects 1-15, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NOs: 19-22.

[0048] Aspect 17 is the polynucleotide sequence of any one of aspects 1-16, wherein the transgene comprises a sequence encoding MEGF10.

[0049] Aspect 18 is the polynucleotide sequence of any one of aspects 1-17, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 23-25.

[0050] Aspect 19 is the polynucleotide sequence of any one of aspects 1-18, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 23-25.

[0051] Aspect 20 is the polynucleotide sequence of any one of aspects 1-19, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NO: 26-28.

[0052] Aspect 21 is the polynucleotide sequence of any one of aspects 1-20, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NO: 26-28.

[0053] Aspect 22 is the polynucleotide sequence of any one of aspects 1-21, further comprising a 5' untranslated region (UTR), a 3' UTR, one or more synthetic intron, one or more polyadenylation site, a sequence encoding one or more fluorophores, a sequence encoding one or more inhibitory oligonucleotides, and / or a sequence encoding one or more tags.

[0054] Aspect 23 is the polynucleotide sequence of aspect 22, wherein the promoter comprises a glial fibrillary acidic protein (GFAP) promoter (pGFAP).

[0055] Aspect 24 is the polynucleotide sequence of aspect 22 or 23, wherein the promoter comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 42.

[0056] Aspect 25 is the polynucleotide sequence of any one of aspects 22-24, wherein the promoter comprises a sequence according to SEQ ID NO: 42.

[0057] Aspect 26 is the polynucleotide sequence of any one of aspects 22-25, wherein the 3' UTR comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 63-64.

[0058] Aspect 27 is the polynucleotide sequence of any one of aspects 22-26, wherein the 3' UTR comprises a sequence according to one or more of SEQ ID NOs: 63-64.

[0059] Aspect 28 is the polynucleotide sequence of any one of aspects 22-27, wherein the at least one synthetic intron comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 43.

[0060] Aspect 29 is the polynucleotide sequence of any one of aspects 22-28, wherein the at least one synthetic intron comprises a sequence according to SEQ ID NO: 43.

[0061] Aspect 30 is the polynucleotide sequence of any one of aspects 22-29, comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 46.

[0062] Aspect 31 is the polynucleotide sequence of any one of aspects 22-30, comprising a sequence according to SEQ ID NO: 46.

[0063] Aspect 32 is the polynucleotide sequence of any one of aspects 22-31, comprising at least one adeno-associated virus (AAV) inverted terminal repeat sequence (ITR) and / or at least one long-terminal repeat (LTR) sequence, and wherein the AAV ITR comprises an AAV 3' ITR and / or an AAV 5' ITR.

[0064] Aspect 33 is the polynucleotide sequence of aspect 32, wherein the AAV 3' ITR and / or AAV 5' ITR comprises a sequence at least or exactly 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NOs: 39 and / or 40.

[0065] Aspect 34 is the polynucleotide sequence of aspects 32 or 33, wherein the AAV 3' ITR and / or AAV 5' ITR comprises a sequence according to SEQ ID NOs: 39 and / or 40.

[0066] Aspect 35 is the polynucleotide sequence of any one of aspects 32-34, wherein the LTR sequence comprises a sequence at least or exactly 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 41.

[0067] Aspect 36 is the polynucleotide sequence of any one of aspects 1-35, comprising or consisting of a sequence at least or exactly 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one or more of SEQ ID NOs: 29-38.

[0068] Aspect 37 is the polynucleotide sequence of any one of aspects 1-36, comprising a sequence according to any one or more of SEQ ID NOs: 29-38.

[0069] Aspect 37.1 is the polynucleotide sequence of any one of aspects 1-36, wherein the transgene comprises a human or humanized coding sequence, and / or encodes a human, or humanized, polypeptide.

[0070] Aspect 38 is the polynucleotide sequence of any one of aspects 1-37.1, wherein the polynucleotide sequence is comprised in a retroviral capsid.

[0071] Aspect 39 is a composition comprising the polynucleotide sequence of any one of aspects 1-37 or the polynucleotide sequence comprised in a retroviral capsid of aspect 38.

[0072] Aspect 40 is an adeno-associated virus (AAV) particle comprising the polynucleotide sequence of any one of aspects 1-38 comprised in an AAV capsid.

[0073] Aspect 41 is the AAV particle of aspect 40, comprising an AAV1, AAV2, AAV4, AAV5, AAV8, and / or AAV9 capsid.

[0074] Aspect 42 is the AAV particle of aspect 40 or 41, wherein the AAV particle comprises an AAV2 / 1, AAV2 / 2, AAV2 / 3, AAV2 / 4, AAV2 / 5, AAV2 / 6, AAV2 / 8, or AAV2 / 9 pseudotype.

[0075] Aspect 43 is the AAV particle of any one of aspects 40-42, wherein the AAV particle comprises an AAV2 / 9 pseudotype.

[0076] Aspect 44 is the AAV particle of any one of aspects 40-43, wherein the AAV particle is capable of retrograde infection.

[0077] Aspect 45 is a composition comprising the AAV particle according to any one of aspects 40-44.

[0078] Aspect 46 is a lentiviral particle comprising the polynucleotide sequence of any one of aspects 1-38 comprised in a lentiviral capsid.

[0079] Aspect 47 is a composition comprising the lentiviral particle according to aspect 46.

[0080] Aspect 48 is a cell transfected and / or transduced with the polynucleotide sequence, composition, lentiviral particle, and / or AAV particle of any one of aspects 1-47.

[0081] Aspect 49 is the cell of aspect 48, wherein the cell comprises a neuron and / or neuroglial cell.

[0082] Aspect 50 is the cell of aspect 49, wherein the neuroglial cell comprises an astrocyte, an oligodendrocyte, and / or a microglial cell.

[0083] Aspect 51 is the cell of any one of aspects 48-50, wherein the cell comprises, consists essentially of, or consists of an astrocyte.

[0084] Aspect 52 is the cell of any one of aspects 48-51, wherein the cell is a human cell.

[0085] Aspect 53 is a population of cells according to aspects 48-52.

[0086] Aspect 54 is a composition comprising the cell or population of cells according to any one of aspects 48-53.

[0087] Aspect 55 is a pharmacologically acceptable composition comprising the polynucleotide sequence, composition, lentiviral particle, AAV particle, cell, or population of cells according to any one of aspects 1-54.

[0088] Aspect 56 is a method of modulating astrocyte functionality comprising contacting the astrocyte with the polynucleotide sequence, composition, lentiviral particle, AAV particle, and / or cell of any one of aspects 1-55.

[0089] Aspect 57 is the method of aspect 56, wherein the modulating astrocyte functionality comprises transgenically overexpressing NFIA, SOX9, A2M, and / or MEGF 10.

[0090] Aspect 58 is the method of aspect 56 or 57, wherein the modulating astrocyte functionality comprises increasing astrocyte phagocytic activity, increasing astrocyte regulation of synaptic function, increasing astrocyte synaptogenesis, increasing astrocyte sensing and response to neurotransmission, increasing astrocyte uptake of plaques, increasing astrocyte clearance of plaques, increasing astrocyte calcium activity, and / or increasing astrocyte morphological complexity.

[0091] Aspect 59 is use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of aspects 1-55 in the production of a medicament for modulating astrocyte functionality in a subject in need thereof.

[0092] Aspect 60 is a method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of aspects 1-56 to the subject.

[0093] Aspect 61 is the method of aspect 60, comprising administering an AAV particle and / or lentiviral particle.

[0094] Aspect 62 is the method of aspect 60 or 61, wherein the neurological disorder comprises a neurodevelopmental disorder.

[0095] Aspect 63 is the method of aspect 60 or 61, wherein the neurological disorder comprises a neurodegenerative disorder.

[0096] Aspect 64 is the method of aspect 63, wherein the neurological disorder is characterized by loss of synapses, by aberrant synapse pruning, and / or by undesirable accumulation of molecules.

[0097] Aspect 65 is the method of any one of aspects 60-64, wherein the neurological disorder is characterized by an undesirable accumulation of molecules.

[0098] Aspect 66 is the method of aspect 65, wherein the molecules comprise amyloid beta (AP), mutant huntingtin, tau protein, and / or alpha-synuclein.

[0099] Aspect 67 is the method of any one of aspects 65-66, comprising suppressing onset of undesirable accumulation of molecules in the subject.

[0100] Aspect 68 is the method of any one of aspects 65-67, comprising suppressing plaque formation in the subject.

[0101] Aspect 69 is the method of any one of aspects 65-68, comprising significantly reducing and / or eliminating undesirable accumulation of molecules in the subject.

[0102] Aspect 70 is the method of aspect 69, wherein significantly reducing and / or eliminating undesirable accumulation of molecules comprises a decrease greater than 40%, 45%, 50%, 55%, or 60%.

[0103] Aspect 71 is the method of any one of aspects 63-67, wherein the neurological disorder comprises Alzheimer’s disease, Huntington disease, Parkinson’s disease, frontal -temporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Pick disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, primary age- related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, corticobasal syndrome, Richardson syndrome, pure akinesia with gait freezing, cerebellar ataxia, vanishing white matter (VWM) disease, autism spectrum disorders (ASDs), down syndrome, hyperekplexia, epilepsy, other developmental neurological disorders (e.g., applicable rare but impactful neurological diseases, e.g., applicable diseases described by the National Institute of Neurological Disorders and Stroke), and / or aging-related cognitive decline.

[0104] Aspect 72 is the method of aspect 71, wherein the neurological disorder comprises Alzheimer’s disease.

[0105] Aspect 73 is the method of any one of aspects 60-72, wherein the administering comprises injecting into the central nervous system.

[0106] Aspect 74 is the method of any one of aspects 60-73, wherein the administering comprises injecting into the peripheral nervous system.

[0107] Aspect 75 is the method of any one of aspects 60-74, wherein the administering comprises injecting into the cerebral spinal fluid (CSF).

[0108] Aspect 76 is the method of any one of aspects 60-75, wherein the administering comprises intracranial injection.

[0109] Aspect 77 is the method of any one of aspects 60-76, wherein the administering comprises intracranial injection into the hippocampus and / or cortex.

[0110] Aspect 78 is the method of any one of aspects 60-77, wherein the administering occurs prior to and / or after an onset of symptoms of the neurological disorder in the subject.

[0111] Aspect 79 is the method of aspect 78, wherein the administering occurs prior to the onset of symptoms of the neurological disorder in the subject.

[0112] Aspect 80 is the method of aspect 78, wherein the administering occurs after the onset of symptoms of the neurological disorder in the subject.

[0113] Aspect 81 the method of any one of aspects 60-80, wherein the administering occurs multiple times.

[0114] Aspect 82 is the method of any one of aspects 60-81, comprising suppressing onset of Ap plaque formation in the subject.

[0115] Aspect 83 is the method of any one of aspects 60-82, comprising suppressing Ap plaque formation in the subject.

[0116] Aspect 84 is the method of any one of aspects 60-83, comprising significantly reducing and / or eliminating Ap plaques in the subject.

[0117] Aspect 85 is the method of any one of aspects 60-84, comprising preserving neuronal integrity in the subject.

[0118] Aspect 86 is the method of any one of aspects 60-85, comprising suppressing progression of benchmarks of disorder pathogenesis in the subject.

[0119] Aspect 87 is the method of aspect 86, comprising suppressing progression of benchmarks of Alzheimer’s Disease pathogenesis in the subject.

[0120] Aspect 88 is the method of any one of aspects 60-87, comprising restoring cognitive deficits in the subject.

[0121] Aspect 89 is the method of any one of aspects 60-77, comprising restoring cognitive function levels of the subject to match cognitive function levels equivalent to those demonstrated prior to onset of the neurological disorder.

[0122] Aspect 90 is use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of aspects 1-56 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof.

[0123] Aspect 91 is a method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Alzheimer's Disease prior to, during, and / or after an undesirable accumulation of Ap plaques, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of aspects 1-56 to a subject.

[0124] Aspect 92 is the method of aspect 91, comprising administering the lentiviral particle and / or AAV particle to the subject.

[0125] Aspect 93 is the method of aspect 91 or 92, wherein the administering comprises intracranial injection.

[0126] Aspect 94 is the method of any one of aspects 91-93, wherein the administering occurs prior to and / or after an onset of symptoms of Alzheimer’s Disease.

[0127] Aspect 95 is the method of any one of aspects 91-94, wherein the administering occurs more than once.

[0128] Aspect 96 is the method of any one of aspects 91-95, wherein the administering increases astrocyte uptake and / or clearance of Ap plaques.

[0129] Aspect 97 is the method of any one of aspects 91-96, comprising preserving neuronal integrity in the subject.

[0130] Aspect 98 is use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of aspects 1-56 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Alzheimer's Disease prior to, during, and / or after an undesirable accumulation of Ap plaques in a subject in need thereof.

[0131] Aspect 99 is a method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Huntington disease prior to, during, and / or after an undesirable accumulation of mutant huntingtin, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of aspects 1-56 to a subject.

[0132] Aspect 100 is the method of aspect 99, comprising administering the lentiviral particle and / or AAV particle to the subject.

[0133] Aspect 101 is the method of aspect 99 or 100, wherein the administering comprises intracranial injection.

[0134] Aspect 102 is the method of any one of aspects 99-101, wherein the administering occurs prior to and / or after an onset of symptoms of Huntington disease.

[0135] Aspect 103 is the method of any one of aspects 99-102, wherein the administering occurs more than once.

[0136] Aspect 104 is the method of any one of aspects 99-103, wherein the administering increases astrocyte uptake and / or clearance of mutant huntingtin.

[0137] Aspect 105 is the method of any one of aspects 99-104, comprising preserving neuronal integrity in the subject.

[0138] Aspect 106 is use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of aspects 1-56 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Huntingtondisease prior to, during, and / or after an undesirable accumulation of mutant huntingtin in a subject in need thereof.

[0139] Aspect 107 is a method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Parkinson’s disease prior to, during, and / or after an undesirable accumulation of alpha-synuclein and / or tau protein, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of aspects 1-56 to a subject.

[0140] Aspect 108 is the method of aspect 107, comprising administering the lentiviral particle and / or AAV particle to the subject.

[0141] Aspect 109 is the method of aspect 107 or 108, wherein the administering comprises intracranial injection.

[0142] Aspect 110 is the method of any one of aspects 107-109, wherein the administering occurs prior to and / or after an onset of symptoms of Parkinson’s disease.

[0143] Aspect 111 is the method of any one of aspects 107-110, wherein the administering occurs more than once.

[0144] Aspect 112 is the method of any one of aspects 107-111, wherein the administering increases astrocyte uptake and / or clearance of alpha-synuclein and / or tau protein.

[0145] Aspect 113 is the method of any one of aspects 107-112, comprising preserving neuronal integrity in the subject.

[0146] Aspect 114 is use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of aspects 1-56 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Parkinson’s disease prior to, during, and / or after an undesirable accumulation of alpha-synuclein and / or tau protein in a subject in need thereof.

[0147] Aspect 115 is a method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing frontal-temporal dementia prior to, during, and / or after an undesirable accumulation of tau protein, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of aspects 1-56 to a subject.

[0148] Aspect 116 is the method of aspect 115, comprising administering the lentiviral particle and / or AAV particle to the subject.

[0149] Aspect 117 is the method of aspect 115 or 116, wherein the administering comprises intracranial injection.

[0150] Aspect 118 is the method of any one of aspects 115-117, wherein the administering occurs prior to and / or after an onset of symptoms of frontal-temporal dementia.

[0151] Aspect 119 is the method of any one of aspects 115-118, wherein the administering occurs more than once.

[0152] Aspect 120 is the method of any one of aspects 115-119, wherein the administering increases astrocyte uptake and / or clearance of tau protein.

[0153] Aspect 121 is the method of any one of aspects 115-120, comprising preserving neuronal integrity in the subject.

[0154] Aspect 122 is use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of aspects 1-56 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing frontal- temporal dementia prior to, during, and / or after an undesirable accumulation of tau protein in a subject in need thereof.

[0155] Aspect 123 is a method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of aspects 1-56 to a subject.

[0156] Aspect 124 is the method of aspect 123, comprising administering the lentiviral particle and / or AAV particle to the subject.

[0157] Aspect 125 is the method of aspect 123 or 124, wherein the administering comprises intracranial injection.

[0158] Aspect 126 is the method of any one of aspects 123-125, wherein the administering occurs prior to and / or after an onset of symptoms of the neurological disorder.

[0159] Aspect 127 is the method of any one of aspects 123-126, wherein the administering occurs more than once.

[0160] Aspect 128 is the method of any one of aspects 123-127, wherein the administering increases astrocyte uptake and / or clearance of undesirable molecules and / or plaques.

[0161] Aspect 129 is the method of any one of aspects 123-128, comprising preserving neuronal integrity in the subject.

[0162] Aspect 130 is a kit comprising the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of aspects 1-55.

[0163] Aspect 131 is use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of aspects 1-55 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0164] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. Certain inventions described herein may be better understood by reference to one or more of these drawings in combination with the detailed description of specific aspects presented herein.

[0165] Unless otherwise specified, statistical analysis was performed using / -tests or ANOVA depending on the number of groups and time points, with p < 0.05 considered statistically significant. Bonferroni post-hoc analyses were performed after detecting significant ANOVA effects. Unpaired Student’s two-tailed t test was utilized for FIGs. 2D-2F, 3C, 4F, 41, 5B, 6G, 7E, 8C-8D, 8G, and 9C). Where appropriate, nonparametric analyses were performed when data failed normality or equal variance tests. Non-significant results are depicted with “ns” or left unlabeled, while significant results are represented by one or more asterisk. Unless otherwise specified, assays and analyses were performed on murine models.

[0166] FIGs. 1A-1G, Loss of NFIA or SOX9 accelerated A|J plaque formation. FIG. 1A Depicts a bioinformatics workflow of scRNA-seq data from human AD and control datasets. FIG. IB Depicts co-immunostaining for NFIA / GFAP and SOX9 / GFAP in the hippocampus of human AD samples and age-matched controls. FIG. 1C Depicts quantification of NFIA and SOX9 expression from AD and control samples; data was derived from 2 samples, 2 sections per sample. FIG. ID Depicts a schematic illustrating mouse lines used to knockout NFIA or SOX9 in NLGF- APP models and a timeline for a tamoxifen schedule. FIG. IE Depicts co-immunostaining for NFIA / GFAP and SOX9 / GFAP in NFIA-cKO; AD or SOX9-cKO; AD models. Single channel for Sox9 or NFIA immunostain are shown in the right panels. FIG. IF Depicts co-immunostaining for Ap / Lampl in control and NFIA-cKO; AD or SOX9-cKO; AD models. Left panel shows a composite of DAPI, Lampl, and Ap immunostains; middle panel shows a single channel immunostain for Lampl; and right panel shows single channel immunostain for Ap. FIG. 1G Depicts quantification of Lampl and Ap plaques from these experimental groups; data was derived from 6 samples, 4 sections per sample. ***p<0.005.

[0167] FIGs. 2A-2F, Overexpression of NFIA or SOX9 restored cognitive function. FIG. 2A Depicts a schematic and timeline of AAV-NFIA (aka “AAV-GFAP-NFIA”) or AAV-SOX9 (aka “AAV-GFAP-SOX9”) overexpression in astrocytes of NLGF-APP model mice. FIGs. 2B- 2C Depict co-immunostaining for SOX9 / AP (FIG. 2B) or NFIA / Ap (FIG. 2C) in mice injected with control AAV-GFAP-Con and AAV-SOX9 or AAV-NFIA. Note the control virus was injected in the hemisphere contralateral to AAV-NFIA or AAV-SOX9. The results showed marked reductions in Ap plaque levels in the hemispheres receiving the test AAV. FIG. 2D Depicts co- immunostaining for Ap / Lampl in mice injected with control AAV-GFAP-Con and AAV-SOX9or AAV-NFIA; single channel for Lamp 1 immunostain is shown in the right panels; quantification was derived from 6 samples, 3 sections per sample. The results showed a significant reduction in Ap area and Lampl area in the hemispheres receiving the test AAV. FIG. 2E Depicts a schematic for a novel object recognition (NOR) assay (left panel) and the corresponding quantification (middle and right panel). Data was derived from at least 6 animals per experimental group. The data showed a significant increase in interactions with novel objects and in discrimination index in 8 month old (8 m) AD mice receiving AAV-S0X9 (AD Sox9 over 8 m) or AAV-NFIA (AD NFIA over 8 m) relative to control AD mice receiving control AAV only (AD 8 m). FIG. 2F Depicts a schematic for a novel place recognition (NPR) assay (left panel) and the corresponding quantification (right panel). The data showed a significant increase in discrimination index in 8 month old (8 m) AD mice receiving AAV-S0X9 (AD Sox9 over 8 m) or AAV-NFIA (AD NFIA over 8 m) relative to control AD mice receiving control AAV only (AD 8 m), with the test mice displaying discrimination index similar to age matched control WT mice (WT 8 m). Data was derived from at least 6 animals per experimental group. **p<0.01, ***p<0.005.

[0168] FIGs. 3A-3E, Overexpression of NFIA or SOX9 in AD mice increased uptake of Ap by astrocytes. FIGs. 3A-3B Depict co-immunostaining of SOX9 (FIG. 3A) or NFIA (FIG. 3B) with Ap, in NLGF-APP; Aldhlll-GFP mice. The results showed a dramatic reduction in Ap in mice receiving AAV-SOX9 (AD-Sox9 over 8 m) or AAV-NFIA (AD-NFIA over 8 m) relative to controls (AD 8 m). FIG. 3C Depicts a Sholl analysis of astrocyte intersections from the control and NFIA or SOX9 overexpression models. Quantification was derived from 4 animals, 3 sections per animal. The results showed mice receiving AAV-SOX9 (AD-Sox9 over 8 m; identified as “ii”) or AAV-NFIA (AD-NFIA over 8 m; identified as “iii”) had significantly increased GFP Sholl analysis levels relative to controls (AD 8 m; identified as “i”). FIG. 3D-3E Are high magnification images depicting Ap plaque uptake and Lampl levels within NFIA or SOX9 overexpressing astrocytes, from the cortex (FIG. 3D) and hippocampus (FIG. 3E). From top to bottom, the first row shows a composite image of Aldhlll-GFP, Lampl, and Ap immunostains; the second row shows a composite image of Lampl and Ap immunostains; the third row shows single channel images of Ap immunostain; the fourth row shows single channel images of Lampl immunostains; and the fifth row shows 3D rendering of astrocytes phagocytosing Ap plaques. 3D rendering of the results showed increased levels of overlap between Ap plaques and Lampl in test mice relative to controls, indicating increased lysosomal localization of phagocytosed Ap.

[0169] FIGs. 4A-4I, NFIA and SOX9 regulated the expression of A2M and MEGF10. FIG. 4A Is a heatmap depicting RNA-Seq expression of key genes associated with Ap plaque processing from hippocampal astrocytes from NFIA-cKO and SOX9-cKO mice. The results showed a reduction in A2M expression in both knockout conditions relative to wild type animals.FIG. 4B Depicts immunostaining for A2M (“A2m”) and Aidhill -GFP (“GFP”) in WT control (WT), SOX9-cKO, and NFIA-cKO astrocytes. From top to bottom, the first row shows a composite image of GFP and A2m immunostains; the second row shows single channel images for A2m immunostain; and the third row shows 3D rendering of astrocyte volume and A2m clusters. The results showed decreased astrocytic A2M protein levels in NFIA-cKO and SOX9- cKO mice. FIG. 4C Depicts quantification of A2M staining shown in FIG. 4B, derived from 3 animals per group, 3 sections per animal. FIG. 4D Depicts immunostaining for A2M (“A2m”) and Aldhlll-GFP (“GFP”) in control NLGF-APP mice at 4 months of age or in age matched NLGF- APP mice with conditional knockout of SOX9 (AD-Sox9 cKO 4m) or NFIA (AD-NFIA cKO 4m). From top to bottom, the first row shows a composite image of GFP and A2m immunostains; the second row shows single channel images for A2m immunostain; and the third row shows 3D rendering of astrocyte volume and A2m clusters. The results showed reduced levels of A2M in conditional knockout mice relative to AD mice. FIG. 4E Depicts immunostaining for A2M (“A2m”) and Aldhlll-GFP (“GFP”) in control NLGF-APP mice at 8 months of age or in age matched NLGF-APP mice overexpressing SOX9 (AD-Sox9 over 8 m) or NFIA (AD-NFIA over 8 m). From top to bottom, the first row shows a composite image of GFP and A2m immunostains; the second row shows single channel images for A2m immunostain; and the third row shows 3D rendering of astrocyte volume and A2m clusters. The results showed increased levels of A2M in test overexpression mice relative to control AD mice. FIG. 4F Depicts quantification for A2M staining shown in FIGs. 4D-4E, derived from 4 animals per group, 3 sections per animal. The results showed significantly reduced A2M levels in AD Sox9-cKO or AD NFIA-cKO mice relative to AD control mice, and significant increases in A2M levels in AD mice receiving AAV- Sox9 (Sox9 over) or AAV-NFIA (NFIA over) relative to AD control mice. FIGs. 4G-4H Depict immunostaining in the cortex (FIG. 4G) or hippocampus (FIG. 4H) for MEGF10 (“Megfl 0”) and Aldhlll-GFP in control NLGF-APP mice at 8 months of age or in age matched NLGF-APP mice treated with AAV-SOX9 or AAV-NFIA. From left to right, the first column shows composite images of Aldhlll-GFP and Megfl 0 immunostaining; the second column shows single channel images for Megfl 0 immunostaining; and the third row shows 3D rendering images of astrocyte volume and Megfl 0 protein. The results showed increased levels of MEGF10 in test animals relative to controls. FIG. 41 Depicts quantification of MEGF10 staining shown in FIGs. 4G-4H, derived from 4 animals per group, 3 sections per animal. The results showed significant increases in MEGF10 levels in the hippocampus and cortex of test mice (AD-NFIA over 8 m (identified as “iii”), or AD-Sox9 over 8 m (identified as “ii”)) relative to controls (AD 8 m (identified as “i”)).

[0170] FIGs. 5A-5D, Show elevated expression of NFIA and SOX9 in NLGF-APP model mice. FIG. 5A Depicts levels of Ap, NFIA, and SOX9 in Aldhlll-GFP expressing astrocytes inWT (Con) orNLGF-APP (NLGF / NLGF) mice. The results showed increased levels ofNFIA, and SOX9 in Aldhlll-GFP expressing NLGF-APP (NLGF / NLGF) mice relative to controls. From left to right, the third and fifth columns show single channel images of Sox9 and NFIA immunostaining, respectively. FIG. 5B Depicts quantification of NFIA and SOX9 expression in WT (con) or NLGF-APP (NLGF) astrocytes imaged in FIG. 5 A. The results showed significant increases in the levels of NFIA and SOX9 in NLGF-APP animals relative to controls. FIG. 5C Depicts immunostaining demonstrating increased expression over time of Ap and Lampl over a 2-8 month time course in NLGF-APP mice. From top to bottom, the first row shows composite images of DAPI, LAMP1, and Ap staining; the second row shows single channel images of Ap staining; and the third row shows single channel images of Lampl staining. FIG. 5D Depicts quantification of the animals depicted in FIG. 5C, showing increases of Ap and LAMP expression over time.

[0171] FIGs. 6A-6G, Show confirmation of AAV mediated overexpression of SOX9 and NFIA in astrocytes in NLGF-APP model. FIG. 6A Depicts a simplified schematic of AAV viruses used herein (e.g., SEQ ID NOs: 30 and 33). FIGs. 6B-6C Depict immunostaining for SOX9 or NFIA in the cortex and hippocampus after control (AAV-GFAP-Con), AAV-SOX9 (FIG. 6B), or AAV-NFIA (FIG. 6C) injection. In FIG. 6B, the right panels show single channel images of Sox9 immunostaining. In FIG. 6C, the right panels show single channel images ofNFIA immunostaining. The results showed increased expression of SOX9 or NFIA in test animals compared to control. FIG. 6D Depicts immunostaining demonstrating expression of Ap and LAMP1 in WT (intact) orNLGF-APP (NLGF / NLGF) at 6 or 8 months of age. From top to bottom, the first row shows composite images of DAPI, LAMP1, and Ap staining; the second row shows single channel images of Ap staining; and the third row shows single channel images of Lampl staining. FIGs. 6E-6F Depict schematics of AAV-SOX9 or AAV-NFIA injection into mouse brain. FIG. 6G Depicts immunostaining and quantification for Ap and NeuN (neuronal marker) in the cortex and hippocampus in control AD animals (AD 8 m) or after AAV-SOX9 (AD-Sox9 over 8 m) or AAV-NFIA (AD-NFIA over 8 m) injection into AD animals. From top to bottom, the first row shows composite images of NeuN, Ap, and DAPI staining in the cortex; the second row shows single channel images of NeuN staining in the cortex; the third row shows composite images of NeuN, Ap, and DAPI staining in the hippocampus; and the fourth row shows single channel images of NeuN staining in the hippocampus. The results showed significantly increased levels of NeuN (quantifying neuron levels), in both the hippocampus and cortex of animals receiving AAV-SOX9 or AAV-NFIA relative to controls. AD 8m is identified as “i,” AD- Sox9over8m is identified as “ii,” and AD-NFIAover8m is identified as “iii.”

[0172] FIGs. 7A-7E, Show analysis of A|J plaque buildup in SOX9-cKO;APP and NFIA- cKO;APP mouse lines. FIG. 7A Depicts immunostaining demonstrating expression of Ap and LAMP1 in WT (Intact) or NLGF-APP (NLGF / NLGF) animals at 4 or 8 months of age. From top to bottom, the first row shows composite images of DAPI, Lampl, and Ap stains; the second row shows single channel images of Ap immunostaining; and the third row shows single channel images of Lampl immunostaining. As anticipated, the results showed increased levels of Ap and LAMP1 in NLGF / NLGF animals relative to controls. FIG. 7B Depicts immunostaining for NeuN and Ap in the cortex of WT (Con) or NLGF-APP (AD) mice at 4 and 8 months of age. From top to bottom, the first row shows composite images of NeuN, Ap, and DAPI staining; the second row shows single channel images of NeuN immunostaining; and the third row shows composite images of DAPI and Ap stains. The dotted line represents the area of Ap plaques. The results showed that Ap plaque buildup increased over time and resulted in reduced neuronal cell numbers. FIGs. 7C- 7D Depict immunostaining for NeuN and Ap in control NLGF-APP mice (AD) at 4 months of age or in age matched SOX9-cKO;APP (AD-Sox9cKO 4 m) and NFIA-cKO;APP (AD-NFIAcKO 4 m) mouse lines in the cortex (FIG. 7C) and the hippocampus (FIG. 7D). For FIG. 7C, the top row shows composite images of NeuN, Ap, and DAPI stains; and the bottom row shows single channel images of NeuN immunostaining. For FIG. 7D, the left column shows composite images of NeuN, Ap, and DAPI stains; and the right column shows single channel images of NeuN immunostaining. The results showed increased levels of Ap and decreased levels of NeuN in the conditional knockout mice relative to controls. FIG. 7E Depicts quantification of the results shown in FIGs. 7C-7D, where at 4 months of age AD-Sox9cKO mice (identified as “ii”) and AD- NFIAcKO mice (identified as “iii”) displayed significantly reduced levels of NeuN expressing neurons in both the hippocampus and the cortex relative to age matched control AD mice (identified as “i”).

[0173] FIGs. 8A-8H, Show analysis of loss of Ap plaque uptake by astrocytes in the SOX9- cKO;APP and NFIA-cKO;APP mouse lines. FIGs. 8A-8B Depict immunostaining demonstrating expression of Ap and LAMP1 and showing GFP labelled astrocytes (Aldhlll-GFP) in WT animals (Intact), and at 4 or 8 months of age in NLGF-APP mice in the cortex (FIG. 8A) or hippocampus (FIG. 8B); note the uptake of Ap plaques in astrocytes is demonstrated on the bottom rows (3-D structure). From top to bottom, the first row shows composites images of Aldhlll-GFP, Lampl, and Ap staining; the second row shows single channel images of Lampl staining; the third row shows single channel images of Ap staining; and the fourth row shows composite images of Lampl and Ap staining. FIGs. 8C-8D Depict quantification of astrocyte uptake of Ap in NLGF-APP (NLGF) mouse models at 4 months and 8 months of age as shown in FIGs. 8A-8B. The results indicated significantly increased levels of astrocyte phagocytosis of Apin NLGF mouse models at both 4 and 8 months of age relative to WT animals (Intact). Furthermore, the data indicated the levels of astrocyte phagocytosis of Ap was significantly increased between 4 and 8 months of age in NLGF animals. FIGs. 8E-8F Depict immunostaining demonstrating expression of Ap and LAMP1 and showing GFP labelled astrocytes (Aldhlll-GFP) in NLGF-APP (AD) animals at 4 months of age, and in age matched S0X9-cK0;APP (AD- Sox9cKO 4 m) mice or age matched NFIA-cKO;APP (AD-NFIAcKO 4 m) mice in the cortex (FIG. 8E) or the hippocampus (FIG. 8F); note the loss of uptake of Ap plaques in astrocytes is demonstrated on the bottom row (3-D structure). From top to bottom, the first row shows composite images of Aldhlll-GFP, Lampl, and Ap stains; the second row shows composite images of Lampl and Ap stains; the third row shows single channel images of Ap staining; and the fourth tow shows single channel images of Lampl staining. The dotted square represents the region shown in the 3D rendering. FIGs. 8G-8H Depict quantification of astrocyte uptake of Ap as imaged in FIGs. 8E-8F. The data showed significant reductions in the astrocyte phagocytic index in AD-Sox9cKO (identified as “ii”) and AD-NFIAcKO (identified as “iii”) animals relative to AD controls (identified as “i”).

[0174] FIGs. 9A-9C, Show reduced expression of MEGF10 in astrocytes from the SOX9- cKO;APP and NFIA-cKO;APP mouse lines. FIGs. 9A-9B Depict immunostaining for MEGF10 in Aldhlll-GFP astrocytes from the NLGF-APP (AD), SOX9-cKO;APP (AD-Sox9cKO), or NFIA-cKO;APP (AD-NFIAcKO) mouse lines. The top row shows composite images of Aldhlll- GFP and Megfl 0 staining; the middle row shows single channel images of Megfl 0 staining; and the third row shows 3D rendering of astrocyte volume and Megfl 0 proteins. FIG. 9C Depicts quantification of MEGF10 as imaged in FIGs. 9A-9B. The data indicated significantly reduced levels of MEGF10 in the cortex and hippocampus of AD-Sox9cKO (identified as “ii”) and AD- NFIAcKO (identified as “iii”) relative to AD controls (identified as “i”).

[0175] FIGs. 10A-10F, Show exemplary constructs utilized in experiments described herein. FIG. 10A maps a pGFAP driven NFIA overexpression construct (comprising SEQ ID NO: 29). FIG. 10B maps a pGFAP driven NFIA overexpression construct (comprising SEQ IDNO: 30). FIG. 10C maps a pGFAP driven Sox9 overexpression construct (comprising SEQ IDNO: 33). FIG. 10D maps a pGFAP driven Sox9 overexpression construct (comprising SEQ IDNO: 34). FIG. 10E maps a pGFAP driven MEGF10 overexpression construct (comprising SEQID NO: 37). FIG. 10F maps a pGFAP driven A2M overexpression construct (comprising SEQ ID NO: 38).

