WO2025090427A1 - Glial-targeted relief of hyperexcitability in neurodegenerative diseases - Google Patents

Abstract

This disclosure relates to relief of hyperexcitability and related therapeutic agents and methods for treatment of neurodegenerative diseases.

Description

UR6-23082/161118-04901 Glial-Targeted Relief of Hyperexcitability in Neurodegenerative Diseases CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 63/592,271 filed on October 23, 2023. The content of the application is incorporated herein by reference in its entirety. GOVERNMENT INTERESTS This invention was made with government support under AG072298 awarded by the National Institutes of Health. The government has certain rights in the invention. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (161118.04901SeqList.xml; Size: (7,578 bytes; and Date of Creation: October 15, 2024) is herein incorporated by reference in its entirety. FIELD OF THE INVENTION This disclosure relates to relief of hyperexcitability and related therapeutic agents and methods for treatment of neurodegenerative diseases. BACKGROUND Neurodegenerative diseases, which are characterized by the progressive loss of structure or function of neurons in the brain or peripheral nervous system, affect millions of people worldwide. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Aging is the most important risk factor for developing neurodegenerative diseases. Both the incidence and prevalence of neurodegenerative diseases, including Alzheimer’s and Huntington’s diseases, the frontotemporal dementias (FTD) and the FTD-amyotrophic lateral sclerosis complex, as well as Parkinson’s disease, Lewy body disease, and multisystem atrophy, all increase with age. Each of these disorders is characterized by progressive neuronal loss, which is closely linked to symptomatic disease progression and functional deterioration. Yet normal aging, in contrast, has been shown to result in synaptic loss without substantial declines in neuronal density. Despite intensive research in this field, which has focused primarily on the potential 1 163642794.2 UR6-23082/161118-04901 neurotoxicity of amyloid, tau and synuclein proteins, and on that of neuroinflammation, understanding of the pathobiology of neuronal loss in neurodegenerative disorders remains limited. There is an unmet need for novel therapeutic agents and methods for treating neurodegenerative diseases. SUMMARY This disclosure addresses the need mentioned above in a number of aspects. In one aspect, the disclosure provides a method of (i) reducing brain hyperexcitability or (ii) treating a condition mediated by brain hyperexcitability in a subject in need thereof. The method comprises increasing the level or activity of Na⁺, K⁺ ATPase in a glial cell of the subject. In another aspect, the disclosure features a method of lowering the brain interstitial potassium level in a subject in need thereof. The method comprises increasing the level or activity of Na⁺, K⁺ ATPase in a glial cell of the subject. In each of the methods described above, the subject can have a condition mediated by neuronal hyperexcitability. In some embodiments, the brain interstitial potassium level is restored to about ±30% of that of normal healthy adult human brain. In each of the methods described above, the increasing can comprise reducing the expression level of a FXYD1 gene in the glial cell. In one embodiment, the reducing comprises administering to the subject an agent that reduces the expression level of the FXYD1 gene in the glial cell. In some embodiments, the agent can comprise or encode an inhibitory nucleic acid or a CRISPR/Cas system. In some embodiments, the inhibitory nucleic acid comprises an RNA molecule, such as small interfering RNA (siRNA), short hammerhead RNA (shRNA), or microRNA (miRNA). In some embodiments, the agent is or comprises an expression cassette or a vector comprising a sequence encoding the inhibitory nucleic acid or encoding one or more components of the CRISPR/Cas system. In some embodiments, the sequence is operably linked to a cell-type selective or cell type-specific regulatory sequence. In some embodiments, the cell-type selective or cell type-specific regulatory sequence comprises a promoter or an enhancer or both. The promoter can be a glial cell-specific promoter or a regulatable promoter. The vector can be a viral vector. In each of the methods described above, the glial cell can be an astrocyte, a glial progenitor cell, or an oligodendrocyte. The condition mentioned above can be a UR6-23082/161118-04901 neurodegenerative disease. Examples of the condition or neurodegenerative disease include amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, Huntington's disease, and schizophrenia. In some embodiments, the inhibitory nucleic acid or siRNA molecule comprises or encodes a sequence that is at least 75% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100) complementary to a segment of the FXYD1 gene or RNA. In some embodiments, the CRISPR/Cas system comprises or encodes a guide RNA (gRNA) sequence that is at least 75% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100) complementary to a segment of the FXYD1 gene or RNA. In a further aspect, the disclosure provides an inhibitory nucleic acid or siRNA molecule comprises or encodes a sequence that is at least 75% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100) complementary to a segment of the FXYD1 gene or RNA. In yet another aspect, the disclosure provides a pharmaceutical composition comprising (i) the inhibitory nucleic acid or siRNA molecule disclosed herein and (ii) a pharmaceutically acceptable carrier or excipient. The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objectives, and advantages of the disclosure will be apparent from the description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows detailed information with regards to individual data sources of differentially expressed gene (DEG) lists that were obtained from astrocytic transcriptome data in mouse models of normal aging, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. FIG. 2 is a diagram showing a proposed model: Extracellular K⁺ is elevated in neurodegenerative diseases, in contrast to its typical relative decline in normal healthy aging. As the major role of K⁺ buffering, the dysregulated key genes in astrocytes, such as Fxyd1, contribute to increase cortical [K+]e via impaired buffering in AD and ALS models. Chronic elevation of extracellular K⁺ generates hyperexcitability and reduces neuronal counts in disease models. DETAILED DESCRIPTION OF THE INVENTION This disclosure relates to treating neurodegenerative diseases and relief of hyperexcitability as disrupted ion homeostasis can be a driving force in neurodegenerative UR6-23082/161118-04901 pathology. Certain aspects of this disclosure are based, at least in part, on unexpected discoveries of astrocytic genes that are dysregulated in neurodegenerative disease‐derived astrocytes, but not in otherwise healthy aged astrocytes. For example, by meta‐analysis of a large set of databases covering gene expression by both murine and human astrocytes, as derived from both wild‐type and aged cells and compared to age‐matched cells sourced from patients with a variety of neurodegenerative disorders, the inventors identified astrocytic genes that are dysregulated in neurodegenerative disease‐ derived astrocytes, but not in otherwise healthy aged astrocytes. In doing so, the inventors investigated data derived from both human cells and animal models of amyotrophic lateral sclerosis, Alzheimer's and Huntington's diseases. 1. Neurodegenerative disease and Hyperexcitability A “neurodegenerative disorder” refers to a disease condition involving neural loss mediated or characterized at least partially by at least one of deterioration of neural stem cells and/or progenitor cells. Non-limiting examples of neurological diseases and/or disorders of the present disclosure include polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado-Joseph disease), type 6, type 7, and type 17)), other trinucleotide repeat expansion disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Guillain-Barré syndrome, ischemia stroke, Krabbe disease, kuru, Lewy body dementia, multiple sclerosis, multiple system atrophy, non-Huntingtonian type of Chorea, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, progressive supranuclear palsy, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy (SMA), SteeleRichardson-Olszewski disease, schizophrenia, late onset psychosis, autism spectrum disorder, a movement disorder, and Tabes dorsalis. In some contexts neurodegenerative disorders encompass neurological injuries or damages to the CNS or PNS associated with physical injury (e.g., head trauma, mild to severe traumatic brain injury (TBI), diffuse axonal injury, cerebral contusion, acute brain swelling, and the like). UR6-23082/161118-04901 In some embodiments the neurodegenerative disorder is a disorder that is associated with neuronal hyperexcitability. A common feature in most neurodegenerative diseases is neuronal hyperexcitability, an aberrant electrical activity or a state in which neural networks exhibit an increased likelihood to be excited or activated. Neuronal hyperexcitability may be involved in spinal cord injury, stroke, traumatic brain injury, hearing loss, epilepsy, painful neuropathies, attention deficit hyperactivity disorder, autism, central pain syndromes, neurodegenerative diseases, multiple sclerosis, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease, frontotemporal dementia, schizophrenia, Rasmussen's encephalitis, Huntington's disease, alcoholism or alcohol withdrawal and over-rapid benzodiazepine withdrawal. The extracellular concentration of brain potassium, [K⁺]e, a potent modulator of cortical network activity, is altered in neurodegeneration, compared to that of normal healthy aging. To this end, the inventors studied a variety of murine models, and examined whether disrupted extracellular K⁺ is potentially critical to degenerative neuronal loss, due to its impact on neuronal membrane potential and enablement of pathological hyperexcitability. Because of the causal role of dysregulated high interstitial potassium in the network hyperexcitability and excitotoxicity in these neurodegenerative disorders, the inventors focused on genes involved in glial potassium transport, which are disrupted in each condition, but which are not dysregulated in normal healthy aging. The inventors identified potassium regulatory genes that were dysregulated in disease‐derived astrocytes but not in normally‐aged astrocytes. Among these was FXYD1, which is known to negatively regulate Na/K‐ATPase. It was found that FXYD1 is aberrantly over‐expressed in astrocytes derived from each of these disease conditions, but not in normal wild‐type aged astrocytes. The astrocytic over‐expression of FXYD1 would be expected to suppress Na/K‐ATPase activity, and by so doing raise extracellular hence and brain interstitial K, which in turn would increase neuronal network excitability, and its associated long‐term excitotoxicity. As such, glial‐specific knock‐down of FXYD1 gene expression can be used as a therapeutic strategy, in that its glial‐targeted suppression can allow one to relieve both the network hyperexcitability and excitotoxicity that characterize these neurodegenerative disorders. As disclosed herein, this may be accomplished by, e.g., plasmid or viral delivery of FXYD1 shRNAi or CRISPR‐mediated epigenetic knock‐ down vectors to central astrocytes, targeting the latter by means of glialspecific regulatory sequences, and/or the use of viral vectors with cell‐type specific binding or infection. Shown below are an exemplary protein sequence of Homo sapiens FXYD1 and nucleic acid sequences encoding the proteins and corresponding mRNAs. UR6-23082/161118-04901 MASLGHILVFCVGLLTMAKAESPKEHDPFTYDYQSLQIGGLVIAGILFILGILIVLSRRCRC KFNQQQRTGEPDEEEGTFRSSIRRLSTRRR (SEQ ID NO: 1) A. Homo sapiens FXYD domain containing ion transport regulator 1 (FXYD1), transcript variant a, mRNA; NCBI Reference Sequence: NM_005031.5 (SEQ ID NO: 2) 1 ccttttctcg ttgctgccca gggaggagac ggggtgacct ttcccacagg ggcagcctgt 61 ggcgatgtgg cagctgggcc tcaccccggc agggctgtgc gtgaccccct gagtggggga 121 aggcaggctg ttgccatggt ggcctgagcg agcagaattc ctccagggac aatggcgtct 181 cttggccaca tcttggtttt ctgtgtgggt ctcctcacca tggccaaggc agaaagtcca 241 aaggaacacg acccgttcac ttacgactac cagtccctgc agatcggagg cctcgtcatc 301 gccgggatcc tcttcatcct gggcatcctc atcgtgctga gcagaagatg ccggtgcaag 361 ttcaaccagc agcagaggac tggggaaccc gatgaagagg agggaacttt ccgcagctcc 421 atccgccgtc tgtccacccg caggcggtag aaacacctgg agcgatggaa tccggccagg 481 actcccctgg cacctgacat ctcccacgct ccacctgcgc gcccaccgcc ccctccgccg 541 ccccttcccc agccctgccc ccgcagactc cccctgccgc caagacttcc aataaaacgt 601 gcgttcctct cgacagcact ttgtcggtct cggtccctca gcgcgaaacg ccagcgccac 661 tgggccccag ca B. Homo sapiens FXYD domain containing ion transport regulator 1 (FXYD1), transcript variant b, mRNA; NCBI Reference Sequence: NM_021902.4 (SEQ ID NO: 3) 1 aaagtgctca gcccccgggg cacagcagga cgtttggggg ccttctttca gcaggggaca 61 gcccgattgg ggacaatggc gtctcttggc cacatcttgg ttttctgtgt gggtctcctc 121 accatggcca aggcagaaag tccaaaggaa cacgacccgt tcacttacga ctaccagtcc 181 ctgcagatcg gaggcctcgt catcgccggg atcctcttca tcctgggcat cctcatcgtg 241 ctgagcagaa gatgccggtg caagttcaac cagcagcaga ggactgggga acccgatgaa 301 gaggagggaa ctttccgcag ctccatccgc cgtctgtcca cccgcaggcg gtagaaacac 361 ctggagcgat ggaatccggc caggactccc ctggcacctg acatctccca cgctccacct 421 gcgcgcccac cgccccctcc gccgcccctt ccccagccct gcccccgcag actccccctg 481 ccgccaagac ttccaataaa acgtgcgttc ctctcgacag cactttgtcg gtctcggtcc 541 ctcagcgcga aacgccagcg ccactgggcc ccagca C. Homo sapiens FXYD domain containing ion transport regulator 1 (FXYD1), transcript variant c, mRNA; NCBI Reference Sequence: NM_001278717.2 (SEQ ID NO: 4) 1 atggcgtctc ttggccacat cttggttttc tgtgtgggtc tcctcaccat ggccaaggca 61 gaaagtccaa aggaacacga cccgttcact tacgactacc agtccctgca gatcggaggc 121 ctcgtcatcg ccgggatcct cttcatcctg ggcatcctca tcgtgctgag cagaagatgc 181 cggtgcaagt tcaaccagca gcagaggact ggggaacccg atgaagagga gggaactttc 241 cgcagctcca tccgccgtct gtccacccgc aggcggtag D. Homo sapiens FXYD domain containing ion transport regulator 1 (FXYD1), transcript variant d, mRNA; NCBI Reference Sequence: NM_001278718.2 (SEQ ID NO: 5) 1 gggcggagag ggcagggagc tgggatttcg cggggcacag tgaggccggg catgtaggca 61 ggtgggactt gggcgtgccc tgctgtctcc tgctctgtgt ttgtgtgagg cagcgcctcc 121 tctgccctgc cagggacaat ggcgtctctt ggccacatct tggttttctg tgtgggtctc 181 ctcaccatgg ccaaggcaga aagtccaaag gaacacgacc cgttcactta cgactaccag 241 tccctgcaga tcggaggcct cgtcatcgcc gggatcctct tcatcctggg catcctcatc 301 gtgctgagca gaagatgccg gtgcaagttc aaccagcagc agaggactgg ggaacccgat UR6-23082/161118-04901 361 gaagaggagg gaactttccg cagctccatc cgccgtctgt ccacccgcag gcggtagaaa 421 cacctggagc gatggaatcc ggccaggact cccctggcac ctgacatctc ccacgctcca 481 cctgcgcgcc caccgccccc tccgccgccc cttccccagc cctgcccccg cagactcccc 541 ctgccgccaa gacttccaat aaaacgtgcg ttcctctcga cagcactttg tcggtctcgg 601 tccctcagcg cgaaacgcca gcgccactgg gccccagca One way to address the aberrant overexpression of FXYD1 is through the use of RNA interference to reduce expression of the FXYD1 gene. This can be accomplished with a microRNA-based gene therapy. For example, an administration of an AAV vector delivering an expression cassette of a therapeutic miRNA precursor that targets FXYD1 mRNA can be used to activate the endogenous mRNA silencing machinery to reduce FXYD1 translation in glial cells (e.g., glial progenitor cells, astrocytes, or oligodendrocytes). Moreover, the use of AAV vectors with higher tropism for such glial cells can be used to improve safety and therapeutic efficacy. An antisense oligonucleotide strategy can be used to suppress the overexpression of FXYD1 too. In some embodiments, the present disclosure employs viral vectors such as AAV vectors to deliver therapeutic nucleic acids, such as siRNAs, targeting one or more genes or RNAs encoding proteins of toxic gain-of-function, into cells with high efficiency. In some embodiments, the AAV vectors encoding RNAi molecules, e.g., siRNA molecules of the present disclosure may increase the delivery of active agents into glial cells (e.g., glial progenitor cells, astrocytes, or oligodendrocytes). The therapeutic nucleic acids or polynucleotides may be able to inhibit gene expression (e.g., mRNA level) of a toxic gain-of- function protein significantly inside cells; therefore, ameliorating defects induced or caused by the protein inside the cells such as inhibiting the activity of the sodium/potassium-transporting ATPase and/or aggregation of protein and formation of inclusions. Such inhibitory nucleic acids, e.g., siRNAs. may be used for treating various inherited and/or acquired neurodegenerative disorders. According to the present disclosure, methods for treating and/or ameliorating the disorder in a patient comprises administering to the patient an effective amount of at least one therapeutic nucleic acid (e.g., a polynucleotide encoding one or more siRNA duplexes) into cells and allowing the inhibition/silence of the gene expression. 