[0176] FIGs. 11A-11M, Show age-specific requirement for Sox9 in hippocampal astrocytes. FIG. 11A shows a schematic illustration for RNAseq from sorted mouse astrocytes from the hippocampus for animals aged 18 months (18m) or 4 months (4m). FIGs. 11B-11C showGO analysis for each group for up-regulated genes (FIG. 11B; log2FC >+l and -value <0.005) and downregulated genes (FIG. 11C; log2FC <-l and -value <0.005); n=3 each of 4 months and 18 months. FIG. 11D is a Venn diagram of the nominated transcription factor candidates from differentially expressed genes (DEGs) between 18m and 4m old animals. FIG. HE shows representative confocal Z-stack images of Sox9 (red) and Aldhlll-GFP (“GFP,” green) in the hippocampus at 4 months and 18 months. The left column shows composite images of GFP and Sox9 staining, while the right column shows single channel images of Sox9 staining. Scale bars, 20 pm. FIG. HF shows quantification bar graphs of Sox9 intensities in astrocytes of each group; n= 6 for each group. FIG. 11G shows a schematic illustration of astrocyte-specific Sox9 conditional knock-out and control mouse lines and the tamoxifen treatment strategy. FIG. 11H shows representative confocal Z-stack images of Sox9 (red) and Alhlll-GFP (“GFP,” green) in the hippocampus Con and Sox9cKO mice at 4 months and 18 months. Scale bars, 20 pm. FIG. HI shows quantification of the number of intersections by Sholl analysis of hippocampal astrocytes between Con and Sox9cKO mice at 4 months and 18 months. n= 6 for each group. Con 4m is identified as “i;” Sox9cKO-4m is identified as “ii;” Con 18m is identified as “iii;” and Sox9cKO-18m is identified as “iv.” FIG. HJ shows long-term potentiation (LTP) traces from Con and Sox9cKO mice hippocampal slices at 4 months and 18 months. Con 4m is identified as “i;” Sox9cKO-4m is identified as “ii;” Con 18m is identified as “iii;” and Sox9cKO-18m is identified as “iv.” FIG. HK shows quantification of LTP. n= 7 for each group. FIG. HL shows representative images and traces between Con and Sox9cKO mice at 18 months showing spontaneous GCaMP6 activity in astrocytes from the hippocampus. In the images on the left, the red (inner) line denotes soma, and the green (outer) line depicts approximate territory; traces are from soma. FIG. HM shows quantification of somatic AF / F GCaMP6 signal amplitude and frequency derived from 5 mice of each group. Two-sided unpaired Student’s t-test (FIGs. HG, 11K, 11M) and Two-way ANOVA with Sidak’s correction (FIG. HI) were used for analysis. The mean ± s.e.m. n.s: not significant, * / ?-value < 0.05, ** / >-value < 0.01, *** / >-value < 0.005, and **** / 2-value < 0.001.

[0177] FIGs. 12A-12K, Show that loss of Sox9 in astrocytes promoted the onset of A|J plaque formation. FIG. 12A shows top 5 related phenotype-genotype integrator association (PhenGenl) analyses of the aged astrocyte-specific DEGs from Sox9cKO. FIGs. 12B-12C show representative confocal Z-stack images of Sox9 (red) and GFAP (green) in human hippocampal tissues of age-matched control (Human Con) and AD patients (Human AD) (FIG. 12B), Sox9 (red) and GFP (green) in mouse hippocampal tissues in WT; Aldhlll-GFP (WT) and APP-NLGF; Aldhlll-GFP (AD) (FIG. 12C). Scale bars, 50 pm. FIG. 12D shows quantification bar graphs of Sox9 intensities in astrocytes of each group. n= 4 human hippocampal tissues of each group (upperpanel), and n= 5 mice of each group (lower panel). FIG. 12E shows heatmaps comparing ChIP Sox9 at 4 kb from the peak center in hippocampal astrocytes from WT; Aldhlll-GFP (WT) and APP-NLGF; Aldhlll-GFP (AD) at 6 months. Each sample was created by combining tissues obtained from 6 mice of each group. Venn diagram reveals the number of WT-specific, AD- specific, and overlapping genes of ChIP-Sox9. FIG. 12F shows Gene Ontology (GO) analysis of genes at Sox9 peaks in hippocampal astrocytes from WT and AD animals. FIG. 12G shows scRNA-seq Dimplots of total cell clusters and astrocytes-specific clusters between WT and APP- NLGF animals at 6 months. FIG. 12H shows Venn diagrams revealing the number of shared genes between ChIP data from AD-Sox9 and DEGs from scRNAseq between WT and APP-NLGF animals at 6 months of age. GO analysis of shared 399 genes (bottom). FIG. 121 shows a schematic illustration for astrocyte-specific Sox9 conditional knock-out mouse line with control mouse in an APP-NLGF mouse line, and the treatment strategy for tamoxifen. FIG. 12J shows representative confocal Z-stack images of Ap (green) and Lampl (red) in mouse hippocampal tissues between AD-Sox9con and AD-Sox9cKO animals at 4 months of age. The left column shows composite images of Ap, Lampl, and DAPI stains; the middle column shows single channel images of Ap staining; and the right column shows single channel images of Lampl staining. Scale bars, 500 pm. FIG. 12K shows quantification bar graphs of Ap and Lampl -positive plaque area percentage in the cortex and hippocampus between AD-Sox9con and AD-Sox9cKO animals at 4 months of age. n= 5 mice for each group. Two-sided unpaired Student’s t-test (FIGs. 12D, 12K) was used for analysis. The mean ± s.e.m. **** / ?-value < 0.001.

[0178] FIGs. 13A-13J, Overexpression of Sox9 preserved cognitive function in AD mouse models. FIG. 13A shows a schematic illustration of AAV-GFAP-Sox9ov injection (right hemisphere, AAV-Sox9ov) and AAV-GFAP-Con injection (left hemisphere, AAV-Con) in the cortex and hippocampus of APP-NLGF mice. A timeline of injection and analysis is shown below. FIG. 13B shows representative confocal Z-stack images of Ap (red) and DAPI (blue) from a brain injected with AAV-Con (left) and AAV-Sox9ov (right). Scale bar, 50 pm. FIG. 13C shows representative confocal Z-stack images of Lampl (red) and DAPI (blue) from brains injected with AAV-Con and AAV-Sox9ov. Scale bar, 50 pm. FIGs. 13D-13E show quantification bar graphs of Ap-positive (FIG. 13D) and Lampl -positive (FIG. 13E) plaque area percentage in the cortex and hippocampus from each group. n=5 mice for each group. FIGs. 13F-13H show graphical illustrations for longitudinal memory behavior tracking test by novel object recognition (NOR) and novel place recognition (NPR). WT-Con (AAV-GFAP-Con injected WT mice), AD-Con (AAV-GFP-Con injected AD mice), and AD-Sox9ov (AAV-GFAP-Sox9ov injected AD mice). FIGs. 13I-13J show discrimination indexes of NOR (FIG. 131) and NPR (FIG. 13J) tests for each group. WT-AAV-Con is identified as “i,” AD-AAV-Con is identified as “ii,” and AD-AAV-Sox9ov is identified as “iii .” n= 6 mice for each group. One-way ANOVA followed by Tukey’s comparisons test (FIGs. 13D, 13E) and Two-way ANOVA with Sidak’s correction (FIGs. 131, 13J) were used for analysis. The mean ± s.e.m. n,s: not significant and **** / ?-value < 0.001.

[0179] FIGs. 14A-14K, Sox9 promoted astrocytic phagocytosis of A|J. FIG. 14A shows a schematic illustration for fluorescence-activated cell sorting (FACS) of astrocytes for RNAseq with mCherry tagged AAV-GFAP-mCherry-Con (AAV-mCh-Con) and AAV-GFAP-mCherry- Sox9ov (AAV-mCh-Sox9ov) injection in the hippocampus of AD mice. FIG. 14B shows GO analysis of DEGs between AAV-mCh-Sox9ov and AAV-mCh-Con: log2FC > 2 fold or < -2 fold, and -value < 0.001. n=3 of AAV-mCh-Con and n=4 of AAV-mCh-Sox9ov. FIG. 14C shows representative confocal Z-stack images of GFP-positive astrocytes (green) and Ap (red) on the hippocampus in AAV-GFAP-Con (AAV-Con) and AAV-GFAP-Sox9ov (AAV-Sox9ov) injected APP-NLGF; Aldhlll-GFP (AD) mice. Scale bars, 20 pm. FIG. 14D shows quantification of the number of intersections by Sholl analysis of hippocampal astrocytes in AAV-Con with AAV- Sox9ov. n=5 mice for each group. AAV-con is identified as “i,” and AAV-Sox9ov is identified as “ii.” FIG. 14E shows representative confocal Z-stack images of GFP-positive astrocytes (blue) co-stained with lysosomes membrane marker (Lampl, red) and Ap (green) on the hippocampus in AAV-Con and AAV-Sox9ov injected AD mice. The right panels are 3-D reconstructed enlarged images of dotted boxes in the left panels, showing engulfed Ap inside astrocytes. Scale bars, 10 pm (left panel) and 5 pm (3-D reconstruction image). FIG. 14F shows quantification bar graphs of the areas of engulfed Ap by astrocytes normalized by astrocyte cell body area. n=5 mice for each group. FIG. 14G shows a schematic illustration of injection of AAV-Synapsin-APP (APPNL'F), AAV-Con, and AAV-Sox9ov in the hippocampus of WT; Aldhlll-GFP (WT) mice. FIG. 14H shows representative confocal Z-stack images of GFP-positive astrocytes in the hippocampus of WT mice after injection of each virus. The right panels are 3-D reconstructed enlarged images of astrocytes from the left panels. Scale bars, 20 pm. FIG. 141 shows quantification of the number of intersections by Sholl analysis (using IMARIS®) between AAV-con and AAV-Sox9ov of astrocytes in the hippocampus. n=5 mice for each group. APPNL-F / Con is identified as “i,” and APPNL-F / Sox9ov is identified by “ii.” FIG. 14J shows representative confocal Z-stack images of GFP-positive astrocytes (blue) co-stained with lysosomes membrane marker (Lampl, red) and Ap (green). The right panels are 3-D reconstructed enlarged images of dotted boxes in the left panels, showing engulfed Ap inside astrocytes. Yellow arrowheads point to engulfed Ap. Scale bars, 10 pm (left panel) and 2 pm (3-D reconstruction image). FIG. 14K shows quantification bar graphs of the areas of engulfed Ap by astrocytes normalized to astrocyte cell body area. n=5 mice of each group. Two-sided unpaired Student’ s t-test (FIGs. 14F, 14K) and Two-way ANOVA with Sidak’scorrection (FIGs. 14D, 141) were used for analysis. The mean ± s.e.m. *** / ?-value < 0.005, and **** / ?-value < 0.001.

[0180] FIGs. 15A-15N, MEGF10 promoted phagocytosis and preserved cognitive function. FIGs. 15A-15B show representative confocal Z-stack images of GFP-positive astrocytes (green) and Megfl 0 (red) in hippocampal astrocytes from AD-Sox9con and AD- Sox9cKO mice (FIG.15A) and AAV-Con and AAV-Sox9ov injected APP-NLGF; Aldhlll-GFP (AD) mice (FIG.15B). lower panels are 3-D reconstructed enlarged images of each GFP-positive astrocyte (green) with MEGF10 (red). Scale bars, 5 pm. FIGs. 15C-15D show quantification bar graphs of MEGF10 intensities in each group. n= 5 mice in each group. FIG. 15E shows a schematic illustration of the timeline for experiments in which AAV-GFAP-Con (AAV-Con) and AAV-GFAP-MEGFlOov (AAV-MEGFlOov) were injected in the hippocampus of AD mice. FIG. 15F shows representative confocal Z-stack images of GFP-positive astrocytes (green) and MEGF10 (red) in hippocampal astrocytes of AAV-Con and AAV-MEGFlOov injected AD mice. Scale bars, 10 pm. FIG. 15G shows quantification bar graphs of MEGF10 intensity in each group. n= 5 mice of each group. FIG. 15H shows a graphical illustrations of a timeline for memory behavior tests by NOR and NPR, in which AAV-GFAP-Con was injected in WT mice (WT-AAV- Con), AAV-GFP-Con was injected in AD mice (AD-AAV-Con), and AAV-GFAP-MEGF10 was injected in AD mice (AD-AAV-MEGF10). FIGs. 151-15 J show discrimination indexes of NOR (FIG. 151) and NPR (FIG. 15J) tests. n=5 mice for each group. FIG. 15K shows representative confocal Z-stack images of Ap (red) and DAPI (blue) in the hippocampus of AAV-Con and AAV- MEGFlOov injected AD mice. Scale bars, 200 pm. FIG. 15L shows representative confocal Z- stack images of GFP-positive astrocytes (blue) co-stained with lysosomes membrane marker (Lampl, red) and Ap (green) in hippocampal astrocytes of AAV-Con and AAV-MEGFlOov injected AD mice. Scale bars, 10 pm. FIGs. 15M-15N show quantification bar graphs of AP- positive plaque area percentage (FIG. 15M) and phagocytotic index (FIG. 15N) in the hippocampus between AAV-Con and AAV-MEGFlOov injected AD mice. n=5 mice of each group. One-way ANOVA followed by Tukey’s comparisons test (FIGs. 151, 15 J) and Two-sided unpaired Student’s t-test. (FIGs. 15C, 15D, 15G, 15M, 15N) were used for analysis. The mean ± s.e.m. * / ?-value < 0.05, *** / ?-value < 0.005 and **** / ?-value < 0.001.

[0181] FIGs. 16A-16F, Shows how astrocyte morphology is altered in the aging brain. FIG. 16A shows a schematic illustration for WT; Aldhlll-GFP mouse. FIG. 16B shows representative confocal Z-stack images of GFP-expressing astrocytes in the hippocampus of mice aged 4 months and 18 months. Scale bars, 20 pm. FIG. 16C shows quantification of the number of intersections by Sholl analysis of hippocampal astrocytes of mice aged 4 months (4m, indicated by “i”) and 18 months (18m, indicated by “ii”). FIG. 16D shows a schematic illustration for WT;Aldhlll-creER; LSL; tdTomato mouse and the timeline for tamoxifen administration. FIG. 16E shows representative confocal Z-stack images of tdTomato-expressing astrocytes in the hippocampus of 4m and 18m mice. Scale bars, 20 pm. FIG. 16F shows quantification of the number of intersections by Sholl analysis of hippocampal astrocytes of 4m (indicated by “i”) and 18m (indicated by “ii”) mice. Two-way ANOVA with Sidak’s correction (FIGs. 16C, 16F) was used for analysis. The mean ± s.e.m. **** / ?-value < 0.001.

[0182] FIGs. 17A-17C, Provides results and analysis of RNAseq from Sox9cKO astrocytes at 4m and 18m. FIG. 17A shows a schematic illustration of process for RNAseq from sorted astrocytes of the hippocampus between Con and Sox9cKO at 4 months and 18 months. n=3 of 4 months, n=3 of 18 months. FIG. 17B shows a Venn diagram of the number of specific DEGs between Con and Sox9cKO animals at 4 months and 18 months. FIG. 17C shows GO analysis for each group of up-regulated genes (FIG. 17B) and downregulated genes (FIG. 17C); each DEGs: log2FC >1 or <-l fold, and -value <0.005.

[0183] FIG. 18A-18C, Shows A|J plaque formation in AD patients and APP-NLGF model mice. FIG. 18A shows a table of information on AD patients’ samples with age-matched controls. FIG. 18B shows representative confocal Z-stack images of GFAP (green) and Ap (red) in the hippocampus of human AD and age-matched controls. The left column shows composite images of GFAP and Ap staining; the middle column shows single channel images of Ap staining; and the right column shows single channel images of GFAP staining. Scale bars, 20 pm. FIG. 18C shows representative confocal Z-stack images of Ap (green) and Lampl (red) in the hippocampus of APP-NLGF mice from 2 months to 8 months and WT mice. Scale bars, 500 pm.

[0184] FIGs. 19A-19F, Shows successful astrocyte-specific manipulation of Sox9 in APP- NLGF mice. FIG. 19A shows representative confocal Z-stack images of GFP (green) and Sox9 (red) in the hippocampus of AD-Sox9con and AD-Sox9cKO mice. Scale bars, 50 pm. FIG. 19B shows quantification bar graphs of Sox9 intensity in each group (left panel), and number of GFP- positive astrocytes between AD-Sox9con and AD-Sox9cKO (right panel). n=5 mice of each group. FIG. 19C shows quantification of intersections by Sholl analysis of hippocampal astrocytes from AD-Sox9con (identified as “i”) and AD-Sox9cKO (identified as “ii”) mice. n=5 mice of each group. FIG. 19D shows a schematic illustration of injection of AAV-GFAP-Sox9ov or AAV- GFAP-Con in the cortex and hippocampus of APP-NLGF mice. FIG. 19E shows representative confocal Z-stack images of Sox9 (green) and DAPI (blue) in the cortex and hippocampus in APP- NLGF mice. The top row shows composite images of DAPI and Sox9 stains, while the bottom row shows single channel images of Sox9 staining in higher magnification. FIG. 19F shows quantification bar graphs of Sox9 intensity in each group. n=5 mice of each group. Two-sided unpaired Student’s t-test (FIGs. 19A, 19B, 19F) and Two-way ANOVA with Sidak’s correction(FIG. 19C) were used for analysis. The mean ± s.e.m. n.s: not significant, *** / ?-value < 0.005, and **** / ?-value < 0.001.

[0185] FIGs. 20A-20B, Provides an analysis of NeuN neurons after Sox9 manipulation. FIG. 20A shows representative confocal Z-stack images of Ap (green), NeuN (red), and DAPI (blue) in the cortex (CTX, upper panels) and hippocampus (HC, lower panels) between AD- Sox9con and AD-Sox9cKO. For images from the cortex, the top row shows composite images of Ap, NeuN, and DAPI stains, while the bottom row shows single channel images of NeuN staining. For images from the hippocampus, the left column shows composite images of Ap, NeuN, and DAPI stains, while the right column shows single channel images of NeuN staining. Quantification bar graphs of NeuN-positive area in each group are shown on the right. n= 5 mice for each group. FIG. 20B shows representative confocal Z-stack images of Ap (green), NeuN (red), and DAPI (blue) in the cortex (CTX, upper panels) and hippocampus (HC, lower panels) between AAV-Con and AAV-Sox9ov. For images from the cortex, the top row shows composite images of Ap, NeuN, and DAPI stains, while the bottom row shows single channel images of NeuN staining. For images from the hippocampus, the left column shows composite images of Ap, NeuN, and DAPI stains, while the right column shows single channel images of NeuN staining. Quantification bar graphs of NeuN-positive area in each group are shown on the right. n= 5 mice of each group. Two-sided unpaired Student’s t-test (FIGs. 20A, 20B) was used for analysis. The mean ± s.e.m. ** / ?-value < 0.01, and *** / ?-value < 0.005.

[0186] FIGs. 21A-21H, Provides an analysis of Ap phagocytosis by astrocytes in APP- NLGF. FIGs. 21A, 21B, 21D, 21E, and 21G show representative confocal Z-stack images of GFP-positive astrocytes (blue) co-stained with lysosomes membrane marker (Lampl, red) and Ap (green) in the cortex (FIG. 21A) and hippocampus (FIG. 21B) of WT and APP-NLGF mice; in the cortex (FIG. 21D) and hippocampus (FIG. 21E) of AD-Sox9con and AD-Sox9cKO; and in the cortex (FIG. 21G) in AAV-Con and AAV-Sox9ov mice. Scale bars, 10 pm, 5 pm. FIGs. 21C, 21F, and 21H show quantification bar graphs of the area of engulfed Ap by astrocytes normalized to astrocyte cell body area. n=5 mice of each group. Two-sided unpaired Student’s t-test (FIGs. 21C, 21G, 21H) was used for analysis. The mean ± s.e.m. *** / ?-value < 0.005, and **** / ?-value < 0.001.

[0187] FIGs. 22A-22C, AAV-APPNL Fsystem was used to analyze A phagocytosis by astrocytes. FIGs. 22A shows a schematic illustration for injection of AAV-Synapsin-APP (APPNL'F) in the hippocampus of WT; Aldhlll-GFP (WT) mice. FIG. 22B shows representative confocal Z-stack images of GFP-positive astrocytes (green), Ap (red), and DAPI (blue) in the hippocampus of WT mice. Scale bars, 100 pm. Quantification bar graphs of Ap intensity in each group are shown on the right. n=5 mice of each group. FIG. 22C shows representative confocalZ-stack images of GFP-positive astrocytes (blue) co-stained with lysosomes membrane marker (Lampl, purple) and Ap (green) in the hippocampus of WT and APP-NLGF mice. Scale bars, 10 pm. Quantification bar graphs of the areas of engulfed Ap by astrocytes normalized to astrocyte cell body area are shown on the right. n=5 mice of each group. A two-sided unpaired Student’s t- test (FIGs. 22B, 22C) was used for analysis. The mean ± s.e.m. *** / ?-value < 0.005, and value < 0.001.

[0188] FIGs. 23A-23F, Describes expression of phagocytosis receptors in astrocytes after Sox9 manipulation. FIGs. 23A shows representative confocal Z-stack images of GFP-positive astrocytes (green) co-stained with LRP1 (red), and quantification of LRP1 intensity in AD- Sox9con and AD-Sox9cKO mice; n=5 mice per group. FIGs. 23B shows representative confocal Z-stack images of GFP-positive astrocytes (green) co-stained with CD36 (red), and quantification of CD36 intensity in AD-Sox9con and AD-Sox9cKO mice; n=5 mice per group. FIGs. 23C shows representative confocal Z-stack images of GFP-positive astrocytes (green) co-stained with RAGE (red), and quantification of RAGE intensity in AD-Sox9con and AD-Sox9cKO mice; n=5 mice per group. Scale bars, 5 pm. FIGs. 23D-23E show representative confocal Z-stack images of GFP- positive astrocytes (green) co-stained MEGF10 in AD-Sox9con and AD-Sox9cKO mice (FIG. 23D); or in AAV-Con and AAV-Sox9ov mice (FIG. 23E). Scale bars, 5 pm (FIG. 23D), 10 pm (FIG. 23E). FIG. 23F shows quantification bar graphs of the MEGF10 intensity in each group. n=5 mice of each group. Two-sided unpaired Student’s t-test (FIGs. 23 A, 23B, 23C, 23F) was used for analysis. The mean ± s.e.m. n,s: not significant, *** / ?-value < 0.005, and **** / ?-value < 0.001.DETAILED DESCRIPTION

[0189] The work described herein provides at least new compositions and methods for treatment of neurological disorders associated with accumulation of non-desirable and / or detrimental molecules, such as plaques. In certain aspects, constructs, particles, polypeptides, polynucleotides, and / or compositions described herein can be utilized in methods for treatment of, prevention of, and / or amelioration of symptoms associated with neurological disorders.

[0190] Use of the one or more compositions may be employed based on methods described herein. Other aspects are discussed throughout this application. Any aspect discussed with respect to one aspect of the disclosure applies to other aspects of the disclosure as well and vice versa. The aspects in the Example section are understood to be aspects that are applicable to all aspects of the technology described herein.

[0191] The inventors have long studied astrocytes and the transcription factors that control their function in brain circuits, including Nuclear Factor IA (NFIA). Recently, the inventorsdiscovered that NFIA contributes to astrocyte mediated regulation of brain circuits and memory in the brain, and found that NFIA’s expression was elevated in reactive astrocytes associated with human Alzheimer’s Disease (AD). Although reactive astrocytes have been described as being closely associated with degenerating neurons across multiple brain regions in patients with AD, it was largely unknown how these cells contributed to the initiation and progression of AD. Moreover, it was unknown how astrocytic NFIA regulated functions of astrocytes and reactive astrocytes in the context of AD initiation and progression. As discussed herein, the inventors created a new mouse line (e.g., NFIA-cKO; AD) to facilitate elucidation of the role of NFIA in AD. These mice were produced by intercrossing the inventor’s NFIA knockout mouse line with the NLGF-APP mouse model of AD. Using this mouse model the inventors found that genetic knockout of NFIA in astrocytes accelerated Ap plaque formation. This surprising result led the inventors to question whether overexpression of NFIA may suppress Ap plaque formation in the NLGF-APP AD models. To test this, novel adeno associated viruses (AAVs) were generated that enabled astrocyte specific NFIA overexpression, herein termed AAV-NFIA.

[0192] To determine whether AAV-NFIA could suppress Ap plaque formation, said AAV particles were injected it into the hippocampus of AD mice prior to or after plaque formation, and brains were harvested at time periods (e.g., 2 months, 4 months) after injection. The results revealed a surprising and dramatic decrease in Ap plaque formation in the hippocampus and cortex of these mice. Bolstered by these results, the inventors asked whether AAV-NFIA could clear or remove existing Ap plaques. In the AD mouse model, Ap plaques began to form in the hippocampus at around 4 months of age, therefore, the inventors injected AAV-NFIA into the hippocampus of these mice at 6 months, harvesting the mice two months later at 8 months. Strikingly, brain sectioning revealed that mice receiving the AAV-NFIA particles had a dramatic reduction in Ap plaques in both the cortex and hippocampus relative to control animals. These data suggested that delivery of AAV-NFIA to astrocytes could improve astrocytes ability to actively remove existing Ap plaques. These results suggested that overexpression of NFIA in astrocytes (e.g., such as but not limited to, overexpression using AAV-NFIA) could be used to reduce accumulation of plaque load in AD patients with existing Ap plaques and stymie the progression of neurodegeneration and cognitive decline associated with AD. More broadly, these observation suggested that overexpression of NFIA (e.g., overexpression using AAV-NFIA) could be used to reduce accumulation of molecules associated with pathological states in various neurological disorders, such as but not limited to Parkinson’s, Huntington’s Disease, frontal- temporal dementia, and AD.

[0193] Astrocytes perform a range of diverse functions that are essential for normal brain function, including facilitating neurotransmission, buffering neuroactive compounds, engenderingsynapse formation, and maintenance of the blood-brain-barrier (BBB). Another key function of astrocytes is their response to injury or degenerative states, where they acquire “reactive” properties that can both aid in recovery from an insult and have detrimental effects in restoration of normal function1-3. Spinal cord injury serves as an archetype for this dichotomy, where reactive astrocytes are required early after injury to preserve healthy tissue, then at later stages of recovery they can impede axon regeneration3'6. Similarly, neurodegenerative diseases exhibit varied roles for reactive astrocytes in pathogenesis, where manipulation of reactive astrocytes results in a spectrum of outcomes ranging from beneficial to detrimental7-1h Nevertheless, given their ubiquity in degenerative diseases and their potential impact in pathogenesis, coupled with observations that many disease causing genes are also expressed in astrocytes, targeting astrocytes as a prospective intervention for these diseases has gained significant traction12. To achieve desired results and avoid detrimental results (e.g., results that exasperate a disease and / or disorder of interest), it is critical to first dissect how these diverse roles of reactive astrocytes in degenerative disease are regulated at the molecular and transcriptional level.

[0194] The process by which normal astrocytes transition to a reactive state remains enigmatic, likely reflecting a combination of the loss of normal functions, coupled with a gain of abnormal or reactive functions1-2’13. These transitions occur in the context of diverse astrocyte subpopulations that reside in the brain, against the backdrop of disease specific insults. Together, these features illustrate the likelihood of disease-specific reactive astrocyte states that are encoded by genetic and environmental factors, within existing cellular populationslj 14

[0195] Among degenerative neurological diseases, AD provides a framework for examining how astrocyte function evolves during disease progression, as existing models progress at relatively modest rates, in the context of defined genetic insults, with clear neuropathological benchmarks. Accordingly, studies have identified core features of reactive astrocytes in AD including synaptic dysregulation, decreased territories, impaired BBB, and altered Ca2+ activities, further reinforcing the model of impaired astrocytic function, coupled with acquisition of new properties12, 15'18. Although several groups have cataloged how astrocyte functions are altered in AD, the underlying mechanisms that drive these alterations during AD progression have hitherto remained poorly defined.

[0196] Astrocyte function is dictated in part by their interactions with neurons, with neuronal activity overseeing dynamic transcriptional states in mature and developing astrocytes19'21. Among astrocyte transcription factors linked to neuronal activity that regulate astrocyte function are Nuclear Factor I-A (NFIA) and SOX9, both of which have been shown to play region-specific roles in maintaining astrocyte morphology and neuronal circuit function, in the hippocampus and olfactory bulb, respectively22'23. That NFIA and SOX9 play central roles in normal astrocytefunctions that are disrupted in reactive astrocytes in AD, suggests that they may also contribute to AD pathogenesis. Studies have shown that NFIA and SOX9 are expressed in reactive astrocytes and may contribute to the production of reactive astrocyte responses after stroke injury and in Parkinson’s models, respectively24'25. This evidence suggests that NFIA and SOX9 may contribute to reactive astrocyte responses, however roles for NFIA and SOX9 in AD remained undefined. Furthermore, given the defined roles of these TFs in normal astrocyte function, mapping how their transcriptional networks are altered in AD may provide insight into how normal transcriptional programs are subverted during neurodegeneration.

[0197] In some aspects, provided herein are means of increasing an astrocytes usefulness in promoting healthy neuronal functional. In some aspects, provided herein are means for astrocytes usefulness in maintaining healthy neuronal function. In some aspects, provided herein are means for transgenically increasing the activity (e.g., overexpressing, inhibiting an inhibitor, etc.) of one or more of NFIA, SOX9, A2M, and / or MEGF10, in astrocytes, wherein the increasing the activity provides modulated functionality to the astrocytes. In some aspects, modulated functionality is improved functionality regarding maintenance and / or promotion of healthy neuronal functions. In some aspects, improved functionality can comprise, consist essentially of, or consist of increased astrocyte morphological complexity, increased astrocyte phagocytic activity, increased astrocyte modulation of synaptic function, increased astrocyte synaptogenesis, increased astrocyte sensing or response to neurotransmission, increased astrocyte prevention of plaque buildup, increased astrocyte uptake of plaques, increased calcium activity, increased astrocyte morphological complexity, and / or increased astrocyte clearance of plaques. In some aspects, improved functionality can comprise, consist essentially of, or consist of increased nervous system cell morphological complexity, increased nervous system cell phagocytic activity, increased nervous system cell synaptic function, increased nervous system cell synaptogenesis, increased nervous system cell neurotransmission, increased nervous system cell prevention of plaque buildup, increased nervous system cell uptake of plaques, and / or increased nervous system cell clearance of plaques.

[0198] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the measurement or quantitation method.

[0199] The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0200] The phrase “and / or” means “and” or “or”. To illustrate, A, B, and / or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of Band C, or a combination of A, B, and C. In other words, “and / or” operates as an inclusive or. It is specifically contemplated that A, B, or C may be specifically excluded from an aspect.

[0201] The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0202] The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of’ any of the ingredients or steps disclosed throughout the specification. Compositions and methods “consisting essentially of’ any of the ingredients or steps disclosed limits the scope of the claim to the specified materials or steps which do not materially affect the basic and novel characteristic of the claimed invention.

[0203] The term sequence as used herein in reference to a polynucleotide refers to the nucleotide sequence such as “A” for adenosine, “G” for guanine, “C” for cytosine, “T” for thymine, “U” for uracil, “I” for inosine, and “N” for “A” / “C” / “U” / “T” / “G” / ‘T”

[0204] As used herein, the terms “individual," “subject,” and “patient” are used interchangeably and can refer to a human or non-human.

[0205] The term “effective,” as that term is used in the specification and / or claims, means adequate to accomplish a desired, expected, or intended result.

[0206] The terms “inhibiting” or “reducing” or “preventing” or “avoiding” or any variation of these terms, when used in the claims and / or the specification, includes any measurable decrease or complete inhibition to achieve a desired result.

[0207] As used herein, a “protein” “peptide” or “polypeptide” refers to a molecule comprising at least five amino acid residues. As used herein, the term “wild-type” refers to the endogenous version of a molecule that occurs naturally in an organism. In some aspects, wild-type versions of a protein or polypeptide are employed, however, in many aspects of the disclosure, a modified protein or polypeptide is employed. The terms described above may be used interchangeably. A “modified protein” or “modified polypeptide” or “engineered protein” or “engineered polypeptide” or a “variant” refers to a protein or polypeptide whose chemical structure, particularly its amino acid sequence, is altered with respect to the wild-type protein or polypeptide. In some aspects, a modified / variant protein or polypeptide has at least one modified activity or function (recognizing that proteins or polypeptides may have multiple activities or functions). It is specifically contemplated that a modified / variant protein or polypeptide may be altered with respect to one activity or function yet retain a wild-type activity or function in other respects, such as catalytic activity, RNA-binding activity, DNA-binding activity, etc.

[0208] Where a protein is specifically mentioned herein, it is in general a reference to a native (wild-type) or recombinant (modified) protein or, optionally, a protein in which any signal sequence has been removed. The protein may be isolated directly from the organism of which it is native, produced by recombinant DNA / exogenous expression methods, or produced by solid phase peptide synthesis (SPPS) or other in vitro methods. In particular aspects, there are isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide (e.g., an enzymatic domain, such as a deaminase domain, or a fragment thereof). The term “recombinant” may be used in conjunction with a polypeptide or the name of a specific polypeptide, and this generally refers to a polypeptide produced from a nucleic acid molecule that has been manipulated in vitro or that is a replication product of such a molecule.

[0209] In certain aspects the size of a protein or polypeptide (wild-type or modified) may comprise, but is not limited to, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 1000, 1200, 1400, 1600, 1800, or 2000 amino acid residues or nucleic acid residues or greater, and any range derivable therein, or derivative of a corresponding amino sequence described or referenced herein. It is contemplated that polypeptides may be mutated by truncation, rendering them shorter than their corresponding wild-type form, also, they might be altered by fusing or conjugating a heterologous protein or polypeptide sequence with a particular function (e.g., for targeting, localization, linking, etc.).

[0210] In certain aspects, nucleic acid sequences can exist in a variety of instances such as: isolated segments and recombinant vectors of incorporated sequences or recombinant polynucleotides encoding an enzyme, or a fragment, derivative, or variant thereof, polynucleotides sufficient for targeting a complex to specific loci, polynucleotides sufficient to mediate RNA modification, polynucleotides sufficient for use as hybridization probes, PCR primers or sequencing primers for identifying, analyzing, mutating or amplifying a polynucleotide encoding a polypeptide, anti-sense nucleic acids for inhibiting and / or modifying expression of a polynucleotide, ancillary components of CRISPR / Cas systems, functional oligonucleotides, donor constructs, rescue constructs, and complementary sequences of the foregoing described herein. Nucleic acids encoding fusion proteins that include the proteins / polypeptides described herein arealso contemplated. The nucleic acids can be single-stranded or double-stranded and can comprise RNA and / or DNA nucleotides and artificial variants thereof (e.g., peptide nucleic acids, etc.).

[0211] The term “polynucleotide” refers to a nucleic acid molecule that either is recombinant or has been isolated from total genomic nucleic acid. Included within the term “polynucleotide” are oligonucleotides (e.g., nucleic acids typically 200 residues or less, or 100 residues or less in length), recombinant vectors, including, for example, plasmids, cosmids, phage, viruses, and the like. Polynucleotides include, in certain aspects, regulatory sequences, isolated substantially away from their naturally occurring genes or protein encoding sequences. Polynucleotides may be single- stranded (coding or antisense) or double- stranded, and may be RNA, DNA (genomic, cDNA or synthetic), analogs thereof, or a combination thereof. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide.

[0212] In certain respects, the term “gene,” “polynucleotide,” or “nucleic acid” is used to refer to a nucleic acid that encodes a protein, polypeptide, or peptide (including any sequences required for proper transcription, post-translational modification, or localization), or a functional RNA species, such as but not limited to, CRISPR / Cas system ancillary components, linking elements, targeting RNAs, etc. As will be understood by those in the art, this term encompasses genomic sequences, expression cassettes, cDNA sequences, and smaller engineered nucleic acid segments that express, or may be adapted to express, proteins, polypeptides, domains, peptides, fusion proteins, mutants, and functional RNA species. A nucleic acid encoding all or part of a polypeptide and / or functional RNA species may contain a contiguous nucleic acid sequence encoding all or a portion of such a polypeptide and / or functional RNA species. It also is contemplated that a particular polypeptide and / or functional RNA species may be encoded by nucleic acids containing variations having slightly different nucleic acid sequences but, nonetheless, encode the same or substantially similar protein and / or RNA species.

[0213] In certain aspects, there are polynucleotide variants having substantial identity to the sequences disclosed herein; those comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or higher sequence identity, including all values and ranges there between, compared to a polynucleotide sequence provided herein using the methods known in the art and / or described herein (e.g., BLAST analysis using standard parameters). In certain aspects, the isolated polynucleotide will comprise a nucleotide sequence encoding a polypeptide and / or functional RNA species that has at least 90%, 95%, or above, identity to an amino acid sequence and / or RNA sequence described herein, over the entire length of the sequence; or a nucleotide sequence complementary to said isolated polynucleotide.

[0214] The recitations “sequence identity,” “percent identity,” or for example, “comprising a sequence 90% identical to” or “having at least 90% sequence identity to,” as used herein, refer tothe extent that sequences are identical on an amino acid-by-amino acid basis, or a nucleotide-by- nucleotide basis, or over a window of comparison. Thus, a “percentage of sequence identity” can be calculated by comparing two optimally aligned sequences (e.g., nucleic acid) over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U) or the identical amino acid residue (e.g., alanine (Ala), proline (Pro), serine (Ser), threonine (Thr), glycine (Gly), valine (Vai), leucine (Leu), isoleucine (He), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), asparagine (Asn), glutamine (Gin), cysteine (Cys), and methionine (Met)) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0215] Calculations of sequence similarity or sequence identity between sequences (the terms are used interchangeably herein) can be performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some aspects, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch, J. Mol. Biol.. 1970; 48: 444-453) algorithm, which has been incorporated into the GAP program in the GCG software package, using either a BLOSUM 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. 0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0216] Nucleic acid segments, regardless of the length of the coding sequence itself, may be combined with other nucleic acid sequences, such as promoters, polyadenylation signals, enhancers, destabilization sites, restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length may vary considerably. The nucleic acids can be any length. They can be, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 175, 200, 250, 300, 350, 400, 450, 500, 750, 1000, 1500, 3000, 5000 or more nucleotides in length, and / or can comprise one or more additional sequences, for example, regulatory sequences, and / or be a part of a larger nucleic acid, for example, a vector. It is therefore contemplated that a nucleic acid fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant nucleic acid protocol. In some cases, a nucleic acid sequence may encode a polypeptide sequence with additional heterologous coding sequences, for example to allow for purification of the polypeptide, transport, secretion,post-translational modification, or for therapeutic benefits such as targeting or efficacy. As discussed above, a tag or other heterologous polypeptide may be added to the modified polypeptide-encoding sequence, wherein “heterologous” refers to a polypeptide that is not the same as the modified polypeptide.

[0217] The term “amyloid-beta,” “amyloid-0,” “Abeta”, or “A0,” are used interchangeably and refer to all amyloid-0 peptides, which are a family of up to 43 amino acids in length found extracellularly after the cleavage of the amyloid precursor protein (APP). The term A0 is used to refer generally to the amyloid-0 peptides in any form. For example, an A0 peptide may be an “A01-42” peptide, which refers to a fragment corresponding to amino acids 1 to 42 of A0 (amino acids 597-638 of the APP sequence (Johnson-Wood et al (1997) PNAS 94, 1550-1555)), or an “A01-4O” refers to a fragment corresponding to amino acids 1 to 40 of A0 (amino acids 597-636 of the APP sequence). The term A0 may refer to an “A04O / 42” peptide which comprises both the A04O and A042 isoforms.

[0218] As used herein “astrocyte functionality” refers to any functions performed by astrocytes in the central nervous system. For example, astrocytes contribute to maintenance of the blood-brain barrier, phagocytosis, lactate shuttling, ion buffering, neurotransmitter uptake and recycling, metabolic processing, and regulation of synaptic activity or synaptic transmission. Also included are intrinsic astrocyte properties, such as for example, astrocyte morphology, polarization, contact with other cells or targets (e.g., vasculature or synapses), membrane potential, calcium fluctuations, calcium signaling, expression and release of gliotransmitters, and expression of transporters and receptors.

[0219] It is specifically contemplated that any limitation discussed with respect to one aspect of the invention may apply to any other aspect of the invention. Furthermore, any composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any composition of the invention. Aspects of an aspect set forth in the Examples are also aspects that may be implemented in the context of aspects discussed elsewhere in a different Example or elsewhere in the application, such as in the Summary, Detailed Description, Claims, and Brief Description of the Drawings.

[0220] A variety of aspects are discussed throughout this application. Any aspect discussed with respect to one aspect applies to other aspects as well and vice versa. Each aspect described herein is understood to be aspects that are applicable to all aspects. It is contemplated that any aspect discussed herein can be implemented with respect to any method or composition, and vice versa. Furthermore, compositions and kits can be used to achieve methods disclosed herein.

[0221] Any method in the context of a therapeutic, diagnostic, or physiologic purpose or effect may also be described in “use” claim language such as “use of’ any compound, composition, oragent discussed herein for achieving or implementing a described therapeutic, diagnostic, or physiologic purpose or effect.

[0222] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific aspects of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.I. Neurological disorders

[0223] In some aspects, technologies described herein are suitable for prevention of, treatment of, amelioration of symptoms associated with, delay the onset of, or reduce of risk of, one or more neurological disorders. In certain aspects, a neurological disorder is a central nervous system disorder (CNS). In certain aspects, a neurological disorder is a peripheral nervous system disorder (PNS). In some aspects, a neurological disorder can be at least in part characterized by aberrant or deficient glial cell (e.g., astrocyte, oligodendrocyte, and / or microglial cell) activation and / or phagocytosis.

[0224] In some aspects, comparisons between populations (e.g., cells, subjects, animals, treatment groups, etc. are relative to one or more appropriate control groups. One skilled in the art will recognize appropriate control groups to which comparisons can be and / or are drawn.

[0225] In some aspects, the present disclosure provides technologies suitable for treatment of a CNS disease, wherein said CNS disease is a CNS infectious disease, a CNS degenerative disease, a CNS auto-immune disease, a CNS tumor disease, a CNS genetic disease, a cerebrovascular disease, a CNS injury, and / or a CNS structural defect. In some aspects, a CNS disease is not a CNS infectious disease, a CNS degenerative disease, a CNS auto-immune disease, a CNS tumor disease, a CNS genetic disease, a cerebrovascular disease, a CNS injury, and / or a CNS structural defect.

[0226] In certain aspects, the present disclosure provides technologies suitable for modification (e.g., promotion or inhibition) of glial NFIA, SOX9, A2M, and / or MEGF10 gene activity. In certain aspects, the present disclosure provides technologies suitable for promotion of glial NFIA, SOX9, A2M, and / or MEGF10 gene activity. In certain aspects, the present disclosure provides technologies suitable for modification (e.g., promotion or inhibition) of astrocyte NFIA, SOX9, A2M, and / or MEGF10 gene activity. In certain aspects, the present disclosure provides technologies suitable for promotion of astrocyte NFIA, SOX9, A2M, and / or MEGF10 gene activity.

[0227] In certain aspects, the present disclosure provides technologies suitable for modification (e.g., promotion or inhibition) of glial NFIA, SOX9, A2M, and / or MEGF10 protein levels. In certain aspects, the present disclosure provides technologies suitable for promotion of glial NFIA, SOX9, A2M, and / or MEGF10 protein levels. In certain aspects, the present disclosure provides technologies suitable for modification (e.g., promotion or inhibition) of astrocytic NFIA, SOX9, A2M, and / or MEGF10 protein levels. In certain aspects, the present disclosure provides technologies suitable for promotion of astrocytic NFIA, SOX9, A2M, and / or MEGF10 protein levels.

[0228] In certain aspects, the present disclosure provides technologies suitable for modification (e.g., promotion or inhibition) of glial NFIA, SOX9, A2M, and / or MEGF10 protein activity. In certain aspects, the present disclosure provides technologies suitable for promotion of glial NFIA, SOX9, A2M, and / or MEGF10 protein activity. In certain aspects, the present disclosure provides technologies suitable for modification (e.g., promotion or inhibition) of astrocytic NFIA, SOX9, A2M, and / or MEGF10 protein activity. In certain aspects, the present disclosure provides technologies suitable for promotion of astrocytic NFIA, SOX9, A2M, and / or MEGF10 protein activity.

[0229] In certain aspects, the present disclosure provides technologies suitable for promotion of glial NFIA, SOX9, A2M, and / or MEGF10 gene and / or protein activity, such as but not limited to, increased expressed, hyperactivity, and / or relief of inhibition. In certain aspects, the present disclosure provides technologies suitable for promotion of astrocytic NFIA, SOX9, A2M, and / or MEGF10 gene and / or protein activity, such as but not limited to, increased expressed, hyperactivity, and / or relief of inhibition.

[0230] In certain aspects, the present disclosure provides technologies suitable for neuronal population stabilization and / or retention via NFIA, SOX9, A2M, and / or MEGF 10 promotion (e.g., transcriptional upregulation, translational upregulation, protein stabilization, protein activation, etc.). In some aspects, methods and compositions provided herein comprising NFIA, SOX9, A2M, and / or MEGF10 modulation results in marked changes in accumulation of CNS plaques, such as Ap plaque formation and / or retention. In some aspects, methods and compositions provided herein comprising NFIA, SOX9, A2M, and / or MEGF 10 modulation provide improved cognitive capacity (e.g., memory, learning, language, motor control, visuospatial skills, etc.). In some aspects, methods and compositions provided herein comprising NFIA, SOX9, A2M, and / or MEGF 10 modulation provide improved neuronal survival. In some aspects, methods and compositions provided herein facilitate reduction of CNS plaque levels.

[0231] In some aspects, the present disclosure provides technologies for improving one or more characteristic of cognitive capacity in a subject by greater than, at least, or equal to a fold-change of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 fold, or greater than 10 fold, or any range derivable therein, relative to a subject that was not treated with technologies provided herein or was treated with a control.

[0232] In some aspects, the present disclosure provides technologies for improving neuronal survival in a subject by greater than or equal to, or at least a fold-change of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0,8.5, 9.0, 9.5, or 10 fold, or greater than 10 fold, or any range derivable therein, relative to a subject that was not treated with technologies provided herein or was treated with a control.

[0233] In some aspects, the present disclosure provides technologies for reducing the level of CNS plaques in a subject by greater than or equal to, or at least a fold-change of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 fold, or greater than 10 fold, or any range derivable therein, relative to a subject that was not treated with technologies provided herein or was treated with a control.

[0234] In certain aspects, the present disclosure provides technologies suitable for generating marked changes in astrocyte functionality, such as increased astrocyte phagocytosis, increased astrocyte intracellular degradation / clearance of plaques, and / or increased astrocyte morphological complexity (e.g., Scholl scores).

[0235] In some aspects, the present disclosure provides technologies for increasing astrocyte phagocytosis of plaques in a subject by greater than or equal to, or at least a fold-change of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 fold, or greater than 10 fold, or any range derivable therein, relative to a subject that was not treated with technologies provided herein or was treated with a control.

[0236] In some aspects, the present disclosure provides technologies for increasing astrocyte intracellular degradation / clearance of plaques in a subject by greater than or equal to, or at least a fold-change of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0,4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 fold, or greater than 10 fold, or any range derivable therein, relative to a subject that was not treated with technologies provided herein or was treated with a control.

[0237] In some aspects, the present disclosure provides technologies for increasing astrocyte Scholl scores in a subject by greater than or equal to, or at least a fold-change of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 fold, or greater than 10 fold, or any range derivable therein, relative to a subject that was not treated with technologies provided herein or was treated with a control.

[0238] In some aspects, a neurological disorder is characterized in part by neurodegeneration. Increasing evidence demonstrates the importance of neuronal loss, synapse dysfunction, and / or synapse loss in several neurodegenerative disorders (e.g., major depressive disorder (MDD), schizophrenia, Alzheimer’s disease, Huntington disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), demyelinating diseases (e.g., Multiple Sclerosis (MS)), aging, etc.).

[0239] In some aspects, a neurological disorder suitable for treatment, prevention, delaying the onset of, and / or ameliorating the symptoms of includes but is not limited to: Alzheimer’s disease, Huntington disease, Parkinson’s disease, frontal -temporal dementia, amyotrophic lateral sclerosis (ALS), Pick disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, corticobasal syndrome, Richardson syndrome, pure akinesia with gait freezing, cerebellar ataxia, vanishing white matter (VWM) disease, autism spectrum disorders (ASDs), down syndrome, hyperekplexia, stroke, traumatic brain injury, epilepsy, other developmental neurological disorders (e.g., applicable rare but impactful neurological diseases, e.g., applicable diseases described by the National Institute of Neurological Disorders and Stroke), and / or aging-related cognitive decline. In some aspects, a neurological disorder does not comprise Alzheimer’s disease, Huntington disease, Parkinson’s disease, frontal -temporal dementia, amyotrophic lateral sclerosis (ALS), major depressive disorder, schizophrenia, multiple sclerosis, Pick disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, corticobasal syndrome, Richardson syndrome, pure akinesia with gait freezing, cerebellar ataxia, vanishing white matter (VWM) disease, autism spectrum disorders (ASDs), down syndrome, hyperekplexia, stroke, traumatic brain injury, epilepsy, other developmental neurological disorders (e.g., applicable rare but impactful neurological diseases, e.g., applicable diseases described by the National Institute of Neurological Disorders and Stroke), and / or aging-related cognitive decline.

[0240] In some aspects, a neurological disorder is Alzheimer’s disease. In some aspects, a neurological disorder is Huntington disease. In some aspects, a neurological disorder is Parkinson’s disease. In some aspects, a neurological disorder is frontal -temporal dementia. In some aspects, a neurological disorder is CTE. In some aspects, a neurological disorder is ageing- related cognitive decline.

[0241] In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated, and / or is treated using teachings described herein is Major Depressive Disorder. In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated,and / or is treated using teachings described herein is Schizophrenia. In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated, and / or is treated using teachings described herein is Alzheimer’s disease. In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated, and / or is treated using teachings described herein is Huntington disease. In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated, and / or is treated using teachings described herein is Parkinson’s disease. In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated, and / or is treated using teachings described herein is Amyotrophic lateral sclerosis. In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated, and / or is treated using teachings described herein is a demyelination disorder (e.g., Multiple Sclerosis).

[0242] In some aspects, a disorder that is reduced in likelihood, is prevented, has its symptoms ameliorated, and / or is treated using teachings described herein is aging. In some aspects, aging is considered broadly, and encompasses age related neurodegeneration that occurs any time after development has ceased, e.g., any time after the age of 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or above, or any value therebetween. In certain aspects, aging related neurodegeneration is that which occurs in individuals older than 60, 65, or 70.

[0243] In some aspects, a neurological disorder is characterized in part by aberrant microglial mediated phagocytosis and related synaptic abnormalities. Increasing evidence demonstrates the importance of synapse dysfunction as a major determinant of several neurodevel opmental diseases (e.g., autism spectrum disorders (ASDs), Down syndrome, Hyperekplexia (startle disease), epilepsy, other developmental neurological disorders (e.g., applicable rare but impactful neurological diseases, e.g., applicable diseases described by the National Institute of Neurological Disorders and Stroke), etc.). In some aspects, a disorder that is reduced in likelihood, is prevented, has it’s symptoms ameliorated, and / or is treated using teachings described herein are ASDs. In some aspects, a disorder that is reduced in likelihood, is prevented, has it’s symptoms ameliorated, and / or is treated using teachings described herein is Down Syndrome. In some aspects, a disorder that is reduced in likelihood, is prevented, has it’s symptoms ameliorated, and / or is treated using teachings described herein is Hyperekplexia. In some aspects, a disorder that is reduced in likelihood, is prevented, has it’s symptoms ameliorated, and / or is treated using teachings described herein is epilepsy. In some aspects, a disorder that is reduced in likelihood, is prevented, has it’s symptoms ameliorated, and / or is treated using teachings described herein is a developmental neurological disorders (e.g., applicable rare but impactful neurological diseases, e.g., applicable diseases described by the National Institute of Neurological Disorders and Stroke).A. Alzheimer’s Disease Diagnosis

[0244] As used herein, “diagnosing” or “identifying a patient or subject having Alzheimer's disease” refers to a process of determining if an individual is afflicted with Alzheimer's disease or a stage that progresses to Alzheimer's disease. A diagnosis of Alzheimer's disease may be based on neuropsychological diagnosis, including cognitive tests, genetic tests, and / or biochemical tests. An individual of “possible” or “probable” diagnosis may be considered as an individual afflicted with AD.

[0245] Neurocognitive evaluation for diagnosing or staging AD are known in the art and include, for example, the National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association criteria. Other methods include those developed by Dubois et al. 2007 Lancet Neurol 6: 734-746; Albert et al. 2011 Alzheimers Dement 7: 270-279; McKhann et al. 2011 Alzheimers Dement 7: 263-269; Sperling et al. 2011 Alzheimers Dement 7: 280-292; and / or US11179375B2 issued on 23 November 2021, all of which are incorporate herein by reference in their entirety.

[0246] AD disease diagnosis may be solely determined or supplemented by imaging techniques. Suitable imaging technologies include computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and / or positron emission tomography (PET). These imaging procedures can be used to detect atrophy in the central nervous system and / or detect molecules, such as aggregated molecules.

[0247] Radiopharmaceutical diagnosis, which utilizes radioactive isotopes to detect features or molecules in the body, can be used to detect molecules associated with AD. Florbetapir (AMYVID®), Flutemetamol (VIZAMYL®), and Florbetaben (NEURACEQ®) bind to Ap and can be used to detect Ap deposits or aggregates in the central nervous system. Flortaucipir (TAUVID®) binds to tau and can be used to detect neurofibrillary tangles in the central nervous system. Detection of Ap deposits or aggregates using radioisotopes may be used alone or in combination with other diagnostic methods to diagnose AD in an individual. Detection of the amount and / or location of Ap deposits or aggregates using radioisotopes may be considered in the diagnosis. Ap deposits or aggregates may be measured overtime to track AD progression in an individual before, after, or during treatment.

[0248] Any other methods know in the art to measure Ap levels or aggregates may be used alone or in combination with other diagnostic methods to diagnose AD in an individual. In some aspects, Ad diagnosis comprises measuring the amount of Ap or Ap aggregates in a biological sample from an individual. Methods to measure Ap or Ap aggregates in a biological sample known to one of skill in the art include Misfolded Protein Assay (MPA) (Lau et al., 2007, PNAS, 104: 11551), ELISA, seeded multimerization, nanoparticle based detection, nanoscale optical biosensormethod, dual color FRET detection with flow cytometry, and dual color single aggregate FCS detection (Funke et al., Current Alzheimer Research, 2009, 6: 285-289). Illustrative reagents useful for obtaining a measurement or level of Ap aggregate include mAh 158 (Englund et al. J. Neurochem 2007, 103: 334-345) and antibodies described by Kayed et al. (Science, 2003, 300: 486-489 and Mol. Neurodegeneration, 2007, 2: 18), which bind specifically to Ap aggregates. Other antibodies known to those of skill in the art may also be used.

[0249] In some aspects, a first amount of Ap or Ap aggregates is determined and compared to a second amount of Ap or Ap aggregates that is determined. In some aspects, an amount of Ap or Ap aggregates in a first sample from an individual is compared to an amount of Ap or Ap aggregates in a second sample from the individual to determine changes in the amount of Ap or Ap aggregates in the individual. In some aspects, an amount of Ap or Ap aggregates is determined before or during treatment with compositions or methods of the disclosure. In some aspects, an amount of Ap or Ap aggregates is determined during or after treatment with compositions or methods of the disclosure. In some aspects, an amount of Ap or Ap aggregates is determined 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, months, and / or years, before, during, or after treatment with a composition or method of the disclosure. In some aspects, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more amounts of Ap or Ap aggregates are determined from the same individual. In some aspects, an amount of Ap or Ap aggregates is determined from a sample of an individual. In some aspects, a sample may comprise blood, plasma, cerebrospinal fluid, or a nervous system biopsy.II. Therapeutic compositions

[0250] In some aspects, provided herein are compositions and / or methods of use of said compositions suitable for modifying NFIA, SOX9, A2M, and / or MEGF10 gene activity in the nervous system. As used herein, “gene activity” refers to creation of transcriptional and / or translational products produced using the noted gene as a template. For example, NFIA, SOX9, A2M, and / or MEGF10 gene activity includes but is not limited to transcription of coding and / or non-coding transcript variants, transcription of intron and / or 5 ' or 3 ' untranslated region embedded regulatory elements, translation of an encoded transcript, etc. Additionally, for example, a gene activity modifier may include a transcriptional or translational inhibitor and / or promoter.

[0251] In some aspects, provided herein is the use of compositions and / or methods suitable for modifying NFIA, SOX9, A2M, and / or MEGF10 protein levels. In some aspects, compositions and / or methods are suitable for modifying NFIA, SOX9, A2M, and / or MEGF10 protein levelsspecifically in the nervous system. In some aspects, compositions and / or methods are suitable for modifying NFIA, SOX9, A2M, and / or MEGF10 protein levels specifically in astrocytes.

[0252] In some aspects, provided herein is the use of compositions and / or methods suitable for modifying NFIA, SOX9, A2M, and / or MEGF10 protein activity. In some aspects, compositions and / or methods are suitable for modifying NFIA, SOX9, A2M, and / or MEGF10 protein activity specifically in the nervous system. In some aspects, compositions and / or methods are suitable for modifying NFIA, SOX9, A2M, and / or MEGF10 protein activity specifically in astrocytes.

[0253] As described herein, the term “modifying” can include promotion or inhibition of the modified character. For example, a modifier may be described to either increase or decrease the level and / or activity of the modified character.

[0254] In some aspects, methods and compositions provided herein can delay the onset of hallmarks (e.g., cognitive decline, neuroinflammation, neuronal loss, plaque buildup, etc.) of a neurological disorder. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of a neurological disorder by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 months. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of a neurological disorder by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 years.

[0255] In some aspects, methods and compositions provided herein can delay the onset of hallmarks (e.g., cognitive decline, neuroinflammation, neuronal loss, plaque buildup, etc.) of Alzheimer’s disease. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of Alzheimer’s disease by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, or 50, or more than 50 months. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of Alzheimer’s disease by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 years.

[0256] In some aspects, methods and compositions provided herein can delay the onset of hallmarks (e.g., cognitive decline, neuroinflammation, neuronal loss, plaque buildup, etc.) of Parkinson’s disease. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of Parkinson’s disease by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, or 50, or more than 50 months. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of Parkinson’s disease by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 years.

[0257] In some aspects, methods and compositions provided herein can delay the onset of hallmarks (e.g., cognitive decline, neuroinflammation, neuronal loss, plaque buildup, etc.) of Huntington disease. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of Huntington disease by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 months. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of Huntington disease by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 years.

[0258] In some aspects, methods and compositions provided herein can delay the onset of hallmarks (e.g., cognitive decline, neuroinflammation, neuronal loss, plaque buildup, etc.) of frontal-temporal dementia. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of frontal-temporal dementia by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 months. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of frontal -temporal dementia by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 years.

[0259] In some aspects, methods and compositions provided herein can delay the onset of hallmarks (e.g., cognitive decline, neuroinflammation, neuronal loss, plaque buildup, etc.) of CTE. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of frontal-temporal dementia by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, or 50, or more than 50 months. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of CTE by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, or 50, or more than 50 years.

[0260] In some aspects, methods and compositions provided herein can delay the onset of hallmarks (e.g., cognitive decline, neuroinflammation, neuronal loss, plaque buildup, etc.) of aging related cognitive decline. In some aspects, methods and compositions provided herein can delaythe onset of hallmarks of frontal-temporal dementia by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 months. In some aspects, methods and compositions provided herein can delay the onset of hallmarks of aging related cognitive decline by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or more than 50 years.A. Inhibitory Oligonucleotides

[0261] In some aspects, disclosed are compositions and methods that relate to the use of inhibitory oligonucleotides that inhibit an inhibitor of gene expression of NFIA, SOX9, A2M, and / or MEGF 10 (e.g., said inhibitory oligonucleotide acts in a promotive manner for NFIA, SOX9, A2M, and / or MEGF 10 gene activity). In some aspects, such an inhibitory oligonucleotide specifically inhibits a negative regulator of NFIA, SOX9, A2M, and / or MEGF10 gene activity. In some aspects, such an inhibitory oligonucleotide specifically inhibits nuclear factor I B (NFIB, NF1-B, identified as US NIH National Library of Medicine NCBI Gene ID: 4781) and / or nuclear factor I X (NFIX, NF1-X, identified as US NIH National Library of Medicine NCBI Gene ID: 4784).

[0262] In some aspects, inhibitory oligonucleotides can include but is not limited to siRNA (small interfering RNA), short hairpin RNA (shRNA), double-stranded RNA, an antisense oligonucleotide (ASO), a ribozyme, and an oligonucleotide encoding any thereof. An inhibitory oligonucleotide may inhibit the transcription of a gene or prevent the translation of a gene transcript in a cell. An inhibitory oligonucleotide acid may be from 16 to 1000 nucleotides long, and in certain aspects from 18 to 100 nucleotides long. An inhibitory oligonucleotide may have at least or may have at most 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 50, 60, 70, 80, or 90 (or any range derivable therein) nucleotides. An inhibitory oligonucleotide may be DNA, RNA, or a cDNA that encodes an inhibitory RNA.

[0263] As used herein, “isolated” means altered or removed from the natural state through human intervention. For example, an siRNA naturally present in a living animal is not “isolated,” but a synthetic siRNA, or an siRNA partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated siRNA can exist in substantially purified form, or can exist in a non-native environment such as, for example, a cell into which the siRNA has been delivered.

[0264] Inhibitory oligonucleotides are well known in the art. For example, siRNA and doublestranded RNA have been described in U.S. Patents 6,506,559 and 6,573,099, as well as in U.S. Patent Publications 2003 / 0051263, 2003 / 0055020, 2004 / 0265839, 2002 / 0168707, 2003 / 0159161, and 2004 / 0064842, all of which are herein incorporated by reference in their entirety.

[0265] Particularly, in some aspects, an inhibitory oligonucleotide may be capable of decreasing the expression of a negative regulator of NFIA, SOX9, A2M, and / or MEGF10 by at least 10%, 20%, 30%, or 40%, more particularly by at least 50%, 60%, or 70%, and most particularly by at least 75%, 80%, 90%, 95%, 99%, or more, or any range or value in between the foregoing. Alternatively in other aspects, an inhibitory oligonucleotide may be capable of decreasing the expression of a NFIA, SOX9, A2M, and / or MEGF10 (e.g., neuronal NFIA, SOX9, A2M, and / or MEGF10) negative regulator by at least 10%, 20%, 30%, or 40%, more particularly by at least 50%, 60%, or 70%, and most particularly by at least 75%, 80%, 90%, 95%, 99%, or more, or any range or value in between the foregoing.

[0266] In some aspects, the oligonucleotide is, is at least, or at most 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100% identical or complementary to a region of any of SEQ ID NOs: 46. In some aspects, the region is a region having, having at least, or having at most 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides, or any range derivable therein, starting at any position of SEQ ID NO: 46. In some aspects, the oligonucleotide is, is at least, or at most 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100% identical or complementary to a genomic region and / or transcript of NFIB (NCBI Gene ID: 4781) and / or NFIX (NCBI Gene ID: 4784).

[0267] In further aspects, there are synthetic inhibitory oligonucleotides that are inhibitors of NFIA, SOX9, A2M, and / or MEGF 10 negative regulators.

[0268] An inhibitory oligonucleotide may be between 17 to 25 nucleotides in length and comprises a 5' to 3' sequence that is at least 90% complementary to the 5' to 3' sequence of a mature target mRNA. In certain aspects, an inhibitory oligonucleotide molecule is 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length, or any range derivable therein. Moreover, an inhibitory oligonucleotide molecule has a sequence (from 5' to 3') that is or is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 or 100% complementary, or any range derivable therein, to the 5' to 3' sequence of a mature target mRNA, particularly a mature, naturally occurring mRNA. One of skill in the art can use a portion of a probe sequence that iscomplementary to the sequence of a mature mRNA as the sequence for an mRNA inhibitor. Moreover, that portion of the probe sequence can be altered so that it is still 90% complementary to the sequence of a mature mRNA.

[0269] In some aspects, the inhibitory oligonucleotide is an analog and may include modifications, particularly modifications that increase nuclease resistance, improve binding affinity, and / or improve binding specificity. For example, when the sugar portion of a nucleoside or nucleotide is replaced by a carbocyclic moiety, it is no longer a sugar. Moreover, when other substitutions, such a substitution for the inter-sugar phosphodiester linkage are made, the resulting material is no longer a true species. All such compounds are considered to be analogs. Throughout this specification, reference to the sugar portion of a nucleic acid species shall be understood to refer to either a true sugar or to a species taking the structural place of the sugar of wild type nucleic acids. Moreover, reference to inter-sugar linkages shall be taken to include moieties serving to join the sugar or sugar analog portions in the fashion of wild type nucleic acids.

[0270] In some aspects, the present disclosure concerns modified oligonucleotides, e.g., oligonucleotide analogs or oligonucleosides, and methods for effecting the modifications. These modified oligonucleotides and oligonucleotide analogs may exhibit increased chemical and / or enzymatic stability relative to their naturally occurring counterparts. Extracellular and intracellular nucleases generally do not recognize and therefore do not bind to the backbone-modified compounds. When present as the protonated acid form, the lack of a negatively charged backbone may facilitate cellular penetration.

[0271] In some aspects, modified internucleoside linkages are intended to replace naturally- occurring phosphodiester-5 '-methylene linkages with four atom linking groups to confer nuclease resistance and enhanced cellular uptake to the resulting compound.

[0272] In some aspects, modifications may be achieved using solid supports which may be manually manipulated or used in conjunction with a DNA synthesizer using methodology commonly known to those skilled in DNA synthesizer art. Generally, as a non-limiting example, the procedure involves functionalizing the sugar moieties of two nucleosides which will be adjacent to one another in the selected sequence. In a 5' to 3' sense, an “upstream” synthon such as structure H is modified at its terminal 3' site, while a “downstream” synthon such as structure Hl is modified at its terminal 5' site.

[0273] In some aspects, oligonucleosides linked by hydrazines, hydroxylarnines, and other linking groups can be protected by a dimethoxytrityl group at the 5 '-hydroxyl and activated for coupling at the 3 '-hydroxyl with cyanoethyldiisopropyl-phosphite moieties. These compounds can be inserted into any desired sequence by standard, solid phase, automated DNA synthesis techniques. For example, one of the more popular processes is the phosphoramidite technique. Insome aspects, oligonucleotides containing a uniform backbone linkage can be synthesized by use of CPG-solid support and standard nucleic acid synthesizing machines such as Applied Biosystems Inc. 380B and 394 and Milligen / Biosearch 7500 and 8800s. For example, the initial nucleotide (number 1 at the 3 '-terminus) is attached to a solid support such as controlled pore glass. In sequence specific order, each new nucleotide is attached either by manual manipulation or by the automated synthesizer system.

[0274] In some aspects, free amino groups can be alkylated with, for example, acetone and sodium cyanoboro hydride in acetic acid. The alkylation step can be used to introduce other, useful, functional molecules on the macromolecule. Such useful functional molecules include but are not limited to reporter molecules, RNA cleaving groups, groups for improving the pharmacokinetic properties of an oligonucleotide, and groups for improving the pharmacodynamic properties of an oligonucleotide. Such molecules can be attached to or conjugated to the macromolecule via attachment to the nitrogen atom in the backbone linkage. Alternatively, such molecules can be attached to pendent groups extending from a hydroxyl group of the sugar moiety of one or more of the nucleotides. Examples of such other useful functional groups are provided by WO1993007883, which is herein incorporated by reference, and in other of the above-referenced patent applications.

[0275] Solid supports may include any of those known in the art for polynucleotide synthesis, including controlled pore glass (CPG), oxalyl controlled pore glass, TentaGel Support — an aminopolyethyleneglycol derivatized support or Poros — a copolymer of polystyrene / divinylbenzene. Attachment and cleavage of nucleotides and oligonucleotides can be effected via standard procedures. As used herein, the term solid support further includes any linkers (e.g., long chain alkyl amines and succinyl residues) used to bind a growing oligonucleoside to a stationary phase such as CPG. In some aspects, the oligonucleotide may be further defined as having one or more locked nucleotides, ethylene bridged nucleotides, peptide nucleic acids, or a 5'(E)-vinyl- phosphonate (VP) modification. In some aspects, an inhibitory oligonucleotide has one or more phosphorothioated DNA or RNA bases.B. Proteins and Polypeptides

[0276] In some aspects, disclosed herein are compositions and methods that relate to the use of proteins or polypeptides that modulate (e.g., inhibit or promote) activity and / or protein levels of NFIA, SOX9, A2M, and / or MEGF10. In some aspects, such a protein or polypeptide specifically promotes activity and / or protein levels or NFIA, SOX9, A2M, and / or MEGF10.

[0277] In some aspects, disclosed herein are compositions and methods that relate to the use of proteins or polypeptides that modulate (e.g., inhibit or promote) activity and / or protein levelsof a regulator of NFIA, SOX9, A2M, and / or MEGF10 protein activity and / or levels (e.g., said protein or polypeptide acts in a promotive manner for NFIA, SOX9, A2M, and / or MEGF 10 protein activity and / or levels). In some aspects, such proteins or polypeptides that modulate activity and / or protein levels of a regulator of NFIA, SOX9, A2M, and / or MEGF10.

[0278] In some aspects, disclosed herein are compositions and methods that relate to the use of proteins or polypeptides that act to promote activity and / or protein levels of NFIA, SOX9, A2M, and / or MEGF 10. In some aspects, such a protein or polypeptide specifically promotes activity and / or protein levels of neuronal NFIA, SOX9, A2M, and / or MEGF 10. In some aspects, such a protein or polypeptide specifically promotes activity and / or protein levels or astrocyte NFIA, SOX9, A2M, and / or MEGF 10.

[0279] As used herein, a “protein” or “polypeptide” refers to a molecule comprising at least five amino acid residues. As used herein, the term “wild-type” refers to the endogenous version of a molecule that occurs naturally in an organism. In some aspects, wild-type versions of a protein or polypeptide are employed, however, in many aspects of the disclosure, a modified protein or polypeptide is employed. The terms described above may be used interchangeably. A “modified protein” or “modified polypeptide” or a “variant” refers to a protein or polypeptide whose chemical structure, particularly its amino acid sequence, is altered with respect to the wild-type protein or polypeptide. In some aspects, a modified / variant protein or polypeptide has at least one modified activity or function (recognizing that proteins or polypeptides may have multiple activities or functions). It is specifically contemplated that a modified / variant protein or polypeptide may be altered with respect to one activity or function yet retain a wild-type activity or function in other respects, such as immunogenicity.

[0280] Where a protein is specifically mentioned herein, it is in general a reference to a native (wild-type) or recombinant (modified) protein or, optionally, a protein in which any signal sequence has been removed. The protein may be isolated directly from the organism of which it is native, produced by recombinant DNA / exogenous expression methods, or produced by solidphase peptide synthesis (SPPS) or other in vitro methods. In particular aspects, there are isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide (e.g., an antibody or fragment thereof). The term “recombinant” may be used in conjunction with a polypeptide or the name of a specific polypeptide, and this generally refers to a polypeptide produced from a nucleic acid molecule that has been manipulated in vitro or that is a replication product of such a molecule.