2. Nucleic Acids Certain aspects of the disclosure provide one or more inhibitory nucleic acids (e.g., inhibitory RNA molecules), polynucleotides encoding such inhibitory nucleic acids, and transgenes engineered to express such inhibitory nucleic acids. The one or more inhibitory nucleic acids may target the same gene (e.g., hybridize or specifically bind to a same mRNA UR6-23082/161118-04901 sequence or different mRNA sequences of the same gene) or different genes (e.g., hybridize or specifically bind to mRNAs of different genes). A. Inhibitory Nucleic Acids An inhibitory nucleic acid refers to a nucleic acid that can bind to a target nucleic acid (e.g., a target RNA) in a cell and reduce or inhibit the level or function of the target nucleic acid in the cell. Example of the inhibitory nucleic acid include antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, small interfering (si)RNA compounds, single- or double-stranded RNA interference (RNAi) compounds, modified bases/locked nucleic acids (LNAs), peptide nucleic acids (PNAs), and other oligomeric compounds or oligonucleotide mimetics that specifically hybridize to at least a portion of a target nucleic acid and modulate its level or function. In some embodiments, the inhibitory nucleic acid can be an antisense RNA, an antisense DNA, a chimeric antisense oligonucleotide, an antisense oligonucleotide comprising modified linkages, an interference RNA (iRNA), a short or small interfering RNA (siRNA), a micro RNA or micro interfering RNA (miRNA), a small temporal RNA (stRNA), a short hairpin RNA (shRNA), a small RNA-induced gene activation agent (RNAa), a small activating RNA (saRNA), or combinations thereof. In some examples, the inhibitory nucleic acid is an inhibitory RNA molecule that mediates RNA interference. RNA interference (RNAi) is a process discovered in 1998 (Fire et al., 1998) by which cells regulate gene expression. A double-stranded RNA (dsRNA) in the cell cytoplasm triggers the RNAi pathway in which the double-stranded RNA is processed into small double-stranded fragments of approximately 21–23 nucleotides in length by the RNAse III-like enzyme DICER. These double-stranded fragments are integrated into a multi-subunit protein called the RNA- induced silencing complex (RISC). The RISC contains Argonaute proteins that unwind the double-stranded fragment into a passenger strand that is removed from the complex and a guide strand that is complementary to a target sequence in a specific mRNA and which directs the RISC complex to cleave or suppress the translation of the specific target mRNA molecule (Kotowska-Zimmer et al., 2021). In this way the gene that encoded the mRNA molecule is rendered essentially inactive or “silenced.” RNAi technology may employ three kinds of tools: synthetic siRNAs, vector-based shRNAs, and artificial miRNAs (amiRNAs). Synthetic siRNAs are exogenous double stranded RNAs that must be delivered into cells and must overcome stability and pharmacokinetic challenges. shRNAs are artificial RNA molecules with a tight hairpin loop structure that are UR6-23082/161118-04901 delivered to cells using plasmids or viral expression vectors. shRNAs are typically transcribed from strong pol III promoters (e.g., U6 or H1) and enter the RNAi pathway as hairpins. However, transcription driven by strong pol III promoters can produce supraphysiologic levels of shRNA that saturate the endogenous miRNA biogenesis machinery, resulting in toxicity. AmiRNAs embed a target-specific shRNA insert in a scaffold based on a natural primary miRNA (pri-miRNA). This ensures proper processing and transport similar to endogenous miRNAs, resulting in lower toxicity (Kotowska-Zimmer et al., 2021). In some embodiments of this disclosure, the inhibitory RNA molecule can be an siRNA, a miRNA (including an amiRNA), or an shRNA. An siRNA is known in the art as a double-stranded RNA molecule of approximately 19-25 (e.g., 19-23) base pairs in length that induces RNAi in a cell. In some embodiments, the siRNA sequence can also be inserted into an artificial miRNA scaffold ("shmiRNA"). An shRNA is known in the art as an RNA molecule comprising approximately 19-25 (e.g., 19-23) base pairs of double stranded RNA linked by a short loop (e.g., about 4-11 nucleotides) that induces RNAi in a cell. An miRNA is known in the art as an RNA molecule that induces RNAi in a cell comprising a short (e.g., 19-25 base pairs) sequence of double-stranded RNA linked by a loop and containing one or more additional sequences of double-stranded RNA comprising one or more bulges (e.g., mis-paired or unpaired base pairs). As used herein, the term "miRNA" encompasses endogenous miRNAs as well as exogenous or heterologous miRNAs. In some embodiments, "miRNA" may refer to a pri-miRNA or a pre-miRNA. During miRNA processing, a pri-miRNA transcript is produced. The pri-miRNA is processed by Drosha- DGCR8 to produce a pre-miRNA by excising one or more sequences to leave a pre-miRNA with a 5' flanking region, a guide strand, a loop region, a non-guide strand, and a 3' flanking region; or a 5' flanking region, a non-guide strand, a loop region, a guide strand, and a 3' flanking region. The pre-miRNA is then exported to the cytoplasm and processed by Dicer to yield a siRNA with a guide strand and a non-guide (or passenger) strand. The guide strand is then used by the RISC complex to catalyze gene silencing, e.g., by recognizing a target RNA sequence complementary to the guide strand. Further description of miRNAs may be found, e.g., in WO 2008/150897. The recognition of a target sequence by a miRNA is primarily determined by pairing between the target and the miRNA seed sequence, e.g., nucleotides 1-8 (5' to 3') of the guide strand (see, e.g., Boudreau, R. L. et al. (2013) Nucleic Acids Res.41:e9). In some embodiments of this disclosure, an inhibitory RNA molecule forms a hairpin structure. Generally, hairpin-forming RNAs are arranged into a self-complementary "stem- UR6-23082/161118-04901 loop" structure that includes a single nucleic acid encoding a stem portion having a duplex comprising a sense strand (e.g., passenger strand) connected to an antisense strand (e.g., guide strand) by a loop sequence. The passenger strand and the guide strand share complementarity. In some embodiments, the passenger strand and guide strand share 100% complementarity. In some embodiments, the passenger strand and guide strand share at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% complementarity. A passenger strand and a guide strand may lack complementarity due to a base-pair mismatch. In some embodiments, the passenger strand and guide strand of a hairpin-forming RNA may have at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 at least 8, at least 9, or at least 10 mismatches. Generally, the first 2-8 nucleotides of the stem (relative to the loop) are referred to as "seed" residues and play an important role in target recognition and binding. The first residue of the stem (relative to the loop) is referred to as the "anchor" residue. In some embodiments, hairpin-forming RNA have a mismatch at the anchor residue. In some embodiments, an inhibitory RNA molecule is processed in a cell (or subject) to form a "mature miRNA". Mature miRNA is the result of a multistep pathway which is initiated through the transcription of primary miRNA from its miRNA gene or intron, by RNA polymerase II or III generating the initial precursor molecule in the biological pathway resulting in miRNA. Once transcribed, pri-miRNA (often over a thousand nucleotides long with a hairpin structure) is processed by the Drosha enzyme which cleaves pri-miRNA near the junction between the hairpin structure and the ssRNA, resulting in precursor miRNA (pre- miRNA). The pre-miRNA is exported to the cytoplasm where is further reduced by Dicer enzyme at the pre-miRNA loop, resulting in duplexed miRNA strands. Of the two strands of a miRNA duplex, one arm, the guide strand (miR), is typically found in higher concentrations and binds and associates with the Argonaute protein which is eventually loaded into the RNA-inducing silencing complex. The guide strand miRNA-RISC complex helps regulates gene expression by binding to its complementary sequence of mRNA, often in the 3' UTR of the mRNA. The non-guide strand of the miRNA duplex is known as the passenger strand and is often degraded, but may persist and also act either intact or after partial degradation to have a functional role in gene expression. In some embodiments, a transgene is engineered to express an inhibitory nucleic acid (e.g., an miRNA) having a guide strand that targets a human gene. "Targeting" refers to hybridization or specific binding of an inhibitory nucleic acid to its cognate (e.g., complementary) sequence on a target gene (e.g., mRNA transcript of a target gene). In some embodiments, an inhibitory nucleic acid that targets a gene transcript shares a region of UR6-23082/161118-04901 complementarity with the target gene that is 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, or 30 nucleotides in length. In some embodiments, a region of complementarity is more than 30 nucleotides in length. Typically, the guide strand may target a human gene transcript associated with a disease or disorder. Examples include that for FXYD1. In some embodiments, a guide strand that targets any of the gene transcripts can be complementary to a segment of the sequences set forth above, such as SEQ ID NOs: 2-4. In some embodiments, the inhibitory nucleic acid is 5 to 300 bases in length (e.g., 10- 30, 15-25, 19-22, 25-50, 40-90, 60-90, 75-100, 90-150, 110-200, 150-250, 200-300, etc. nucleotides in length). The inhibitory nucleic acid sequence encoding a pre-miRNA or mature miRNA may be 10-50, or 5-50 bases length. Scaffold In certain embodiments, an inhibitory RNA molecule may be encoded in an inhibitory nucleic acid that comprises a molecular scaffold. As used herein a "molecular scaffold" is a framework or starting molecule that forms the sequence or structural basis against which to design or make a subsequent molecule. In some embodiments, the molecular scaffold comprises at least one 5' flanking, or one 3' flanking region, or both. As a non-limiting example, the 5' or 3' flanking region may comprise a 5' or 3' flanking sequence which may be of any length and may be derived in whole or in part from wild type microRNA sequence or be a completely artificial sequence. In some embodiments, one or both of the 5' and 3' flanking sequences may be absent. In some embodiments the 5' and 3' flanking sequences may be of the same or different length. In some embodiments the 5' or 3' flanking sequence may be from 1-10 nucleotides in length, from 5-15 nucleotides in length, from 10-30 nucleotides in length, from 20-50 nucleotides in length, greater than 40 nucleotides in length, greater than 50 nucleotides in length, greater than 100 nucleotides in length or greater than 200 nucleotides in length. In some embodiments, an inhibitory nucleic acid sequence comprising or encoding a pri-miRNA scaffold and is at least 200, 250, 260, 270, 280, 290, or 300 bases in length. In some embodiments, the inhibitory nucleic acid comprises or consists of a sequence of bases at least 80% or 90% complementary to, e.g., at least 5, 10, 15, 20, 25 or 30 bases of, or up to 30 or 40 bases of, a target nucleic acid (e.g., a human mRNA, such as that of FXYD1), or comprises a sequence of bases with up to 3 mismatches (e.g., up to 1, or up to 2 mismatches) over 10, 15, 20, 25 or 30 bases of the target nucleic acid. UR6-23082/161118-04901 In some embodiments, an inhibitory nucleic acid is an artificial miRNA (amiRNA). An amiRNA is derived by modifying a native miRNA to replace natural targeting regions of pre- mRNA with a targeting region of interest. For example, a naturally occurring, expressed miRNA can be used as a scaffold or backbone (e.g., a pri-miRNA scaffold), with the stem sequence replaced by that of an miRNA targeting a gene of interest. An artificial precursor microRNA (pre-amiRNA) is normally processed such that one single stable small RNA is preferentially generated. Forming a stem of a stem loop structure is a minimum of the inhibitory nucleic acid encoding at least one siRNA, miRNA, shRNA or other RNAi agent described herein. In some embodiments, the siRNA, miRNA, shRNA, or other RNAi agent described herein comprises at least one nucleic acid sequence which is in part complementary or will hybridize to a target sequence. In some embodiments, the 5' arm of the stem loop structure of the inhibitory nucleic acid comprises a nucleic acid sequence encoding an anti-sense sequence (i.e., a guide sequence/strand). In some other embodiments, the 3' arm of the stem loop structure of the inhibitory nucleic acid comprises a nucleic acid sequence encoding the anti-sense/guide sequence. In certain embodiments, separating the sense sequence and antisense sequence of the stem loop structure of the inhibitory nucleic acid is a loop sequence (also known as a loop motif, linker or linker motif). The loop sequence may be of any length, between 4-30 nucleotides, between 4-20 nucleotides, between 4-15 nucleotides, between 5-15 nucleotides, between 6-12 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, and/or 15 nucleotides. Some aspects of the disclosure relate to a nucleic acid sequence encoding a guide strand targeting a human gene that is inserted in a human or non-human (e.g., mouse) pri-miRNA scaffold. In some embodiments, a pri-miRNA scaffold can be selected from mir-16-1, miR-21, miR-23a, miRNA-30a, miR-31, miR-122, miR-155, or miR-451. In some embodiments, the pri-miRNA scaffold flanks an inhibitory nucleic acid targeting a human mRNA (such as that of FXYD1) or a target sequence thereof. Accordingly, the inhibitory nucleic acids can be used to mediate gene silencing, specifically FXYD1, via interaction with RNA transcripts or alternately by interaction with particular gene sequences, wherein such interaction results in gene silencing either at the transcriptional level or post-transcriptional level such as, for example, but not limited to, RNAi or through cellular processes that modulate the chromatin structure or methylation patterns of UR6-23082/161118-04901 the target and prevent transcription of the target gene, with the nucleotide sequence of the target thereby mediating silencing. These inhibitory nucleic acids can comprise short double-stranded regions of RNA. The double stranded RNA molecules can comprise two distinct and separate strands that can be symmetric or asymmetric and are complementary, i.e., two single-stranded RNA molecules, or can comprise one single-stranded molecule in which two complementary portions, e.g., a sense region and an antisense region, are base-paired, and are covalently linked by one or more single-stranded “hairpin” areas (i.e. loops) resulting in, for example, a single-stranded short- hairpin polynucleotide or a circular single-stranded polynucleotide. The linker can be polynucleotide linker or a non-nucleotide linker. In some embodiments, the linker is a non-nucleotide linker. In some embodiments, a hairpin or circular inhibitory nucleic acid molecule contains one or more loop motifs, wherein at least one of the loop portion of the molecule is biodegradable. For example, a single-stranded hairpin molecule can be designed such that degradation of the loop portion of the molecule in vivo can generate a double-stranded siRNA molecule with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising 1, 2, 3 or 4 nucleotides. Or alternatively, a circular inhibitory nucleic acid molecule can be designed such that degradation of the loop portions of the molecule in vivo can generate, for example, a double-stranded siRNA molecule, with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising about 2 nucleotides. In symmetric inhibitory nucleic acid molecules, each strand, the sense (passenger) strand and antisense (guide) strand, can be independently about 15 to about 40 (e.g., about 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 in length. In asymmetric inhibitory nucleic acid molecules, the antisense region or strand of the molecule can be about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in length, wherein the sense region is about 3 to about 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) nucleotides in length. In yet other embodiments, inhibitory nucleic acid molecules described herein can comprise single stranded hairpin siRNA molecules, wherein the molecules can be about 25 to about 70 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length. UR6-23082/161118-04901 In still other embodiments, the molecules may comprise single-stranded circular siRNA molecules, wherein the molecules are about 38 to about 70 (e.g., about 38, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length. In various symmetric embodiments, the inhibitory nucleic acid duplexes described herein independently