[0281] In some aspects, technologies provided herein comprise use of an anti-NFIA, SOX9, A2M, and / or MEGF 10 antibody. In some aspects, an anti-NFIA, SOX9, A2M, and / or MEGF 10 antibody can be an agonistic antibody. In some aspects, an anti-NFIA, SOX9, A2M, and / orMEGF10 antibody can be an antagonistic antibody. In some aspects, a protein or polypeptide is a mimetic, antagonist, and / or agonist of NFIA, SOX9, A2M, and / or MEGF10.

[0282] In certain aspects the size of a protein or polypeptide (wild-type or modified) may comprise, but is not limited to, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400, 1500, 1750, 2000, 2250, 2500 amino acid residues or greater, and any range derivable therein, or derivative of a corresponding amino sequence described or referenced herein. It is contemplated that polypeptides may be mutated by truncation, rendering them shorter than their corresponding wild-type form, also, they might be altered by fusing or conjugating a heterologous protein or polypeptide sequence with a particular function (e.g., for targeting or localization, for enhanced immunogenicity, for purification purposes, etc.). As used herein, the term “domain” refers to any distinct functional or structural unit of a protein or polypeptide, and generally refers to a sequence of amino acids with a structure or function recognizable by one skilled in the art.

[0283] The polypeptides, proteins, or polynucleotides encoding such polypeptides or proteins of the disclosure may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (or any derivable range therein) or more variant amino acids or nucleic acid substitutions or be at least 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any derivable range therein) similar, identical, or homologous with at least, or at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169,170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207,208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 300, 400, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700,2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300,4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900,6000, 6500, 7000, 7500, 8000, 8500, or 9000, or more contiguous amino acids or nucleic acids, or any range derivable therein, of any of SEQ ID NOs: 1-64.

[0284] In some aspects, the protein or polypeptide may comprise amino acids 1 to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107.108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126,127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164,165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183,184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240,241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259,260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278,279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316,317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335,336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354,355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373,374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392,393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411,412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430,431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449,450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468,469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487,488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506,507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525,526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544,545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563,564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582,583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601,602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620,621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639,640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658,659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677,678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696,697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715,716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734,735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753,754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772,773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791,792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810,811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829,830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848,849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867,868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886,887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905,906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924,925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943,944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962,963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981,982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016,1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032,1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048,1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064,1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080,1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096,1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112,1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128,1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144,1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160,1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176,1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192,1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208,1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224,1225, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240,1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256,1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272,1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288,1289, 1290, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304,1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320,1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336,1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348, 1349, 1350, 1351, 1352,1353, 1354, 1355, 1356, 1357, 1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368,1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384,1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400,1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416,1417, 1418, 1419, 1420, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432,1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448,1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464,1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480,1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1493, 1494, 1495, 1496,1497, 1498, 1499, 1500, 1501, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512,1513, 1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528,1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1538, 1539, 1540, 1541, 1542, 1543, 1544,1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560,1561, 1562, 1563, 1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576,1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588, 1589, 1590, 1591, 1592,1593, 1594, 1595, 1596, 1597, 1598, 1599, or 1600 (or any derivable range therein) of any of SEQ ID NOs: 6-10, 13-14, 19-22, or 26-28.

[0285] In some aspects, the protein, polypeptide, or nucleic acid may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127,, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146,, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165,, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184,, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203,, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222,, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260,, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279,, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298,, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317,, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336,, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355,, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374,, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393,, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412,, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431,, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450,, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469,, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488,, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507,, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526,, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545,, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564,, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583,, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602,, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621,, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640,, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659,, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678,, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697,, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716,, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735,, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754,, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773,, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792,793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811,812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830,831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849,850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868,869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887,888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906,907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925,926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944,945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963,964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982,983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700,2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300,4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900,6000, 6500, 7000, 7500, 8000, 8500, or 9000 (or any derivable range therein) or more contiguous amino acids or nucleic acids from any of SEQ ID NOs: 1-64.

[0286] In some aspects, the polypeptide, protein, or nucleic acid may comprise at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102,103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121,122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140,141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159,160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178,179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197,198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216,217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235,236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254,255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273,274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292,293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311,312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330,331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349,350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368,369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 29( )0, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700,3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6500, 7000, 7500, 8000, 8500, or 9000 (or any derivable range therein) contiguous amino acids or nucleic acids of any of SEQ ID NOs: 1-64 that are at least, at most, or exactly 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any derivable range therein) similar, identical, or homologous with one of any of SEQ ID NOs: 1-64.

[0287] In some aspects there is a nucleic acid molecule or polypeptide starting at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82.83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, IOC i, 101, 102, 103 , 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125,126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144,145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182,183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201,202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239,240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258,259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277,278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296,297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315,316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334,335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353,354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391,392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410,411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429,430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448,449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467,468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486,487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505,506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524,525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1420, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1493, 1494, 1495, 1496, 1497, 1498, 1499, 1500, 1501, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528, 1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1538, 1539, 1540, 1541, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561, 1562, 1563, 1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588, 1589, 1590, 1591, 1592, 1593, 1594, 1595, 1596, 1597, 1598, 1599, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6500, 7000, 7500 , 8000, 8500, or 9000 (or any value therebetween) of any of SEQ ID NOs: 1-64 and comprising at least, at most, or exactly 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110,1, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129,0, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,9, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167,8, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186,7, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205,6, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224,5, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243,4, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262,3, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281,2, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300,1, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319,0, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338,9, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357,8, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376,7, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395,6, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414,5, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433,4, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452,3, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471,2, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490,1, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509,0, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528,9, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547,8, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566,7, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585,6, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604,5, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623,4, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642,3, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661,2, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680,1, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699,0, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718,9, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737,8, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756,757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965966. 967. 968. 969. 970. 971. 972. 973. 974. 975. 976. 977. 978. 979. 980. 981. 982. 983. 984985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355,1356, 1357, 1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371,1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1387,1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1401, 1402, 1403,1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419,1420, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435,1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451,1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467,1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 1481, 1482, 1483,1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1493, 1494, 1495, 1496, 1497, 1498, 1499,1500, 1501, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1515,1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528, 1529, 1530, 1531,1532, 1533, 1534, 1535, 1536, 1537, 1538, 1539, 1540, 1541, 1542, 1543, 1544, 1545, 1546, 1547,1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561, 1562, 1563,1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1578, 1579,1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588, 1589, 1590, 1591, 1592, 1593, 1594, 1595,1596, 1597, 1598, 1599, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700,2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300,4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900,6000, 6500, 7000, 7500, 8000, 8500, or 9000 (or any derivable range therein) contiguous amino acids or nucleic acids of any of SEQ ID NOs: 1-64.

[0288] The nucleotide as well as the protein, polypeptide, and peptide sequences for various genes have been previously disclosed, and may be found in the recognized computerized databases. Two commonly used databases are the National Center for Biotechnology Information’ s Genbank and GenPept databases (on the World Wide Web at ncbi.nlm.nih.gov / ) and The Universal Protein Resource (UniProt; on the World Wide Web at uniprot.org). The coding regions for these genes may be amplified and / or expressed using the techniques disclosed herein or as would be known to those of ordinary skill in the art.

[0289] It is contemplated that in compositions of the disclosure, there can be between about 0.001 mg and about 10 mg of total polypeptide, peptide, and / or protein per ml. The concentration of protein in a composition can be about, at least about or at most about 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0 mg / ml or more (or any range derivable therein).

[0290] It is contemplated that in compositions of the disclosure, the concentration of oligonucleotide in a composition can be about, at least about or at most about 0.001, 0.010, 0.050,0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0 mg / ml or more (or any range derivable therein).

[0291] In some aspects, the amino acid subunits of a protein are modified to create an equivalent, or even improved, second-generation variant polypeptide or peptide. For example, certain amino acids may be substituted for other amino acids in a protein or polypeptide sequence with or without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies or binding sites on substrate molecules. Since it is the interactive capacity and nature of a protein that defines that protein’ s functional activity, certain amino acid substitutions can be made in a protein sequence and in its corresponding DNA coding sequence, and nevertheless produce a protein with similar or desirable properties. It is thus contemplated by the inventors that various changes may be made in the DNA sequences of genes which encode proteins without appreciable loss of their biological utility or activity.

[0292] The term “functionally equivalent codon” is used herein to refer to codons that encode the same amino acid, such as the six different codons for arginine. Also considered are “neutral substitutions” or “neutral mutations” which refers to a change in the codon or codons that encode biologically equivalent amino acids.

[0293] Amino acid sequence variants of the disclosure can be substitutional, insertional, or deletion variants. A variation in a polypeptide of the disclosure may affect 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more non-contiguous or contiguous amino acids of the protein or polypeptide, as compared to wild-type. A variant can comprise an amino acid sequence that is at least 50%, 60%, 70%, 80%, or 90%, including all values and ranges there between, identical to any sequence provided or referenced herein. A variant can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more substitute amino acids.

[0294] It also will be understood that amino acid and nucleic acid sequences may include additional residues, such as additional N- or C-terminal amino acids, or 5' or 3' sequences, respectively, and yet still be essentially identical as set forth in one of the sequences disclosed herein, so long as the sequence meets the criteria set forth above, including the maintenance of biological protein activity where protein expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences that may, for example, include various non-coding sequences flanking either of the 5' or 3' portions of the coding region.

[0295] Deletion variants typically lack one or more residues of the native or wild type protein. Individual residues can be deleted or a number of contiguous amino acids can be deleted. A stop codon may be introduced (by substitution or insertion) into an encoding nucleic acid sequence to generate a truncated protein.

[0296] Insertional mutants typically involve the addition of amino acid residues at a nonterminal point in the polypeptide. This may include the insertion of one or more amino acid residues. Terminal additions may also be generated and can include fusion proteins which are multimers or concatemers of one or more peptides or polypeptides described or referenced herein.

[0297] Substitutional variants typically contain the exchange of one amino acid for another at one or more sites within the protein or polypeptide, and may be designed to modulate one or more properties of the polypeptide, with or without the loss of other functions or properties. Substitutions may be conservative, that is, one amino acid is replaced with one of similar chemical properties. “Conservative amino acid substitutions” may involve exchange of a member of one amino acid class with another member of the same class. Conservative substitutions are well known in the art and include, for example, the changes of: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine. Conservative amino acid substitutions may encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics or other reversed or inverted forms of amino acid moieties.

[0298] Alternatively, substitutions may be “non-conservative”, such that a function or activity of the polypeptide is affected. Non-conservative changes typically involve substituting an amino acid residue with one that is chemically dissimilar, such as a polar or charged amino acid for a nonpolar or uncharged amino acid, and vice versa. Non-conservative substitutions may involve the exchange of a member of one of the amino acid classes for a member from another class.C. Vectors and Transgenes

[0299] In some aspects, disclosed herein are compositions and methods that relate to the use of vectors that modulate (e.g., promote or inhibit) gene activity, protein levels, and / or protein activity. In some aspects, disclosed herein are compositions and methods that utilize vectors that promote gene activity, protein levels, and / or the protein activity of NFIA, SOX9, A2M, and / or MEGF10. In some aspects, vectors modulate gene activity, protein levels, and / or protein activity in a cell specific manner. In some aspects, vectors modulate gene activity, protein levels, and / or protein activity in a neuron specific manner. In some aspects, vectors modulate gene activity, protein levels, and / or protein activity in an astrocyte specific manner. In some aspects, vectorsinhibit the gene activity, protein levels, and / or protein activity of negative regulators of NFIA, SOX9, A2M, and / or MEGF 10.

[0300] In some aspects, disclosed herein are compositions and methods that relate to the use of vectors that modulate gene activity, protein levels, and / or protein activity of NFIA, SOX9, A2M, and / or MEGF 10. In some aspects, disclosed herein are compositions and methods that relate to the use of vectors that promote gene activity, protein levels, and / or protein activity of NFIA, SOX9, A2M, and / or MEGF 10. In some aspects, vectors can modulate gene activity, protein levels, and / or protein activity of a regulator of NFIA, SOX9, A2M, and / or MEGF 10. In some aspects, vectors specifically promote gene activity, protein levels, and / or protein activity of astrocytic NFIA, SOX9, A2M, and / or MEGF 10.

[0301] In some aspects, a vector comprises a transgene. As used herein, a “transgene” is any exogenous oligonucleotide that acts as a template for transcription and / or translation of a functional product.Nuclear Factor I A (NFIA)

[0302] In some aspects, a protein, polypeptide, or oligonucleotide that is modified (including by activity and / or expression) according to the present disclosure is a Nuclear Factor I A (NFIA) gene product. As defined herein, a gene product is any molecule created using a noted gene as a template, e.g., a polypeptide fragment, a domain, a complete protein, a protein variant, a noncoding RNA, a regulatory RNA, an mRNA transcript, etc.

[0303] Nuclear Factor I A (NFIA; also known as CTF, NF1-A, NFI-A, NFI-L, BRMUTD, NF-I / A; and identified as US NIH National Library of Medicine NCBI Gene ID: 4774) is a member of the nuclear factor 1 (NF1) family of transcription factors, which function as cellular transcription factors and as replication factors for adenovirus type 2 DNA replication. NFIA has been described as functioning in astrocyte-mediated regulation of brain circuits and memory in the brain, and its expression has been reported to be elevated in reactive astrocytes associated with human Alzheimer’s Disease, although functional consequences associated therewith have hitherto not been characterized.

[0304] In certain aspects, provided herein are methods of treating a neurological disorder comprising engineered overexpression of NFIA in a subject in need thereof. In certain aspects, overexpression of NFIA in a subject in need thereof comprises, consists essentially of, or consists of overexpression of NFIA in astrocytes. In some aspects, a transgene comprises a sequence encoding a human NFIA transcript. In some aspects, a transgene comprises a sequence encoding a human NFIA polypeptide.

[0305] In some aspects, provided herein are constructs suitable for transgenic engineered over expression of NFIA. In some aspects, provided herein are polynucleotides encoding NFIA. Insome aspects, NFIA comprises, consists essentially of, or consists of a polynucleotide sequence and / or amino acid sequence that is, or is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein, identical to one or more of SEQ ID NOs: 1-10.SEQ ID NO: 1 - Mouse NFIA transcript variant 2 nucleic acid coding sequence -ATGTATTCTCCGCTCTGTCTCACCCAGGATGAGTTTCATCCTTTCATTGAAGCACTTCTGCCCC ATGTCCGCGCCTTCGCCTACACATGGTTCAACCTGCAGGCCCGAAAGCGGAAATACTTCAAAAA ACATGAGAAGCGCATGTCGAAAGAAGAGGAGAGGGCCGTGAAGGATGAACTGCTAAGCGAGAAG CCCGAGGTCAAGCAGAAGTGGGCTTCCCGACTTCTGGCCAAGTTACGGAAAGATATCCGACCCG AGTACCGAGAGGATTTTGTTCTTACAGTTACAGGGAAAAAACCTCCATGCTGTGTTCTTTCCAA CCCTGATCAGAAAGGCAAGATGCGGAGAATTGACTGCCTCCGCCAGGCAGATAAAGTATGGAGG TTGGACCTCGTCATGGTGATCTTGTTCAAAGGTATTCCGCTGGAAAGTACTGATGGCGAGCGCC TTGTAAAGAGTCCACAGTGCTCTAATCCAGGGCTCTGTGTCCAGCCCCATCACATAGGGGTTTC T GTAAAGGAAC T CGAT T TAT AT T T GGCATAC T T T GTACAT GCAGCAGAT T CAAGT CAAT C T GAA AGTCCCAGCCAGCCAAGTGAAGCTGACATTAAGGACCAGCCAGAAAATGGACATTTGGGCTTCC AG GAG AG C T T T G T GAG AT GAG G T G T T T T GAG T G T GAG T GAG C T AG T AAGAG T G T C AC AAAC AC C AATAGCTGCAGGAACCGGCCCCAATTTTTCTCTCTCTGATTTGGAAAGTTCTTCATACTACAGC ATGAGTCCAGGAGCAATGAGGAGGTCTCTGCCCAGCACATCCTCTACCAGCTCTACAAAGCGCC TCAAGTCTGTGGAGGATGAAATGGACAGTCCTGGTGAAGAACCATTTTACACAGGCCAAGGGCG CTCCCCAGGGAGTGGCAGCCAGTCCAGTGGATGGCATGAAGTAGAGCCAGGCTTGCCATCTCCA AGCACACTGAAGAAGTCTGAGAAGTCTGGTTTCAGCAGCCCCTCCCCTTCGCAGACCTCCTCCC TGGGAACAGCATTCACACAGCATCACCGACCTGTCATTACAGGACCCAGAGCAAGTCCACATGC GACGCCATCGACTCTCCACTTTCCAACGTCACCCATCATCCAGCAGCCTGGGCCTTACTTCTCA CACCCAGCCATCCGTTACCACCCTCAGGAGACGCTGAAAGAGTTTGTCCAACTTGTCTGTCCTG ATGCTGGTCAGCAAGCTGGACAGGTGGGGTTCCTCAATCCCAATGGAAGCAGTCAAGGCAAGGT GCACAACCCATTCCTCCCCACCCCAATGTTGCCGCCGCCGCCACCACCACCGATGGCCAGGCCT GTGCCTCTGCCCATGCCAGACACCAAGCCTCCAACCACATCAACAGAAGGAGGTGCAGCCTCCC CCACCTCACCGACCTACTCGACACCCAGCACCTCCCCCGCAAACCGATTCGTCAGTGTTGGACC ACGGGATCCAAGCTTTGTAAATATCCCTCAACAGACACAGTCCTGGTACCTGGGATAA ( SEQID NO : 1 )SEQ ID NO: 2 - Human NFIA transcript variant 1 (tvl) nucleic acid coding sequence -ATGTATTCTCCGCTCTGTCTCACCCAGGATGAATTTCATCCTTTCATCGAAGCACTTCTGCCCC ACGTCCGAGCCTTTGCCTACACATGGTTCAACCTGCAGGCCCGAAAACGAAAATACTTCAAAAA AC AT GAAAAG C G T AT G T C AAAAGAAGAAGAGAGAG C C G T GAAG GAT GAAT TGC T AAG T GAAAAA CCAGAGGTCAAGCAGAAGTGGGCATCTCGACTTCTGGCAAAGTTGCGGAAAGATATCCGACCCG AATATCGAGAGGATTTTGTTCTTACAGTTACAGGGAAAAAACCTCCATGTTGTGTTCTTTCCAA CCCAGACCAGAAAGGCAAGATGCGAAGAATTGACTGCCTCCGCCAGGCAGATAAAGTCTGGAGG TTGGACCTTGTTATGGTGATTTTGTTTAAAGGTATTCCGCTGGAAAGTACTGATGGCGAGCGCC TTGTAAAGTCCCCACAATGCTCTAATCCAGGGCTCTGTGTCCAACCCCATCACATAGGGGTTTC T GT TAAGGAAC T CGAT T TAT AT T T GGCATAC T T T GT GCAT GCAGCAGAT T CAAGT CAAT C T GAA AGTCCCAGCCAGCCAAGTGACGCTGACATTAAGGACCAGCCAGAAAATGGACATTTGGGCTTCC AG GAC AG T T T T G T C AC AT C AG GTGTTTTTAGTGT C AC T GAG C T AG T AAGAG T G T C AC AGAC AC C AATAGCTGCAGGAACTGGCCCAAATTTTTCTCTCTCAGATTTGGAAAGTTCTTCATACTACAGC ATGAGTCCAGGAGCAATGAGGAGGTCTTTACCCAGCACATCCTCTACGAGCTCCACAAAGCGCC TCAAGTCTGTGGAGGATGAAATGGACAGTCCTGGTGAGGAGCCATTTTATACAGGCCAAGGGCG CTCCCCAGGAAGTGGCAGTCAGTCAAGTGGATGGCATGAAGTGGAGCCAGGAATGCCATCTCCA ACCACACTGAAGAAGTCGGAGAAGTCTGGTTTCAGCAGCCCCTCCCCTTCACAGACCTCCTCCCTGGGAACGGCGTTCACACAGCATCACCGACCTGTCATTACAGGACCCAGAGCAAGTCCGCATGC AACACCATCGACTCTTCATTTCCCGACATCACCCATTATCCAGCAGCCTGGGCCTTACTTCTCA CACCCAGCCATCCGCTATCACCCTCAGGAGACGCTGAAAGAATTTGTCCAACTTGTCTGCCCTG ATGCTGGTCAGCAGGCTGGACAGGTGGGGTTCCTCAATCCCAATGGGAGCAGCCAAGGCAAGGT GCACAACCCATTCCTTCCCACCCCAATGTTGCCACCGCCACCGCCACCACCGATGGCCAGGCCT GTGCCTCTGCCGGTGCCAGACACAAAGCCTCCAACCACGTCAACAGAAGGAGGTGCAGCCTCCC CCACGTCACCAACCTACTCGACACCCAGCACCTCCCCCGCAAACCGATTCGTCAGTGTTGGACC ACGGGATCCAAGCTTTGTAAATATCCCTCAACAGACACAGTCCTGGTACCTGGGATAA ( SEQ ID NO : 2 )SEQ ID NO: 3 - Human NFIA transcript variant 2 (tv2) nucleic acid coding sequence -ATGTATTCTCCGCTCTGTCTCACCCAGGATGAATTTCATCCTTTCATCGAAGCACTTCTGCCCC ACGTCCGAGCCTTTGCCTACACATGGTTCAACCTGCAGGCCCGAAAACGAAAATACTTCAAAAA AC AT GAAAAG C G T AT G T C AAAAGAAGAAGAGAGAG C C G T GAAG GAT GAAT TGC T AAG T GAAAAA CCAGAGGTCAAGCAGAAGTGGGCATCTCGACTTCTGGCAAAGTTGCGGAAAGATATCCGACCCG AATATCGAGAGGATTTTGTTCTTACAGTTACAGGGAAAAAACCTCCATGTTGTGTTCTTTCCAA CCCAGACCAGAAAGGCAAGATGCGAAGAATTGACTGCCTCCGCCAGGCAGATAAAGTCTGGAGG TTGGACCTTGTTATGGTGATTTTGTTTAAAGGTATTCCGCTGGAAAGTACTGATGGCGAGCGCC TTGTAAAGTCCCCACAATGCTCTAATCCAGGGCTCTGTGTCCAACCCCATCACATAGGGGTTTC T GT TAAGGAAC T CGAT T TAT AT T T GGCATAC T T T GT GCAT GCAGCAGAT T CAAGT CAAT C T GAA AGTCCCAGCCAGCCAAGTGACGCTGACATTAAGGACCAGCCAGAAAATGGACATTTGGGCTTCC AG GAC AG T T T T G T C AC AT C AG GTGTTTTTAGTGT C AC T GAG C T AG T AAGAG T G T C AC AGAC AC C AATAGCTGCAGGAACTGGCCCAAATTTTTCTCTCTCAGATTTGGAAAGTTCTTCATACTACAGC ATGAGTCCAGGAGCAATGAGGAGGTCTTTACCCAGCACATCCTCTACGAGCTCCACAAAGCGCC TCAAGTCTGTGGAGGATGAAATGGACAGTCCTGGTGAGGAGCCATTTTATACAGGCCAAGGGCG CTCCCCAGGAAGTGGCAGTCAGTCAAGTGGATGGCATGAAGTGGAGCCAGGAATGCCATCTCCA ACCACACTGAAGAAGTCGGAGAAGTCTGGTTTCAGCAGCCCCTCCCCTTCACAGACCTCCTCCC TGGGAACGGCGTTCACACAGCATCACCGACCTGTCATTACAGGACCCAGAGCAAGTCCGCATGC AACACCATCGACTCTTCATTTCCCGACATCACCCATTATCCAGCAGCCTGGGCCTTACTTCTCA CACCCAGCCATCCGCTATCACCCTCAGGAGACGCTGAAAGAATTTGTCCAACTTGTCTGCCCTG ATGCTGGTCAGCAGGCTGGACAGGTGGGGTTCCTCAATCCCAATGGGAGCAGCCAAGGCAAGGT GCACAACCCATTCCTTCCCACCCCAATGTTGCCACCGCCACCGCCACCACCGATGGCCAGGCCT GTGCCTCTGCCGGTGCCAGACACAAAGCCTCCAACCACGTCAACAGAAGGAGGTGCAGCCTCCC CCACGTCACCAATCCTGGTACCTGGGATAAAAGTTGCAGCGTCCCACCATCCACCAGACAGACC ACCTGACCCCTTCTCAACTCTGTAA ( SEQ ID NO : 3 )SEQ ID NO: 4 - Human NFIA transcript variant 3 (tv3) nucleic acid coding sequence -ATGGATGAATTTCATCCTTTCATCGAAGCACTTCTGCCCCACGTCCGAGCCTTTGCCTACACAT GGTTCAACCTGCAGGCCCGAAAACGAAAATACTTCAAAAAACATGAAAAGCGTATGTCAAAAGA AGAAGAGAGAGCCGTGAAGGATGAATTGCTAAGTGAAAAACCAGAGGTCAAGCAGAAGTGGGCA TCTCGACTTCTGGCAAAGTTGCGGAAAGATATCCGACCCGAATATCGAGAGGATTTTGTTCTTA CAGTTACAGGGAAAAAACCTCCATGTTGTGTTCTTTCCAACCCAGACCAGAAAGGCAAGATGCG AAGAATTGACTGCCTCCGCCAGGCAGATAAAGTCTGGAGGTTGGACCTTGTTATGGTGATTTTG TTTAAAGGTATTCCGCTGGAAAGTACTGATGGCGAGCGCCTTGTAAAGTCCCCACAATGCTCTA ATCCAGGGCTCTGTGTCCAACCCCATCACATAGGGGTTTCTGTTAAGGAACTCGATTTATATTT GGCATACTTTGTGCATGCAGCAGATTCAAGTCAATCTGAAAGTCCCAGCCAGCCAAGTGACGCT GACATTAAGGACCAGCCAGAAAATGGACATTTGGGCTTCCAGGACAGTTTTGTCACATCAGGTG TTTTTAGTGTCACTGAGCTAGTAAGAGTGTCACAGACACCAATAGCTGCAGGAACTGGCCCAAA TTTTTCTCTCT CAGAT T T GGAAAGT T C T T CAT AC TACAGCAT GAGT CCAGGAGCAAT GAGGAGG TCTTTACCCAGCACATCCTCTACGAGCTCCACAAAGCGCCTCAAGTCTGTGGAGGATGAAATGG ACAGTCCTGGTGAGGAGCCATTTTATACAGGCCAAGGGCGCTCCCCAGGAAGTGGCAGTCAGTC AAGTGGATGGCATGAAGTGGAGCCAGGAATGCCATCTCCAACCACACTGAAGAAGTCGGAGAAGTCTGGTTTCAGCAGCCCCTCCCCTTCACAGACCTCCTCCCTGGGAACGGCGTTCACACAGCATC AC C GAG C T G T C AT TAG AG GAG C C AGAG C AAG T C C G C AT G C AAC AC CATC GAC TCTTCATTTCCC GACATCACCCATTATCCAGCAGCCTGGGCCTTACTTCTCACACCCAGCCATCCGCTATCACCCT CAGGAGACGCTGAAAGAATTTGTCCAACTTGTCTGCCCTGATGCTGGTCAGCAGGCTGGACAGG TGGGGTTCCTCAATCCCAATGGGAGCAGCCAAGGCAAGGTGCACAACCCATTCCTTCCCACCCC AATGTTGCCACCGCCACCGCCACCACCGATGGCCAGGCCTGTGCCTCTGCCGGTGCCAGACACA AAGCCTCCAACCACGTCAACAGAAGGAGGTGCAGCCTCCCCCACGTCACCAACCTACTCGACAC CCAGCACCTCCCCCGCAAACCGATTCGTCAGTGTTGGACCACGGGATCCAAGCTTTGTAAATAT CCCTCAACAGACACAGTCCTGGTACCTGGGATAA ( SEQ ID NO : 4 )SEQ ID NO: 5 - Human NFIA transcript variant 4 (tv4) nucleic acid coding sequence -ATGCAAATGTGCCGCCCGGCCTCCTCCTCGGTTCTCTACGTGCCCACGCGGTGGCCCGGGGGGT GCGGGGCAACCTGGCAAAGTTGCCCAAGTCCTCCACCGAGACGCACACGCATACCCCAGCGCCC GGCAGTTATGTATTCTCCGCTCTGTCTCACCCAGGATGAATTTCATCCTTTCATCGAAGCACTT CTGCCCCACGTCCGAGCCTTTGCCTACACATGGTTCAACCTGCAGGCCCGAAAACGAAAATACT T C AAAAAAC AT GAAAAG C G T AT G T C AAAAGAAGAAGAGAGAG C C G T GAAG GAT GAAT TGC T AAG TGAAAAACCAGAGGTCAAGCAGAAGTGGGCATCTCGACTTCTGGCAAAGTTGCGGAAAGATATC CGACCCGAATATCGAGAGGATTTTGTTCTTACAGTTACAGGGAAAAAACCTCCATGTTGTGTTC TTTCCAACCCAGACCAGAAAGGCAAGATGCGAAGAATTGACTGCCTCCGCCAGGCAGATAAAGT CTGGAGGTTGGACCTTGTTATGGTGATTTTGTTTAAAGGTATTCCGCTGGAAAGTACTGATGGC GAGCGCCTTGTAAAGTCCCCACAATGCTCTAATCCAGGGCTCTGTGTCCAACCCCATCACATAG GGGTTTCTGTTAAGGAACTCGATTTATATTTGGCATACTTTGTGCATGCAGCAGATTCAAGTCA ATCTGAAAGTCCCAGCCAGCCAAGTGACGCTGACATTAAGGACCAGCCAGAAAATGGACATTTG GGCTTCCAGGACAGTTTTGTCACATCAGGTGTTTTTAGTGTCACTGAGCTAGTAAGAGTGTCAC AGACACCAATAGC T GCAGGAAC T GGCCCAAAT T T T T C T C T C T CAGAT T T GGAAAGT T C T T CATA CTACAGCATGAGTCCAGGAGCAATGAGGAGGTCTTTACCCAGCACATCCTCTACGAGCTCCACA AAGCGCCTCAAGTCTGTGGAGGATGAAATGGACAGTCCTGGTGAGGAGCCATTTTATACAGGCC AAGGGCGCTCCCCAGGAAGTGGCAGTCAGTCAAGTGGATGGCATGAAGTGGAGCCAGGAATGCC ATCTCCAACCACACTGAAGAAGTCGGAGAAGTCTGGTTTCAGCAGCCCCTCCCCTTCACAGACC TCCTCCCTGGGAACGGCGTTCACACAGCATCACCGACCTGTCATTACAGGACCCAGAGCAAGTC CGCATGCAACACCATCGACTCTTCATTTCCCGACATCACCCATTATCCAGCAGCCTGGGCCTTA CTTCTCACACCCAGCCATCCGCTATCACCCTCAGGAGACGCTGAAAGAATTTGTCCAACTTGTC TGCCCTGATGCTGGTCAGCAGGCTGGACAGGTGGGGTTCCTCAATCCCAATGGGAGCAGCCAAG GCAAGGTGCACAACCCATTCCTTCCCACCCCAATGTTGCCACCGCCACCGCCACCACCGATGGC CAGGCCTGTGCCTCTGCCGGTGCCAGACACAAAGCCTCCAACCACGTCAACAGAAGGAGGTGCA GCCTCCCCCACGTCACCAACCTACTCGACACCCAGCACCTCCCCCGCAAACCGATTCGTCAGTG TTGGACCACGGGATCCAAGCTTTGTAAATATCCCTCAACAGACACAGTCCTGGTACCTGGGATA A ( SEQ ID NO : 5 )SEQ ID NO: 6 - Mouse NFIA isoform 2 amino acid sequence -MYSPLCLTQDEFHPFIEALLPHVRAFAYTWFNLQARKRKYFKKHEKRMSKEEERAVKDELLSEK PEVKQKWASRLLAKLRKDIRPEYREDFVLTVTGKKPPCCVLSNPDQKGKMRRIDCLRQADKVWR LDLVMVILFKGI PLESTDGERLVKSPQCSNPGLCVQPHHIGVSVKELDLYLAYFVHAADSSQSE SPSQPSEADIKDQPENGHLGFQDS FVTSGVFSVTELVRVSQTPIAAGTGPNFSLSDLESSSYYS MSPGAMRRSLPSTSSTSSTKRLKSVEDEMDSPGEEPFYTGQGRSPGSGSQSSGWHEVEPGLPSP STLKKSEKSGFSSPSPSQTSSLGTAFTQHHRPVI TGPRASPHATPSTLHFPTSPI IQQPGPYFS HPAIRYHPQETLKEFVQLVCPDAGQQAGQVGFLNPNGSSQGKVHNPFLPTPMLPPPPPPPMARP VPLPMPDTKPPTTSTEGGAASPTSPTYSTPSTSPANRFVSVGPRDPS FVNI PQQTQSWYLG ( SEQ ID NO : 6 )SEQ ID NO: 7 - Human NFIA isoform 1 amino acid sequence -MYSPLCLTQDEFHPFIEALLPHVRAFAYTWFNLQARKRKYFKKHEKRMSKEEERAVKDELLSEK PEVKQKWASRLLAKLRKDIRPEYREDFVLTVTGKKPPCCVLSNPDQKGKMRRIDCLRQADKVWR LDLVMVILFKGIPLESTDGERLVKSPQCSNPGLCVQPHHIGVSVKELDLYLAYFVHAADSSQSE SPSQPSDADIKDQPENGHLGFQDSFVTSGVFSVTELVRVSQTPIAAGTGPNFSLSDLESSSYYS MSPGAMRRSLPSTSSTSSTKRLKSVEDEMDSPGEEPFYTGQGRSPGSGSQSSGWHEVEPGMPSP TTLKKSEKSGFSSPSPSQTSSLGTAFTQHHRPVITGPRASPHATPSTLHFPTSPI IQQPGPYFSHPAIRYHPQETLKEFVQLVCPDAGQQAGQVGFLNPNGSSQGKVHNPFLPTPMLPPPPPPPMARP VPLPVPDTKPPTTSTEGGAASPTSPTYSTPSTSPANRFVSVGPRDPSFVNIPQQTQSWYLG( SEQ ID NO : 7 )SEQ ID NO: 8 - Human NFIA isoform 2 amino acid sequence -MYSPLCLTQDEFHPFIEALLPHVRAFAYTWFNLQARKRKYFKKHEKRMSKEEERAVKDELLSEK PEVKQKWASRLLAKLRKDIRPEYREDFVLTVTGKKPPCCVLSNPDQKGKMRRIDCLRQADKVWR LDLVMVILFKGIPLESTDGERLVKSPQCSNPGLCVQPHHIGVSVKELDLYLAYFVHAADSSQSE SPSQPSDADIKDQPENGHLGFQDSFVTSGVFSVTELVRVSQTPIAAGTGPNFSLSDLESSSYYS MSPGAMRRSLPSTSSTSSTKRLKSVEDEMDSPGEEPFYTGQGRSPGSGSQSSGWHEVEPGMPSP TTLKKSEKSGFSSPSPSQTSSLGTAFTQHHRPVITGPRASPHATPSTLHFPTSPI IQQPGPYFSHPAIRYHPQETLKEFVQLVCPDAGQQAGQVGFLNPNGSSQGKVHNPFLPTPMLPPPPPPPMARP VPLPVPDTKPPTTSTEGGAASPTSPILVPGIKVAASHHPPDRPPDPFSTL ( SEQ ID NO : 8 )SEQ ID NO: 9 - Human NFIA isoform 3 amino acid sequence -MDEFHPFIEALLPHVRAFAYTWFNLQARKRKYFKKHEKRMSKEEERAVKDELLSEKPEVKQKWA SRLLAKLRKDIRPEYREDFVLTVTGKKPPCCVLSNPDQKGKMRRIDCLRQADKVWRLDLVMVIL FKGIPLESTDGERLVKSPQCSNPGLCVQPHHIGVSVKELDLYLAYFVHAADSSQSESPSQPSDA DIKDQPENGHLGFQDSFVTSGVFSVTELVRVSQTPIAAGTGPNFSLSDLESSSYYSMSPGAMRR SLPSTSSTSSTKRLKSVEDEMDSPGEEPFYTGQGRSPGSGSQSSGWHEVEPGMPSPTTLKKSEK SGFSSPSPSQTSSLGTAFTQHHRPVITGPRASPHATPSTLHFPTSPI IQQPGPYFSHPAIRYHPQETLKEFVQLVCPDAGQQAGQVGFLNPNGSSQGKVHNPFLPTPMLPPPPPPPMARPVPLPVPDT KPPTTSTEGGAASPTSPTYSTPSTSPANRFVSVGPRDPSFVNIPQQTQSWYLG ( SEQ ID NO : 9 )SEQ ID NO: 10 - Human NFIA isoform 4 amino acid sequence -MQMCRPASSSVLYVPTRWPGGCGATWQSCPSPPPRRTRIPQRPAVMYSPLCLTQDEFHPFIEAL LPHVRAFAYTWFNLQARKRKYFKKHEKRMSKEEERAVKDELLSEKPEVKQKWASRLLAKLRKDI RPEYREDFVLTVTGKKPPCCVLSNPDQKGKMRRIDCLRQADKVWRLDLVMVILFKGIPLESTDG ERLVKSPQCSNPGLCVQPHHIGVSVKELDLYLAYFVHAADSSQSESPSQPSDADIKDQPENGHL GFQDSFVTSGVFSVTELVRVSQTPIAAGTGPNFSLSDLESSSYYSMSPGAMRRSLPSTSSTSST KRLKSVEDEMDSPGEEPFYTGQGRSPGSGSQSSGWHEVEPGMPSPTTLKKSEKSGFSSPSPSQT SSLGTAFTQHHRPVITGPRASPHATPSTLHFPTSPI IQQPGPYFSHPAIRYHPQETLKEFVQLVCPDAGQQAGQVGFLNPNGSSQGKVHNPFLPTPMLPPPPPPPMARPVPLPVPDTKPPTTSTEGGA ASPTSPTYSTPSTSPANRFVSVGPRDPSFVNIPQQTQSWYLG ( SEQ ID NO : 10 )SRY-box Transcription Factor 9 (SOX9)

[0306] In some aspects, a protein, polypeptide, or oligonucleotide that is modified (including by activity and / or expression) according to the present disclosure is a SRY-box Transcription Factor 9 (SOX9) gene product.

[0307] SRY-box Transcription Factor 9 (SOX9; also known as CMD1, SRA1, CMPD1, SRXX2, SRXY10; and identified as US NIH National Library of Medicine NCBI Gene ID: 6662) is a member of the HMG-box class of DNA-binding proteins, and recognizes the CCTTGAG sequence. SOX9 has been suggested as a mediator of astrocyte differentiation and maturation, and has been implicated in AD, although functional consequences associated therewith have hitherto not been characterized.

[0308] In certain aspects, provided herein are methods of treating a neurological disorder comprising engineered overexpression of SOX9 in a subject in need thereof. In certain aspects, overexpression of SOX9 in a subject in need thereof comprises, consists essentially of, or consists of overexpression of SOX9 in astrocytes. In some aspects, a transgene comprises a sequence encoding a human SOX9 transcript. In some aspects, a transgene comprises a sequence encoding a human SOX9 polypeptide.

[0309] In some aspects, provided herein are constructs suitable for transgenic engineered over expression of SOX9. In some aspects, provided herein are polynucleotides encoding SOX9. In some aspects, SOX9 comprises, consists essentially of, or consists of a polynucleotide sequence and / or amino acid sequence that is, or is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein, identical to one or more of SEQ ID NOs: 11-14.SEQ ID NO: 11 - Mouse SOX9 nucleic acid coding sequence -ATGAATCTCCTGGACCCCTTCATGAAGATGACCGACGAGCAGGAGAAGGGCCTGTCTGGCGCCC CCAGCCCCACCATGTCGGAGGACTCGGCTGGTTCGCCCTGTCCCTCGGGCTCCGGCTCGGACAC GGAGAACACCCGGCCCCAGGAGAACACCTTCCCCAAGGGCGAGCCGGATCTGAAGAAGGAGAGC GAGGAAGATAAGTTCCCCGTGTGCATCCGCGAGGCGGTCAGCCAGGTGCTGAAGGGCTACGACT GGACGCTGGTGCCCATGCCCGTGCGCGTCAACGGCTCCAGCAAGAACAAGCCACACGTCAAGCG ACCCATGAACGCCTTCATGGTGTGGGCGCAGGCTGCGCGCAGGAAGCTGGCAGACCAGTACCCG CATCTGCACAACGCGGAGCTCAGCAAGACTCTGGGCAAGCTCTGGAGGCTGCTGAACGAGAGCG AGAAGAGACCCTTCGTGGAGGAGGCGGAGCGGCTGCGCGTGCAGCACAAGAAAGACCACCCCGA TTACAAGTACCAGCCCCGGCGGAGGAAGTCGGTGAAGAACGGACAAGCGGAGGCCGAAGAGGCC ACGGAACAGACTCACATCTCTCCTAATGCTATCTTCAAGGCGCTGCAAGCCGACTCCCCACATT CCTCCTCCGGCATGAGTGAGGTGCACTCCCCGGGCGAGCACTCTGGGCAATCTCAGGGTCCGCC GACCCCACCCACCACTCCCAAAACCGACGTGCAAGCTGGCAAAGTTGATCTGAAGCGAGAGGGG CGCCCTCTGGCAGAGGGGGGCAGACAGCCCCCCATCGACTTCCGCGACGTGGACATCGGTGAAC TGAGCAGCGACGTCATCTCCAACATTGAGACCTTCGACGTCAATGAGTTTGACCAATACTTGCC ACCCAACGGCCACCCAGGGGTTCCGGCCACCCACGGCCAGGTCACCTACACTGGCAGTTACGGC ATCAGCAGCACCGCACCCACCCCTGCGACCGCGGGCCACGTGTGGATGTCGAAGCAGCAGGCGC CGCCCCCTCCTCCGCAGCAGCCTCCGCAGGCCCCGCAAGCCCCACAGGCGCCTCCGCAGCAGCA AGCACCCCCGCAGCAGCCGCAGGCACCCCAGCAGCAGCAGGCACACACGCTCACCACGCTGAGC AGCGAGCCAGGCCAGTCCCAGCGAACGCACATCAAGACGGAGCAGCTGAGCCCCAGCCACTACA GCGAGCAGCAGCAGCACTCCCCGCAACAGATCTCCTACAGCCCCTTCAACCTTCCTCACTACAG CCCCTCCTACCCGCCCATCACCCGCTCGCAATACGACTACGCTGACCATCAGAACTCCGGCTCC TACTACAGTCACGCAGCCGGCCAGGGCTCAGGGCTCTACTCCACCTTCACTTACATGAACCCCGCGCAGCGCCCCATGTACACCCCCATCGCTGACACCTCCGGGGTCCCTTCCATCCCGCAGACCCACAGCCCGCAGCACTGGGAACAACCAGTCTACACACAGCTCACCAGACCC ( SEQ ID NO : 11 )SEQ ID NO: 12 - Human SOX9 nucleic acid coding sequence -ATGAATCTCCTGGACCCCTTCATGAAGATGACCGACGAGCAGGAGAAGGGCCTGTCCGGCGCCC CCAGCCCCACCATGTCCGAGGACTCCGCGGGCTCGCCCTGCCCGTCGGGCTCCGGCTCGGACAC CGAGAACACGCGGCCCCAGGAGAACACGTTCCCCAAGGGCGAGCCCGATCTGAAGAAGGAGAGC GAGGAGGACAAGTTCCCCGTGTGCATCCGCGAGGCGGTCAGCCAGGTGCTCAAAGGCTACGACT GGACGCTGGTGCCCATGCCGGTGCGCGTCAACGGCTCCAGCAAGAACAAGCCGCACGTCAAGCG GCCCATGAACGCCTTCATGGTGTGGGCGCAGGCGGCGCGCAGGAAGCTCGCGGACCAGTACCCG CACTTGCACAACGCCGAGCTCAGCAAGACGCTGGGCAAGCTCTGGAGACTTCTGAACGAGAGCGAGAAGCGGCCCTTCGTGGAGGAGGCGGAGCGGCTGCGCGTGCAGCACAAGAAGGACCACCCGGA TTACAAGTACCAGCCGCGGCGGAGGAAGTCGGTGAAGAACGGGCAGGCGGAGGCAGAGGAGGCC ACGGAGCAGACGCACATCTCCCCCAACGCCATCTTCAAGGCGCTGCAGGCCGACTCGCCACACT CCTCCTCCGGCATGAGCGAGGTGCACTCCCCCGGCGAGCACTCGGGGCAATCCCAGGGCCCACC GACCCCACCCACCACCCCCAAAACCGACGTGCAGCCGGGCAAGGCTGACCTGAAGCGAGAGGGG CGCCCCTTGCCAGAGGGGGGCAGACAGCCCCCTATCGACTTCCGCGACGTGGACATCGGCGAGC TGAGCAGCGACGTCATCTCCAACATCGAGACCTTCGATGTCAACGAGTTTGACCAGTACCTGCC GCCCAACGGCCACCCGGGGGTGCCGGCCACGCACGGCCAGGTCACCTACACGGGCAGCTACGGC ATCAGCAGCACCGCGGCCACCCCGGCGAGCGCGGGCCACGTGTGGATGTCCAAGCAGCAGGCGC CGCCGCCACCCCCGCAGCAGCCCCCACAGGCCCCGCCGGCCCCGCAGGCGCCCCCGCAGCCGCA GGCGGCGCCCCCACAGCAGCCGGCGGCACCCCCGCAGCAGCCACAGGCGCACACGCTGACCACG CTGAGCAGCGAGCCGGGCCAGTCCCAGCGAACGCACATCAAGACGGAGCAGCTGAGCCCCAGCC ACTACAGCGAGCAGCAGCAGCACTCGCCCCAACAGATCGCCTACAGCCCCTTCAACCTCCCACACTACAGCCCCTCCTACCCGCCCATCACCCGCTCACAGTACGACTACACCGACCACCAGAACTCC AGCTCCTACTACAGCCACGCGGCAGGCCAGGGCACCGGCCTCTACTCCACCTTCACCTACATGA ACCCCGCTCAGCGCCCCATGTACACCCCCATCGCCGACACCTCTGGGGTCCCTTCCATCCCGCA GACCCACAGCCCCCAGCACTGGGAACAACCCGTCTACACACAGCTCACTCGACCTTGA ( SEQID NO : 12 )SEQ ID NO: 13 - Mouse SOX9 amino acid sequence -MNLLDPFMKMTDEQEKGLSGAPSPTMSEDSAGSPCPSGSGSDTENTRPQENTFPKGEPDLKKES EEDKFPVCIREAVSQVLKGYDWTLVPMPVRVNGSSKNKPHVKRPMNAFMVWAQAARRKLADQYP HLHNAELSKTLGKLWRLLNESEKRPFVEEAERLRVQHKKDHPDYKYQPRRRKSVKNGQAEAEEA TEQTHISPNAI FKALQADSPHSSSGMSEVHSPGEHSGQSQGPPTPPTTPKTDVQAGKVDLKREGRPLAEGGRQPPIDFRDVDIGELSSDVISNIETFDVNEFDQYLPPNGHPGVPATHGQVTYTGSYG ISSTAPTPATAGHVWMSKQQAPPPPPQQPPQAPQAPQAPPQQQAPPQQPQAPQQQQAHTLTTLS SEPGQSQRTHIKTEQLSPSHYSEQQQHSPQQISYSPFNLPHYSPSYPPITRSQYDYADHQNSGS YYSHAAGQGSGLYSTFTYMNPAQRPMYTPIADTSGVPS IPQTHSPQHWEQPVYTQLTRP ( SEQ ID NO : 13 )SEQ ID NO: 14 - Human SOX9 amino acid sequence -MNLLDPFMKMTDEQEKGLSGAPSPTMSEDSAGSPCPSGSGSDTENTRPQENTFPKGEPDLKKES EEDKFPVCIREAVSQVLKGYDWTLVPMPVRVNGSSKNKPHVKRPMNAFMVWAQAARRKLADQYP HLHNAELSKTLGKLWRLLNESEKRPFVEEAERLRVQHKKDHPDYKYQPRRRKSVKNGQAEAEEA TEQTHISPNAI FKALQADSPHSSSGMSEVHSPGEHSGQSQGPPTPPTTPKTDVQPGKADLKREGRPLPEGGRQPPIDFRDVDIGELSSDVISNIETFDVNEFDQYLPPNGHPGVPATHGQVTYTGSYG ISSTAATPASAGHVWMSKQQAPPPPPQQPPQAPPAPQAPPQPQAAPPQQPAAPPQQPQAHTLTT LSSEPGQSQRTHIKTEQLSPSHYSEQQQHSPQQIAYSPFNLPHYSPSYPPITRSQYDYTDHQNS SSYYSHAAGQGTGLYSTFTYMNPAQRPMYTPIADTSGVPS IPQTHSPQHWEQPVYTQLTRP ( SEQ ID NO : 14 )Alpha-2-Macroglobulin (A2M)

[0310] In some aspects, a protein, polypeptide, or oligonucleotide that is modified (including by activity and / or expression) according to the present disclosure is an alpha-2 -macroglobulin (A2M) gene product

[0311] alpha-2 -macroglobulin (A2M; also known as A2MD, CPAMD5, FWP007, S863-7; and identified as US NIH National Library of Medicine NCBI Gene ID: 2) is a protease inhibitor and cytokine transporter. A2M uses a bait-and-trap mechanism to inhibit a broad spectrum of proteases, including trypsin, thrombin, and collagenase, and can also disrupt inflammatory cascades by inhibiting inflammatory cytokines. A2M has been implicated in Alzheimer's disease (AD) due to its ability to mediate the clearance and degradation of A-beta.

[0312] In certain aspects, provided herein are methods of treating a neurological disorder comprising engineered overexpression of A2M in a subject in need thereof. In certain aspects, overexpression of A2M in a subject in need thereof comprises, consists essentially of, or consists of overexpression of A2M in astrocytes. In some aspects, a transgene comprises a sequence encoding a human A2M transcript. In some aspects, a transgene comprises a sequence encoding a human A2M polypeptide.