may comprise about 15 to about 40 base pairs (e.g., about 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). In yet other embodiments, where the inhibitory nucleic acid molecules described herein are asymmetric, the molecules may comprise about 3 to 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) base pairs). In still other embodiments, where the inhibitory nucleic acid molecules are hairpin or circular structures, the molecules can comprise about 3 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs. The sense strand and antisense strands or sense region and antisense regions of the inhibitory nucleic acid molecules can be complementary. Also, the antisense strand or antisense region can be complementary to a nucleotide sequence or a portion thereof of a target RNA (e.g., that of FXYD1). The sense strand or sense region if the inhibitory nucleic acid can comprise a nucleotide sequence of the target gene or a portion thereof. In some embodiments, the inhibitory nucleic acid can be optimized (based on sequence) or chemically modified to minimize degradation prior to and/or upon delivery to the tissue of interest. Commercially available sources for these interfering nucleic acids include, but are not limited to, Thermo-Fisher Scientific/Ambion, Origene, Qiagen, Dharmacon, and Santa Cruz Biotechnology. In some embodiments, such optimizations and/or modifications may be made to assure sufficient payload of the inhibitory nucleic acid is delivered to the tissue of interest. Other embodiments include the use of small molecules, aptamers, or oligonucleotides designed to decrease the expression of a target gene by either binding to a gene's DNA to limit expression, e.g., antisense oligonucleotides, or impose post-transcriptional gene silencing (PTGS) through mechanisms that include, but are not limited to, binding directly to the targeted transcript or gene product or one or more other proteins in such a way that said gene's expression is reduced; or the use of other small molecule decoys that reduce the specific gene's expression. Any inhibitory nucleic acid molecule or construct described herein can comprise one or more chemical modifications. Modifications can be used to improve in vitro or in vivo characteristics such as stability, activity, toxicity, immune response (e.g., prevent stimulation UR6-23082/161118-04901 of an interferon response, an inflammatory or pro-inflammatory cytokine response, or a Toll- like Receptor (TlF) response), and/or bioavailability. Chemically modified molecules exhibit improved RNAi activity compared to corresponding unmodified or minimally modified molecules. The chemically modified motifs disclosed herein provide the capacity to maintain RNAi activity that is substantially similar to unmodified or minimally modified active siRNA while at the same time providing nuclease resistance and pharmacokinetic properties suitable for use in therapeutic applications. In various embodiments, the inhibitory nucleic acid molecules described herein can comprise modifications wherein any (e.g., one or more or all) nucleotides present in the sense and/or antisense strand are modified nucleotides. In some embodiments, the molecules can be partially modified (e.g., about 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, 45, 50, 55, 60, 65, 70, 75, 80 nucleotides are modified) with chemical modifications. In other embodiments, the molecules may be completely modified (e.g., 100% modified) with chemical modifications. The chemical modification within a single molecule can be the same or different. In some embodiments, at least one strand has at least one chemical modification. In other embodiments, each strand has at least one chemical modifications, which can be the same or different, such as, sugar, base, or backbone (i.e., internucleotide linkage) modifications. In other embodiments, a molecules may contain at least 2, 3, 4, 5, or more different chemical modifications. Non-limiting examples of suitable chemical modifications include those disclosed in, e.g., U.S. Patent No.8202979 and U.S.20050266422 and include sugar, base, and phosphate, non-nucleotide modifications, and/or any combination thereof. In various embodiments, a majority of the pyrimidine nucleotides present in the double- stranded inhibitory nucleic acid molecule comprises a sugar modification. In yet other embodiments, a majority of the purine nucleotides present in the double-stranded molecule comprises a sugar modification. In certain instances, the purines and pyrimidines are differentially modified at the 2′-sugar position (i.e., at least one purine has a different modification from at least one pyrimidine in the same or different strand at the 2′-sugar position). In certain specific embodiments, at least one modified nucleotide is a 2′-deoxy-2-fluoro nucleotide, a 2′-deoxy nucleotide, or a 2′-O-alkyl (e.g., 2′-O-methyl) nucleotide. In yet other embodiments, at least one nucleotide has a ribo-like, Northern or A form helix configuration (see e.g., Saenger, Principles of Nucleic Acid Structure, Springer-Verlag ed., 1984). Non- UR6-23082/161118-04901 limiting examples of nucleotides having a Northern configuration include locked nucleic acid (LNA) nucleotides (e.g., 2′-O, 4′-C-methylene-(D-ribofuranosyl) nucleotides); 2′- methoxyethoxy (MOE) nucleotides; 2′-methyl-thio-ethyl nucleotides, 2′-deoxy-2′-fluoro nucleotides, 2′-deoxy-2′-chloro nucleotides, 2′-azido nucleotides, 2′-O-trifluoromethyl nucleotides, 2′-O-ethyl-trifluoromethoxy nucleotides, 2′-O-difluoromethoxy-ethoxy nucleotides, 4′-thio nucleotides and 2′-O-methyl nucleotides. The inhibitory nucleic acids described herein can be obtained using a number of techniques known to those of skill in the art. For example the inhibitory nucleic acids can be chemically synthesized or may be encoded by plasmid (e.g., transcribed as sequences that automatically fold into duplexes with hairpin loops). siRNA can also be generated by cleavage of longer dsRNA. In some embodiments, inhibitory nucleic acids are chemically synthesized. Oligonucleotides (e.g., certain modified oligonucleotides or portions of oligonucleotides lacking ribonucleotides) can be synthesized using protocols known in the art, for example as described in Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995, Nucleic Acids Res.23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio., 74, 59, Brennan et al., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. Alternatively, the inhibitory nucleic acids can be synthesized separately and joined together post-synthetically, for example, by ligation (Moore et al., 1992, Science 256, 9923; Draper et al., International PCT Publication No. WO 93/23569; Shabarova et al., 1991, Nucleic Acids Research 19, 4247; Bellon et al., 1997, Nucleosides &Nucleotides, 16, 951; Bellon et al., 1997, Bioconjugate Chem.8, 204), or by hybridization following synthesis and/or deprotection. In some embodiments, inhibitory nucleic acids can be expressed and delivered from transcription units inserted into recombinant DNA or RNA vectors. The recombinant vectors can be DNA plasmids or viral vectors. Viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. B. CRISPR/Cas System In one aspect, suppressing or knocking down of one or more of the genes described herein can also be achieved via a CRISPR-Cas guided nuclease using a CRISPR/Cas system UR6-23082/161118-04901 and related methods known in the art. See, e.g., US11225659B2, WO2021168799A1, WO2022188039A1, WO2022188797A1, WO2022068912A1, and WO2022047624A1. See also Gimenez et al., “CRISPR-on System for the Activation of the Endogenous human INS gene,” Gene Therapy 23: 543-547 (2016); Wiedenheft et al., “RNA-Guided Genetic Silencing Systems in Bacteria and Archaea,” Nature 482:331-338 (2012); Zhang et al., “Multiplex Genome Engineering Using CRISPR/Cas Systems,” Science 339(6121):819-23 (2013); and Gaj et al., “ZFN, TALEN, and CRISPR/Cas-based Methods for Genome Engineering,” Cell 31(7):397-405 (2013), which are hereby incorporated by reference in their entirety. CRISPR-Cas system is a genetic technique which allows for sequence-specific control of gene expression in prokaryotic and eukaryotic cells by guided nuclease double-stranded DNA cleavage. It is based on the bacterial immune system-derived CRISPR (clustered regularly interspaced palindromic repeats) pathway. In another aspect, this application provides a complex comprising: (i) a protein composition that comprise a Cas protein, or orthologs, homologs, derivatives, conjugates, functional fragments thereof, conjugates thereof, or fusions thereof; and (ii) a polynucleotide composition, comprising a CRISPR RNA and a programmable spacer sequence or guide sequence complementary to at least a portion of a target RNA or DNA. The programmable guide RNA, CRISPR RNA and the Cas protein together form a CRISPR/Cas-based module for sequence targeting and recognition. The target RNA can be any RNA molecule of interest, including naturally-occurring and engineered RNA molecules. The target RNA can be an mRNA, a tRNA, a ribosomal RNA (rRNA), a microRNA (miRNA), an interfering RNA (siRNA), a ribozyme, a riboswitch, a satellite RNA, a microswitch, a microzyme, or a viral RNA. In some embodiments, the target nucleic acid is associated with a condition or disease, such as a condition or disorder mediated by disrupted ion homeostasis and/or hyperexcitability, and related disorders as described herein. Thus, in some embodiments, the systems described herein can be used to treat such a condition or disease by targeting these nucleic acids. For instance, the target nucleic acid associated with a condition or disease may be an RNA molecule that is overexpressed in a diseased cell, an old or older cell, or a senescent cell. The target nucleic acid may also be a toxic RNA and/or a mutated RNA (e.g., an mRNA molecule having a splicing defect or a mutation). The target nucleic acid may also be an miRNA. For example, the target nucleic acid may be that of a gene whose increased activity has been linked to loss of [K+]e homeostasis and pathological increases in extracellular K⁺ which contribute to hyperexcitability and neuronal loss in neurodegenerative diseases. UR6-23082/161118-04901 Various Cas proteins can be used in this invention. A Cas protein, CRISPR-associated protein, or CRISPR protein, used interchangeably, refers to a protein of or derived from a CRISPR-Cas Class 1 or Class 2, including type I, type II, type III, type IV, type V, or type VI system, which has an RNA-guided DNA-binding. Non-limiting examples of suitable CRISPR/Cas proteins include Cas3, Cas4, Cas5, Cas5e (or CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8a1, Cas8a2, Cas8b, Cas8c, Cas9, Cas10, Cas10d, Cas13, Cas13e, Cas13f, CasF, CasG, CasH, Csy1, Csy2, Csy3, Cse1 (or CasA), Cse2 (or CasB), Cse3 (or CasE), Cse4 (or CasC), Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csz1, Csx15, Csf1, Csf2, Csf3, Csf4, and Cu1966. See e.g., US11225659B2, WO2021168799A1, WO2022188039A1, WO2022188797A1, WO2022068912A1, WO2022047624A1, WO2014144761, WO2014144592, WO2013176772, US20140273226, and US20140273233, the contents of which are incorporated herein by reference in their entireties. C. Recombinant Nucleic Acids Recombinant nucleic acids of the present disclosure include inhibitory nucleic acids described above as well as plasmids and vector genomes that comprise an inhibitory nucleic acid. A recombinant nucleic acid, plasmid or vector genome may comprise regulatory sequences to modulate propagation (e.g., of a plasmid) and/or control expression of a transgene (e.g., an inhibitory nucleic acid). Recombinant nucleic acids may also be provided as a component of a viral vector (e.g., an rAAV vector). Generally, a viral vector includes a vector genome comprising a recombinant nucleic acid packaged in a capsid. D. Regulatory elements The present disclosure includes a recombinant nucleic acid including a transgene (e.g., one encoding an RNA) and various regulatory or control elements (e.g., a woodchuck hepatitis post-transcriptional regulatory element). Typically, regulatory elements are nucleic acid sequence(s) that influence expression of an operably linked polynucleotide. The precise nature of regulatory elements useful for gene expression will vary from organism to organism and from cell type to cell type including, for example, a promoter, enhancer, intron etc., with the intent to facilitate proper heterologous polynucleotide transcription and/or translation. Regulatory control can be affected at the level of transcription, translation, splicing, message stability, etc. Typically, a regulatory control element that modulates transcription is juxtaposed near the 5’ end of the transcribed polynucleotide (i.e., upstream). Regulatory control elements UR6-23082/161118-04901 may also be located at the 3’ end of the transcribed sequence (i.e., downstream) or within the transcript (e.g., in an intron). Regulatory control elements can be located at a distance away from the transcribed sequence (e.g., 1 to 100, 100 to 500, 500 to 1000, 1000 to 5000, 5000 to 10,000 or more nucleotides). However, due to the length of a vector genome (e.g., an AAV vector genome), regulatory control elements are typically within 1 to 1000 nucleotides from the polynucleotide. Promoter As used herein, the term “promoter,” such as a “eukaryotic promoter,” refers to a nucleotide sequence that initiates transcription of a particular gene, or one or more coding sequences in eukaryotic cells (e.g., glial progenitor cells, astrocytes, or oligodendrocytes). A promoter can work with other regulatory elements or regions to direct the level of transcription of the gene or coding sequence(s). These regulatory elements include, for example, transcription binding sites, repressor and activator protein binding sites, and other nucleotide sequences known to act directly or indirectly to regulate the amount of transcription from the promoter, including, for example, attenuators, enhances and silencers. The promoter is most often located on the same strand and near the transcription start site, 5’ of the gene or coding sequence to which it is operably linked. A promoter is generally 100 – 1000 nucleotides in length. A promoter typically increases gene expression relative to expression of the same gene in the absence of a promoter. As used herein, a “core promoter” or “minimal promoter” refers to the minimal portion of a promoter sequence required to properly initiate transcription. It may include any of the following: a transcription start site, a binding site for RNA polymerase and a general transcription factor binding site. A promoter may also comprise a proximal promoter sequence (5’ of a core promoter) that contains other primary regulatory elements (e.g., enhancer, silencer, boundary element, insulator) as well as a distal promoter sequence (3’ of a core promoter). Examples of suitable a promoter include adenoviral promoters, such as the adenoviral major late promoter; heterologous promoters, such as the cytomegalovirus (CMV) promoter; the respiratory syncytial virus promoter; the Rous Sarcoma Virus (RSV) promoter; the albumin promoter; inducible promoters, such as the Mouse Mammary Tumor Virus (MMTV) promoter; the metallothionein promoter; heat shock promoters; the α-1-antitrypsin promoter; the hepatitis B surface antigen promoter; the transferrin promoter; the apolipoprotein A-1 promoter; chicken β-actin (CBA) promoter, the elongation factor 1a promoter (EF1a), the hybrid form of the CBA promoter (CBh promoter), and the CAG promoter (cytomegalovirus early enhancer element and the promoter, the first exon, and the first intron of chicken beta-actin gene and the splice UR6-23082/161118-04901 acceptor of the rabbit beta-globin gene) (Alexopoulou et al. (2008) BioMed. Central Cell Biol. 9:2). A promoter may be constitutive, tissue-specific or regulated. Constitutive promoters are those which cause an operably linked gene to be expressed at all times. In some embodiments, a constitutive promoter is active in most eukaryotic tissues under most physiological and developmental conditions. Regulated promoters are those which can be activated or deactivated. Regulated promoters include inducible promoters, which are usually “off” but which may be induced to turn “on,” and “repressible” promoters, which are usually “on” but may be turned “off.” Many different regulators are known, including temperature, hormones, cytokines, heavy metals and regulatory proteins. The distinctions are not absolute; a constitutive promoter may often be regulated to some degree. In some cases, an endogenous pathway may be utilized to provide regulation of the transgene expression, e.g., using a promoter that is naturally downregulated when the pathological condition improves. A tissue-specific promoter is a promoter that is active in only specific types of tissues, cells or organs. Typically, a tissue-specific promoter is recognized by transcriptional activator elements that are specific to a particular tissue, cell and/or organ. For example, a tissue-specific promoter may be more active in one or several particular tissues (e.g., two, three or four) than in other tissues. In some embodiments, expression of a gene modulated by a tissue-specific promoter is much higher in the tissue for which the promoter is specific than in other tissues. In some embodiments, there may be little, or substantially no activity, of the promoter in any tissue other than the one for which it is specific. Enhancer In another aspect, a recombinant nucleic acid described herein can further comprise an enhancer to increase expression of the transgene (e.g., a RNA molecule disclosed herein). Typically, an enhancer element is located upstream of a promoter element but may also be located downstream or within another sequence (e.g., a transgene). An enhancer may be located 100 nucleotides, 200 nucleotides, 300 nucleotides or more upstream or downstream of a modified nucleic acid. An enhancer typically increases expression of a transgene (e.g., encoding an inhibitory nucleic acid) beyond the increased expression provided by a promoter element alone. Many enhancers are known in the art, including, but not limited to, the cytomegalovirus major immediate-early enhancer. More specifically, the CMV MIE promoter comprises three regions: the modulator, the unique region and the enhancer (Isomura and Stinski (2003) J. UR6-23082/161118-04901 Virol.77(6):3602-3614). The CMV enhancer region can be combined with another promoter, or a portion thereof, to form a hybrid promoter to further increase expression of a nucleic acid operably linked thereto. For example, a CBA promoter, or a portion thereof, can be combined with a CMV promoter/enhancer, or a portion thereof, to make a version of CBA termed the “CBh” promoter, which stands for chicken beta-actin hybrid promoter, as described in Gray et al. (2011, Human Gene Therapy 22:1143-1153). Like promoters, enhancers may be constitutive, tissue-specific or regulated. Fillers, Spacers and Stuffers As disclosed herein, a recombinant nucleic acid can be used in an rAAV vector. In that case, the recombinant nucleic acid may include an additional nucleic acid element to adjust the length of the nucleic acid to near, or at the normal size (e.g., approximately 4.7 to 4.9 kilobases), of the viral genomic sequence acceptable for AAV packaging into an rAAV vector (Grieger and Samulski (2005) J. Virol. 