[0313] In some aspects, provided herein are constructs suitable for transgenic engineered over expression of A2M. In some aspects, provided herein are polynucleotides encoding A2M. In some aspects, A2M comprises, consists essentially of, or consists of a polynucleotide sequence and / or amino acid sequence that is, or is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein, identical to one or more of SEQ ID NOs: 15-22.SEQ ID NO: 15 - A2M nucleic acid coding sequence -ATGGGGAAGAACAAACTCCTTCATCCAAGTCTGGTTCTTCTCCTCTTGGTCCTCCTGCCCACAG ACGCCTCAGTCTCTGGAAAACCGCAGTATATGGTTCTGGTCCCCTCCCTGCTCCACACTGAGAC CACTGAGAAGGGCTGTGTCCTTCTGAGCTACCTGAATGAGACAGTGACTGTAAGTGCTTCCTTG GAGTCTGTCAGGGGAAACAGGAGCCTCTTCACTGACCTGGAGGCGGAGAATGACGTACTCCACT GTGTCGCCTTCGCTGTCCCAAAGTCTTCATCCAATGAGGAGGTAATGTTCCTCACTGTCCAAGT GAAAGGACCAACCCAAGAATTTAAGAAGCGGACCACAGTGATGGTTAAGAACGAGGACAGTCTG G T C T T T G T C C AGAC AGAC AAAT C AAT C T AC AAAC C AG G G C AGAC AG T GAAAT T T C G T G T T G T C T C CAT G GAT GAAAAC T T T C AC C C C C T GAAT GAG T T GAT T C C AC TAG TAT AC AT T C AG GAT C C C AA AGGAAATCGCATCGCACAATGGCAGAGTTTCCAGTTAGAGGGTGGCCTCAAGCAATTTTCTTTT CCCCTCTCATCAGAGCCCTTCCAGGGCTCCTACAAGGTGGTGGTACAGAAGAAATCAGGTGGAA G GAC AGAG C AC C C T T T C AC C G T G GAG GAAT T T G T T C T T C C C AAG T T T GAAG T AC AAG T AAC AG T G C C AAAGAT AAT C AC C AT C T T G GAAGAAGAGAT GAAT G T AT C AG TGTGTGGCC TAT AC AC AT ATGGGAAGCCTGTCCCTGGACATGTGACTGTGAGCATTTGCAGAAAGTATAGTGACGCTTCCGACT GCCACGGTGAAGATTCACAGGCTTTCTGTGAGAAATTCAGTGGACAGCTAAACAGCCATGGCTG CTTCTATCAGCAAGTAAAAACCAAGGTCTTCCAGCTGAAGAGGAAGGAGTATGAAATGAAACTTCACACTGAGGCCCAGATCCAAGAAGAAGGAACAGTGGTGGAATTGACTGGAAGGCAGTCCAGTG AAAT C AC AAGAAC C AT AAC C AAAC TCTCATTTGT GAAAG T G GAG T GAG AC T T T C GAC AG G GAAT TCCCTTCTTTGGGCAGGTGCGCCTAGTAGATGGGAAAGGCGTCCCTATACCAAATAAAGTCATA TTCATCAGAGGAAATGAAGCAAACTATTACTCCAATGCTACCACGGATGAGCATGGCCTTGTAC AGTTCTCTATCAACACCACCAATGTTATGGGTACCTCTCTTACTGTTAGGGTCAATTACAAGGA TCGTAGTCCCTGTTACGGCTACCAGTGGGTGTCAGAAGAACACGAAGAGGCACATCACACTGCT TATCTTGTGTTCTCCCCAAGCAAGAGCTTTGTCCACCTTGAGCCCATGTCTCATGAACTACCCT GTGGCCATACTCAGACAGTCCAGGCACATTATATTCTGAATGGAGGCACCCTGCTGGGGCTGAA GAAGCTCTCCTTCTATTATCTGATAATGGCAAAGGGAGGCATTGTCCGAACTGGGACTCATGGA CTGCTTGTGAAGCAGGAAGACATGAAGGGCCATTTTTCCATCTCAATCCCTGTGAAGTCAGACA TTGCTCCTGTCGCTCGGTTGCTCATCTATGCTGTTTTACCTACCGGGGACGTGATTGGGGATTC TGCAAAATATGATGTTGAAAATTGTCTGGCCAACAAGGTGGATTTGAGCTTCAGCCCATCACAA AGTCTCCCAGCCTCACACGCCCACCTGCGAGTCACAGCGGCTCCTCAGTCCGTCTGCGCCCTCC GTGCTGTGGACCAAAGCGTGCTGCTCATGAAGCCTGATGCTGAGCTCTCGGCGTCCTCGGTTTA CAACCTGCTACCAGAAAAGGACCTCACTGGCTTCCCTGGGCCTTTGAATGACCAGGACGATGAA GAC T G C AT C AAT CGTCATAATGTCTATATTAATG GAAT C AC AT AT AC T C C AG TAT C AAG T AC AA AT GAAAAGGATAT GTACAGC T T CC TAGAGGACAT GGGC T TAAAGGCAT T CACCAAC T CAAAGAT T C G T AAAC C C AAAAT G T G T C C AC AG C T T C AAC AG T AT GAAAT G C AT G GAC C T GAAG G T C T AC G T GTAGGTTTTTATGAGTCAGATGTAATGGGAAGAGGCCATGCACGCCTGGTGCATGTTGAAGAGC CTCACACGGAGACCGTACGAAAGTACTTCCCTGAGACATGGATCTGGGATTTGGTGGTGGTAAA CTCAGCAGGTGTGGCTGAGGTAGGAGTAACAGTCCCTGACACCATCACCGAGTGGAAGGCAGGG GCCTTCTGCCTGTCTGAAGATGCTGGACTTGGTATCTCTTCCACTGCCTCTCTCCGAGCCTTCC AGCCCTTCTTTGTGGAGCTCACAATGCCTTACTCTGTGATTCGTGGAGAGGCCTTCACACTCAA GGCCACGGTCCTAAACTACCTTCCCAAATGCATCCGGGTCAGTGTGCAGCTGGAAGCCTCTCCC GCCTTCCTAGCTGTCCCAGTGGAGAAGGAACAAGCGCCTCACTGCATCTGTGCAAACGGGCGGC AAACTGTGTCCTGGGCAGTAACCCCAAAGTCATTAGGAAATGTGAATTTCACTGTGAGCGCAGA GGCACTAGAGTCTCAAGAGCTGTGTGGGACTGAGGTGCCTTCAGTTCCTGAACACGGAAGGAAA GAC AC AG T C AT C AAG CCTCTGTTGGTT GAAC C T GAAG GAC T AGAGAAG GAAAC AAC AT T C AAC T CCCTACTTTGTCCATCAGGTGGTGAGGTTTCTGAAGAATTATCCCTGAAACTGCCACCAAATGT GGTAGAAGAATCTGCCCGAGCTTCTGTCTCAGTTTTGGGAGACATATTAGGCTCTGCCATGCAA AACACACAAAATCTTCTCCAGATGCCCTATGGCTGTGGAGAGCAGAATATGGTCCTCTTTGCTC C T AAC AT CTATGTACTGGATTATC T AAAT GAAAC AC AG C AG C T T AC T C C AGAGAT C AAG T C C AA GGCCATTGGCTATCTCAACACTGGTTACCAGAGACAGTTGAACTACAAACACTATGATGGCTCC TACAGCACCTTTGGGGAGCGATATGGCAGGAACCAGGGCAACACCTGGCTCACAGCCTTTGTTC TGAAGACTTTTGCCCAAGCTCGAGCCTACATCTTCATCGATGAAGCACACATTACCCAAGCCCT CATATGGCTCTCCCAGAGGCAGAAGGACAATGGCTGTTTCAGGAGCTCTGGGTCACTGCTCAAC AATGCCATAAAGGGAGGAGTAGAAGATGAAGTGACCCTCTCCGCCTATATCACCATCGCCCTTC TGGAGATTCCTCTCACAGTCACTCACCCTGTTGTCCGCAATGCCCTGTTTTGCCTGGAGTCAGC CTGGAAGACAGCACAAGAAGGGGACCATGGCAGCCATGTATATACCAAAGCACTGCTGGCCTAT GCTTTTGCCCTGGCAGGTAACCAGGACAAGAGGAAGGAAGTACTCAAGTCACTTAATGAGGAAG CTGTGAAGAAAGACAACTCTGTCCATTGGGAGCGCCCTCAGAAACCCAAGGCACCAGTGGGGCA TTTTTACGAACCCCAGGCTCCCTCTGCTGAGGTGGAGATGACATCCTATGTGCTCCTCGCTTAT CTCACGGCCCAGCCAGCCCCAACCTCGGAGGACCTGACCTCTGCAACCAACATCGTGAAGTGGA TCACGAAGCAGCAGAATGCCCAGGGCGGTTTCTCCTCCACCCAGGACACAGTGGTGGCTCTCCA TGCTCTGTCCAAATATGGAGCAGCCACATTTACCAGGACTGGGAAGGCTGCACAGGTGACTATC CAGTCTTCAGGGACATTTTCCAGCAAATTCCAAGTGGACAACAACAACCGCCTGTTACTGCAGC AGGTCTCATTGCCAGAGCTGCCTGGGGAATACAGCATGAAAGTGACAGGAGAAGGATGTGTCTA C C T C C AGAC AT C C T T GAAAT AC AAT AT T C T C C C AGAAAAG GAAGAG T T C C C C T T T G C T T T AG GA GTGCAGACTCTGCCTCAAACTTGTGATGAACCCAAAGCCCACACCAGCTTCCAAATCTCCCTAA GTGTCAGTTACACAGGGAGCCGCTCTGCCTCCAACATGGCGATCGTTGATGTGAAGATGGTCTC TGGCTTCATTCCCCTGAAGCCAACAGTGAAAATGCTTGAAAGATCTAACCATGTGAGCCGGACA GAAG T C AG C AG C AAC CATGTCTTGATTTACCTT GAT AAG G T G T C AAAT C AGAC AC T GAG C T T G T T C T T C AC G G T T C T G C AAGAT G T C C C AG T AAGAGAT C T GAAAC C AG C C AT AG T GAAAG T C T AT GATTACTACGAGACGGATGAGTTTGCAATTGCTGAGTACAATGCTCCTTGCAGCAAAGATCTTGGAAATGCTTGA ( SEQ ID NO : 15 )SEQ ID NO: 16 - Human A2M isoform A nucleic acid coding sequence -ATGGGGAAGAACAAACTCCTTCATCCAAGTCTGGTTCTTCTCCTCTTGGTCCTCCTGCCCACAG ACGCCTCAGTCTCTGGAAAACCGCAGTATATGGTTCTGGTCCCCTCCCTGCTCCACACTGAGAC CACTGAGAAGGGCTGTGTCCTTCTGAGCTACCTGAATGAGACAGTGACTGTAAGTGCTTCCTTG GAGTCTGTCAGGGGAAACAGGAGCCTCTTCACTGACCTGGAGGCGGAGAATGACGTACTCCACT GTGTCGCCTTCGCTGTCCCAAAGTCTTCATCCAATGAGGAGGTAATGTTCCTCACTGTCCAAGT GAAAGGACCAACCCAAGAATTTAAGAAGCGGACCACAGTGATGGTTAAGAACGAGGACAGTCTG G T C T T T G T C C AGAC AGAC AAAT C AAT C T AC AAAC C AG G G C AGAC AG T GAAAT T T C G T G T T G T C T C CAT G GAT GAAAAC T T T C AC C C C C T GAAT GAG T T GAT T C C AC TAG TAT AC AT T C AG GAT C C C AA AGGAAATCGCATCGCACAATGGCAGAGTTTCCAGTTAGAGGGTGGCCTCAAGCAATTTTCTTTT CCCCTCTCATCAGAGCCCTTCCAGGGCTCCTACAAGGTGGTGGTACAGAAGAAATCAGGTGGAA G GAC AGAG C AC C C T T T C AC C G T G GAG GAAT T T G T T C T T C C C AAG T T T GAAG T AC AAG T AAC AG T G C C AAAGAT AAT C AC C AT C T T G GAAGAAGAGAT GAAT G T AT C AG TGTGTGGCC TAT AC AC AT AT GGGAAGCCTGTCCCTGGACATGTGACTGTGAGCATTTGCAGAAAGTATAGTGACGCTTCCGACT GCCACGGTGAAGATTCACAGGCTTTCTGTGAGAAATTCAGTGGACAGCTAAACAGCCATGGCTG CTTCTATCAGCAAGTAAAAACCAAGGTCTTCCAGCTGAAGAGGAAGGAGTATGAAATGAAACTT CACACTGAGGCCCAGATCCAAGAAGAAGGAACAGTGGTGGAATTGACTGGAAGGCAGTCCAGTG AAAT C AC AAGAAC CAT AAC C AAAC TCTCATTTGT GAAAG T G GAC T C AC AC T T T C GAC AG G GAAT TCCCTTCTTTGGGCAGGTGCGCCTAGTAGATGGGAAAGGCGTCCCTATACCAAATAAAGTCATA TTCATCAGAGGAAATGAAGCAAACTATTACTCCAATGCTACCACGGATGAGCATGGCCTTGTAC AGTTCTCTATCAACACCACCAATGTTATGGGTACCTCTCTTACTGTTAGGGTCAATTACAAGGA TCGTAGTCCCTGTTACGGCTACCAGTGGGTGTCAGAAGAACACGAAGAGGCACATCACACTGCT TATCTTGTGTTCTCCCCAAGCAAGAGCTTTGTCCACCTTGAGCCCATGTCTCATGAACTACCCT GTGGCCATACTCAGACAGTCCAGGCACATTATATTCTGAATGGAGGCACCCTGCTGGGGCTGAA GAAGCTCTCCTTCTATTATCTGATAATGGCAAAGGGAGGCATTGTCCGAACTGGGACTCATGGA CTGCTTGTGAAGCAGGAAGACATGAAGGGCCATTTTTCCATCTCAATCCCTGTGAAGTCAGACA TTGCTCCTGTCGCTCGGTTGCTCATCTATGCTGTTTTACCTACCGGGGACGTGATTGGGGATTC TGCAAAATATGATGTTGAAAATTGTCTGGCCAACAAGGTGGATTTGAGCTTCAGCCCATCACAA AGTCTCCCAGCCTCACACGCCCACCTGCGAGTCACAGCGGCTCCTCAGTCCGTCTGCGCCCTCC GTGCTGTGGACCAAAGCGTGCTGCTCATGAAGCCTGATGCTGAGCTCTCGGCGTCCTCGGTTTA CAACCTGCTACCAGAAAAGGACCTCACTGGCTTCCCTGGGCCTTTGAATGACCAGGACAATGAA GAC T G C AT C AAT CGTCATAATGTCTATATTAATG GAAT C AC AT AT AC T C C AG TAT C AAG T AC AA AT GAAAAGGATAT GTACAGC T T CC TAGAGGACAT GGGC T TAAAGGCAT T CACCAAC T CAAAGAT T C G T AAAC C CAAAAT G T G T C C AC AG C T T C AAC AG TAT GAAAT G CAT G GAC C T GAAG G T C TAG G T GTAGGTTTTTATGAGTCAGATGTAATGGGAAGAGGCCATGCACGCCTGGTGCATGTTGAAGAGC CTCACACGGAGACCGTACGAAAGTACTTCCCTGAGACATGGATCTGGGATTTGGTGGTGGTAAA CTCAGCAGGTGTGGCTGAGGTAGGAGTAACAGTCCCTGACACCATCACCGAGTGGAAGGCAGGG GCCTTCTGCCTGTCTGAAGATGCTGGACTTGGTATCTCTTCCACTGCCTCTCTCCGAGCCTTCC AGCCCTTCTTTGTGGAGCTCACAATGCCTTACTCTGTGATTCGTGGAGAGGCCTTCACACTCAA GGCCACGGTCCTAAACTACCTTCCCAAATGCATCCGGGTCAGTGTGCAGCTGGAAGCCTCTCCC GCCTTCCTAGCTGTCCCAGTGGAGAAGGAACAAGCGCCTCACTGCATCTGTGCAAACGGGCGGC AAACTGTGTCCTGGGCAGTAACCCCAAAGTCATTAGGAAATGTGAATTTCACTGTGAGCGCAGA GGCACTAGAGTCTCAAGAGCTGTGTGGGACTGAGGTGCCTTCAGTTCCTGAACACGGAAGGAAA GAC AC AG T C AT C AAG CCTCTGTTGGTT GAAC C T GAAG GAC T AGAGAAG GAAAC AAC AT T C AAC T CCCTACTTTGTCCATCAGGTGGTGAGGTTTCTGAAGAATTATCCCTGAAACTGCCACCAAATGT GGTAGAAGAATCTGCCCGAGCTTCTGTCTCAGTTTTGGGAGACATATTAGGCTCTGCCATGCAA AACACACAAAATCTTCTCCAGATGCCCTATGGCTGTGGAGAGCAGAATATGGTCCTCTTTGCTC C T AAC AT CTATGTACTGGATTATC T AAAT GAAAC AC AG C AG C T T AC T C C AGAGAT C AAG T C C AA GGCCATTGGCTATCTCAACACTGGTTACCAGAGACAGTTGAACTACAAACACTATGATGGCTCCTACAGCACCTTTGGGGAGCGATATGGCAGGAACCAGGGCAACACCTGGCTCACAGCCTTTGTTC TGAAGACTTTTGCCCAAGCTCGAGCCTACATCTTCATCGATGAAGCACACATTACCCAAGCCCT CATATGGCTCTCCCAGAGGCAGAAGGACAATGGCTGTTTCAGGAGCTCTGGGTCACTGCTCAAC AATGCCATAAAGGGAGGAGTAGAAGATGAAGTGACCCTCTCCGCCTATATCACCATCGCCCTTC TGGAGATTCCTCTCACAGTCACTCACCCTGTTGTCCGCAATGCCCTGTTTTGCCTGGAGTCAGC CTGGAAGACAGCACAAGAAGGGGACCATGGCAGCCATGTATATACCAAAGCACTGCTGGCCTAT GCTTTTGCCCTGGCAGGTAACCAGGACAAGAGGAAGGAAGTACTCAAGTCACTTAATGAGGAAG CTGTGAAGAAAGACAACTCTGTCCATTGGGAGCGCCCTCAGAAACCCAAGGCACCAGTGGGGCA TTTTTACGAACCCCAGGCTCCCTCTGCTGAGGTGGAGATGACATCCTATGTGCTCCTCGCTTAT CTCACGGCCCAGCCAGCCCCAACCTCGGAGGACCTGACCTCTGCAACCAACATCGTGAAGTGGA TCACGAAGCAGCAGAATGCCCAGGGCGGTTTCTCCTCCACCCAGGACACAGTGGTGGCTCTCCA TGCTCTGTCCAAATATGGAGCAGCCACATTTACCAGGACTGGGAAGGCTGCACAGGTGACTATC CAGTCTTCAGGGACATTTTCCAGCAAATTCCAAGTGGACAACAACAACCGCCTGTTACTGCAGC AGGTCTCATTGCCAGAGCTGCCTGGGGAATACAGCATGAAAGTGACAGGAGAAGGATGTGTCTA C C T C C AGAC AT C C T T GAAAT AC AAT AT T C T C C C AGAAAAG GAAGAG T T C C C C T T T G C T T T AG GA GTGCAGACTCTGCCTCAAACTTGTGATGAACCCAAAGCCCACACCAGCTTCCAAATCTCCCTAA GTGTCAGTTACACAGGGAGCCGCTCTGCCTCCAACATGGCGATCGTTGATGTGAAGATGGTCTC TGGCTTCATTCCCCTGAAGCCAACAGTGAAAATGCTTGAAAGATCTAACCATGTGAGCCGGACA GAAG T GAG GAG C AAC CATGTCTTGATTTACCTT GAT AAG G T G T GAAAT C AGAC AC T GAG C T T G T T C T T C AC G G T T C T G C AAGAT G T C C C AG T AAGAGAT C T GAAAC C AG C C AT AG T GAAAG T C T AT GA TTACTACGAGACGGATGAGTTTGCAATTGCTGAGTACAATGCTCCTTGCAGCAAAGATCTTGGA AATGCTTGA ( SEQ ID NO : 1 6 )SEQ ID NO: 17 - Human A2M isoform B nucleic acid coding sequence -ATGTTCCT C AC T G T C C AAG T GAAAG GAC C AAC C C AAGAAT T T AAGAAG C G GAC C AC AG T GAT G G TTAAGAACGAGGACAGTCTGGTCTTTGTCCAGACAGACAAATCAATCTACAAACCAGGGCAGAC AGTGAAATTTCGTGTTGTCTCCATGGATGAAAACTTTCACCCCCTGAATGAGTTGATTCCACTA GTATACATTCAGGATCCCAAAGGAAATCGCATCGCACAATGGCAGAGTTTCCAGTTAGAGGGTG GCCTCAAGCAATTTTCTTTTCCCCTCTCATCAGAGCCCTTCCAGGGCTCCTACAAGGTGGTGGT ACAGAAGAAATCAGGTGGAAGGACAGAGCACCCTTTCACCGTGGAGGAATTTGTTCTTCCCAAG T T T GAAG TAG AAG T AAC AG TGC C AAAGAT AAT C AC C AT C T T G GAAGAAGAGAT GAAT G T AT C AG TGTGTGGCCTATACACATATGGGAAGCCTGTCCCTGGACATGTGACTGTGAGCATTTGCAGAAA GTATAGTGACGCTTCCGACTGCCACGGTGAAGATTCACAGGCTTTCTGTGAGAAATTCAGTGGA CAGCTAAACAGCCATGGCTGCTTCTATCAGCAAGTAAAAACCAAGGTCTTCCAGCTGAAGAGGA AGGAGTATGAAATGAAACTTCACACTGAGGCCCAGATCCAAGAAGAAGGAACAGTGGTGGAATT GAC T G GAAG G C AG T C C AG T GAAAT C AC AAGAAC CAT AAC C AAAC TCTCATTTGT GAAAG T G GAC TCACACTTTCGACAGGGAATTCCCTTCTTTGGGCAGGTGCGCCTAGTAGATGGGAAAGGCGTCC C TAT AC C AAAT AAAG T CAT AT T CAT C AGAG GAAAT GAAG C AAAC TAT TAG T C C AAT G C T AC C AC GGATGAGCATGGCCTTGTACAGTTCTCTATCAACACCACCAATGTTATGGGTACCTCTCTTACT GTTAGGGTCAATTACAAGGATCGTAGTCCCTGTTACGGCTACCAGTGGGTGTCAGAAGAACACG AAGAGGCACATCACACTGCTTATCTTGTGTTCTCCCCAAGCAAGAGCTTTGTCCACCTTGAGCC CATGTCTCATGAACTACCCTGTGGCCATACTCAGACAGTCCAGGCACATTATATTCTGAATGGA GGCACCCTGCTGGGGCTGAAGAAGCTCTCCTTCTATTATCTGATAATGGCAAAGGGAGGCATTG TCCGAACTGGGACTCATGGACTGCTTGTGAAGCAGGAAGACATGAAGGGCCATTTTTCCATCTC AATCCCTGTGAAGTCAGACATTGCTCCTGTCGCTCGGTTGCTCATCTATGCTGTTTTACCTACC GGGGACGTGATTGGGGATTCTGCAAAATATGATGTTGAAAATTGTCTGGCCAACAAGGTGGATT TGAGCTTCAGCCCATCACAAAGTCTCCCAGCCTCACACGCCCACCTGCGAGTCACAGCGGCTCC TCAGTCCGTCTGCGCCCTCCGTGCTGTGGACCAAAGCGTGCTGCTCATGAAGCCTGATGCTGAG CTCTCGGCGTCCTCGGTTTACAACCTGCTACCAGAAAAGGACCTCACTGGCTTCCCTGGGCCTT T GAAT GAC C AG GAC AAT GAAGAC T G C AT C AAT CGTCATAATGTCTATATTAATG GAAT C AC AT A TACTCCAGTATCAAGTACAAATGAAAAGGATATGTACAGCTTCCTAGAGGACATGGGCTTAAAG G C AT T C AC C AAC T C AAAGAT T C G T AAAC C C AAAAT G T G T C C AC AG C T T C AAC AG TAT GAAAT G CATGGACCTGAAGGTCTACGTGTAGGTTTTTATGAGTCAGATGTAATGGGAAGAGGCCATGCACG CCTGGTGCATGTTGAAGAGCCTCACACGGAGACCGTACGAAAGTACTTCCCTGAGACATGGATC TGGGATTTGGTGGTGGTAAACTCAGCAGGTGTGGCTGAGGTAGGAGTAACAGTCCCTGACACCA TCACCGAGTGGAAGGCAGGGGCCTTCTGCCTGTCTGAAGATGCTGGACTTGGTATCTCTTCCAC TGCCTCTCTCCGAGCCTTCCAGCCCTTCTTTGTGGAGCTCACAATGCCTTACTCTGTGATTCGT GGAGAGGCCTTCACACTCAAGGCCACGGTCCTAAACTACCTTCCCAAATGCATCCGGGTCAGTG TGCAGCTGGAAGCCTCTCCCGCCTTCCTAGCTGTCCCAGTGGAGAAGGAACAAGCGCCTCACTG CATCTGTGCAAACGGGCGGCAAACTGTGTCCTGGGCAGTAACCCCAAAGTCATTAGGAAATGTG AATTTCACTGTGAGCGCAGAGGCACTAGAGTCTCAAGAGCTGTGTGGGACTGAGGTGCCTTCAG TTCCTGAACACGGAAGGAAAGACACAGTCATCAAGCCTCTGTTGGTTGAACCTGAAGGACTAGA GAAGGAAACAACATTCAACTCCCTACTTTGTCCATCAGGTGGTGAGGTTTCTGAAGAATTATCC CTGAAACTGCCACCAAATGTGGTAGAAGAATCTGCCCGAGCTTCTGTCTCAGTTTTGGGAGACA TATTAGGCTCTGCCATGCAAAACACACAAAATCTTCTCCAGATGCCCTATGGCTGTGGAGAGCA GAATAT GGT CC T C T T T GC T CC TAACAT C TAT GTAC T GGAT TAT C TAAAT GAAACACAGCAGC T T ACTCCAGAGATCAAGTCCAAGGCCATTGGCTATCTCAACACTGGTTACCAGAGACAGTTGAACT ACAAACACTATGATGGCTCCTACAGCACCTTTGGGGAGCGATATGGCAGGAACCAGGGCAACAC CTGGCTCACAGCCTTTGTTCTGAAGACTTTTGCCCAAGCTCGAGCCTACATCTTCATCGATGAA GCACACATTACCCAAGCCCTCATATGGCTCTCCCAGAGGCAGAAGGACAATGGCTGTTTCAGGA GCTCTGGGTCACTGCTCAACAATGCCATAAAGGGAGGAGTAGAAGATGAAGTGACCCTCTCCGC CTATATCACCATCGCCCTTCTGGAGATTCCTCTCACAGTCACTCACCCTGTTGTCCGCAATGCC CTGTTTTGCCTGGAGTCAGCCTGGAAGACAGCACAAGAAGGGGACCATGGCAGCCATGTATATA CCAAAGCACTGCTGGCCTATGCTTTTGCCCTGGCAGGTAACCAGGACAAGAGGAAGGAAGTACT CAAGTCACTTAATGAGGAAGCTGTGAAGAAAGACAACTCTGTCCATTGGGAGCGCCCTCAGAAA CCCAAGGCACCAGTGGGGCATTTTTACGAACCCCAGGCTCCCTCTGCTGAGGTGGAGATGACAT CCTATGTGCTCCTCGCTTATCTCACGGCCCAGCCAGCCCCAACCTCGGAGGACCTGACCTCTGC AACCAACATCGTGAAGTGGATCACGAAGCAGCAGAATGCCCAGGGCGGTTTCTCCTCCACCCAG GACACAGTGGTGGCTCTCCATGCTCTGTCCAAATATGGAGCAGCCACATTTACCAGGACTGGGA AGGCTGCACAGGTGACTATCCAGTCTTCAGGGACATTTTCCAGCAAATTCCAAGTGGACAACAA CAACCGCCTGTTACTGCAGCAGGTCTCATTGCCAGAGCTGCCTGGGGAATACAGCATGAAAGTG AC AG GAGAAG GATGTGTCTACCTC C AGAC AT C C T T GAAAT AC AAT AT T C T C C C AGAAAAG GAAG AGTTCCCCTTTGCTTTAGGAGTGCAGACTCTGCCTCAAACTTGTGATGAACCCAAAGCCCACAC CAGCTTCCAAATCTCCCTAAGTGTCAGTTACACAGGGAGCCGCTCTGCCTCCAACATGGCGATC GTTGATGTGAAGATGGTCTCTGGCTTCATTCCCCTGAAGCCAACAGTGAAAATGCTTGAAAGAT CTAACCATGTGAGCCGGACAGAAGTCAGCAGCAACCATGTCTTGATTTACCTTGATAAGGTGTC AAAT C AGAC AC T GAG C T T G T T C T T C AC G G T T C T G C AAGAT G T C C C AG T AAGAGAT C T GAAAC C A GCCATAGTGAAAGTCTATGATTACTACGAGACGGATGAGTTTGCAATTGCTGAGTACAATGCTC CTTGCAGCAAAGATCTTGGAAATGCTTGA ( SEQ ID NO : 17 )SEQ ID NO: 18 - Human A2M isoform C nucleic acid coding sequence -AT G GAT GAAAAC T T T C AC C C C C T GAAT GAG T T GAT T C C AC TAG TAT AC AT T C AG GAT C C C AAAG GAAATCGCATCGCACAATGGCAGAGTTTCCAGTTAGAGGGTGGCCTCAAGCAATTTTCTTTTCC CCTCTCATCAGAGCCCTTCCAGGGCTCCTACAAGGTGGTGGTACAGAAGAAATCAGGTGGAAGG ACAGAGCACCCTTTCACCGTGGAGGAATTTGTTCTTCCCAAGTTTGAAGTACAAGTAACAGTGC C AAAGAT AAT C AC C AT C T T G GAAGAAGAGAT GAAT G T AT C AG TGTGTGGCC TAT AC AC AT AT G G GAAGCCTGTCCCTGGACATGTGACTGTGAGCATTTGCAGAAAGTATAGTGACGCTTCCGACTGC CACGGTGAAGATTCACAGGCTTTCTGTGAGAAATTCAGTGGACAGCTAAACAGCCATGGCTGCT TCTATCAGCAAGTAAAAACCAAGGTCTTCCAGCTGAAGAGGAAGGAGTATGAAATGAAACTTCA CACTGAGGCCCAGATCCAAGAAGAAGGAACAGTGGTGGAATTGACTGGAAGGCAGTCCAGTGAA AT C AC AAGAAC C AT AAC C AAAC TCTCATTTGT GAAAG T G GAC T C AC AC T T T C GAC AG G GAAT T C CCTTCTTTGGGCAGGTGCGCCTAGTAGATGGGAAAGGCGTCCCTATACCAAATAAAGTCATATT CATCAGAGGAAATGAAGCAAACTATTACTCCAATGCTACCACGGATGAGCATGGCCTTGTACAG TTCTCTATCAACACCACCAATGTTATGGGTACCTCTCTTACTGTTAGGGTCAATTACAAGGATCGTAGTCCCTGTTACGGCTACCAGTGGGTGTCAGAAGAACACGAAGAGGCACATCACACTGCTTA TCTTGTGTTCTCCCCAAGCAAGAGCTTTGTCCACCTTGAGCCCATGTCTCATGAACTACCCTGT GGCCATACTCAGACAGTCCAGGCACATTATATTCTGAATGGAGGCACCCTGCTGGGGCTGAAGA AGCTCTCCTTCTATTATCTGATAATGGCAAAGGGAGGCATTGTCCGAACTGGGACTCATGGACT GCTTGTGAAGCAGGAAGACATGAAGGGCCATTTTTCCATCTCAATCCCTGTGAAGTCAGACATT GCTCCTGTCGCTCGGTTGCTCATCTATGCTGTTTTACCTACCGGGGACGTGATTGGGGATTCTG CAAAATATGATGTTGAAAATTGTCTGGCCAACAAGGTGGATTTGAGCTTCAGCCCATCACAAAG TCTCCCAGCCTCACACGCCCACCTGCGAGTCACAGCGGCTCCTCAGTCCGTCTGCGCCCTCCGT GCTGTGGACCAAAGCGTGCTGCTCATGAAGCCTGATGCTGAGCTCTCGGCGTCCTCGGTTTACA ACCTGCTACCAGAAAAGGACCTCACTGGCTTCCCTGGGCCTTTGAATGACCAGGACAATGAAGA C T G C AT C AAT CGTCATAATGTCTATATTAATG GAAT GAG AT AT AC T C GAG TAT C AAG T AC AAAT GAAAAGGATAT GTACAGC T T CC TAGAGGACAT GGGC T TAAAGGCAT T CACCAAC T CAAAGAT T C G T AAAC C C AAAAT G T G T C C AC AG C T T C AAC AG T AT GAAAT G C AT G GAC C T GAAG G T C T AC G T G T AGGTTTTTATGAGTCAGATGTAATGGGAAGAGGCCATGCACGCCTGGTGCATGTTGAAGAGCCT CACACGGAGACCGTACGAAAGTACTTCCCTGAGACATGGATCTGGGATTTGGTGGTGGTAAACT CAGCAGGTGTGGCTGAGGTAGGAGTAACAGTCCCTGACACCATCACCGAGTGGAAGGCAGGGGC CTTCTGCCTGTCTGAAGATGCTGGACTTGGTATCTCTTCCACTGCCTCTCTCCGAGCCTTCCAG CCCTTCTTTGTGGAGCTCACAATGCCTTACTCTGTGATTCGTGGAGAGGCCTTCACACTCAAGG CCACGGTCCTAAACTACCTTCCCAAATGCATCCGGGTCAGTGTGCAGCTGGAAGCCTCTCCCGC CTTCCTAGCTGTCCCAGTGGAGAAGGAACAAGCGCCTCACTGCATCTGTGCAAACGGGCGGCAA ACTGTGTCCTGGGCAGTAACCCCAAAGTCATTAGGAAATGTGAATTTCACTGTGAGCGCAGAGG CACTAGAGTCTCAAGAGCTGTGTGGGACTGAGGTGCCTTCAGTTCCTGAACACGGAAGGAAAGA C AC AG T C AT C AAG CCTCTGTTGGTT GAAC C T GAAG GAC T AGAGAAG GAAAC AAC AT T C AAC T C C CTACTTTGTCCATCAGGTGGTGAGGTTTCTGAAGAATTATCCCTGAAACTGCCACCAAATGTGG TAGAAGAATCTGCCCGAGCTTCTGTCTCAGTTTTGGGAGACATATTAGGCTCTGCCATGCAAAA CACACAAAATCTTCTCCAGATGCCCTATGGCTGTGGAGAGCAGAATATGGTCCTCTTTGCTCCT AACAT C TAT G TAG T GGAT TAT C T AAAT GAAACACAGCAGC T TAG T C CAGAGAT GAAG T C CAAGG CCATTGGCTATCTCAACACTGGTTACCAGAGACAGTTGAACTACAAACACTATGATGGCTCCTA CAGCACCTTTGGGGAGCGATATGGCAGGAACCAGGGCAACACCTGGCTCACAGCCTTTGTTCTG AAGACTTTTGCCCAAGCTCGAGCCTACATCTTCATCGATGAAGCACACATTACCCAAGCCCTCA TATGGCTCTCCCAGAGGCAGAAGGACAATGGCTGTTTCAGGAGCTCTGGGTCACTGCTCAACAA TGCCATAAAGGGAGGAGTAGAAGATGAAGTGACCCTCTCCGCCTATATCACCATCGCCCTTCTG GAGATTCCTCTCACAGTCACTCACCCTGTTGTCCGCAATGCCCTGTTTTGCCTGGAGTCAGCCT GGAAGACAGCACAAGAAGGGGACCATGGCAGCCATGTATATACCAAAGCACTGCTGGCCTATGC TTTTGCCCTGGCAGGTAACCAGGACAAGAGGAAGGAAGTACTCAAGTCACTTAATGAGGAAGCT GTGAAGAAAGACAACTCTGTCCATTGGGAGCGCCCTCAGAAACCCAAGGCACCAGTGGGGCATT TTTACGAACCCCAGGCTCCCTCTGCTGAGGTGGAGATGACATCCTATGTGCTCCTCGCTTATCT CACGGCCCAGCCAGCCCCAACCTCGGAGGACCTGACCTCTGCAACCAACATCGTGAAGTGGATC ACGAAGCAGCAGAATGCCCAGGGCGGTTTCTCCTCCACCCAGGACACAGTGGTGGCTCTCCATG CTCTGTCCAAATATGGAGCAGCCACATTTACCAGGACTGGGAAGGCTGCACAGGTGACTATCCA GTCTTCAGGGACATTTTCCAGCAAATTCCAAGTGGACAACAACAACCGCCTGTTACTGCAGCAG GTCTCATTGCCAGAGCTGCCTGGGGAATACAGCATGAAAGTGACAGGAGAAGGATGTGTCTACC T C CAGAGAT C C T T GAAAT AC AAT AT T C T C C CAGAAAAG GAAGAG T T C C C C T T T G C T T TAG GAG T GCAGACTCTGCCTCAAACTTGTGATGAACCCAAAGCCCACACCAGCTTCCAAATCTCCCTAAGT GTCAGTTACACAGGGAGCCGCTCTGCCTCCAACATGGCGATCGTTGATGTGAAGATGGTCTCTG GCTTCATTCCCCTGAAGCCAACAGTGAAAATGCTTGAAAGATCTAACCATGTGAGCCGGACAGA AGTCAGCAGCAACCATGTCTTGATTTACCTTGATAAGGTGTCAAATCAGACACTGAGCTTGTTC T T GAG G G T T C T G C AAGAT G T C C GAG T AAGAGAT C T GAAAC GAG C C AT AG T GAAAG TCTATGATT ACTACGAGACGGATGAGTTTGCAATTGCTGAGTACAATGCTCCTTGCAGCAAAGATCTTGGAAA TGCTTGA ( SEQ ID NO : 18 )SEQ ID NO: 19 - A2M amino acid sequence -MGKNKLLHPSLVLLLLVLLPTDASVSGKPQYMVLVPSLLHTETTEKGCVLLSYLNETVTVSASL ESVRGNRSLFTDLEAENDVLHCVAFAVPKSSSNEEVMFLTVQVKGPTQEFKKRTTVMVKNEDSL VFVQTDKS IYKPGQTVKFRWSMDENFHPLNELIPLVYIQDPKGNRIAQWQSFQLEGGLKQFSF PLSSEPFQGSYKVWQKKSGGRTEHPFTVEEFVLPKFEVQVTVPKI ITILEEEMNVSVCGLYTY GKPVPGHVTVS ICRKYSDASDCHGEDSQAFCEKFSGQLNSHGCFYQQVKTKVFQLKRKEYEMKL HTEAQI QEEGTWELTGRQS SE I TRT I TKLS FVKVDSHFRQGI PFFGQVRLVDGKGVP I PNKVI FIRGNEANYYSNATTDEHGLVQFS INTTNVMGTSLTVRVNYKDRSPCYGYQWVSEEHEEAHHTA YLVFSPSKSFVHLEPMSHELPCGHTQTVQAHYILNGGTLLGLKKLSFYYLIMAKGGIVRTGTHG LLVKQEDMKGHFS IS IPVKSDIAPVARLLIYAVLPTGDVIGDSAKYDVENCLANKVDLSFSPSQ SLPASHAHLRVTAAPQSVCALRAVDQSVLLMKPDAELSASSVYNLLPEKDLTGFPGPLNDQDDE DCINRHNVYINGITYTPVSSTNEKDMYSFLEDMGLKAFTNSKIRKPKMCPQLQQYEMHGPEGLR VGFYESDVMGRGHARLVHVEEPHTETVRKYFPETWIWDLVWNSAGVAEVGVTVPDTITEWKAG AFCLSEDAGLGISSTASLRAFQPFFVELTMPYSVIRGEAFTLKATVLNYLPKCIRVSVQLEASP AFLAVPVEKEQAPHCICANGRQTVSWAVTPKSLGNVNFTVSAEALESQELCGTEVPSVPEHGRK DTVIKPLLVEPEGLEKETTFNSLLCPSGGEVSEELSLKLPPNWEESARASVSVLGDILGSAMQ NTQNLLQMPYGCGEQNMVLFAPNIYVLDYLNETQQLTPEIKSKAIGYLNTGYQRQLNYKHYDGS YSTFGERYGRNQGNTWLTAFVLKTFAQARAYI FIDEAHITQALIWLSQRQKDNGCFRSSGSLLN NAIKGGVEDEVTLSAYITIALLEIPLTVTHPWRNALFCLESAWKTAQEGDHGSHVYTKALLAY AFALAGNQDKRKEVLKSLNEEAVKKDNSVHWERPQKPKAPVGHFYEPQAPSAEVEMTSYVLLAY LTAQPAPTSEDLTSATNIVKWITKQQNAQGGFSSTQDTWALHALSKYGAATFTRTGKAAQVTI QSSGTFSSKFQVDNNNRLLLQQVSLPELPGEYSMKVTGEGCVYLQTSLKYNILPEKEEFPFALG VQTLPQTCDEPKAHTSFQISLSVSYTGSRSASNMAIVDVKMVSGFIPLKPTVKMLERSNHVSRT EVSSNHVLI YLDKVSNQTLSLFFTVLQDVPVRDLKPAIVKVYDYYETDEFAIAEYNAPCSKDLG NA ( SEQ ID NO : 19 )SEQ ID NO: 20 - Human A2M isoform A amino acid sequence -MGKNKLLHPSLVLLLLVLLPTDASVSGKPQYMVLVPSLLHTETTEKGCVLLSYLNETVTVSASL ESVRGNRSLFTDLEAENDVLHCVAFAVPKSSSNEEVMFLTVQVKGPTQEFKKRTTVMVKNEDSL VFVQTDKS IYKPGQTVKFRWSMDENFHPLNELIPLVYIQDPKGNRIAQWQSFQLEGGLKQFSF PLSSEPFQGSYKVWQKKSGGRTEHPFTVEEFVLPKFEVQVTVPKI ITILEEEMNVSVCGLYTY GKPVPGHVTVS ICRKYSDASDCHGEDSQAFCEKFSGQLNSHGCFYQQVKTKVFQLKRKEYEMKL HTEAQI QEEGTWELTGRQS SE I TRT I TKLS FVKVDSHFRQGI PFFGQVRLVDGKGVP I PNKVI FIRGNEANYYSNATTDEHGLVQFS INTTNVMGTSLTVRVNYKDRSPCYGYQWVSEEHEEAHHTA YLVFSPSKSFVHLEPMSHELPCGHTQTVQAHYILNGGTLLGLKKLSFYYLIMAKGGIVRTGTHG LLVKQEDMKGHFS IS IPVKSDIAPVARLLIYAVLPTGDVIGDSAKYDVENCLANKVDLSFSPSQ SLPASHAHLRVTAAPQSVCALRAVDQSVLLMKPDAELSASSVYNLLPEKDLTGFPGPLNDQDNE DCINRHNVYINGITYTPVSSTNEKDMYSFLEDMGLKAFTNSKIRKPKMCPQLQQYEMHGPEGLR VGFYESDVMGRGHARLVHVEEPHTETVRKYFPETWIWDLVWNSAGVAEVGVTVPDTITEWKAG AFCLSEDAGLGISSTASLRAFQPFFVELTMPYSVIRGEAFTLKATVLNYLPKCIRVSVQLEASP AFLAVPVEKEQAPHCICANGRQTVSWAVTPKSLGNVNFTVSAEALESQELCGTEVPSVPEHGRK DTVIKPLLVEPEGLEKETTFNSLLCPSGGEVSEELSLKLPPNWEESARASVSVLGDILGSAMQ NTQNLLQMPYGCGEQNMVLFAPNIYVLDYLNETQQLTPEIKSKAIGYLNTGYQRQLNYKHYDGS YSTFGERYGRNQGNTWLTAFVLKTFAQARAYI FIDEAHITQALIWLSQRQKDNGCFRSSGSLLN NAIKGGVEDEVTLSAYITIALLEIPLTVTHPWRNALFCLESAWKTAQEGDHGSHVYTKALLAY AFALAGNQDKRKEVLKSLNEEAVKKDNSVHWERPQKPKAPVGHFYEPQAPSAEVEMTSYVLLAY LTAQPAPTSEDLTSATNIVKWITKQQNAQGGFSSTQDTWALHALSKYGAATFTRTGKAAQVTI QSSGTFSSKFQVDNNNRLLLQQVSLPELPGEYSMKVTGEGCVYLQTSLKYNILPEKEEFPFALG VQTLPQTCDEPKAHTSFQISLSVSYTGSRSASNMAIVDVKMVSGFIPLKPTVKMLERSNHVSRT EVSSNHVLI YLDKVSNQTLSLFFTVLQDVPVRDLKPAIVKVYDYYETDEFAIAEYNAPCSKDLG NA ( SEQ ID NO : 20 )SEQ ID NO: 21 - Human A2M isoform B amino acid sequence -MFLTVQVKGPTQEFKKRTTVMVKNEDSLVFVQTDKS IYKPGQTVKFRWSMDENFHPLNELIPL VYIQDPKGNRIAQWQSFQLEGGLKQFSFPLSSEPFQGSYKVWQKKSGGRTEHPFTVEEFVLPK FEVQVTVPKI ITILEEEMNVSVCGLYTYGKPVPGHVTVS ICRKYSDASDCHGEDSQAFCEKFSG QLNSHGCFYQQVKTKVFQLKRKE YEMKLHTEAQI QEEGTWELTGRQS SE I TRT I TKLS FVKVD SHFRQGIPFFGQVRLVDGKGVPIPNKVI FIRGNEANYYSNATTDEHGLVQFS INTTNVMGTSLT VRVNYKDRSPCYGYQWVSEEHEEAHHTAYLVFSPSKSFVHLEPMSHELPCGHTQTVQAHYILNG GTLLGLKKLSFYYLIMAKGGIVRTGTHGLLVKQEDMKGHFS IS IPVKSDIAPVARLLIYAVLPT GDVIGDSAKYDVENCLANKVDLSFSPSQSLPASHAHLRVTAAPQSVCALRAVDQSVLLMKPDAE LSASSVYNLLPEKDLTGFPGPLNDQDNEDCINRHNVYINGITYTPVSSTNEKDMYSFLEDMGLK AFTNSKIRKPKMCPQLQQYEMHGPEGLRVGFYESDVMGRGHARLVHVEEPHTETVRKYFPETWI WDLVWNSAGVAEVGVTVPDTITEWKAGAFCLSEDAGLGISSTASLRAFQPFFVELTMPYSVIR GEAFTLKATVLNYLPKCIRVSVQLEASPAFLAVPVEKEQAPHCICANGRQTVSWAVTPKSLGNV NFTVSAEALESQELCGTEVPSVPEHGRKDTVIKPLLVEPEGLEKETTFNSLLCPSGGEVSEELS LKLPPNWEESARASVSVLGDILGSAMQNTQNLLQMPYGCGEQNMVLFAPNI YVLDYLNETQQL TPEIKSKAIGYLNTGYQRQLNYKHYDGSYSTFGERYGRNQGNTWLTAFVLKTFAQARAYI FIDE AHITQALIWLSQRQKDNGCFRSSGSLLNNAIKGGVEDEVTLSAYITIALLEIPLTVTHPWRNA LFCLESAWKTAQEGDHGSHVYTKALLAYAFALAGNQDKRKEVLKSLNEEAVKKDNSVHWERPQK PKAPVGHFYEPQAPSAEVEMTSYVLLAYLTAQPAPTSEDLTSATNIVKWITKQQNAQGGFSSTQ DTWALHALSKYGAATFTRTGKAAQVTIQSSGTFSSKFQVDNNNRLLLQQVSLPELPGEYSMKV TGEGCVYLQTSLKYNILPEKEEFPFALGVQTLPQTCDEPKAHTSFQISLSVSYTGSRSASNMAI VDVKMVSGFIPLKPTVKMLERSNHVSRTEVSSNHVLIYLDKVSNQTLSLFFTVLQDVPVRDLKP AIVKVYDYYETDEFAIAEYNAPCSKDLGNA ( SEQ ID NO : 21 )SEQ ID NO: 22 - Human A2M isoform C amino acid sequence -MDENFHPLNELIPLVYIQDPKGNRIAQWQSFQLEGGLKQFSFPLSSEPFQGSYKVWQKKSGGR TEHPFTVEEFVLPKFEVQVTVPKI ITILEEEMNVSVCGLYTYGKPVPGHVTVS ICRKYSDASDC HGEDSQAFCEKFSGQLNSHGCFYQQVKTKVFQLKRKEYEMKLHTEAQIQEEGTWELTGRQSSE I TRT I TKLS FVKVDSHFRQGI PFFGQVRLVDGKGVP I PNKVI FIRGNEANYYSNATTDEHGLVQ FS INTTNVMGTSLTVRVNYKDRSPCYGYQWVSEEHEEAHHTAYLVFSPSKSFVHLEPMSHELPC GHTQTVQAHYILNGGTLLGLKKLSFYYLIMAKGGIVRTGTHGLLVKQEDMKGHFS IS IPVKSDI APVARLLIYAVLPTGDVIGDSAKYDVENCLANKVDLSFSPSQSLPASHAHLRVTAAPQSVCALR AVDQSVLLMKPDAELSASSVYNLLPEKDLTGFPGPLNDQDNEDCINRHNVYINGITYTPVSSTN EKDMYSFLEDMGLKAFTNSKIRKPKMCPQLQQYEMHGPEGLRVGFYESDVMGRGHARLVHVEEP HTETVRKYFPETWIWDLVWNSAGVAEVGVTVPDTITEWKAGAFCLSEDAGLGISSTASLRAFQ PFFVELTMPYSVIRGEAFTLKATVLNYLPKCIRVSVQLEASPAFLAVPVEKEQAPHCICANGRQ TVSWAVTPKSLGNVNFTVSAEALESQELCGTEVPSVPEHGRKDTVIKPLLVEPEGLEKETTFNS LLCPSGGEVSEELSLKLPPNWEESARASVSVLGDILGSAMQNTQNLLQMPYGCGEQNMVLFAP NIYVLDYLNETQQLTPEIKSKAIGYLNTGYQRQLNYKHYDGSYSTFGERYGRNQGNTWLTAFVL KTFAQARAYI FIDEAHITQALIWLSQRQKDNGCFRSSGSLLNNAIKGGVEDEVTLSAYITIALL EIPLTVTHPWRNALFCLESAWKTAQEGDHGSHVYTKALLAYAFALAGNQDKRKEVLKSLNEEA VKKDNSVHWERPQKPKAPVGHFYEPQAPSAEVEMTSYVLLAYLTAQPAPTSEDLTSATNIVKWI TKQQNAQGGFSSTQDTWALHALSKYGAATFTRTGKAAQVTIQSSGTFSSKFQVDNNNRLLLQQ VSLPELPGEYSMKVTGEGCVYLQTSLKYNILPEKEEFPFALGVQTLPQTCDEPKAHTSFQISLS VSYTGSRSASNMAIVDVKMVSGFIPLKPTVKMLERSNHVSRTEVSSNHVLIYLDKVSNQTLSLF FTVLQDVPVRDLKPAIVKVYDYYETDEFAIAEYNAPCSKDLGNA ( SEQ ID NO : 22 )Multiple Endothelial Growth Factor (EGF)-Like Domains 10 (MEGF10)

[0314] In some aspects, a protein, polypeptide, or oligonucleotide that is modified (including by activity and / or expression) according to the present disclosure is a multiple EGF-like domains 10 (MEGF10) gene product.

[0315] Multiple EGF like domains 10 (MEGF10; also known as SR-F3, EMARDD, CMYP10A, CMYP10B; and identified as US NIH National Library of Medicine NCBI Gene ID: 84466) is a member of the multiple EGF-like domains protein family, and plays a role in cell adhesion, motility, and proliferation. MEGF10 is a critical mediator of apoptotic cell phagocytosis as well as Ap peptide uptake in the brain. MEGF10 has been associated with schizophrenia, early- onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) as well as congenital myopathy with minicores.

[0316] In certain aspects, provided herein are methods of treating a neurological disorder comprising engineered overexpression of MEGF10 in a subject in need thereof. In certain aspects, overexpression of MEGF10 in a subject in need thereof comprises, consists essentially of, or consists of overexpression of MEGF10 in astrocytes. In some aspects, a transgene comprises a sequence encoding a human MEGF10 transcript. In some aspects, a transgene comprises a sequence encoding a human MEGF10 polypeptide.