79(15):9933-9944). Such a sequence may be referred to interchangeably as filler, spacer or stuffer. In some embodiments, filler DNA is an untranslated (non-protein coding) segment of nucleic acid. In some embodiments, a filler or stuffer polynucleotide sequence is a sequence between about 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90-90-100, 100-150, 150-200, 200-250, 250-300, 300-400, 400-500, 500- 750, 750-1000, 1000-1500, 1500-2000, 2000-3000 or more in length. AAV vectors typically accept inserts of DNA having a size ranging from about 4 kb to about 5.2 kb or about 4.1 to 4.9 kb for optimal packaging of the nucleic acid into the AAV capsid. In some embodiments, an rAAV vector comprises a vector genome having a total length between about 3.0 kb to about 3.5 kb, about 3.5 kb to about 4.0 kb, about 4.0 kb to about 4.5kb, about 4.5 kb to about 5.0 kb or about 5.0 kb to about 5.2 kb. In some embodiments, an rAAV vector comprises a vector genome having a total length of about 4.7 kb. In some embodiments, an rAAV vector comprises a vector genome that is self-complementary. While the total length of a self-complementary (sc) vector genome in an rAAV vector is equivalent to a single- stranded (ss) vector genome (i.e., from about 4 kb to about 5.2 kb), the nucleic acid sequence (i.e., comprising the transgene, regulatory elements and ITRs) encoding the sc vector genome must be only half as long as a nucleic acid sequence encoding a ss vector genome in order for the sc vector genome to be packaged in the capsid. Introns and Exons In some embodiments, a recombinant nucleic acid disclosed herein includes, for example, an intron, exon and/or a portion thereof. An intron may function as a filler or stuffer polynucleotide sequence to achieve an appropriate length for vector genome packaging into an UR6-23082/161118-04901 rAAV vector. An intron and/or an exon sequence can also enhance expression of a transgene (e.g., an RNA disclosed herein) as compared to expression in the absence of the intron and/or exon element (Kurachi et al. (1995) J. Biol. Chem. 270 (10):576-5281; WO 2017/074526). Furthermore, filler/stuffer polynucleotide sequences (also referred to as “insulators”) are well known in the art and include, but are not limited to, those described in WO 2014/144486 and WO 2017/074526. Polyadenylation Signal Sequence (polyA) Further regulatory elements may include a stop codon, a termination sequence, and a polyadenylation (polyA) signal sequence, such as, but not limited to a bovine growth hormone poly A signal sequence (BHG polyA). A polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic mRNA which guides termination of gene transcription (see, e.g., Goodwin and Rottman J. Biol. Chem. (1992) 267(23):16330-16334). A polyA signal acts as a signal for the endonucleolytic cleavage of the newly formed precursor mRNA at its 3’ end and for addition to this 3’ end of an RNA stretch consisting only of adenine bases. A polyA tail is important for the nuclear export, translation and stability of mRNA. In some embodiments, a poly A can be a SV40 early polyadenylation signal, a SV40 late polyadenylation signal, an HSV thymidine kinase polyadenylation signal, a protamine gene polyadenylation signal, an adenovirus 5 E1b polyadenylation signal, a growth hormone polyadenylation signal, a PBGD polyadenylation signal or an in silico designed polyadenylation signal. 3. Expression Cassettes and Expression Vectors The disclosure also provides an expression cassette, comprising or consisting of a recombinant nucleic acid encoding an inhibitory nucleic acid as described above. Where such recombinant nucleic acid may not already comprise a promoter, the expression cassette may additionally comprise a promoter. Thus, an expression cassette according to the present invention comprises, in 5' to 3' direction, a promoter, a coding sequence, and optionally a terminator or other elements. The expression cassette allows an easy transfer of a nucleic acid sequence of interest into an organism, preferably a cell and preferably a disease cell. The expression cassette of the present disclosure is preferably comprised in a vector. Thus, the vector of the present disclosure allows to transform a cell with a nucleic acid sequence of interest. Correspondingly the disclosure provides a host cell comprising an expression cassette according to the present disclosure or a recombinant nucleic acid according to the UR6-23082/161118-04901 present disclosure. The recombinant nucleic acid may also comprise a promoter or enhancer such as to allow for the expression of the nucleic acid sequence of interest. Exogenous genetic material (e.g., a nucleic acid, an expression cassette, or an expression vector encoding one or more therapeutic or inhibitory RNAs) can be introduced into a target cells of interest in vivo by genetic transfer methods, such as transfection or transduction, to provide a genetically modified cell. Various expression vectors (i.e., vehicles for facilitating delivery of exogenous genetic material into a target cell) are known to one of ordinary skill in the art. As used herein, "exogenous genetic material" refers to a nucleic acid or an oligonucleotide, either natural or synthetic, that is not naturally found in the cells; or if it is naturally found in the cells, it is not transcribed or expressed at biologically significant levels by the cells. Thus, "exogenous genetic material" includes, for example, a non-naturally occurring nucleic acid that can be transcribed into an RNA. As used herein, "transfection of cells" refers to the acquisition by a cell of new genetic material by incorporation of added nucleic acid (DNA, RNA, or a hybrid thereof) without use of a viral delivery vehicle. Thus, transfection refers to the introducing of nucleic acid into a cell using physical or chemical methods. Several transfection techniques are known to those of ordinary skill in the art including: calcium phosphate nucleic acid co-precipitation, strontium phosphate nucleic acid co-precipitation, DEAE-dextran, electroporation, cationic liposome- mediated transfection, and tungsten particle-facilitated microparticle bombardment. In contrast, "transduction of cells" refers to the process of transferring nucleic acid into a cell using a DNA or RNA virus. An RNA virus (e.g., a retrovirus) for transferring a nucleic acid into a cell is referred to herein as a transducing chimeric virus. Exogenous genetic material contained within the virus can be incorporated into the genome of the transduced cell. A cell that has been transduced with a chimeric DNA virus (e.g., an adenovirus carrying a DNA encoding a therapeutic agent), may not have the exogenous genetic material incorporated into its genome but may be capable of expressing the exogenous genetic material that is retained extrachromosomally within the cell. Typically, the exogenous genetic material may include a heterologous gene (coding for a therapeutic RNA or protein) together with a promoter to control transcription of the new gene. The promoter characteristically has a specific nucleotide sequence necessary to initiate transcription. Optionally, the exogenous genetic material further includes additional sequences (i.e., enhancers) required to obtain the desired gene transcription activity. The exogenous genetic material may introduced into the cell genome immediately downstream from the promoter so that the promoter and coding sequence are operatively linked so as to permit UR6-23082/161118-04901 transcription of the coding sequence. A retroviral expression vector may include an exogenous promoter element to control transcription of the inserted exogenous gene. Such exogenous promoters include both constitutive and inducible promoters. Naturally-occurring constitutive promoters control the expression of essential cell functions. As a result, a gene under the control of a constitutive promoter is expressed under all conditions of cell growth. Exemplary constitutive promoters include the promoters for the following genes that encode certain constitutive or "housekeeping" functions: hypoxanthine phosphoribosyl transferase, dihydrofolate reductase, adenosine deaminase, phosphoglycerol kinase, pyruvate kinase, phosphoglycerol mutase, the actin promoter, ubiquitin, elongation factor-1 and other constitutive promoters known to those of skill in the art. In addition, many viral promoters function constitutively in eucaryotic cells. These include the early and late promoters of SV40; the long terminal repeats (LTRs) of Moloney Leukemia Virus and other retroviruses; and the thymidine kinase promoter of Herpes Simplex Virus, among many others. Accordingly, any of the above-referenced constitutive promoters can be used to control transcription of a heterologous gene insert. Genes that are under the control of inducible promoters are expressed only in, or largely controlled by, the presence of an inducing agent, (e.g., transcription under control of the metallothionein promoter is greatly increased in presence of certain metal ions). Inducible promoters include responsive elements (REs) which stimulate transcription when their inducing factors are bound. For example, there are REs for serum factors, steroid hormones, retinoic acid and cyclic AMP. Promoters containing a particular RE can be chosen in order to obtain an inducible response and in some cases, the RE itself may be attached to a different promoter, thereby conferring inducibility to the recombinant gene. Thus, by selecting the appropriate promoter (constitutive versus inducible; strong versus weak), it is possible to control both the existence and level of expression of a therapeutic agent in the genetically modified cell. If the gene encoding the therapeutic agent is under the control of an inducible promoter, delivery of the therapeutic agent in situ is triggered by exposing the genetically modified cell in situ to conditions for permitting transcription of the therapeutic agent, e.g., by injection of specific inducers of the inducible promoters which control transcription of the agent. For example, in situ expression by genetically modified cells of a therapeutic agent encoded by a gene under the control of the metallothionein promoter, is enhanced by contacting the genetically modified cells with a solution containing the appropriate (i.e., inducing) metal ions in situ. UR6-23082/161118-04901 Accordingly, the amount of therapeutic agent that is delivered in situ is regulated by controlling such factors as: (1) the nature of the promoter used to direct transcription of the inserted gene, (i.e., whether the promoter is constitutive or inducible, strong or weak); (2) the number of copies of the exogenous gene that are inserted into the cell; (3) the number of transduced/transfected cells that are administered (e.g., implanted) to the patient; (4) the size of the implant (e.g., graft or encapsulated expression system); (5) the number of implants; (6) the length of time the transduced/transfected cells or implants are left in place; and (7) the production rate of the therapeutic agent by the genetically modified cell. Selection and optimization of these factors for delivery of a therapeutically effective dose of a particular therapeutic agent is deemed to be within the scope of one of ordinary skill in the art without undue experimentation, taking into account the above-disclosed factors and the clinical profile of the patient. In addition to at least one promoter and at least one heterologous nucleic acid encoding the therapeutic agent, the expression vector may include a selection gene, for example, a neomycin resistance gene or a fluorescent protein gene, for facilitating selection of cells that have been transfected or transduced with the expression vector. Alternatively, the cells are transfected with two or more expression vectors, at least one vector containing the gene(s) encoding the therapeutic agent(s), the other vector containing a selection gene. The selection of a suitable promoter, enhancer, selection gene, and/or signal sequence is deemed to be within the scope of one of ordinary skill in the art without undue experimentation. A coding sequence of the present disclosure can be inserted into any type of target or host cell. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means. 4. Carrier/Delivery of polynucleotides As disclosed herein, the polynucleotides or nucleic acid molecules described above can be used for treating a disorder in a subject. Accordingly, this disclosure provides systems and methods for delivery of the polynucleotides to a target cell or a subject. Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). UR6-23082/161118-04901 Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362. Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle). The polynucleotides or nucleic acids described herein (e.g., inhibitory nucleic acids, those encoding a CRISPR-Cas system, expression cassette, and expression vector) can be added directly, or can be complexed with cationic lipids, packaged within liposomes, or as a recombinant plasmid or viral vectors, or otherwise delivered to target cells or tissues. Methods for the delivery of nucleic acid molecules are known in the art. See, e.g., U.S. Pat. No. 6,395,713, WO 94/02595, Akhtar et al., 1992, Trends Cell Bio., 2, 139; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995, Maurer et al., 1999, Mol. Membr. Biol., 16, 129-140; Hofland and Huang, 1999, Handb. Exp. Pharmacol., 137, 165-192; and Lee et al., 2000, ACS Symp. Ser., 752, 184-192. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins (see for example Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; WO 03/47518 and WO 03/46185), poly(lactic-co- glycolic)acid (PLGA) and PLCA microspheres (see for example U.S. Pat. No.6,447,796 and US 2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (see, e.g., WO 00/53722). In one aspect, the present application provides carrier systems containing the nucleic acid molecules described herein. In some embodiments, the carrier system is a lipid-based carrier system, cationic lipid, or liposome nucleic acid complexes, a liposome, a micelle, a virosome, a lipid nanoparticle or a mixture thereof. In other embodiments, the carrier system is a polymer-based carrier system such as a cationic polymer-nucleic acid complex. In additional embodiments, the carrier system is a cyclodextrin-based carrier system such as a UR6-23082/161118-04901 cyclodextrin polymer-nucleic acid complex. In further embodiments, the carrier system is a protein-based carrier system such as a cationic peptide-nucleic acid complex. Preferably, the carrier system in a lipid nanoparticle formulation. Lipid nanoparticle (“LNP”) formulations described herein can be applied to any nucleic acid molecules (e.g., an RNA molecule) or combination of nucleic acid molecules described herein. In certain embodiment, the nucleic acid molecules described herein are formulated as a lipid nanoparticle composition such as is described in U.S. Patent Nos.7514099 and 7404969. In some embodiments, this application features a composition comprising a nucleic acid molecule formulated as any of formulation as described in US 20120029054, such as LNP- 051; LNP-053; LNP-054; LNP-069; LNP-073; LNP-077; LNP-080; LNP-082; LNP-083; LNP-060; LNP-061; LNP-086; LNP-097; LNP-098; LNP-099; LNP-100; LNP-101; LNP-102; LNP-103; or LNP-104. In other embodiments, this disclosure features conjugates and/or complexes of nucleic acid molecules described herein. Such conjugates and/or complexes can be used to facilitate delivery of nucleic acid molecules into a biological system, such as a cell. The conjugates and complexes provided by hereon can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention. Non-limiting, examples of such conjugates are described in e.g., U.S. Pat. Nos.7,833,992; 6,528,631; 6,335,434; 6, 235,886; 6,153,737; 5,214,136; 5,138,045. In various embodiments, polyethylene glycol (PEG) can be covalently attached to nucleic acid molecules described herein. The attached PEG can be any molecular weight, preferably from about 100 to about 50,000 daltons (Da). Accordingly, the disclosure features compositions or formulations comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes) and nucleic acid molecules described herein. See, e.g., WO 96/10391, WO 96/10390, and WO 96/10392). In some embodiments, the nucleic acid molecules can also be formulated or complexed with polyethyleneimine and derivatives thereof, such as polyethyleneimine- polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine- polyethyleneglycol-tri-N-acetylgalactosamine (PEI-PEG-triGAL) derivatives. In one embodiment, the nucleic acid molecules can be formulated in the manner described in U.S. 20030077829. UR6-23082/161118-04901 In other embodiments, nucleic acid molecules described herein can be complexed with membrane disruptive agents such as those described in U.S. 20010007666. In still other embodiments, the membrane disruptive agent or agents and the molecule can be complexed with a cationic lipid or helper lipid molecule, such as those lipids described in U.S. Pat. No. 6,235,310. In certain embodiments, nucleic acid molecules described herein can be complexed with delivery systems as described in U.S. Patent Application Publication Nos.2003077829; 20050287551; 20050164220; 20050191627; 20050118594; 20050153919; 20050085486; and 20030158133; and IWO 00/03683 and WO 02/087541. In some embodiments, a liposomal formulation described herein can comprise a nucleic acid molecule described herein (e.g., an inhibitory nucleic acid) formulated or complexed with compounds and compositions described in U.S. Pat. Nos. 6,858,224; 6,534,484; 6,287,591; 6,835,395; 6,586,410; 6,858,225; 6,815,432; 6,586,001; 6,120,798; 6,977,223; 6,998,115; 5,981,501; 5,976,567; 5,705,385; and U.S. Patent Application Publication Nos.2006/0019912; 2006/0019258; 2006/0008909; 2005/0255153; 2005/0079212; 2005/0008689; 2003/0077829, 2005/0064595, 2005/0175682, 2005/0118253; 2004/0071654; 2005/0244504; 2005/0265961 and 2003/0077829. As disclosed herein, the nucleic acid molecules described above can be used for treating a disorder in a subject. Vectors (such as recombinant plasmids and viral vectors) as discussed above can be used to deliver a therapeutical agent, such as an inhibitory nucleic acid or a CRISPR-Cas system described herein. Delivery of the vectors can be systemic, such as by intravenous or intra-muscular administration, by administration to target cells ex-planted from a subject followed by reintroduction into the subject, or by any other means that would allow for introduction into the desired target cell. Such recombinant vectors can also be administered directly or in conjunction with a suitable delivery reagents, including, for example, the Mirus Transit LT1 lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations (e.g., polylysine) or liposomes lipid-based carrier system, cationic lipid, or liposome nucleic acid complexes, a micelle, a virosome, a lipid nanoparticle. A. Viral Vectors In some embodiments, a polynucleotide encoding a therapeutic agent (e.g., RNA molecule) can be inserted into, or encoded by, vectors such as plasmids or viral vectors. Preferably, the polynucleotide is inserted into, or encoded by, viral vectors. Viral vectors may be Herpesvirus (HSV) vectors, retroviral vectors, adenoviral vectors, AAV vectors, lentiviral UR6-23082/161118-04901 vectors, and the like. In some specific embodiments, the viral vectors are AAV vectors. In some embodiments, the RNA may be encoded by a retroviral vector (See, e.g., U.S. Pat. Nos. 5,399,346; 5,124,263; 4,650,764 and 4,980,289; the content of each of which is incorporated herein by reference in their entirety). Lentiviral vectors Lentiviruses, such as HIV, are “slow viruses.” Vectors derived from lentiviruses can be expressed long-term in the host cells after a few administrations to the patients, e.g., via ex vivo transduced stem cells or progenitor cells. For most diseases and disorders, including genetic diseases, cancer, and neurological disease, long-term expression is crucial to successful treatment. Regarding safety with lentiviral vectors, a number of strategies for eliminating the ability of lentiviral vectors to replicate have now been known in the art. See e.g., US 20210401868 and 20210403517, each of which is incorporated herein by reference in its entirety. For example, the deletion of promoter and enhancer elements from the U3 region of the long terminal repeat (LTR) are thought to have no LTR-directed transcription. The resulting vectors are called “self-inactivating” (SIN). Lentiviral vectors are particularly suitable to achieving long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as CNS cells. They also have the added advantage of low immunogenicity. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers, (e.g., WO01/96584 and WO01/29058; and U.S. Pat. No. 6,326,193). Several vector promoter sequences are available for expression of the transgenes. One example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. Another example of a suitable promoter is EF1a. However, other constitutive promoter sequences can also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase UR6-23082/161118-04901 promoter. Inducible promoters include, but are not limited to a metallothionein promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter. The present disclosure provides a recombinant lentivirus capable of infecting dividing and non-dividing cells, such oligodendrocytes, astrocytes, or glial progenitor cells. The virus is useful for the in vivo and ex vivo transfer and expression of nucleic acid sequences. Lentiviral vectors of the present disclosure may be lentiviral transfer plasmids or infectious lentiviral particles. Construction of lentiviral vectors, helper constructs, envelope constructs, etc., for use in lentiviral transfer systems has been described in, e.g., US 20210401868 and 20210403517, each of which is incorporated herein by reference in its entirety. Adenoviruses Adenoviruses are eukaryotic DNA viruses that can be modified to efficiently deliver a nucleic acid to a variety of cell types in vivo, and have been used extensively in gene therapy protocols, including for targeting genes to neural cells and glial cells. Various replication defective adenovirus and minimum adenovirus vectors have been described for nucleic acid therapeutics (See, e.g., PCT Patent Publication Nos. WO199426914, WO 199502697, WO199428152, WO199412649, WO199502697 and WO199622378; the content of each of which is incorporated by reference in their entirety). Such adenoviral vectors may also be used to deliver therapeutic molecules of the present disclosure to cells. 4. AAV The adeno-associated virus is a widely used gene therapy vector due to its clinical safety record, non-pathogenic nature, ability to infect non-dividing cells (like neurons), and ability to provide long-term gene expression after a single administration (Hocquemiller et al., 2016). Currently, many human and non-human primate AAV serotypes have been identified (Gao et al., 2004). AAV vectors have demonstrated safety in hundreds of clinical trials worldwide, and clinical efficacy has been shown in trials of hemophilia B, spinal muscular atrophy, alpha 1 antitrypson, and Leber congenital amaurosis (Keeler et al., 2017). Three AAV-based gene therapies have been approved. The first, Glybera, was approved by the European Medicines Agency (EMA) in 2012 (though withdrawn in 2017 mainly due to commercial failure). Luxturna was approved by FDA in 2017 for a rare inherited retinal dystrophy, and Zolgensma was approved by FDA in 2019 for spinal muscular atrophy. Because of their safety, nonpathogenic nature, and ability to infect neurons, AAVs such as AAV1, AAV2, AAV4, AAV5, AAV6, AAV8, and AAV9 are commonly used gene therapy vectors for CNS applications. However, after direct CNS infusion, these serotypes exhibit a dominant neuronal tropism and expression in glial cells is low, especially when gene UR6-23082/161118-04901 expression is driven by a constitutive promoter. AAV1/2, AAV2, and AAV8 have been shown transduce oligodendrocytes, but only when oligodendrocyte-specific promoters are used (Chen et al., 1998; Lawlor et al., 2009; Li et al., 2019). Reliance on cell-specific promoters for expression specificity allows for the possibility of nonselective cellular uptake and leaky transgene expression through cryptic promoter activity in non–oligodendrocyte lineage cells. The approach described herein to alleviate these issues includes using AAV serotypes with high tropism for glial cells. Recently, using DNA shuffling and directed evolution, a chimeric AAV capsid with strong selectivity for oligodendrocytes, AAV/Olig001, has been described (Powell et al., 2016). Subsequently, AAV/Olig001 was shown to transduce neonatal oligodendrocytes in a mouse model of Canavan disease (Francis et al., 2021). Other approaches such as random mutagenesis and peptide library insertion can be used to generate capsid libraries that can be screened for tropism and selectivity for glial progenitor cells, astrocytes, or oligodendrocytes. As discussed above, the terms “adeno-associated virus” and/or “AAV” refer to parvoviruses with a linear single-stranded DNA genome and variants thereof. The term covers all subtypes and both naturally occurring and recombinant forms, except where required otherwise. Parvoviruses, including AAV, are useful as gene therapy vectors as they can penetrate a cell and introduce a nucleic acid (e.g., transgene) into the nucleus. In some embodiments, the introduced nucleic acid (e.g., rAAV vector genome) forms circular concatemers that persist as episomes in the nucleus of transduced cells. In some embodiments, a transgene is inserted in specific sites in the host cell genome, for example at a site on human chromosome 19. Site-specific integration, as opposed to random integration, is believed to likely result in a predictable long-term expression profile. The insertion site of AAV into the human genome is referred to as AAVS1. Once introduced into a cell, RNAs or polypeptides encoded by the nucleic acid can be expressed by the cell. Because AAV is not associated with any pathogenic disease in humans, a nucleic acid delivered by AAV can be used to express a therapeutic RNA or polypeptide for the treatment of a disease, disorder and/or condition in a human subject. Multiple serotypes of AAV exist in nature with at least fifteen wild type serotypes having been identified from humans thus far (i.e., AAV1-AAV15). Naturally occurring and variant serotypes are distinguished by having a protein capsid that is serologically distinct from other AAV serotypes. Examples include AAV1, AAV2, AAV, AAV3 (including AAV3A and AAV3B), AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV12, AAVrh10, AAVrh74 (see WO 2016/210170), avian AAV, bovine AAV, canine AAV, equine AAV, UR6-23082/161118-04901 primate AAV, non-primate AAV, and ovine AAV, and recombinantly produced variants (e.g., capsid variants with insertions, deletions and substitutions, etc.), such as variants referred to as AAV2i8, NP4, NP22, NP66, DJ, DJ/8, DJ/9, LK3, RHM4-1, among many others. “Primate AAV” refers to AAV that infect primates, “non-primate AAV” refers to AAV that infect non- primate mammals, “bovine AAV” refers to AAV that infect bovine mammals, and so on. Serotype distinctiveness is determined on the basis of the lack of cross-reactivity between antibodies to one AAV as compared to another AAV. Such cross-reactivity differences are usually due to differences in capsid protein sequences and antigenic determinants (e.g., due to VP1, VP2, and/or VP3 sequence differences of AAV serotypes). However, some naturally occurring AAV or man-made AAV mutants (e.g., recombinant AAV) may not exhibit serological difference with any of the currently known serotypes. These viruses may then be considered a subgroup of the corresponding type, or more simply a variant AAV. Thus, as used herein, the term “serotype” refers to both serologically distinct viruses, as well as viruses that are not serologically distinct but that may be within a subgroup or a variant of a given serotype. A comprehensive list and alignment of amino acid sequences of capsids of known AAV serotypes is provided by Marsic et al. (2014) Molecular Therapy 22(11):1900-1909. Genomic sequences of various serotypes of AAV, as well as sequences of the native ITRs, rep proteins, and capsid subunits are known in the art. Such sequences may be found in the literature or in public databases such as GenBank. See, e.g., GenBank Accession Numbers NC_002077 (AAV1), AF063497 (AAV1), NC_001401 (AAV2), AF043303 (AAV2), NC_001729 (AAV3), NC_001863 (AAV3B), NC_001829 (AAV4), U89790 (AAV4), NC_006152 (AAV5), NC_001862 (AAV6), AF513851 (AAV7), AF513852 (AAV8), and NC_006261 (AAV8); the disclosures of which are incorporated by reference herein. See also, e.g., Srivistava et al. (1983) J. Virology 45:555; Chiorini et al. (1998) J. Virology 71:6823; Chiorini et al. (1999) J. Virology 73: 1309; Bantel-Schaal et al. (1999) J. Virology 73:939; Xiao et al. (1999) J. Virology 73:3994; Muramatsu et al. (1996) Virology 221:208; Shade et al. (1986) J. Virol. 