[0317] In some aspects, provided herein are constructs suitable for transgenic engineered over expression of MEGF10. In some aspects, provided herein are polynucleotides encoding MEGF10. In some aspects, MEGF10 comprises, consists essentially of, or consists of a polynucleotide sequence and / or amino acid sequence that is, or is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein, identical to one or more of SEQ ID NOs: 23-28.SEQ ID NO: 23 - MEGF10 nucleic acid coding sequence -ATGGTTATTTCTTTGAACTCATGCCTGAGCTTTATTTGTTTATTGTTATGCCACTGGATTGGGA CAGCATCACCTCTGAATCTTGAAGACCCTAATGTGTGTAGCCACTGGGAAAGCTACTCAGTGAC T G T G C AAGAG T C AT AC C GAG AT CCCTTTGAT C AAAT T T AC TAG AC GAG C T G C AC T GAC AT T C T A AACTGGTTTAAATGCACGCGGCACAGAGTCAGCTATCGGACAGCCTATCGACATGGGGAGAAGA CTATGTATAGGCGCAAGTCTCAGTGTTGTCCTGGATTTTATGAAAGCGGGGAAATGTGTGTCCC CCACTGTGCTGATAAATGTGTCCATGGTCGCTGTATTGCTCCAAACACCTGTCAGTGTGAGCCT GGCTGGGGAGGGACCAACTGCTCCAGTGCCTGCGATGGTGATCACTGGGGTCCCCACTGCACCA GCCGGTGCCAGTGCAAAAATGGGGCTCTGTGCAACCCCATCACCGGGGCTTGCCACTGTGCTGC GGGCTTCCGGGGCTGGCGCTGCGAGGACCGCTGTGAGCAGGGCACCTATGGTAACGACTGTCAT CAGAGATGCCAGTGCCAGAATGGAGCCACCTGCGACCACGTCACGGGGGAATGCCGCTGCCCAC CAGGATACACCGGAGCCTTCTGTGAGGATCTTTGTCCTCCTGGTAAACATGGTCCACAGTGTGA GCAGAGATGCCCTTGTCAAAATGGAGGAGTGTGTCATCACGTCACTGGAGAATGCTCTTGCCCT TCTGGCTGGATGGGCACAGTGTGTGGTCAGCCTTGCCCCGAGGGTCGCTTTGGAAAGAACTGTTCCCAAGAATGCCAGTGCCATAATGGAGGGACGTGTGATGCTGCCACAGGCCAATGTCATTGCAG TCCAGGATACACAGGGGAACGGTGCCAGGATGAGTGTCCTGTTGGGACCTATGGCGTTCTCTGTGCTGAGACCTGCCAGTGTGTCAACGGAGGGAAGTGTTACCACGTGAGCGGCGCATGCCTCTGTG AAGCAGGCTTTGCTGGCGAGCGCTGCGAAGCACGCCTGTGTCCTGAGGGGCTCTACGGCATCAA ATGTGACAAACGGTGTCCCTGCCACTTGGAAAACACTCATAGCTGTCACCCCATGTCTGGAGAG TGTGCCTGCAAGCCGGGCTGGTCAGGACTCTACTGTAATGAGACATGTTCTCCTGGATTCTACG GGGAAGCTTGCCAGCAGATCTGCAGCTGCCAAAATGGGGCAGACTGTGACAGTGTGACTGGAAA GTGCACCTGTGCCCCAGGATTCAAAGGAATTGACTGCTCTACCCCATGCCCTCTGGGAACCTAT GGGATAAACTGTTCCTCTCGCTGTGGCTGTAAAAATGATGCAGTCTGCTCTCCTGTGGACGGGT CTTGTACTTGCAAGGCAGGCTGGCACGGGGTGGACTGCTCCATCAGATGTCCCAGTGGCACATG GGGCTTTGGCTGTAACTTAACATGCCAGTGCCTCAACGGGGGAGCCTGCAACACCCTGGACGGG ACCTGCACGTGTGCACCTGGATGGCGCGGGGAGAAATGCGAACTTCCCTGCCAGGATGGCACGT ACGGGCTGAACTGTGCTGAGCGCTGCGACTGCAGCCACGCAGATGGCTGCCACCCTACCACGGG CCATTGCCGCTGCCTCCCCGGATGGTCAGGATTGTTTTG ( SEQ ID NO : 23 )SEQ ID NO: 24 - Human MEGF10 isoform A nucleic acid coding sequence -ATGGTTATTTCTTTGAACTCATGCCTGAGCTTTATTTGTTTATTGTTATGCCACTGGATTGGGA CAGCATCACCTCTGAATCTTGAAGACCCTAATGTGTGTAGCCACTGGGAAAGCTACTCAGTGAC T G T G C AAGAG T C AT AC C GAG AT CCCTTTGAT C AAAT T T AC TAG AC GAG C T G C AC T GAC AT T C T A AACTGGTTTAAATGCACGCGGCACAGAGTCAGCTATCGGACAGCCTATCGACATGGGGAGAAGA CTATGTATAGGCGCAAGTCTCAGTGTTGTCCTGGATTTTATGAAAGCGGGGAAATGTGTGTCCC CCACTGTGCTGATAAATGTGTCCATGGTCGCTGTATTGCTCCAAACACCTGTCAGTGTGAGCCT GGCTGGGGAGGGACCAACTGCTCCAGTGCCTGCGATGGTGATCACTGGGGTCCCCACTGCACCA GCCGGTGCCAGTGCAAAAATGGGGCTCTGTGCAACCCCATCACCGGGGCTTGCCACTGTGCTGC GGGCTTCCGGGGCTGGCGCTGCGAGGACCGCTGTGAGCAGGGCACCTATGGTAACGACTGTCAT CAGAGATGCCAGTGCCAGAATGGAGCCACCTGCGACCACGTCACGGGGGAATGCCGCTGCCCAC CAGGATACACCGGAGCCTTCTGTGAGGATCTTTGTCCTCCTGGTAAACATGGTCCACAGTGTGA GCAGAGATGCCCTTGTCAAAATGGAGGAGTGTGTCATCACGTCACTGGAGAATGCTCTTGCCCT TCTGGCTGGATGGGCACAGTGTGTGGTCAGCCTTGCCCCGAGGGTCGCTTTGGAAAGAACTGTT CCCAAGAATGCCAGTGCCATAATGGAGGGACGTGTGATGCTGCCACAGGCCAATGTCATTGCAG TCCAGGATACACAGGGGAACGGTGCCAGGATGAGTGTCCTGTTGGGACCTATGGCGTTCTCTGT GCTGAGACCTGCCAGTGTGTCAACGGAGGGAAGTGTTACCACGTGAGCGGCGCATGCCTCTGTG AAGCAGGCTTTGCTGGCGAGCGCTGCGAAGCACGCCTGTGTCCTGAGGGGCTCTACGGCATCAA ATGTGACAAACGGTGTCCCTGCCACCTGGAAAACACTCATAGCTGTCACCCCATGTCTGGAGAG TGTGCCTGCAAGCCGGGCTGGTCAGGACTCTACTGTAATGAGACATGTTCTCCTGGATTCTACG GGGAAGCTTGCCAGCAGATCTGCAGCTGCCAAAATGGGGCAGACTGTGACAGTGTGACTGGAAA GTGCACCTGTGCCCCAGGATTCAAAGGAATTGACTGCTCTACCCCATGCCCTCTGGGAACCTAT GGGATAAACTGTTCCTCTCGCTGTGGCTGTAAAAATGATGCAGTCTGCTCTCCTGTGGACGGGT CTTGTACTTGCAAGGCAGGCTGGCACGGGGTGGACTGCTCCATCAGATGTCCCAGTGGCACATG GGGCTTTGGCTGTAACTTAACATGCCAGTGCCTCAACGGGGGAGCCTGCAACACCCTGGACGGG ACCTGCACGTGTGCACCTGGATGGCGCGGGGAGAAATGCGAACTTCCCTGCCAGGATGGCACGT ACGGGCTGAACTGTGCTGAGCGCTGCGACTGCAGCCACGCAGATGGCTGCCACCCTACCACGGG CCATTGCCGCTGCCTCCCCGGATGGTCAGGTGTCCACTGTGACAGCGTGTGTGCTGAGGGACGC TGGGGCCCCAACTGCTCCCTGCCCTGCTACTGTAAAAATGGGGCTTCATGCTCCCCTGATGATG GCATCTGCGAGTGTGCACCAGGCTTCCGAGGCACCACTTGTCAGAGGATCTGCTCCCCTGGTTT TTATGGGCATCGCTGCAGCCAGACATGCCCACAGTGCGTTCACAGCAGCGGGCCCTGCCACCAC ATCACCGGCCTGTGTGACTGCTTGCCTGGCTTCACAGGCGCCCTCTGCAATGAAGTGTGTCCCA GTGGCAGATTTGGGAAAAACTGTGCAGGAATTTGTACCTGCACCAACAACGGAACCTGTAACCC CATTGACAGATCTTGTCAGTGTTACCCCGGTTGGATTGGCAGTGACTGCTCTCAACCATGTCCA CCTGCCCACTGGGGCCCAAACTGCATCCACACGTGCAACTGCCATAATGGAGCTTTCTGCAGCG CCTACGATGGGGAATGTAAATGCACTCCTGGCTGGACAGGGCTCTACTGCACTCAGAGATGTCC TCTAGGGTTTTATGGAAAAGATTGTGCACTGATATGCCAATGTCAAAACGGAGCTGACTGCGAC CACATTTCTGGGCAGTGTACTTGCCGCACTGGATTCATGGGACGGCACTGTGAGCAGAAGTGCC CTTCAGGAACATATGGCTATGGCTGTCGCCAGATATGTGATTGTCTGAACAACTCCACCTGCGACCACATCACTGGGACCTGTTACTGCAGCCCCGGATGGAAGGGAGCGAGATGTGATCAAGCTGGT GTTATCATAGTTGGAAATCTGAACAGCTTAAGCCGAACCAGTACTGCTCTCCCTGCTGATTCCT ACCAGATCGGGGCCATTGCAGGCATCATCATTCTTGTCCTAGTTGTTCTCTTCCTACTGGCATT GTTCATTATTTATAGACACAAGCAGAAGGGAAAGGAATCAAGCATGCCAGCAGTTACCTACACC CCTGCTATGAGGGTCGTCAATGCAGATTATACCATTTCAGGAACCCTTCCTCACAGCAATGGTG GAAAC G C T AAT AG C GAG T AC T T GAG C AAT C C GAG T T AC C AC AC G C T C AC C C AG T G T G C C AC AT C C C C T C AC G T C AAC AAC AG G GAC AG GAT GAC T G T C AC GAAG T C AAAAAAC AAT C AAC TGTTTGTG AATCTTAAAAATGTGAACCCTGGGAAGAGAGGCCCTGTGGGGGACTGCACTGGGACATTGCCGG CTGACTGGAAACATGGCGGCTACCTCAACGAGCTCGGTGCTTTTGGACTTGACAGAAGCTATAT GGGAAAATCCTTAAAAGACCTGGGAAAGAATTCTGAATATAATTCAAGTAACTGCTCCCTAAGC AG T T C T GAGAAC C C AT AT G C C AC TAT T AAAGAC C C AC CTGTACTTATCCC GAAAAG C T C AGAG T GTGGTTATGTGGAGATGAAATCGCCGGCACGAAGAGATTCCCCATATGCAGAGATCAATAACTC AAC T T C AG C C AAC AG GAAT G T C T AT GAAG T T GAAC C TAG AG T GAG T G T T G T C C AAG GAG T AT T C AGCAATAATGGGCGTCTCTCCCAGGATCCATATGACCTCCCAAAGAACAGTCACATCCCTTGTC ATTATGACCTGCTGCCAGTCCGAGACAGTTCATCCTCCCCTAAGCAAGAGGACAGTGGTGGTAG CAGCAGCAACAGCAGCAGCAGCAGTGAATGA ( SEQ ID NO : 24 )SEQ ID NO: 25 - Human MEGF10 isoform B nucleic acid coding sequence -ATGGTTATTTCTTTGAACTCATGCCTGAGCTTTATTTGTTTATTGTTATGCCACTGGATTGGGA CAGCATCACCTCTGAATCTTGAAGACCCTAATGTGTGTAGCCACTGGGAAAGCTACTCAGTGAC T G T G C AAGAG T C AT AC C C AC AT CCCTTTGAT C AAAT T T AC TAG AC GAG C T G C AC T GAC AT T C T A AACTGGTTTAAATGCACGCGGCACAGAGTCAGCTATCGGACAGCCTATCGACATGGGGAGAAGA CTATGTATAGGCGCAAGTCTCAGTGTTGTCCTGGATTTTATGAAAGCGGGGAAATGTGTGTCCC CCACTGTGCTGATAAATGTGTCCATGGTCGCTGTATTGCTCCAAACACCTGTCAGTGTGAGCCT GGCTGGGGAGGGACCAACTGCTCCAGTGCCTGCGATGGTGATCACTGGGGTCCCCACTGCACCA GCCGGTGCCAGTGCAAAAATGGGGCTCTGTGCAACCCCATCACCGGGGCTTGCCACTGTGCTGC GGGCTTCCGGGGCTGGCGCTGCGAGGACCGCTGTGAGCAGGGCACCTATGGTAACGACTGTCAT CAGAGATGCCAGTGCCAGAATGGAGCCACCTGCGACCACGTCACGGGGGAATGCCGCTGCCCAC CAGGATACACCGGAGCCTTCTGTGAGGATCTTTGTCCTCCTGGTAAACATGGTCCACAGTGTGA GCAGAGATGCCCTTGTCAAAATGGAGGAGTGTGTCATCACGTCACTGGAGAATGCTCTTGCCCT TCTGGCTGGATGGGCACAGTGTGTGGTCAGCCTTGCCCCGAGGGTCGCTTTGGAAAGAACTGTT CCCAAGAATGCCAGTGCCATAATGGAGGGACGTGTGATGCTGCCACAGGCCAATGTCATTGCAG TCCAGGATACACAGGGGAACGGTGCCAGGATGAGTGTCCTGTTGGGACCTATGGCGTTCTCTGT GCTGAGACCTGCCAGTGTGTCAACGGAGGGAAGTGTTACCACGTGAGCGGCGCATGCCTCTGTG AAGCAGGCTTTGCTGGCGAGCGCTGCGAAGCACGCCTGTGTCCTGAGGGGCTCTACGGCATCAA ATGTGACAAACGGTGTCCCTGCCACCTGGAAAACACTCATAGCTGTCACCCCATGTCTGGAGAG TGTGCCTGCAAGCCGGGCTGGTCAGGACTCTACTGTAATGAGACATGTTCTCCTGGATTCTACG GGGAAGCTTGCCAGCAGATCTGCAGCTGCCAAAATGGGGCAGACTGTGACAGTGTGACTGGAAA GTGCACCTGTGCCCCAGGATTCAAAGGAATTGACTGCTCTACCCCATGCCCTCTGGGAACCTAT GGGATAAACTGTTCCTCTCGCTGTGGCTGTAAAAATGATGCAGTCTGCTCTCCTGTGGACGGGT CTTGTACTTGCAAGGCAGGCTGGCACGGGGTGGACTGCTCCATCAGATGTCCCAGTGGCACATG GGGCTTTGGCTGTAACTTAACATGCCAGTGCCTCAACGGGGGAGCCTGCAACACCCTGGACGGG ACCTGCACGTGTGCACCTGGATGGCGCGGGGAGAAATGCGAACTTCCCTGCCAGGATGGCACGT ACGGGCTGAACTGTGCTGAGCGCTGCGACTGCAGCCACGCAGATGGCTGCCACCCTACCACGGG CCATTGCCGCTGCCTCCCCGGATGGTCAGGATTGTTTTGA ( SEQ ID NO : 25 )SEQ ID NO: 26 - MEGF10 amino acid sequence -MVI SLNSCLS FICLLLCHWIGTASPLNLEDPNVCSHWESYSVTVQESYPHPFDQIYYTSCTDIL NWFKCTRHRVSYRTAYRHGEKTMYRRKSQCCPGFYESGEMCVPHCADKCVHGRCIAPNTCQCEP GWGGTNCSSACDGDHWGPHCTSRCQCKNGALCNPI TGACHCAAGFRGWRCEDRCEQGTYGNDCH QRCQCQNGATCDHVTGECRCPPGYTGAFCEDLCPPGKHGPQCEQRCPCQNGGVCHHVTGECSCP SGWMGTVCGQPCPEGRFGKNCSQECQCHNGGTCDAATGQCHCSPGYTGERCQDECPVGTYGVLCAETCQCVNGGKCYHVSGACLCEAGFAGERCEARLCPEGLYGIKCDKRCPCHLENTHSCHPMSGE CACKPGWSGLYCNETCSPGFYGEACQQICSCQNGADCDSVTGKCTCAPGFKGIDCSTPCPLGTY GINCSSRCGCKNDAVCSPVDGSCTCKAGWHGVDCS IRCPSGTWGFGCNLTCQCLNGGACNTLDG TCTCAPGWRGEKCELPCQDGTYGLNCAERCDCSHADGCHPTTGHCRCLPGWSGLF ( SEQ ID NO : 26 )SEQ ID NO: 27 - Human MEGF10 isoform A amino acid sequence -MVISLNSCLSFICLLLCHWIGTASPLNLEDPNVCSHWESYSVTVQESYPHPFDQIYYTSCTDIL NWFKCTRHRVSYRTAYRHGEKTMYRRKSQCCPGFYESGEMCVPHCADKCVHGRCIAPNTCQCEP GWGGTNCSSACDGDHWGPHCTSRCQCKNGALCNPITGACHCAAGFRGWRCEDRCEQGTYGNDCH QRCQCQNGATCDHVTGECRCPPGYTGAFCEDLCPPGKHGPQCEQRCPCQNGGVCHHVTGECSCP SGWMGTVCGQPCPEGRFGKNCSQECQCHNGGTCDAATGQCHCSPGYTGERCQDECPVGTYGVLC AETCQCVNGGKCYHVSGACLCEAGFAGERCEARLCPEGLYGIKCDKRCPCHLENTHSCHPMSGE CACKPGWSGLYCNETCSPGFYGEACQQICSCQNGADCDSVTGKCTCAPGFKGIDCSTPCPLGTY GINCSSRCGCKNDAVCSPVDGSCTCKAGWHGVDCS IRCPSGTWGFGCNLTCQCLNGGACNTLDG TCTCAPGWRGEKCELPCQDGTYGLNCAERCDCSHADGCHPTTGHCRCLPGWSGVHCDSVCAEGR WGPNCSLPCYCKNGASCSPDDGICECAPGFRGTTCQRICSPGFYGHRCSQTCPQCVHSSGPCHH ITGLCDCLPGFTGALCNEVCPSGRFGKNCAGICTCTNNGTCNPIDRSCQCYPGWIGSDCSQPCP PAHWGPNCIHTCNCHNGAFCSAYDGECKCTPGWTGLYCTQRCPLGFYGKDCALICQCQNGADCD HISGQCTCRTGFMGRHCEQKCPSGTYGYGCRQICDCLNNSTCDHITGTCYCSPGWKGARCDQAG VI IVGNLNSLSRTSTALPADSYQIGAIAGI I ILVLWLFLLALFI I YRHKQKGKESSMPAVTYTPAMRWNADYTISGTLPHSNGGNANSHYFTNPSYHTLTQCATSPHVNNRDRMTVTKSKNNQLFV NLKNVNPGKRGPVGDCTGTLPADWKHGGYLNELGAFGLDRSYMGKSLKDLGKNSEYNSSNCSLS SSENPYATIKDPPVLIPKSSECGYVEMKSPARRDSPYAEINNSTSANRNVYEVEPTVSWQGVF SNNGRLSQDPYDLPKNSHIPCHYDLLPVRDSSSSPKQEDSGGSSSNSSSSSE ( SEQ ID NO : 27 )SEQ ID NO: 28 - Human MEGF10 isoform B amino acid sequence -MVISLNSCLSFICLLLCHWIGTASPLNLEDPNVCSHWESYSVTVQESYPHPFDQIYYTSCTDIL NWFKCTRHRVSYRTAYRHGEKTMYRRKSQCCPGFYESGEMCVPHCADKCVHGRCIAPNTCQCEP GWGGTNCSSACDGDHWGPHCTSRCQCKNGALCNPITGACHCAAGFRGWRCEDRCEQGTYGNDCH QRCQCQNGATCDHVTGECRCPPGYTGAFCEDLCPPGKHGPQCEQRCPCQNGGVCHHVTGECSCP SGWMGTVCGQPCPEGRFGKNCSQECQCHNGGTCDAATGQCHCSPGYTGERCQDECPVGTYGVLC AETCQCVNGGKCYHVSGACLCEAGFAGERCEARLCPEGLYGIKCDKRCPCHLENTHSCHPMSGE CACKPGWSGLYCNETCSPGFYGEACQQICSCQNGADCDSVTGKCTCAPGFKGIDCSTPCPLGTY GINCSSRCGCKNDAVCSPVDGSCTCKAGWHGVDCS IRCPSGTWGFGCNLTCQCLNGGACNTLDG TCTCAPGWRGEKCELPCQDGTYGLNCAERCDCSHADGCHPTTGHCRCLPGWSGLF ( SEQ ID NO : 28 )

[0318] Suitable methods for nucleic acid delivery to effect expression of compositions are anticipated to include virtually any method by which a nucleic acid (e.g., DNA, RNA, including viral and nonviral vectors) can be introduced into a cell, a tissue or an organism, as described herein or as would be known to one of ordinary skill in the art. Such methods include, but are not limited to, direct delivery of DNA such as by injection (U.S. Patents 5,994,624,5,981,274, 5,945,100, 5,780,448, 5,736,524, 5,702,932, 5,656,610, 5,589,466 and 5,580,859, each incorporated herein by reference), including microinjection (Harland and Weintraub, 1985; U.S. Patent 5,789,215, incorporated herein by reference); by electroporation (U.S. Patent No.5,384,253, incorporated herein by reference); by calcium phosphate precipitation (Graham and Van Der Eb, 1973; Chen and Okayama, 1987; Rippe et al., 1990); by using DEAE dextran followed by polyethylene glycol (Gopal, 1985); by direct sonic loading (Fechheimer et al, 1987); by liposome mediated transfection (Nicolau and Sene, 1982; Fraley et al, 1979; Nicolau et al., 1987; Wong et al., 1980; Kaneda et al., 1989; Kato et al, 1991); by microprojectile bombardment (PCT Application Nos. WO 94 / 09699 and 95 / 06128; U.S. Patents 5,610,042; 5,322,783, 5,563,055, 5,550,318, 5,538,877 and 5,538,880, and each incorporated herein by reference); by agitation with silicon carbide fibers (Kaeppler et al, 1990; U.S. Patents 5,302,523 and 5,464,765, each incorporated herein by reference); by Agrobacterium mediated transformation (U.S. Patents 5,591,616 and 5,563,055, each incorporated herein by reference); or by PEG mediated transformation of protoplasts (Omirulleh et al, 1993; U.S. Patents 4,684,611 and 4,952,500, each incorporated herein by reference); by desiccation / inhibition mediated DNA uptake (Potrykus et al., 1985). Other methods include viral transduction, such as gene transfer by lentiviral or retroviral transduction.

[0319] In some aspects, a pharmaceutical composition for use as described herein comprises a vector. In some aspects, a vector is an oligonucleotide vector (e.g., a plasmid, a recombinant viral genome (e.g., a retrovirus genome, e.g., an adeno associated virus (AAV) genome), an artificial chromosome (e.g, a bacterial artificial chromosome, a yeast artificial chromosome, a human artificial chromosome, etc.), etc.), that encodes a functional molecule of interest (e.g, an RNA molecule, a protein, a polypeptide, etc.).

[0320] In some aspects, a vector is a nucleic acid molecule. In some aspects, a vector may be used to express quantities of proteins and / or polypeptides. In some aspects, if the nucleic acid molecules are derived from a non-human animal, a sequence may be humanized and / or otherwise rendered suitable for administration to a human. In some aspects, a nucleic acid molecule may comprise a coding region that has been codon optimized for expression in a human.

[0321] As used herein, the term "cDNA" refers to complementary DNA and corresponds to a DNA molecule, usually synthesized from a single-stranded RNA (such as, e.g., a messenger RNA [mRNA] or a microRNA [miRNA] template in a reaction catalyzed by a reverse transcriptase. In particular, when a cDNA is obtained from reverse transcription of a mRNA, it does not comprise an entire gene coding from a protein, but only the coding sequence of said protein (e.g., exons without introns). In some aspects, a fragment of cDNA can comprise a part of said cDNA encoding the N-terminal part or the C-terminal part of a protein. Such fragment could be useful, e.g., in the case of large cDNAs which cannot be carried by a single viral vector and would thus require the use of, e.g., dual, triple, quadruple, etc., viral vector systems.

[0322] In some aspects, a vector includes at least a fragment of a cDNA sequence comprising a sequence encoding a functional and / or structural portion of an RNA molecule. In some aspects, such an RNA molecule may be a ribosomal RNA, transfer RNA, small nuclear RNA, small nucleolar RNA, micro RNA, long non-coding RNA, short interfering RNA, guide RNA, and / or any functional RNA species.

[0323] In some aspects, vectors comprise a nucleic acid molecule encoding a polypeptide of a desired sequence or a portion thereof (e.g., a fragment containing one or more active and / or characteristic regions of a polypeptide, e.g., ligand binding domains, inhibitory domains, CDRs, variable region domains, etc.).

[0324] In a non-limiting example, to express one or more proteins or polypeptides suitable for use in the present disclosure, nucleic acids (e.g., DNA or RNA) encoding said protein or polypeptides are inserted into expression vectors such that the coding region for said protein or polypeptide is operatively linked to one or more transcriptional and / or translational control sequences.

[0325] In some aspects, where appropriate, vectors used herein contain sequences for plasmid or virus genome maintenance and for cloning and expression of exogenous nucleotide sequences. In some aspects, such sequences, collectively are referred to as “flanking sequences”, and typically include one or more of the following operatively linked nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcriptional termination sequence, a complete intron sequence containing a donor and acceptor splice site, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for inserting the nucleic acid encoding the polypeptide to be expressed, and a selectable marker element. Such sequences and methods of using the same are well known in the art.Vectors

[0326] Among other things, the present disclosure provides that in some aspects, compositions and methods provided herein may comprise a polynucleotide, such as a vector comprising a polynucleotide (e.g., a polynucleotide construct). Vectors comprising polynucleotide constructs according to the present disclosure include all those known in the art, including cosmids, plasmids (e.g., naked or contained in liposomes) and viral constructs (e.g., lentiviral, retroviral, adenoviral, and adeno associated viral constructs) that incorporate a polynucleotide comprising a modulator of NFIA, SOX9, A2M, and / or MEGF10. Those of skill in the art will be capable of selecting suitable constructs, as well as cells, for making any of the polynucleotides described herein. Insome aspects, a construct is a plasmid (i.e., a circular DNA molecule that can autonomously replicate inside a cell). In some aspects, a construct can be a cosmid (e.g., pWE or sCos series).

[0327] In some aspects, a construct is a viral construct. In some aspects, a viral construct is a lentivirus, retrovirus, adenovirus, or adeno-associated virus construct. In some aspects, a construct is an adeno-associated virus (AAV) construct (see, e.g., Asokan et al., Mol. Ther. 20: 699-7080, 2012, which is incorporated herein by reference for the purposes described herein). In some aspects, a viral construct is an adenovirus construct. In some aspects, a viral construct may also be based on or derived from an alphavirus. Alphaviruses include but are not limited to, Sindbis (and VEEV) virus, Aura virus, Babanki virus, Barmah Forest virus, Bebaru virus, Cabassou virus, Chikungunya virus, Eastern equine encephalitis virus, Everglades virus, Fort Morgan virus, Getah virus, Highlands J virus, Kyzylagach virus, Mayaro virus, Me Tri virus, Middelburg virus, Mosso das Pedras virus, Mucambo virus, Ndumu virus, O’nyong-nyong virus, Pixuna virus, Rio Negro virus, Ross River virus, Salmon pancreas disease virus, Semliki Forest virus, Southern elephant seal virus, Tonate virus, Trocara virus, Una virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus, and Whataroa virus. Generally, the genome of such viruses encode nonstructural (e.g., replicon) and structural proteins (e.g., capsid and envelope) that can be translated in the cytoplasm of the host cell. Ross River virus, Sindbis virus, Semliki Forest virus (SFV), and Venezuelan equine encephalitis virus (VEEV) have all been used to develop viral constructs for coding sequence delivery. Pseudotyped viruses may be formed by combining alphaviral envelope glycoproteins and retroviral capsids. Examples of alphaviral constructs can be found in U.S. Publication Nos. 20150050243, 20090305344, and 20060177819; constructs and methods of their making are incorporated herein by reference for the purposes described herein.

[0328] In some aspects, constructs provided herein can be of different sizes. In some aspects, a construct is a plasmid and can include a total length of up to 1 kb, up to 2 kb, up to 3 kb, up to 4 kb, up to 5 kb, up to 6 kb, up to 7 kb, up to 8 kb, up to 9 kb, up to 10 kb, up to 11 kb, up to 12 kb, up to 13 kb, up to 14 kb, or up to 15 kb. In some aspects, a construct is a plasmid and can have a total length in a range of 1 kb to 2 kb, 1 kb to 3 kb, 1 kb to 4 kb, 1 kb to 5 kb, 1 kb to 6 kb, 1 kb to 7 kb, 1 kb to 8 kb, 1 kb to 9 kb, 1 kb to 10 kb, 1 kb to 11 kb, 1 kb to 12 kb, 1 kb to 13 kb, 1 kb to 14 kb, or 1 kb to 15 kb.

[0329] In some aspects, a construct is a viral construct and can have a total number of nucleotides of up to 10 kb. In some aspects, a viral construct can have a total number of nucleotides in the range of 1 kb to 2 kb, 1 kb to 3 kb, 1 kb to 4 kb, 1 kb to 5 kb, 1 kb to 6 kb, 1 kb to 7 kb, 1 kb to 8 kb, 1 kb to 9 kb, 1 kb to 1 0 kb, 2 kb to 3 kb, 2 kb to 4 kb, 2 kb to 5 kb, 2 kb to 6 kb, 2 kb to 7 kb, 2 kb to 8 kb, 2 kb to 9 kb, 2 kb to 10 kb, 3 kb to 4 kb, 3 kb to 5 kb, 3 kb to 6 kb, 3 kb to 7 kb, 3 kb to 8 kb, 3 kb to 9 kb, 3 kb to 10 kb, 4 kb to 5 kb, 4 kb to 6kb, 4 kb to 7 kb, 4 kb to 8 kb, 4 kb to 9 kb, 4 kb to 10 kb, 5 kb to 6 kb, 5 kb to 7 kb, 5 kb to 8 kb, 5 kb to 9 kb, 5 kb to 10 kb, 6 kb to 7 kb, 6 kb to 8 kb, 6 kb to 9 kb, 6 kb to 10 kb,7 kb to 8 kb, 7 kb to 9 kb, 7 kb to 10 kb, 8 kb to 9 kb, 8 kb to 10 kb, or 9 kb to 10 kb.

[0330] In some aspects, a construct is a lentivirus construct and can have a total number of nucleotides of up to 8 kb. In some examples, a lentivirus construct can have a total number of nucleotides of 1 kb to 2 kb, 1 kb to 3 kb, 1 kb to 4 kb, 1 kb to 5 kb, 1 kb to 6 kb, 1 kb to 7 kb, 1 kb to 8 kb, 2 kb to 3 kb, 2 kb to 4 kb, 2 kb to 5 kb, 2 kb to 6 kb, 2 kb to 7 kb, 2 kb to8 kb, 3 kb to 4 kb, 3 kb to 5 kb, 3 kb to 6 kb, 3 kb to 7 kb, 3 kb to 8 kb, 4 kb to 5 kb, 4 kb to 6 kb, 4 kb to 7 kb, 4 kb to 8 kb, 5 kb to 6 kb, 5 kb to 7 kb, 5 kb to 8 kb, 6 kb to 8 kb, 6 kb to 7 kb, or 7 kb to 8 kb.

[0331] In some aspects, a construct is an adenovirus construct and can have a total number of nucleotides of up to 8 kb. In some aspects, an adenovirus construct can have a total number of nucleotides in the range of 1 kb to 2 kb, 1 kb to 3 kb, 1 kb to 4 kb, 1 kb to 5 kb, 1 kb to 6 kb, 1 kb to 7 kb, 1 kb to 8 kb, 2 kb to 3 kb, 2 kb to 4 kb, 2 kb to 5 kb, 2 kb to 6 kb, 2 kb to 7 kb, 2 kb to 8 kb, 3 kb to 4 kb, 3 kb to 5 kb, 3 kb to 6 kb, 3 kb to 7 kb, 3 kb to 8 kb, 4 kb to 5 kb, 4 kb to 6 kb, 4 kb to 7 kb, 4 kb to 8 kb, 5 kb to 6 kb, 5 kb to 7 kb, 5 kb to 8 kb, 6 kb to 7 kb, 6 kb to 8 kb, or 7 kb to 8 kb.

[0332] Any of the constructs described herein can further include a control sequence, e.g., a control sequence selected from the group of a transcription initiation sequence, a transcription termination sequence, a promoter sequence, an enhancer sequence, an RNA splicing sequence, a polyadenylation (poly(A)) sequence, a Kozak consensus sequence, and / or additional untranslated regions which may house pre- or post-transcriptional regulatory and / or control elements. In some aspects, a promoter can be a native promoter, a constitutive promoter, an inducible promoter, and / or a tissue-specific promoter. Non-limiting examples of control sequences are described herein.

[0333] In some aspects, a viral vector may be modified to comprise at least one surface-bound modification such as but not limited to a surface bound saccharide, lipid, carbohydrate, small molecule, etc.

[0334] In some aspects, a viral vector suitable for use according to the present disclosure, is to be administrated at a dose ranging from about 108viral genomes (vg) to about 1015vg, such as from about 108vg to about 1014vg, from about 108vg to about 1013vg, from about 108vg to about 1012vg, from about 108vg to about 1011vg, from about 108vg to about 1010vg, from about 108vg to about 109vg, from about 109vg to about 1015vg, from about 109vg to about 1014vg, from about 109vg to about 1013vg, from about 109vg to about 1012vg, from about 109vg to about 1011vg, from about 109vg to about 1010vg, from about 1010vg to about 1015vg, from about 1010vg toabout 1014vg, from about IO10vg to about 1013vg, from about IO10vg to about 1012vg, from about IO10vg to about 1011vg, from about 1011vg to about 1015vg, from about 1011vg to about 1014vg, from about 1011vg to about 1013vg, from about 1011vg to about 1012vg, from about 1012vg to about 1015vg, from about 1012vg to about 1014vg, from about 1012vg to about 1013vg, from about 1013vg to about 1015vg.

[0335] The term "vector genome", abbreviated as "vg", refers to one or more polynucleotides comprising a set of the polynucleotide sequences of a vector, e.g., a viral vector. A vector genome may be encapsidated in a viral particle. Depending on the particular viral vector, a vector genome may comprise single-stranded DNA, double-stranded DNA, or single-stranded RNA, or doublestranded RNA. A vector genome may include endogenous sequences associated with a particular viral vector and / or any heterologous sequences inserted into a particular viral vector through recombinant techniques (e.g., a transgene). In some aspects, the nucleic acid titer of a viral vector may be measured in terms of vg / mL. Methods suitable for measuring this titer are known in the art, and include, e.g., quantitative PCR.

[0336] In some aspects, a dose of viral vector (e.g., AAV vector) required to achieve a desired effect or a therapeutic effect will vary based on several factors including, but not limited to, the specific route of administration, the level of gene, RNA or protein expression required to achieve a therapeutic effect, the specific disease being treated, and the stability of the gene, RNA or protein product.

[0337] In some aspects, the volume of a viral vector administered to a subject is of about 1 pL±0.5 pL, about 2 pL±0.5 pL, about 3 pL±0.5 pL, about 4 pL±0.5 pL, about 5 pL±0.5 pL, about 6 pL±0.5 pL, about 7 pL±0.5 pL, about 8 pL±0.5 pL, about 9 pL±0.5 pL, about 10 pL±0.5 pL, about 15 pL±5 pL, about 20 pL±5 pL, about 25 pL±5 pL, about 30 pL±5 pL, about 35 pL±5 pL, about 40 pL±5 pL, about 45 pL±5 pL, about 50 pL±5 pL, about 55 pL±5 pL, about 60 pL±5 pL, about 65 pL±5 pL, about 70 pL±5 pL, about 75 pL±5 pL, about 80 pL±5 pL, about 85 pL±5 pL, about 90 pL±5 pL, about 95 pL±5 pL, about 100 pL±5 pL, about 150 pL±50 pL, about 200 pL±50 pL, about 250 pL±50 pL, about 300 pL±50 pL, about 350 pL±50 pL, about 400 pL±50 pL, about 450 pL±50 pL, about 500 pL±50 pL, about 550 pL±50 pL, about 600 pL±50 pL, about 650 pL±50 pL, about 700 pL±50 pL, about 750 pL±50 pL, about 800 pL±50 pL, about 850 pL±50 pL, about 900 pL±50 pL, about 950 pL±50 pL, about 1000 pL±50 pL, about 1.5 mL±250 pL, about 2 mL±250 pL, about 2.5 mL±250 pL, about 3 mL±250 pL, about 3.5 mL±250 pL, about 4 mL±250 pL, about 4.5 mL±250 pL, about 5 mL±250 pL, about 5.5 mL±250 pL, about 6 mL±250 pL, about 6.5 mL±250 pL, about 7 mL±250 pL, about 7.5 mL±250 pL, about 8 mL±250 pL, about 8.5 mL±250 pL, about 9 mL±250 pL, about 9.5 mL±250 pL, about 10 mL±250 pL.

[0338] In some aspects, the rate of administration of a viral vector administered to a subject will also depend, among other things, on the size of the subject, the dose of the viral vector, the volume of the viral vector, and the route of administration. In one non-limiting example, for intracerebral administration, a rate of administration ranging from about 0.1 pL / min to about 1 pL / min or from about 1 pL / min to about 5 pL / min or from about 1 pL / min to about 10 pL / min may be used.

[0339] In some aspects, the rate of administration of a viral vector administered to a subject is about 0.1 pL / min ±0.05 pL / min, about 0.2 pL / min ±0.05 pL / min, about 0.3 pL / min ±0.05 pL / min, about 0.4 pL / min ±0.05 pL / min, about 0.5 pL / min ±0.05 pL / min, about 0.6 pL / min ±0.05 pL / min, about 0.7 pL / min ±0.05 pL / min, about 0.8 pL / min ±0.05 pL / min, about 0.9 pL / min ±0.05 pL / min, about 1 pL / min ±0.5 pL / min, about 2 pL / min ±0. pL / min, about 3 pL / min ±0.5 pL / min, about 4 pL / min ±0.5 pL / min, about 5 pL / min ±0.5 pL / min, about 6 pL / min ±0.5 pL / min, about 7 pL / min ±0.5 pL / min, about 8 pL / min ±0.5 pL / min, about 9 pL / min ±0.5 pL / min, or about 10 pL / min ±0.5 pL / min.

[0340] In some aspects, a total dose or total volume of viral vectors may be administered continuously (e.g., wherein the total dose or total volume of viral vector is injected in a single shot or infusion); or discontinuously (e.g., wherein fractions of the total dose or total volume of viral vectors are injected with intermittent periods between each shot, preferably with short intermittent periods such as periods of time of 15 seconds, 30 seconds, 45 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, or 5 minutes between each shot or infusion).