58:921; Gao et al. (2002) Proc. Nat. Acad. Sci. USA 99: 11854; Moris et al. (2004) Virology 33:375-383; international patent publications WO 00/28061, WO 99/61601, WO 98/11244; WO 2013/063379; WO 2014/194132; WO 2015/121501, and U.S. Patent No. 6,156,303 and U.S. Patent No.7,906,111. As discussed herein, a “recombinant adeno-associated virus” or “rAAV” is distinguished from a wild-type AAV by replacement of all or part of the endogenous viral genome with a non-native sequence. Incorporation of a non-native sequence within the virus UR6-23082/161118-04901 defines the viral vector as a “recombinant” vector, and hence a “rAAV vector.” An rAAV vector can include a heterologous polynucleotide encoding a desired RNA or protein or polypeptide (e.g., an RNA molecule disclosed herein). A recombinant vector sequence may be encapsidated or packaged into an AAV capsid and referred to as an “rAAV vector,” an “rAAV vector particle,” “rAAV viral particle” or simply a “rAAV.” For the production of an rAAV vector , the desired ratio of VP1:VP2:VP3 can be in the range of about 1:1:1 to about 1:1:100, preferably in the range of about 1:1:2 to about 1:1:50, more preferably in the range of about 1:1:5 to about 1:1:20. Although the desired ratio of VP1:VP2 can be 1:1, the ratio range of VP1:VP2 could vary from 1:50 to 50:1. The present disclosure provides for an rAAV vector comprising a polynucleotide sequence not of AAV origin (e.g., a polynucleotide heterologous to AAV). The heterologous polynucleotide may be flanked by at least one, and sometimes by two, AAV terminal repeat sequences (e.g., inverted terminal repeats). The heterologous polynucleotide flanked by ITRs, also referred to herein as a “vector genome,” typically encodes an RNA or a polypeptide of interest, or a gene of interest, such as a target for therapeutic treatment. Delivery or administration of an rAAV vector to a subject (e.g. a patient) provides encoded RNAs/proteins/peptides to the subject. Thus, an rAAV vector can be used to transfer/deliver a heterologous polynucleotide for expression for, e.g., treating a variety of diseases, disorders and conditions. rAAV vector genomes generally retain 145 base ITRs in cis to the heterologous nucleic acid sesquence that replaced the viral rep and cap genes. Such ITRs are useful to produce a recombinant AAV vector; however, modified AAV ITRs and non-AAV terminal repeats including partially or completely synthetic sequences can also serve this purpose. ITRs form hairpin structures and function to, for example, serve as primers for host-cell-mediated synthesis of the complementary DNA strand after infection. ITRs also play a role in viral packaging, integration, etc. ITRs are the only AAV viral elements which are required in cis for AAV genome replication and packaging into rAAV vectors. An rAAV vector genome optionally comprises two ITRs which are generally at the 5’ and 3’ ends of the vector genome comprising a heterologous sequence (e.g., a transgene encoding a gene of interest, or a nucleic acid sequence of interest including, but not limited to, an antisense, and siRNA, a CRISPR molecule, among many others). A 5’ and a 3’ ITR may both comprise the same sequence, or each may comprise a different sequence. An AAV ITR may be from any AAV including by not limited to serotypes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 or any other AAV. UR6-23082/161118-04901 An rAAV vector of the disclosure may comprise an ITR from an AAV serotype (e.g., wild-type AAV2, a fragment or variant thereof) that differs from the serotype of the capsid (e.g., AAV8, Olig001). Such an rAAV vector comprising at least one ITR from one serotype, but comprising a capsid from a different serotype, may be referred to as a hybrid viral vector (see U.S. Patent No.7,172,893). An AAV ITR may include the entire wild type ITR sequence, or be a variant, fragment, or modification thereof, but will retain functionality. In some embodiments, an rAAV vector genome is linear, single-stranded and flanked by AAV ITRs. Prior to transcription and translation of the heterologous gene, a single stranded DNA genome of approximately 4700 nucleotides must be converted to a double-stranded form by DNA polymerases (e.g., DNA polymerases within the transduced cell) using the free 3’-OH of one of the self-priming ITRs to initiate second-strand synthesis. In some embodiments, full length-single stranded vector genomes (i.e., sense and anti-sense) anneal to generate a full length-double stranded vector genome. This may occur when multiple rAAV vectors carrying genomes of opposite polarity (i.e., sense or anti-sense) simultaneously transduce the same cell. Regardless of how they are produced, once double-stranded vector genomes are formed, the cell can transcribe and translate the double-stranded DNA and express the heterologous gene. The efficiency of transgene expression from an rAAV vector can be hindered by the need to convert a single stranded rAAV genome (ssAAV) into double-stranded DNA prior to expression. This step can be circumvented by using a self-complementary AAV genome (scAAV) that can package an inverted repeat genome that can fold into double-stranded DNA without the need for DNA synthesis or base-pairing between multiple vector genomes. See, e.g., U.S. Patent No. 8,784,799; McCarty, (2008) Molec. Therapy 16(10):1648-1656; and McCarty et al., (2001) Gene Therapy 8:1248-1254; McCarty et al., (2003) Gene Therapy 10:2112-2118. A viral capsid of an rAAV vector may be from a wild type AAV or a variant AAV such as AAV1, AAV2, AAV3, AAV3A, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAVrh10, AAVrh74 (see WO2016/210170), AAV12, AAV2i8, AAV1.1, AAV2.5, AAV6.1, AAV6.3.1, AAV9.45, RHM4-1 (SEQ ID NO:5 of WO 2015/013313), RHM15-1, RHM15-2, RHM15-3/RHM15-5, RHM15-4, RHM15-6, AAV hu.26, AAV1.1, AAV2.5, AAV6.1, AAV6.3.1, AAV9,45, AAV2i8, AAV29G, AAV2,8G9, AVV-LK03, AAV2-TT, AAV2-TT-S312N, AAV3B-S312N, AAV avian AAV, bovine AAV, canine AAV, equine AAV, primate AAV, non-primate AAV, snake AAV, goat AAV, shrimp AAV, ovine AAV and variants thereof (see, e.g., Fields et al., VIROLOGY, volume 2, chapter 69 (4^th ed., Lippincott-Raven Publishers). Capsids may be derived from a number of AAV serotypes UR6-23082/161118-04901 disclosed in U.S. Patent No.7,906,111; Gao et al. (2004) J. Virol.78:6381; Morris et al. (2004) Virol. 33:375; WO 2013/063379; WO 2014/194132; and include true type AAV (AAV-TT) variants disclosed in WO 2015/121501, and RHM4-1, RHM15-1 through RHM15-6, and variants thereof, disclosed in WO 2015/013313. A full complement of AAV cap proteins includes VP1, VP2, and VP3. The ORF comprising nucleotide sequences encoding AAV VP capsid proteins may comprise less than a full complement AAV Cap proteins or the full complement of AAV cap proteins may be provided. In some embodiments, an rAAV vector comprising a capsid protein encoded by a nucleotide sequence derived from more than one AAV serotype (e.g., wild type AAV serotypes, variant AAV serotypes) is referred to as a “chimeric vector” or “chimeric capsid” (See U.S. Patent No. 6,491,907, the entire disclosure of which is incorporated herein by reference). In some embodiments, a chimeric capsid protein is encoded by a nucleic acid sequence derived from 2, 3, 4, 5, 6, 7, 8, 9, 10 or more AAV serotypes. In some embodiments, a recombinant AAV vector includes a capsid sequence derived from e.g., AAV1, AAV2, AAV3, AAV3A, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAVrh74, AAVrh10, AAV2i8, or variant thereof, resulting in a chimeric capsid protein comprising a combination of amino acids from any of the foregoing AAV serotypes (see, Rabinowitz et al. (2002) J. Virology 76(2):791-801). Alternatively, a chimeric capsid can comprise a mixture of a VP1 from one serotype, a VP2 from a different serotype, a VP3 from yet a different serotype, and a combination thereof. For example a chimeric virus capsid may include an AAV1 cap protein or subunit and at least one AAV2 cap protein or subunit. A chimeric capsid can, for example include an AAV capsid with one or more B19 cap subunits, e.g., an AAV cap protein or subunit can be replaced by a B19 cap protein or subunit. For example, in one embodiment, a VP3 subunit of an AAV capsid can be replaced by a VP2 subunit of B19. In some embodiments, a chimeric capsid is an Olig001 capsid as described in WO2021221995 and WO2014052789, which are incorporated herein by reference. In some embodiments, chimeric vectors have been engineered to exhibit altered tropism or tropism for a particular tissue or cell type. The term “tropism” refers to preferential entry of the virus into certain cell (e.g., glial progenitor cells, astrocytes, or oligodendrocytes) or tissue types and/or preferential interaction with the cell surface that facilitates entry into certain cell or tissue types. AAV tropism is generally determined by the specific interaction between distinct viral capsid proteins and their cognate cellular receptors (Lykken et al. (2018) J. Neurodev. Disord.10:16). Preferably, once a virus or viral vector has entered a cell, sequences UR6-23082/161118-04901 (e.g., heterologous sequences such as a transgene) carried by the vector genome (e.g., an rAAV vector genome) are expressed. A “tropism profile” refers to a pattern of transduction of one or more target cells in various tissues and/or organs. For example, a chimeric AAV capsid may have a tropism profile characterized by efficient transduction of astrocytes with only low transduction of neurons, oligodendrocytes and other CNS cells. Such a chimeric capsid may be considered “specific for astrocytes” exhibiting tropism for astrocytesif when administered directly into the CNS, preferentially transduces astrocytes over neurons, oligodendrocytes, and other CNS cell types. In some embodiments, at least about 80% of cells that are transduced by a capsid specific for astrocytes are astrocytes, e.g., at least about 85%, 90%, 95%, 96%, 97%, 98% 99% or more of the transduced cells are astrocytes. 5. Viral particles and Productions A viral vector (e.g., rAAV vector) carrying a transgene (e.g., one encoding an RNA disclosed herein) can be assembled from a polynucleotide encoding a transgene, suitable regulatory elements and elements necessary for production of viral proteins which mediate cell transduction. Examples of a viral vector include but are not limited to adenoviral, retroviral, lentiviral, herpesvirus and AAV vectors, and in particular rAAV vector. A vector genome component of an rAAV vector produced according to the methods of the disclosure include at least one transgene (e.g., a polynucleotide encoding the RNA molecule) and associated expression control sequences for controlling expression of the RNA. In a preferred embodiment, a vector genome includes a portion of a parvovirus genome, such as an AAV genome with rep and cap deleted and/or replaced by a transgene and its associated expression control sequences. The transgene is typically inserted adjacent to one or two (i.e., is flanked by) AAV ITRs or ITR elements adequate for viral replication, in place of the nucleic acid encoding viral rep and cap proteins. Other regulatory sequences suitable for use in facilitating tissue-specific expression of the transgene in the target cell (e.g., a glial progenitor cell, an astrocyte, or an oligodendrocyte) may also be included. A. Packaging cell One skilled in the art would appreciate that an rAAV vector comprising a transgene, and lacking virus proteins needed for viral replication (e.g., cap and rep), cannot replicate since such proteins are necessary for virus replication and packaging. Cap and rep genes may be UR6-23082/161118-04901 supplied to a cell (e.g., a host cell, e.g., a packaging cell) as part of a plasmid that is separate from a plasmid supplying the vector genome with the transgene. Packaging cell or producer cell means a cell or cell line which may be transfected with a vector, plasmid or DNA construct, and provides in trans all the missing functions which are required for the complete replication and packaging of a viral vector. The required genes for rAAV vector assembly include the vector genome (e.g., a transgene encoding an RNA, regulatory elements, and ITRs), AAV rep gene, AAV cap gene, and certain helper genes from other viruses such as, e.g., adenovirus. One of ordinary skill would understand that the requisite genes for AAV production can be introduced into a packaging cell in various ways including, for example, transfection of one or more plasmids. However, in some embodiments, some genes (e.g., rep, cap, helper) may already be present in a packaging cell, either integrated into the genome or carried on an episome. In some embodiments, a packaging cell expresses, in a constitutive or inducible manner, one or more missing viral functions. Any suitable packaging cell known in the art may be employed in the production of a packaged viral vector. Mammalian cells or insect cells are preferred. Examples of cells useful for the production of a packaging cell in the practice of the disclosure include, for example, human cell lines, such as PER.C6, WI38, MRC5, A549, HEK293 cells (which express functional adenoviral E1 under the control of a constitutive promoter), B-50 or any other HeLa cell, HepG2, Saos-2, HuH7, and HT1080 cell lines. Suitable non-human mammalian cell lines include, for example, VERO, COS-1, COS-7, MDCK, BHK21-F, HKCC or CHO cells. In some embodiments, a packaging cell is capable of growing in suspension culture. In some embodiments, a packaging cell is capable of growing in serum-free media. For example, HEK293 cells are grow in suspension in serum free medium. In another embodiment, a packaging cell is a HEK293 cell as described in U.S. Patent No. 9,441,206 and deposited as American Type Culture Collection (ATCC) No. PTA 13274. Numerous rAAV packaging cell lines are known in the art, including, but not limited to, those disclosed in WO 2002/46359. A cell line for use as a packaging cell includes insect cell lines. Any insect cell which allows for replication of AAV and which can be maintained in culture can be used in accordance with the present disclosure. Examples include Spodoptera frugiperda, such as the Sf9 or Sf21 cell lines, Drosophila spp. cell lines, or mosquito cell lines, e.g., Aedes albopictus derived cell lines. A preferred cell line is the Spodoptera frugiperda Sf9 cell line. The following references are incorporated herein for their teachings concerning use of insect cells for expression of heterologous polypeptides, methods of introducing nucleic acids into such cells, and methods of maintaining such cells in culture: Methods in Molecular Biology, ed. Richard, UR6-23082/161118-04901 Humana Press, NJ (1995); O’Reilly et al., Baculovirus Expression Vectors: A Laboratory Manual, Oxford Univ. Press (1994); Samulski et al. (1989) J. Virol.63:3822-3828; Kajigaya et al. (1991) Proc. Nat’l. Acad. Sci. USA 88: 4646-4650; Ruffing et al. (1992) J. Virol. 66:6922-6930; Kimbauer et al. (1996) Virol. 219:37-44; Zhao et al. (2000) Virol. 272:382- 393; and U.S. Pat. No.6,204,059. As a further alternative, viral vectors of the disclosure may be produced in insect cells using baculovirus vectors to deliver the rep/cap genes and rAAV template as described, for example, by Urabe et al. (2002) Human Gene Therapy 13:1935-1943. When using baculovirus production for AAV, in some embodiments, a vector genome is self-complementary. In some embodiments, a host cell is a baculovirus-infected cell (e.g., an insect cell) comprising, optionally, additional nucleic acids encoding baculovirus helper functions, thereby facilitating production of a viral capsid. A packaging cell generally includes one or more viral vector functions along with helper functions and packaging functions sufficient to result in replication and packaging of the viral vector. These various functions may be supplied together, or separately, to the packaging cell using a genetic construct such as a plasmid or an amplicon, and they may exist extrachromosomally within the cell line, or integrated into the host cell’s chromosomes. B. Helper function AAV cannot replicate in a cell without co-infection of the cell by a helper virus. Helper functions include helper virus elements needed for establishing active infection of a packaging cell, which is required to initiate packaging of the viral vector. Helper viruses include, typically, adenovirus or herpes simplex virus. Adenovirus helper functions typically include adenovirus components adenovirus early region 1A (E1a), E1b, E2a, E4, and viral associated (VA) RNA. Helper functions (e.g., E1a, E1b, E2a, E4, and VA RNA) can be provided to a packaging cell by transfecting the cell with one or more nucleic acids encoding various helper elements. Alternatively, a host cell (e.g., a packaging cell) can comprise a nucleic acid encoding the helper protein. For instance, HEK293 cells were generated by transforming human cells with adenovirus 5 DNA and now express a number of adenoviral genes, including, but not limited to E1 and E3 (see, e.g., Graham et al. (1977) J. Gen. Virol. 36:59-72). Thus, those helper functions can be provided by the HEK 293 packaging cell without the need of supplying them to the cell by, e.g., a plasmid encoding them. In some embodiments, a packaging cell is transfected with at least (i) a plasmid comprising a vector genome comprising a transgene and AAV ITRs and further comprising at UR6-23082/161118-04901 least one of the following regulatory elements: an enhancer, a promoter, an exon, an intron, and a poly A, (ii) a plasmid comprising a rep gene (e.g., AAV2 rep) and a cap gene (e.g., Olig001 cap) and (iii) a plasmid comprising a helper function. Any method of introducing a nucleotide sequence carrying a helper function into a cellular host for replication and packaging may be employed, including but not limited to, electroporation, calcium phosphate precipitation, microinjection, cationic or anionic liposomes, and liposomes in combination with a nuclear localization signal. In some embodiments, helper functions are provided by transfection using a virus vector, or by infection using a helper virus, standard methods for producing viral infection may be used. The vector genome may be any suitable recombinant nucleic acid, such as a DNA or RNA construct and may be single stranded, double stranded, or duplexed (i.e., self- complementary as described in WO 2001/92551). C. Production of Packaged Viral Vector Viral vectors can be made by several methods known to skilled artisans (see, e.g., WO 2013/063379). A preferred method is described in Grieger, et al. (2015) Molecular Therapy 24(2):287-297, the contents of which are incorporated by reference herein for all purposes. Briefly, efficient transfection of HEK293 cells is used as a starting point, wherein an adherent HEK293 cell line from a qualified clinical master cell bank is used to grow in animal component-free suspension conditions in shaker flasks and WAVE bioreactors that allow for rapid and scalable rAAV production. Using a triple transfection method (e.g., WO 96/40240), a HEK293 cell line suspension can generate greater than 1x10⁵ vector genome containing particles (vg)/cell, or greater than 1x10¹⁴ vg/L of cell culture, when harvested 48 hours post- transfection. More specifically, triple transfection refers a method whereby a packaging cell is transfected with three plasmids: one plasmid encodes the AAV rep and cap genes, another plasmid encodes various helper functions (e.g., adenovirus or HSV proteins such as E1a, E1b, E2a, E4, and VA RNA, and another plasmid encodes a transgene (e.g., an RNA described herein) and various elements to control expression of the transgene. Single-stranded vector genomes are packaged into capsids as the plus strand or minus strand in about equal proportions. In some embodiments of an rAAV vector, a vector genome is in the plus strand polarity (i.e., the sense or coding sequence of the DNA strand). In some embodiments an rAAV vector, a vector is in the minus strand polarity (i.e., the antisense or template DNA strand). Given the nucleotide sequence of a plus strand in its 5’ to 3’ orientation, UR6-23082/161118-04901 the nucleotide sequence of a minus strand in its 5’ to 3’ orientation can be determined as the reverse-complement of the nucleotide sequence of the plus strand. To achieve the desired yields, a number of variables are optimized such as selection of a compatible serum-free suspension media that supports both growth and transfection, selection of a transfection reagent, transfection conditions and cell density. An rAAV vector may be purified by methods standard in the art such as by column chromatography or cesium chloride gradients. Methods for purifying rAAV vectors are known in the art and include methods described in Clark et al. (1999) Human Gene Therapy 10(6):1031-1039; Schenpp and Clark (2002) Methods Mol. Med.69:427-443; U.S. Patent No. 6,566,118 and WO 98/09657. A universal purification strategy, based on ion exchange chromatography methods, may be used to generate high purity vector preps of AAV serotypes 1-6, 8, 9 and various chimeric capsids. In some embodiment, this process can be completed within one week, result in high full to empty capsid ratios (>90% full capsids), provide post-purification yields (>1x10¹³ vg/L) and purity suitable for clinical applications. In some embodiments, such a method is universal with respect to all serotypes and chimeric capsids. Scalable manufacturing technology may be utilized to manufacture GMP clinical and commercial grade rAAV vectors (e.g., for the treatment of an inherited or acquired neurodegenerative disorder). After rAAV vectors of the present disclosure have been produced and purified, they can be titered (e.g., the amount of rAAV vector in a sample can be quantified) to prepare compositions for administration to subjects, such as human subjects with an inherited or acquired neurodegenerative disorder. rAAV vector titering can be accomplished using methods know in the art. In some embodiments, the number of viral particles, including particles containing a vector genome and “empty” capsids that do not contain a vector genome, can be determined by electron microscopy, e.g., transmission electron microscopy (TEM). Such a TEM-based method can provide the number of vector particles (or virus particles in the case of wild type AAV) in a sample. In some embodiments, rAAV vector genomes can be titered using quantitative PCR (qPCR) using primers against sequences in the vector genome, for example ITR sequences, and/or sequences in the transgene or regulatory elements. By performing qPCR in parallel on dilutions of a standard of known concentration, such as a plasmid containing the sequence of the vector genome, a standard curve can be generated permitting the concentration of the rAAV vector to be calculated as the number of vector genomes (vg) per unit volume such as UR6-23082/161118-04901 microliters or milliliters. By comparing the number of vector particles as measured by, e.g., electron microscopy, to the number of vector genomes in a sample, the number of empty capsids can be determined. Because the vector genome contains the therapeutic transgene, vg/kg or vg/ml of a vector sample may be more indicative of the therapeutic amount of the vector that a subject will receive than the number of vector particles, some of which may be empty and not contain a vector genome. Once the concentration of rAAV vector genomes in the stock solution is determined, it can be diluted into or dialyzed against suitable buffers for use in preparing a composition for administration to subjects (e.g., subjects with an inherited or acquired neurodegenerative disorder). 6. Uses and Treatment Methods A nucleic acid (such as an RNA molecule or polynucleotide encoding the RNA molecule) as disclosed herein may be used for gene therapy treatment and/or prevention of a disease, disorder or condition. In particular, it can be used for treating or preventing a disease, disorder or condition associated with deficiency or dysfunction by targeting a particular target gene (e.g., FXYD1), and of any other condition and or illness in which reducing the expression of the related target gene may produce a therapeutic benefit or improvement, e.g., a disease, disorder or condition mediated by, or associated with, an increase in the level or function of the related protein (e.g., FXYD1) compared with the level or function of the protein in an otherwise healthy individual. The vector genome and/or an rAAV vector described herein can be used for gene therapy treatment and/or prevention of the same disease, disorder or condition. In some embodiments, methods of the disclosure include use of an rAAV vector, or a pharmaceutical composition thereof, in the treatment of the disease, disorder or condition in a subject. In some embodiments, methods of the disclosure include use of an rAAV vector, or pharmaceutical composition thereof, to decrease the level of a gene of interest (e.g., FXYD1) in a subject in need thereof. The nucleic acid, a vector genome, and/or an rAAV vector described above can be used in the preparation of a medicament for use in the treatment and/or prevention of a disease, disorder or condition associated with or caused by deficiency or dysfunction (e.g., neurodegenerative diseases) and of any other condition or illness in which down-regulation of the related protein(s) may produce a therapeutic benefit or improvement. In certain embodiments, compositions described herein can be administered in combination with cognitive enhancing (nootropic) agents. Exemplary agents include any drugs, supplements, or other substances that improve cognitive function, particularly executive UR6-23082/161118-04901 functions, memory, creativity, or motivation, in healthy individuals. Non limiting examples include racetams (e.g., piracetam, oxiracetam, and aniracetam), nutraceuticals (e.g., bacopa monnieri, panax ginseng, ginko biloba, and GABA), stimulants (e.g., amphetamine pharmaceuticals, methylphenidate, eugeroics, xanthines, and nicotine), L-Theanine, Tolcapone, Levodopa, Atomoxetine, and Desipramine. The overall dosage of a therapeutic agent (e.g., an RNA molecule, a polynucleotide encoding the RNA molecule, a vector genome, or a vector, such as an rAAV vector, or a cell) will be a therapeutically effective amount depending on several factors including the overall health of a subject, the subject's disease state, severity of the condition, the observation of improvements and the formulation and route of administration of the selected agent(s). Determination of a therapeutically effective amount is within the capability of those skilled in the art. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the subject's condition. In other embodiments, the cell or nucleotide compositions may be administered in an amount effective to promote survival of CNS neurons in a subject by an increase in the number of surviving neurons of at least 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, or 1000% as compared to the number of surviving neurons in an untreated CNS neurons or subject. In some embodiments, the subject is also administered a second agent to treat or prevent a neurological disease or disorder. In some embodiments, the first and second agent are co-formulated. In some embodiments, the first and second agent are administered simultaneously. In some embodiments, the first and second agent are administered within a time of each other to produce overlapping therapeutic effects in the patient. When the first and second agent are administered simultaneously or within a time of each other to produce overlapping therapeutic effects, the agents may be administered by the same or a different route of administration (e.g., oral versus infusion). 7. Pharmaceutical Compositions The present disclosure provides a pharmaceutical composition, or medicament, for preventing or treating an inherited or acquired neurodegenerative disorder. In some embodiments, a pharmaceutical composition comprises one or more of the above-described UR6-23082/161118-04901 RNA molecule, polynucleotide, expression cassette, expression vector (e.g., viral vector genome, expression vector, rAAV vector), and host cell. The pharmaceutical composition further comprises a pharmaceutically-acceptable carrier, adjuvant, diluent, excipient and/or other medicinal agents. A pharmaceutically acceptable carrier, adjuvant, diluent, excipient or other medicinal agent is one that is not biologically or otherwise undesirable, e.g., the material may be administered to a subject without causing undesirable biological effects which outweigh the advantageous biological effects of the material. Any suitable pharmaceutically acceptable carrier or excipient can be used in the preparation of a pharmaceutical composition according to the invention (See e.g., Remington The Science and Practice of Pharmacy, Adeboye Adejare (Editor) Academic Press, November 2020). A pharmaceutical composition is typically sterile, pyrogen-free and stable under the conditions of manufacture and storage. A pharmaceutical composition may be formulated as a solution (e.g., water, saline, dextrose solution, buffered solution, or other pharmaceutically sterile fluid), microemulsion, liposome, or other ordered structure suitable to accommodate a high product (e.g., viral vector particles, microparticles or nanoparticles) concentration. In some embodiments, a pharmaceutical composition comprising the above-described RNA molecule, polynucleotide, expression cassette, expression vector, vector genome, host cell or rAAV vector of the disclosure is formulated in water or a buffered saline solution. A carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by use of a coating such as lecithin, by maintenance of a required particle size, in the case of dispersion, and by the use of surfactants. In some embodiments, it may be preferable to include isotonic agents, for example, a sugar, a polyalcohol such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged adsorption of an injectable composition can be brought about by including, in the composition, an agent which delays absorption, e.g., a monostearate salt and gelatin. In some embodiments, a nucleic acid, vector and/or host cell of the disclosure may be administered in a controlled release formulation, for example, in a composition which includes a slow-release polymer or other carrier that protects the product against rapid release, including an implant and microencapsulated delivery system. In some embodiments, a pharmaceutical composition of the disclosure is a parenteral pharmaceutical composition, including a composition suitable for intravenous, intraarterial, subcutaneous, intradermal, intraperitoneal, intramuscular, intraarticular, intraparenchymal UR6-23082/161118-04901 (IP), intrathecal (IT), intracerebroventricular (ICV) and/or intracisternal magna (ICM) administration. In some embodiments, a pharmaceutical composition of this disclosure is formulated for administration by ICV injection. In some embodiments, an rAAV vector is formulated in 350 mM NaCl and 5% D-sorbitol in PBS. 8. Methods of Administration The above-described RNA molecule, or polynucleotide, or a vector (e.g., vector genome, rAAV vector) may be administered to a subject (e.g., a patient) in order to treat the subject. Administration of a vector to a human subject, or an animal in need thereof, can be by any means known in the art for administering a vector. A target cell of a vector of the present disclosure includes cells of the CNS, preferably glial progenitor cells, astrocytes, or oligodendrocytes . A vector can be administered in addition to, and as an adjunct to, the standard of care treatment. That is, the vector can be co-administered with another agent, compound, drug, treatment or therapeutic regimen, either simultaneously, contemporaneously, or at a determined dosing interval as would be determined by one skilled in the art using routine methods. Uses disclosed herein include administration of an rAAV vector of the disclosure at the same time, in addition to and/or on a dosing schedule concurrent with, the standard of care for the disease as known in the art. In some embodiments, a combination composition includes one or more immunosuppressive agents. In some embodiments, a combination composition includes an rAAV vector comprising a transgene (e.g., a polynucleotide encoding an RNA molecule disclosed herein) and one or more immunosuppressive agents. In some embodiments, a method includes administering or delivering an rAAV vector comprising the transgene to a subject and administering an immunosuppressive agent to the subject either prophylactically prior to administration of the vector, or after administration of the vector (i.e., either before or after symptoms of a response against the vector and/or the protein provided thereby are evident). In one embodiment, a vector of the disclosure (e.g., an rAAV vector) is administered systemically. Exemplary methods of systemic administration include, but are not limited to, intravenous (e.g., portal vein), intraarterial (e.g., femoral artery, hepatic artery), intravascular, subcutaneous, intradermal, intraperitoneal, transmucosal, intrapulmonary, intralymphatic and intramuscular administration, and the like, as well as direct tissue or organ injection. One skilled in the art would appreciate that systemic administration can deliver a nucleic acid to all tissues. In some embodiments, direct tissue or organ administration includes administration to UR6-23082/161118-04901 areas directly affected by deficiency (e.g., brain and/or central nervous system). In some embodiments, vectors of the disclosure, and pharmaceutical compositions thereof, are administered to the brain parenchyma (i.e., by intraparenchymal administration), to the spinal canal or the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) (i.e., by intrathecal administration), to a ventricle of the brain (i.e., by intracerebroventricular administration) and/or to the cisterna magna of the brain (i.e., by intracisternal magna administration). Accordingly, in some embodiments, a vector of the present disclosure is administered by direct injection into the brain (e.g., into the parenchyma, ventricle, cisterna magna, etc.) and/or into the CSF (e.g., into the spinal canal or subarachnoid space) to treat a neurodegenerative disorder. A target cell of a vector of the present disclosure includes a cell located in the cortex, subcortical white matter of the corpus callosum, striatum and/or cerebellum. In some embodiments, a target cell of a vector of the present disclosure is a glial cell (a glial progenitor cell, an astrocyte, or an oligodendrocytes). Additional routes of administration may also comprise local application of a vector under direct visualization, e.g., superficial cortical application, or other stereotaxic application. In some embodiments, a vector of the disclosure is administered by at least two routes. For example, a vector is administered systemically and also directly into the brain. If administered via at least two routes, the administration of a vector can be, but need not be, simultaneous or contemporaneous. Instead, administration via different routes can be performed separately with an interval of time between each administration. The above-described RNA molecule, or polynucleotide encoding the RNA molecule, or a vector genome, or an rAAV vector comprising the polynucleotide may be used for transduction of a cell ex vivo or for administration directly to a subject (e.g., directly to the CNS of a patient with a disease). In some embodiments, a transduced cell (e.g., a host cell) is administered to a subject to treat or prevent a disease, disorder or condition (e.g., cell therapy for the disease). An rAAV vector comprising a therapeutic nucleic acid (e.g., encoding the RNA molecule) is preferably administered to a cell in a biologically-effective amount. In some embodiments, a biologically-effective amount of a vector is an amount that is sufficient to result in reducing the expression of a related gene in a target cell. In some embodiments, the disclosure includes a method of decreasing the level and/or activity of a gene in a cell by administering to a cell (in vivo, in vitro or ex vivo) a polynucleotide encoding an RNA molecule described herein, either alone or in a vector (including a plasmid, UR6-23082/161118-04901 a virus vector, a nanoparticle, a liposome, or any known method for providing a nucleic acid to a cell). The dosage amount of an rAAV vector depends upon, e.g., the mode of administration, disease or condition to be treated, the stage and/or aggressiveness of the disease, individual subject's condition (age, sex, weight, etc.), particular viral vector, stability of protein to be expressed, host immune response to the vector, and/or gene to be delivered. Generally, doses range from at least 1 x 10⁸, or more, e.g., 1 x 10⁹, 1 x 10¹⁰, 1 x 10¹¹, 1 x 10¹², 1 x 10¹³, 1 x 10¹⁴, 1 x 10¹⁵ or more vector genomes (vg) per kilogram (kg) of body weight of the subject to achieve a therapeutic effect. In some embodiments, a polynucleotide encoding an RNA molecule described herein may be administered as a component of a DNA molecule (e.g., a recombinant nucleic acid) having a regulatory element (e.g., a promoter) appropriate for expression in a target cell (e.g., glial progenitor cells, astrocytes, or oligodendrocytes). The polynucleotide may be administered as a component of a plasmid or a viral vector, such as an rAAV vector. An rAAV vector may be administered in vivo by direct delivery of the vector (e.g., directly to the CNS) to a patient in need of treatment. An rAAV vector may be administered to a patient ex vivo by administration of the vector in vitro to a cell from a donor patient in need of treatment, followed by introduction of the transduced cell back into the donor (e.g., cell therapy). 