[0341] In some aspects, a construct provided herein comprises, consists essentially of, or consists of a polynucleotide sequence and / or amino acid sequence that is, or is at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or any range derivable therein, identical to SEQ ID NO: 38.SEQ ID NO: 38 - Exemplary A2M encoding lentivirus construct (“Lenti-GFAP-A2M”; comprised in FIG. 10F) polynucleotide sequenceGGGTCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGC TTAAGCCTCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTC TGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCGA ACAGGGACTTGAAAGCGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGACTCGGCTTGCTGA AGCGCGCACGGCAAGAGGCGAGGGGCGGCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGA GGCTAGAAGGAGAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCGCGAT GGGAAAAAATTCGGTTAAGGCCAGGGGGAAAGAAAAAATATAAATTAAAACATATAGTATGGGC AAGCAGGGAGCTAGAACGATTCGCAGTTAATCCTGGCCTGTTAGAAACATCAGAAGGCTGTAGA CAAATAC T GGGACAGC TACAACCAT CCC T T CAGACAGGAT CAGAAGAAC T TAGAT CAT TAT ATA ATACAGTAGCAACCCTCTATTGTGTGCATCAAAGGATAGAGATAAAAGACACCAAGGAAGCTTT AGACAAGATAGAGGAAGAGCAAAACAAAAGTAAGACCACCGCACAGCAAGCGGCCGGCCGCTGAT C T T CAGACC T GGAGGAGGAGATAT GAGGGACAAT T GGAGAAGT GAAT TATATAAATATAAAGT AGTAAAAATTGAACCATTAGGAGTAGCACCCACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAA AAAAGAGCAGTGGGAATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGG GCGCAGCGTCAATGACGCTGACGGTACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCA GAACAATTTGCTGAGGGCTATTGAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATC AAGCAGCTCCAGGCAAGAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCCTGGGGA TTTGGGGTTGCTCTGGAAAACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTTGGAGTAA TAAAT C T C T GGAACAGAT T T GGAAT CACACGACC T GGAT GGAGT GGGACAGAGAAAT TAACAAT T ACACAAGC T T AAT ACAC T C C T T AAT T GAAGAAT C GCAAAAC CAGCAAGAAAAGAAT GAACAAG AATTATTGGAATTAGATAAATGGGCAAGTTTGTGGAATTGGTTTAACATAACAAATTGGCTGTG GTATATAAAATTATTCATAATGATAGTAGGAGGCTTGGTAGGTTTAAGAATAGTTTTTGCTGTA CTTTCTATAGT GAAT AGAG T T AG G GAG G GAT AT T GAG CATTATCGTTT C AGAC C GAG C T C C C AA CCCCGAGGGGACCCGACAGGCCCGAAGGAATAGAAGAAGAAGGTGGAGAGAGAGACAGAGACAG ATCCATTCGATTAGTGAACGGATCGGCACTGCGTGCGCCAATTCTGCAGACAAATGGCAGTATT CATCCACAATTTTAAAAGAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGAC ATAATAGCAACAGACATACAAAC TAAAGAAT TACAAAAACAAAT TACAAAAAT T CAAAAT T T T C GGGTTTATTACAGGGACAGCAGAGATCCAGTTTGGTTAGTACCGGGCCCGCTCTAGAGCCATGC TCTAGGAAGATCTAACATATCCTGGTGTGGAGTAGGGGACGCTGCTCTGACAGAGGCTCGGGGG CCTGAGCTGGCTCTGTGAGCTGGGGAGGAGGCAGACAGCCAGGCCTTGTCTGCAAGCAGACCTG GCAGCATTGGGCTGGCCGCCCCCCAGGGCCTCCTCTTCATGCCCAGTGAATGACTCACCTTGGC ACAGACACAATGTTCGGGGTGGGCACAGTGCCTGCTTCCCGCCGCACCCCAGCCCCCCTCAAAT GCCTTCCGAGAAGCCCATTGAGCAGGGGGCTTGCATTGCACCCCAGCCTGACAGCCTGGCATCT TGGGATAAAAGCAGCACAGCCCCCTAGGGGCTGCCCTTGCTGTGTGGCGCCACCGGCGGTGGAG AACAAGGCTCTATTCAGCCTGTGCCCAGGAAAGGGGATCAGGGGATGCCCAGGCATGGACAGTG GGTGGCAGGGGGGGAGAGGAGGGCTGTCTGCTTCCCAGAAGTCCAAGGACACAAATGGGTGAGG GGAGAGCTCTCCCCATAGCTGGGCTGCGGCCCAACCCCACCCCCTCAGGCTATGCCAGGGGGTG TTGCCAGGGGCACCCGGGCATCGCCAGTCTAGCCCACTCCTTCATAAAGCCCTCGCATCCCAGG AGCGAGCAGAGCCAGAGCAGGTTGGAGAGGAGACGCATCACCTCCGCTGCTCGCAAGCTTTATT GCGGTAGTTTATCACAGTTAAATTGCTAACGCAGTCAGTGCTTCTGACACAACAGTCTCGAACT TAAGCTGCAGAAGTTGGTCGTGAGGCACTGGGCAGGTAAGTATCAAGGTTACAAGACAGGTTTA AGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGAAGACTCTTGCGTTTCTGATAGGCACCT ATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGTTCAATTACA GCTCTTAAGGCTAGAGTACTTAATACGACTCACTATAGGCTAGCAACATGGGGAAGAACAAACT CCTTCATCCAAGTCTGGTTCTTCTCCTCTTGGTCCTCCTGCCCACAGACGCCTCAGTCTCTGGA AAACCGCAGTATATGGTTCTGGTCCCCTCCCTGCTCCACACTGAGACCACTGAGAAGGGCTGTG TCCTTCTGAGCTACCTGAATGAGACAGTGACTGTAAGTGCTTCCTTGGAGTCTGTCAGGGGAAA CAGGAGCCTCTTCACTGACCTGGAGGCGGAGAATGACGTACTCCACTGTGTCGCCTTCGCTGTC C CAAAG T C T T CAT C GAAT GAG GAG G T AAT G T T C C T GAG T G T C CAAG T GAAAG GAG CAAC C CAAG AATTTAAGAAGCGGACCACAGTGATGGTTAAGAACGAGGACAGTCTGGTCTTTGTCCAGACAGA CAAAT GAAT C TAG AAAC GAG G G C AGAC AG T GAAAT T T C G T G T T G T C T C CAT G GAT GAAAAC T T T C AC C C C C T GAAT GAG T T GAT T C C AC TAG TAT AC AT T C AG GAT C C CAAAG GAAAT C G C AT C G C AC AATGGCAGAGTTTCCAGTTAGAGGGTGGCCTCAAGCAATTTTCTTTTCCCCTCTCATCAGAGCC CTTCCAGGGCTCCTACAAGGTGGTGGTACAGAAGAAATCAGGTGGAAGGACAGAGCACCCTTTC AC C G T G GAG GAAT TTGTTCTTCC CAAG T T T GAAG T AC AAG T AAC AG TGC C AAAGAT AAT C AC C A TCTTGGAAGAAGAGATGAATGTATCAGTGTGTGGCCTATACACATATGGGAAGCCTGTCCCTGG ACATGTGACTGTGAGCATTTGCAGAAAGTATAGTGACGCTTCCGACTGCCACGGTGAAGATTCA CAGGCTTTCTGTGAGAAATTCAGTGGACAGCTAAACAGCCATGGCTGCTTCTATCAGCAAGTAA AAACCAAGGTCTTCCAGCTGAAGAGGAAGGAGTATGAAATGAAACTTCACACTGAGGCCCAGAT CCAAGAAGAAGGAACAGTGGTGGAATTGACTGGAAGGCAGTCCAGTGAAATCACAAGAACCATA ACCAAACTCTCATTTGTGAAAGTGGACTCACACTTTCGACAGGGAATTCCCTTCTTTGGGCAGG TGCGCCTAGTAGATGGGAAAGGCGTCCCTATACCAAATAAAGTCATATTCATCAGAGGAAATGA AGCAAACTATTACTCCAATGCTACCACGGATGAGCATGGCCTTGTACAGTTCTCTATCAACACC ACCAATGTTATGGGTACCTCTCTTACTGTTAGGGTCAATTACAAGGATCGTAGTCCCTGTTACGGCTACCAGTGGGTGTCAGAAGAACACGAAGAGGCACATCACACTGCTTATCTTGTGTTCTCCCC AAGCAAGAGCTTTGTCCACCTTGAGCCCATGTCTCATGAACTACCCTGTGGCCATACTCAGACA GTCCAGGCACATTATATTCTGAATGGAGGCACCCTGCTGGGGCTGAAGAAGCTCTCCTTCTATT ATCTGATAATGGCAAAGGGAGGCATTGTCCGAACTGGGACTCATGGACTGCTTGTGAAGCAGGA AGACATGAAGGGCCATTTTTCCATCTCAATCCCTGTGAAGTCAGACATTGCTCCTGTCGCTCGG TTGCTCATCTATGCTGTTTTACCTACCGGGGACGTGATTGGGGATTCTGCAAAATATGATGTTG AAAATTGTCTGGCCAACAAGGTGGATTTGAGCTTCAGCCCATCACAAAGTCTCCCAGCCTCACA CGCCCACCTGCGAGTCACAGCGGCTCCTCAGTCCGTCTGCGCCCTCCGTGCTGTGGACCAAAGC GTGCTGCTCATGAAGCCTGATGCTGAGCTCTCGGCGTCCTCGGTTTACAACCTGCTACCAGAAA AGGACCTCACTGGCTTCCCTGGGCCTTTGAATGACCAGGACGATGAAGACTGCATCAATCGTCA TAATGTCTATATTAATG GAAT GAG AT AT AC T C GAG TAT C AAG T AC AAAT GAAAAG GAT AT G TAG AGCTTCCTAGAGGACATGGGCTTAAAGGCATTCACCAACTCAAAGATTCGTAAACCCAAAATGT GTCCACAGCTTCAACAGTATGAAATGCATGGACCTGAAGGTCTACGTGTAGGTTTTTATGAGTC AGATGTAATGGGAAGAGGCCATGCACGCCTGGTGCATGTTGAAGAGCCTCACACGGAGACCGTA CGAAAGTACTTCCCTGAGACATGGATCTGGGATTTGGTGGTGGTAAACTCAGCAGGTGTGGCTG AGGTAGGAGTAACAGTCCCTGACACCATCACCGAGTGGAAGGCAGGGGCCTTCTGCCTGTCTGA AGATGCTGGACTTGGTATCTCTTCCACTGCCTCTCTCCGAGCCTTCCAGCCCTTCTTTGTGGAG CTCACAATGCCTTACTCTGTGATTCGTGGAGAGGCCTTCACACTCAAGGCCACGGTCCTAAACT ACCTTCCCAAATGCATCCGGGTCAGTGTGCAGCTGGAAGCCTCTCCCGCCTTCCTAGCTGTCCC AGTGGAGAAGGAACAAGCGCCTCACTGCATCTGTGCAAACGGGCGGCAAACTGTGTCCTGGGCA GTAACCCCAAAGTCATTAGGAAATGTGAATTTCACTGTGAGCGCAGAGGCACTAGAGTCTCAAG AGCTGTGTGGGACTGAGGTGCCTTCAGTTCCTGAACACGGAAGGAAAGACACAGTCATCAAGCC T C T G T T G G T T GAAC C T GAAG GAC T AGAGAAG GAAAC AAC AT T C AAC T C C C T AC T T T G T C C AT C A GGTGGTGAGGTTTCTGAAGAATTATCCCTGAAACTGCCACCAAATGTGGTAGAAGAATCTGCCC GAGCTTCTGTCTCAGTTTTGGGAGACATATTAGGCTCTGCCATGCAAAACACACAAAATCTTCT CCAGATGCCCTATGGCTGTGGAGAGCAGAATATGGTCCTCTTTGCTCCTAACATCTATGTACTG GAT TAT C TAAAT GAAACACAGCAGC T TAG T CCAGAGAT GAAG T CCAAGGC CAT T GGC TAT C T GA ACACTGGTTACCAGAGACAGTTGAACTACAAACACTATGATGGCTCCTACAGCACCTTTGGGGA GCGATATGGCAGGAACCAGGGCAACACCTGGCTCACAGCCTTTGTTCTGAAGACTTTTGCCCAA GCTCGAGCCTACATCTTCATCGATGAAGCACACATTACCCAAGCCCTCATATGGCTCTCCCAGA GGCAGAAGGACAATGGCTGTTTCAGGAGCTCTGGGTCACTGCTCAACAATGCCATAAAGGGAGG AGTAGAAGATGAAGTGACCCTCTCCGCCTATATCACCATCGCCCTTCTGGAGATTCCTCTCACA GTCACTCACCCTGTTGTCCGCAATGCCCTGTTTTGCCTGGAGTCAGCCTGGAAGACAGCACAAG AAGGGGACCATGGCAGCCATGTATATACCAAAGCACTGCTGGCCTATGCTTTTGCCCTGGCAGG TAACCAGGACAAGAGGAAGGAAGTAC T CAAGT GAG T TAAT GAGGAAGC T GT GAAGAAAGACAAC TCTGTCCATTGGGAGCGCCCTCAGAAACCCAAGGCACCAGTGGGGCATTTTTACGAACCCCAGG CTCCCTCTGCTGAGGTGGAGATGACATCCTATGTGCTCCTCGCTTATCTCACGGCCCAGCCAGC CCCAACCTCGGAGGACCTGACCTCTGCAACCAACATCGTGAAGTGGATCACGAAGCAGCAGAAT GCCCAGGGCGGTTTCTCCTCCACCCAGGACACAGTGGTGGCTCTCCATGCTCTGTCCAAATATG GAGCAGCCACATTTACCAGGACTGGGAAGGCTGCACAGGTGACTATCCAGTCTTCAGGGACATT TTCCAGCAAATTCCAAGTGGACAACAACAACCGCCTGTTACTGCAGCAGGTCTCATTGCCAGAG CTGCCTGGGGAATACAGCATGAAAGTGACAGGAGAAGGATGTGTCTACCTCCAGACATCCTTGA AATACAATATTCTCCCAGAAAAGGAAGAGTTCCCCTTTGCTTTAGGAGTGCAGACTCTGCCTCA AAC T T G T GAT GAAC C C AAAG C C C AC AC C AG C T T C C AAAT C T C C C T AAG T G T C AG T T AC AC AG G G AGCCGCTCTGCCTCCAACATGGCGATCGTTGATGTGAAGATGGTCTCTGGCTTCATTCCCCTGA AGCCAACAGTGAAAATGCTTGAAAGATCTAACCATGTGAGCCGGACAGAAGTCAGCAGCAACCA TGTCTTGATTTACCTTGATAAGGTGTCAAATCAGACACTGAGCTTGTTCTTCACGGTTCTGCAA GAT G T C C GAG T AAGAGAT C T GAAAC GAG C C AT AG T GAAAG T C TAT GAT TAG TAG GAGAC G GAT G AGTTTGCAATTGCTGAGTACAATGCTCCTTGCAGCAAAGATCTTGGAAATGCTTGAAGAGTCGA CCCGGGCGGCCGCATAACTTCGTATAGTATAAATTATACGAAGTTATAAGCCTTGTTTCCAGAA TCGTATCTTACGATTTTCAAGAGAAATCGTAAGATACGATTCTGGTTTTTTCTCGAGGTCGACG GTATCGATAAGCTCGCTTCACGAGATCATGTTTAAGGGTTCCGGTTCCACTAGGTACAATTCGA TAT GAAG CTTATCGATAAT GAAC C T C T G GAT T AC AAAAT T T G T GAAAGAT T GAC TGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTG CTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGA GTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACT GGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTG CCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCAC TGACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGCTCGCCTGTGTTGCC ACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTC CTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAG TCGGATCTCCCTTTGGGCCGCCTCCCCGCATCGATACCGTCGACCTCGATCGAGACCTAGAAAA ACATGGAGCAATCACAAGTAGCAATACAGCAGCTACCAATGCTGATTGTGCCTGGCTAGAAGCA CAAGAGGAGGAGGAGGTGGGTTTTCCAGTCACACCTCAGGTACCTTTAAGACCAATGACTTACA AGGCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCTAATTCACTC C C AAC GAAGAC AAGAT AT CCTTGATCTGTGGATCTAC C AC AC AC AAG GCTACTTCCCTGATTGG CAGAACTACACACCAGGGCCAGGGATCAGATATCCACTGACCTTTGGATGGTGCTACAAGCTAG TACCAGTTGAGCAAGAGAAGGTAGAAGAAGCCAATGAAGGAGAGAACACCCGCTTGTTACACCC TGTGAGCCTGCATGGGATGGATGACCCGGAGAGAGAAGTATTAGAGTGGAGGTTTGACAGCCGC CTAGCATTTCATCACATGGCCCGAGAGCTGCATCCGGACTGTACTGGGTCTCTCTGGTTAGACC AGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTT GCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTC AGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCA ( SEQ ID NO : 38 ) a. AAV particles

[0342] Among other things, the present disclosure provides AAV particles that comprise a polynucleotide construct encoding a modulator of NFIA, SOX9, A2M, and / or MEGF10, and an AAV capsid. In some aspects, AAV particles can be described as having a serotype, which is a description of the construct strain and the capsid strain. For example, in some aspects an AAV particle may be described as AAV2, wherein the particle has an AAV2 capsid and a construct that comprises characteristic AAV2 Inverted Terminal Repeats (ITRs). In some aspects, an AAV particle may be described as a pseudotype, wherein the capsid and construct are derived from different AAV strains, for example, AAV2 / 9 would refer to an AAV particle that comprises a construct utilizing the AAV2 ITRs and an AAV9 capsid. Additional examples of pseudotyped AAV vectors include, but are not limited to, AAV2 / 1, AAV2 / 2, AAV2 / 3, AAV2 / 4, AAV2 / 5, AAV2 / 6, AAV2 / 7, AAV2 / 8 and AAV2 / 9.

[0343] In some aspects, AAV particles suitable for use according to the present disclosure may comprise or be derived from any natural or recombinant AAV serotype. In some aspects, an AAV according to the present invention is selected from natural serotypes such as AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAV12; or pseudotypes, chimeras, and variants thereof.

[0344] As used herein, the term “chimera” when referring to an AAV vector, or a “chimeric AAV vector”, refers to an AAV vector which comprises a capsid containing VP1, VP2 and VP3 proteins from at least two different AAV serotypes; or alternatively, which comprises VP1, VP2 and VP3 proteins, at least one of which comprises at least a portion from another AAV serotype.Examples of chimeric AAV vectors include, but are not limited to, AAV-DJ, AAV-DJ / 8, AAV2G9, AAV2i8, AAV2i8G9, AAV8G9, and AAV9il.

[0345] As used herein, the term "pseudotype" when referring to an AAV vector, or a "pseudotyped AAV vector", refers to an AAV vector which comprises the genome of one AAV serotype packaged in the capsid of another AAV serotype. These pseudotypes are denoted using a slash or a hyphen, so that "AAV2 / 5" or "AAV2-5" indicates an AAV vector comprising a serotype 2 genome, packaged into a serotype 5 capsid. Examples of pseudotyped AAV vectors include, but are not limited to, AAV2 / 1, AAV2 / 2, AAV2 / 3, AAV2 / 4, AAV2 / 5, AAV2 / 6, AAV2 / 7, AAV2 / 8 and AAV2 / 9.

[0346] In some aspects, AAV variants include vectors which have been genetically modified, e.g., by substitution, deletion or addition of one or several amino acid residues in one of the capsid proteins. Examples of such variants include, but are not limited to, AAV2 with one or more of Y444F, Y500F, Y730F and / or S662V mutations; AAV3 with one or more of Y705F, Y731F and / or T492V mutations; AAV6 with one or more of S663 V and / or T492V mutations, etc.

[0347] In some aspects, an AAV serotype and / or pseudotype according to the present invention is selected from the group comprising or consisting of AAV1, AAV2, AAV3, AAV 4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV106.1 / hu.37, AAV1 14.3 / hu.4O, AAV127.2 / hu.41, AAV127.5 / hu.42, AAV128.1 / hu.43, AAV128.3 / hu.44, AAV130.4 / hu.48, AAV145.1 / hu.53, AAV145.5 / hu.54, AAV145.6 / hu.55, AAV16.12 / hu. l l, AAV16.3, AAV16.8 / hu. lO, AAV161.1O / hu.6O, AAV161.6 / hu.61, AAVl-7 / rh.48, AAVl-8 / rh.49, AAV2i8, AAV2i8G9, AAV2-15 / rh.62, AAV223.1, AAV223.2, AAV223.4, AAV223.5, AAV223.6, AAV223.7, AAV2-3 / rh.61, AAV24.1, AAV2-4 / rh.5O, AAV2-5 / rh.51, AAV2.5T, AAV27.3, AAV29.3 / bb. l, AAV29.5 / bb.2, AAV2G9, AAV3B, AAV3.1 / hu.6, AAV3.1 / hu.9, AAV3-1 l / rh.53, AAV3-3, AAV33.12 / hu. l7, AAV33.4 / hu. l5, AAV33.8 / hu. l6, AAV3-9 / rh.52, AAV3a, AAV3b, AAV4-19 / rh.55, AAV42.12, AAV42-10, AAV42-11, AAV42-12, AAV42-13, AAV42-15, AAV42-lb, AAV42-2, AAV42-3a, AAV42-3b, AAV42-4, AAV42-5a, AAV42-5b, AAV42-6b, AAV42-8, AAV42-aa, AAV43-1, AAV43-12, AAV43-20, AAV43-21, AAV43-23, AAV43-25, AAV43-5, AAV4-4, AAV44.1, AAV44.2, AAV44.5, AAV46.2 / hu.28, AAV46.6 / hu.29, AAV4-8 / rh.64, AAV4-9 / rh.54, AAV52.1 / hu.20,AAV52 / hu. l9, AAV5-22 / rh.58, AAV5-3 / r...

Claims

WHAT IS CLAIMED IS:

1. An engineered polynucleotide sequence comprising a transgene operably linked to a heterologous promoter, wherein the transgene encodes SRY-box transcription factor 9 (SOX9), Nuclear Factor 1A (NFIA), alpha-2-macroglobulin (A2M), and / or multiple endothelial growth factor like domains 10 (MEGF10).

2. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence encoding NFIA.

3. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 1-5.

4. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 1-5.

5. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 6-10.

6. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NOs: 6-10.

7. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence encoding SOX9.

8. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 11-12.

9. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 11-12.

10. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NOs: 13-14.

11. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NOs: 13-14.

12. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence encoding A2M.

13. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 15-18.

14. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 15-18.

15. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NO: 19-22.

16. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NOs: 19-22.

17. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence encoding MEGF10.

18. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 23-25.

19. The polynucleotide sequence of claim 1, wherein the transgene comprises a sequence according to one or more of SEQ ID NOs: 23-25.

20. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NO: 26-28.

21. The polynucleotide sequence of claim 1, wherein the transgene encodes a polypeptide according to one or more of SEQ ID NO: 26-28.

22. The polynucleotide sequence of claim 1, further comprising a 5' untranslated region (UTR), a 3' UTR, one or more synthetic intron, one or more polyadenylation site, a sequence encodingone or more fluorophores, a sequence encoding one or more inhibitory oligonucleotides, and / or a sequence encoding one or more tags.

23. The polynucleotide sequence of claim 22, wherein the promoter comprises a glial fibrillary acidic protein (GFAP) promoter (pGFAP).

24. The polynucleotide sequence of claim 22, wherein the promoter comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 42.

25. The polynucleotide sequence of claim 22, wherein the promoter comprises a sequence according to SEQ ID NO: 42.

26. The polynucleotide sequence of claims 22, wherein the 3' UTR comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of SEQ ID NOs: 63-64.

27. The polynucleotide sequence of claim 22, wherein the 3' UTR comprises a sequence according to one or more of SEQ ID NOs: 63-64.

28. The polynucleotide sequence of claim 22, wherein the at least one synthetic intron comprises a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 43.

29. The polynucleotide sequence of claim 22, wherein the at least one synthetic intron comprises a sequence according to SEQ ID NO: 43.

30. The polynucleotide sequence of claim 22, comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 46.

31. The polynucleotide sequence of claim 22, comprising a sequence according to SEQ ID NO: 46.

32. The polynucleotide sequence of claim 22, comprising at least one adeno-associated virus (AAV) inverted terminal repeat sequence (ITR) and / or at least one long-terminal repeat (LTR) sequence, and wherein the AAV ITR comprises an AAV 3' ITR and / or an AAV 5' ITR.

33. The polynucleotide sequence of claim 32, wherein the AAV 3' ITR and / or AAV 5' ITR comprises a sequence at least or exactly 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NOs: 39 and / or 40.

34. The polynucleotide sequence of claim 32, wherein the AAV 3' ITR and / or AAV 5' ITR comprises a sequence according to SEQ ID NOs: 39 and / or 40.

35. The polynucleotide sequence of claim 32, wherein the LTR sequence comprises a sequence at least or exactly 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 41.

36. The polynucleotide sequence of claim 1, comprising a sequence 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 29-38.

37. The polynucleotide sequence of claims 1, comprising a sequence according to any one of SEQ ID NOs: 29-38.

38. The polynucleotide sequence of claim 1, wherein the transgene comprises a human or humanized coding sequence, and / or encodes a human or humanized, polypeptide.

39. The polynucleotide sequence of claim 1, wherein the polynucleotide sequence is comprised in a retroviral capsid.

40. A composition comprising the polynucleotide sequence of claim 1 or the polynucleotide sequence comprised in a retroviral capsid of claim 39.

41. An adeno-associated virus (AAV) particle comprising the polynucleotide sequence of claim 1 comprised in an AAV capsid.

42. The AAV particle of claim 41, comprising an AAV1, AAV2, AAV4, AAV5, AAV8, and / or AAV9 capsid.

43. The AAV particle of claim 41, wherein the AAV particle comprises an AAV2 / 1, AAV2 / 2, AAV2 / 3, AAV2 / 4, AAV2 / 5, AAV2 / 6, AAV2 / 8, or AAV2 / 9 pseudotype.

44. The AAV particle of claim 41, wherein the AAV particle comprises an AAV2 / 9 pseudotype.

45. The AAV particle of claim 41, wherein the AAV particle is capable of retrograde infection.

46. A composition comprising the AAV particle according to claim 41.

47. A lentiviral particle comprising the polynucleotide sequence of claim 1 comprised in a lentiviral capsid.

48. A composition comprising the lentiviral particle according to claim 47.

49. A cell transfected and / or transduced with the polynucleotide sequence, composition, lentiviral particle, and / or AAV particle of any one of claims 1-48.

50. The cell of claim 49, wherein the cell comprises or is a neuron and / or neuroglial cell.

51. The cell of claim 50, wherein the neuroglial cell comprises an astrocyte, an oligodendrocyte, and / or a microglial cell.

52. The cell of claim 49, wherein the cell comprises an astrocyte.

53. The cell of claim 49, wherein the cell is a human cell.

54. A population of cells according to claim 49.

55. A composition comprising the cell or population of cells according to any one of claims 49-54.

56. A pharmacologically acceptable composition comprising the polynucleotide sequence, composition, lentiviral particle, AAV particle, cell, or population of cells according to any one of claims 1-55.

57. A method of modulating astrocyte functionality comprising contacting the astrocyte with the polynucleotide sequence, composition, lentiviral particle, AAV particle, and / or cell of any one of claims 1-56.

58. The method of claim 57, wherein the modulating astrocyte functionality comprises transgenically overexpressing NFIA, SOX9, A2M, and / or MEGF 10.

59. The method of claim 57 or 58, wherein the modulating astrocyte functionality comprises increasing astrocyte phagocytic activity, increasing astrocyte regulation of synaptic function, increasing astrocyte synaptogenesis, increasing astrocyte sensing and response to neurotransmission, increasing astrocyte uptake of plaques, increasing astrocyte clearance of plaques, increasing astrocyte calcium activity, and / or increasing astrocyte morphological complexity.

60. Use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of claims 1-56 in the production of a medicament for modulating astrocyte functionality in a subject in need thereof.

61. A method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of claims 1-57 to the subject.

62. The method of claim 61, comprising administering an AAV particle and / or lentiviral particle.

63. The method of claim 61 or 62, wherein the neurological disorder comprises a neurodevelopmental disorder.

64. The method of claim 61 or 62, wherein the neurological disorder comprises a neurodegenerative disorder.

65. The method of claim 64, wherein the neurological disorder is characterized by loss of synapses, by aberrant synapse pruning, and / or by undesirable accumulation of molecules.

66. The method of any one of claims 61-65, wherein the neurological disorder is characterized by an undesirable accumulation of molecules.

67. The method of claim 66, wherein the molecules comprise amyloid beta (AP), mutant huntingtin, tau protein, and / or alpha-synuclein.

68. The method of any one of claims 66-67, comprising suppressing onset of undesirable accumulation of molecules in the subject.

69. The method of any one of claims 66-68, comprising suppressing plaque formation in the subject.

70. The method of any one of claims 66-69, comprising significantly reducing and / or eliminating undesirable accumulation of molecules in the subject.

71. The method of claim 70, wherein significantly reducing and / or eliminating undesirable accumulation of molecules comprises a decrease greater than 40%, 45%, 50%, 55%, or 60%.

72. The method of any one of claims 54-68, wherein the neurological disorder comprises Alzheimer’s disease, Huntington disease, Parkinson’s disease, frontal -temporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Pick disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, corticobasal syndrome, Richardson syndrome, pure akinesia with gait freezing, cerebellar ataxia, vanishing white matter (VWM) disease, autism spectrum disorders (ASDs), down syndrome, hyperekplexia, epilepsy, other developmental neurological disorders (e.g., applicable rare but impactful neurological diseases, e.g., applicable diseases described by the National Institute of Neurological Disorders and Stroke), and / or aging-related cognitive decline.

73. The method of claim 72, wherein the neurological disorder comprises Alzheimer’ s disease.

74. The method of any one of claims 61-73, wherein the administering comprises injecting into the central nervous system.

75. The method of any one of claims 61-74, wherein the administering comprises injecting into the peripheral nervous system.

76. The method of any one of claims 61-75, wherein the administering comprises injecting into the cerebral spinal fluid (CSF).

77. The method of any one of claims 61-76, wherein the administering comprises intracranial injection.

78. The method of any one of claims 61-77, wherein the administering comprises intracranial injection into the hippocampus and / or cortex.

79. The method of any one of claims 61-78, wherein the administering occurs prior to and / or after an onset of symptoms of the neurological disorder in the subject.

80. The method of claim 79, wherein the administering occurs prior to the onset of symptoms of the neurological disorder in the subject.

81. The method of claim 79, wherein the administering occurs after the onset of symptoms of the neurological disorder in the subject.

82. The method of any one of claims 61-81, wherein the administering occurs multiple times.

83. The method of any one of claims 61-82, comprising suppressing onset of Ap plaque formation in the subject.

84. The method of any one of claims 61-83, comprising suppressing Ap plaque formation in the subject.

85. The method of any one of claims 61-84, comprising significantly reducing and / or eliminating Ap plaques in the subject.

86. The method of any one of claims 61-85, comprising preserving neuronal integrity in the subject.

87. The method of any one of claims 61-86, comprising suppressing progression of benchmarks of disorder pathogenesis in the subject.

88. The method of claim 87, comprising suppressing progression of benchmarks of Alzheimer’s Disease pathogenesis in the subject.

89. The method of any one of claims 61-88, comprising restoring cognitive deficits in the subject.

90. The method of any one of claims 61-78, comprising restoring cognitive function levels of the subject to match cognitive function levels equivalent to those demonstrated prior to onset of the neurological disorder.

91. Use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of claims 1-57 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof.

92. A method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Alzheimer's Disease prior to, during, and / or after an undesirable accumulation of Ap plaques, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of claims 1-57 to a subject.

93. The method of claim 92, comprising administering the lentiviral particle and / or AAV particle to the subject.

94. The method of claim 92 or 93, wherein the administering comprises intracranial injection.

95. The method of any one of claims 92-94, wherein the administering occurs prior to and / or after an onset of symptoms of Alzheimer’s Disease.

96. The method of any one of claims 92-95, wherein the administering occurs more than once.

97. The method of any one of claims 92-96, wherein the administering increases astrocyte uptake and / or clearance of Ap plaques.

98. The method of any one of claims 92-97, comprising preserving neuronal integrity in the subject.

99. Use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of claims 1-57 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Alzheimer's Disease prior to, during, and / or after an undesirable accumulation of Ap plaques in a subject in need thereof.

100. A method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Huntington disease prior to, during, and / or after an undesirable accumulation of mutant huntingtin, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of claims 1-57 to a subject.

101. The method of claim 100, comprising administering the lentiviral particle and / or AAV particle to the subject.

102. The method of claim 100 or 101, wherein the administering comprises intracranial injection.

103. The method of any one of claims 100-102, wherein the administering occurs prior to and / or after an onset of symptoms of Huntington disease.

104. The method of any one of claims 100-103, wherein the administering occurs more than once.

105. The method of any one of claims 100-104, wherein the administering increases astrocyte uptake and / or clearance of mutant huntingtin.

106. The method of any one of claims 100-105, comprising preserving neuronal integrity in the subject.

107. Use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of claims 1-57 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Huntington disease prior to, during, and / or after an undesirable accumulation of mutant huntingtin in a subject in need thereof.

108. A method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Parkinson’ s disease prior to, during, and / or after an undesirable accumulation of alpha-synuclein and / or tau protein, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of claims 1-57 to a subject.

109. The method of claim 108, comprising administering the lentiviral particle and / or AAV particle to the subject.

110. The method of claim 108 or 109, wherein the administering comprises intracranial injection.

111. The method of any one of claims 108-110, wherein the administering occurs prior to and / or after an onset of symptoms of Parkinson’s disease.

112. The method of any one of claims 108-111, wherein the administering occurs more than once.

113. The method of any one of claims 108-112, wherein the administering increases astrocyte uptake and / or clearance of alpha-synuclein and / or tau protein.

114. The method of any one of claims 108-113, comprising preserving neuronal integrity in the subject.

115. Use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of claims 1-57 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing Parkinson’s disease prior to, during, and / or after an undesirable accumulation of alpha-synuclein and / or tau protein in a subject in need thereof.

116. A method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing frontal-temporal dementia prior to, during, and / or after an undesirableaccumulation of tau protein, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of claims 1-57 to a subject.

117. The method of claim 116, comprising administering the lentiviral particle and / or AAV particle to the subject.

118. The method of claim 116 or 117, wherein the administering comprises intracranial injection.

119. The method of any one of claims 116-118, wherein the administering occurs prior to and / or after an onset of symptoms of frontal-temporal dementia.

120. The method of any one of claims 116-119, wherein the administering occurs more than once.

121. The method of any one of claims 116-120, wherein the administering increases astrocyte uptake and / or clearance of tau protein.

122. The method of any one of claims 116-121, comprising preserving neuronal integrity in the subject.

123. Use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of claims 1-57 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing frontal-temporal dementia prior to, during, and / or after an undesirable accumulation of tau protein in a subject in need thereof.

124. A method of delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof, the method comprising administering the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of claims 1-57 to a subject.

125. The method of claim 124, comprising administering the lentiviral particle and / or AAV particle to the subject.

126. The method of claim 124 or 125, wherein the administering comprises intracranial injection.

127. The method of any one of claims 124-126, wherein the administering occurs prior to and / or after an onset of symptoms of the neurological disorder.

128. The method of any one of claims 124-127, wherein the administering occurs more than once.

129. The method of any one of claims 124-128, wherein the administering increases astrocyte uptake and / or clearance of undesirable molecules and / or plaques.

130. The method of any one of claims 124-129, comprising preserving neuronal integrity in the subject.

131. A kit comprising the polynucleotide sequence, lentiviral particle, AAV particle, cell, and / or composition of any one of claims 1-48.

132. Use of a composition comprising the polynucleotide sequence, viral particle, and / or cell of any one of claims 1-57 in the production of a medicament for delaying the onset of, treating, slowing the progression of, reducing the risk of, and / or preventing a neurological disorder in a subject in need thereof.

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