9. Kit The present disclosure provides a kit with packaging material and one or more components therein. A kit typically includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo or ex vivo, of the components therein. A kit can contain a collection of such components, e.g., the above-described RNA molecule, polynucleotide, nucleic acid, expression cassette, expression vector (e.g., viral vector genome, expression vector, rAAV vector), and host cell, and optionally a second active agent such as a compound, therapeutic agent, drug or composition. A kit refers to a physical structure that contains one or more components of the kit. Packaging material can maintain the components in a sterile manner and can be made of material commonly used for such purposes (e.g., paper, glass, plastic, foil, ampules, vials, tubes, etc). A label or insert can include identifying information of one or more components therein, dose amounts, clinical pharmacology of the active ingredients(s) including mechanism of action, pharmacokinetics and pharmacodynamics. A label or insert can include information UR6-23082/161118-04901 identifying manufacture, lot numbers, manufacture location and date, expiration dates. A label or insert can include information on a disease (e.g., an inherited or acquired neurodegenerative disorder) for which a kit component may be used. A label or insert can include instructions for a clinician or subject for using one or more of the kit components in a method, use or treatment protocol or therapeutic regimen. Instructions can include dosage amounts, frequency of duration and instructions for practicing any of the methods, uses, treatment protocols or prophylactic or therapeutic regimens described herein. A label or insert can include information on potential adverse side effects, complications or reaction, such as a warning to a subject or clinician regarding situations where it would not be appropriate to use a particular composition. 10. Definitions As used herein, the terms “nucleic acid sequence,” “nucleotide sequence,” and “polynucleotide” refer interchangeably to any molecule composed of or comprising monomeric nucleotides connected by phosphodiester linkages. A nucleic acid may be an oligonucleotide or a polynucleotide. Nucleic acid sequences are presented herein in the direction from the 5’ to the 3’ direction. A nucleic acid sequence (i.e., a polynucleotide) of the present disclosure can be a deoxyribonucleic acid (DNA) molecule or ribonucleic acid (RNA) molecule and refers to all forms of a nucleic acid such as, double stranded molecules, single stranded molecules, small or short hairpin RNA (shRNA), micro interfering RNA or micro RNA (miRNA), small or short interfering RNA (siRNA), trans-splicing RNA, antisense RNA, messenger RNA, transfer RNA, ribosomal RNA. Where a polynucleotide is a DNA molecule, that molecule can be a gene, a cDNA, an antisense molecule or a fragment of any of the foregoing molecules. Nucleotides are indicated herein by a single letter code: adenine (A), guanine (G), thymine (T), cytosine (C), inosine (I) and uracil (U). A nucleotide sequence may be chemically modified or artificial. Nucleotide sequences include peptide nucleic acids (PNA), morpholinos and locked nucleic acids (LNA), as well as glycol nucleic acids (GNA) and threose nucleic acids (TNA). Each of these sequences is distinguished from naturally- occurring DNA or RNA by changes to the backbone of the molecule. Also, phosphorothioate nucleotides may be used. Other deoxynucleotide analogs include methylphosphonates, phosphoramidates, phosphorodithioates, N3’-P5’-phosphoramidates, and oligoribonucleotide phosphorothioates and their 2’-0-allyl analogs and 2’-0-methylribonucleotide methylphosphonates which may be used in a nucleotide sequence of the disclosure. UR6-23082/161118-04901 In some embodiments a nucleic acid may comprise one or more non-standard nucleotides, which may be naturally occurring or non-naturally occurring (i.e., artificial; not found in nature) in various embodiments and/or may contain a modified sugar or modified backbone linkage. Nucleic acid modifications (e.g., base, sugar, and/or backbone modifications), non-standard nucleotides or nucleosides, etc., such as those known in the art as being useful in the context of RNA interference (RNAi), aptamer, CRISPR technology, polypeptide production, reprogramming, or antisense-based molecules for research or therapeutic purposes may be incorporated in various embodiments. Such modifications may, for example, increase stability (e.g., by reducing sensitivity to cleavage by nucleases), decrease clearance in vivo, increase cell uptake, or confer other properties that improve the translation, potency, efficacy, specificity, or otherwise render the nucleic acid more suitable for an intended use. Various non-limiting examples of nucleic acid modifications are described in, e.g., Deleavey G F, et al., Chemical modification of siRNA. Curr. Protoc. Nucleic Acid Chem.2009; 39:16.3.1-16.3.22; Crooke, S T (ed.) Antisense drug technology: principles, strategies, and applications, Boca Raton: CRC Press, 2008; Kurreck, J. (ed.) Therapeutic oligonucleotides, RSC biomolecular sciences. Cambridge: Royal Society of Chemistry, 2008; U.S. Pat. Nos. 4,469,863; 5,536,821; 5,541,306; 5,637,683; 5,637,684; 5,700,922; 5,717,083; 5,719,262; 5,739,308; 5,773,601; 5,886,165; 5,929, 226; 5,977,296; 6,140,482; 6,455,308 and/or in PCT application publications WO 00/56746 and WO 01/14398. Different modifications may be used in the two strands of a double-stranded nucleic acid. A nucleic acid may be modified uniformly or on only a portion thereof and/or may contain multiple different modifications. Where the length of a nucleic acid or nucleic acid region is given in terms of a number of nucleotides (nt) it should be understood that the number refers to the number of nucleotides in a single-stranded nucleic acid or in each strand of a double-stranded nucleic acid unless otherwise indicated. An “oligonucleotide” is a relatively short nucleic acid, typically between about 5 and about 100 nt long. In some embodiments, a protein or a nucleic acid is isolated. As used herein, the term "isolated" means artificially produced. As used herein with respect to nucleic acids, the term "isolated" means: (i) amplified in vitro by, for example, polymerase chain reaction (PCR); (ii) recombinantly produced by cloning; (iii) purified, as by cleavage and gel separation; or (iv) synthesized by, for example, chemical synthesis. An isolated nucleic acid is one which is readily manipulable by recombinant DNA techniques well known in the art. Thus, a nucleotide sequence contained in a vector in which 5' and 3' restriction sites are known or for which polymerase chain reaction (PCR) primer sequences have been disclosed is considered isolated UR6-23082/161118-04901 but a nucleic acid sequence existing in its native state in its natural host is not. An isolated nucleic acid may be substantially purified, but need not be. For example, a nucleic acid that is isolated within a cloning or expression vector is not pure in that it may comprise only a tiny percentage of the material in the cell in which it resides. Such a nucleic acid is isolated, however, as the term is used herein because it is readily manipulable by standard techniques known to those of ordinary skill in the art. As used herein with respect to proteins or peptides, the term "isolated" refers to a protein or peptide that has been isolated from its natural environment or artificially produced (e.g., by chemical synthesis, by recombinant DNA technology, etc.). In some embodiments, any one or more thymidine (T) nucleotides or uridine (U) nucleotides in a sequence provided herein may be replaced with any other nucleotide suitable for base pairing (e.g., via a Watson-Crick base pair) with an adenosine nucleotide. For example, T may be replaced with U, and U may be replaced with T. “Heterologous" means derived from a genotypically distinct entity from that of the rest of the entity to which it is compared or into which it is introduced or incorporated. For example, a polynucleotide introduced by genetic engineering techniques into a different cell type is a heterologous polynucleotide (and, when expressed, can encode a heterologous polypeptide). Similarly, a cellular sequence (e.g., a gene or portion thereof) that is incorporated into a viral vector is a heterologous nucleotide sequence with respect to the vector. The term "transgene" refers to a heterologous polynucleotide that is introduced into a cell and is capable of being transcribed into RNA and optionally, translated and/or expressed under appropriate conditions. In aspects, it confers a desired property to a cell into which it was introduced, or otherwise leads to a desired therapeutic or diagnostic outcome. In another aspect, it may be transcribed into a molecule that mediates RNA interference, such as miRNA, siRNA, or shRNA. As used herein, the term “recombinant,” refers to a vector, polynucleotide (e.g., a recombinant nucleic acid), polypeptide or cell that is the product of various combinations of cloning, restriction or ligation steps (e.g. relating to a polynucleotide or polypeptide comprised therein), and/or other procedure that results in a construct that is distinct from a product found in nature. A recombinant virus or vector (e.g., rAAV vector) comprises a vector genome comprising a recombinant nucleic acid (e.g., a nucleic acid comprising a transgene and one or more regulatory elements). The terms respectively include replicates of the original polynucleotide construct and progeny of the original virus construct. As used herein, the term “operably linked” refers to a linkage of nucleic acid sequence (or polypeptide) elements in a functional relationship. A nucleic acid is operably linked when UR6-23082/161118-04901 it is placed into a functional relationship with another nucleic acid sequence. For instance, a promoter or other transcription regulatory sequence (e.g., an enhancer) is operably linked to a coding sequence if it affects the transcription of the coding sequence. In some embodiments, operably linked means that nucleic acid sequences being linked are contiguous. In some embodiments, operably linked does not mean that nucleic acid sequences are contiguously linked, rather intervening sequences are between those nucleic acid sequences that are linked. A "recombinant AAV vector (rAAV vector)" refers to a polynucleotide vector comprising one or more heterologous sequences (i.e., nucleic acid sequence not of AAV origin) that are flanked by at least one, and in embodiments two, AAV inverted terminal repeat sequences. Such rAAV vectors can be replicated and packaged into infectious viral particles when present in a host cell that has been infected with a suitable helper virus (or that is expressing suitable helper functions) and that is expressing AAV rep and cap gene products (i.e. AAV Rep and Cap proteins). When a rAAV vector is incorporated into a larger polynucleotide (e.g., in a chromosome or in another vector such as a plasmid used for cloning or transfection), then the rAAV vector may be referred to as a "pro-vector" which can be "rescued" by replication and encapsidation in the presence of AAV packaging functions and suitable helper functions. An rAAV vector can be in any of a number of forms, including, but not limited to, plasmids, linear artificial chromosomes, complexed with lipids, encapsulated within liposomes, and encapsidated in a viral particle, particularly an AAV particle. A rAAV vector can be packaged into an AAV virus capsid to generate a "recombinant adeno-associated viral particle (rAAV particle)". As used herein, the term “vector” refers to a plasmid, virus (e.g., an rAAV), cosmid, or other vehicle that can be manipulated by insertion or incorporation of a nucleic acid (e.g., a recombinant nucleic acid). A vector can be used for various purposes including, e.g., genetic manipulation (e.g., cloning vector), to introduce/transfer a nucleic acid into a cell, to transcribe or translate an inserted nucleic acid in a cell. In some embodiments a vector nucleic acid sequence contains at least an origin of replication for propagation in a cell. In some embodiments, a vector nucleic acid includes a heterologous nucleic acid sequence, an expression control element(s) (e.g., promoter, enhancer), a selectable marker (e.g., antibiotic resistance), a poly-adenosine (polyA) sequence and/or an ITR. In some embodiments, when delivered to a host cell, the nucleic acid sequence is propagated. In some embodiments, when delivered to a host cell, either in vitro or in vivo, the cell expresses the polypeptide encoded by the heterologous nucleic acid sequence. In some embodiments, when delivered to a host cell, the nucleic acid sequence, or a portion of the nucleic acid sequence is packaged into a capsid. UR6-23082/161118-04901 A host cell may be an isolated cell or a cell within a host organism. In addition to a nucleic acid sequence (e.g., transgene) which encodes an RNA, or a polypeptide or a protein, additional sequences (e.g., regulatory sequences) may be present within the same vector (i.e., in cis to the gene) and flank the gene. In some embodiments, regulatory sequences may be present on a separate (e.g., a second) vector which acts in trans to regulate the expression of the gene. Plasmid vectors may be referred to herein as “expression vectors.” As used herein, the term “vector genome” refers to a recombinant nucleic acid sequence that is packaged or encapsidated to form an rAAV vector. Typically, a vector genome includes a heterologous polynucleotide sequence, e.g., a transgene, regulatory elements, ITRs not originally present in the capsid. In cases where a recombinant plasmid is used to construct or manufacture a recombinant vector (e.g., rAAV vector), the vector genome does not include the entire plasmid but rather only the sequence intended for delivery by the viral vector. This non- vector genome portion of the recombinant plasmid is typically referred to as the “plasmid backbone,” which is important for cloning. selection and amplification of the plasmid, a process that is needed for propagation of recombinant viral vector production, but which is not itself packaged or encapsidated into an rAAV vector. As used herein, the term “viral vector” generally refers to a viral particle that functions as a nucleic acid delivery vehicle and which comprises a vector genome (e.g., comprising a transgene instead of a nucleic acid encoding an AAV rep and cap) packaged within the viral particle (i.e., capsid) and includes, for example, lenti- and parvo- viruses, including AAV serotypes and variants (e.g., rAAV vectors). A recombinant viral vector does not comprise a vector genome comprising a rep and/or a cap gene. As used herein "miRNA scaffold" may refer to a polynucleotide containing (i) a double- stranded sequence targeting a gene of interest for knockdown by RNAi and (ii) additional sequences that form a stem-loop structure resembling that of endogenous miRNAs. A sequence targeting a gene of interest for RNAi (e.g., a short, about 20-nt sequence) may be ligated to sequences that create a miRNA-like stem-loop and a sequence that base pairs with the sequence of interest to form a duplex when the polynucleotide is assembled into the miRNA-like secondary structure. As described herein, this duplex may hybridize imperfectly, e.g., it may contain one or more unpaired or mispaired bases. Upon cleavage of this polynucleotide by Dicer, this duplex containing the sequence targeting a gene of interest may be unwound and incorporated into the RISC complex. A miRNA scaffold may refer to the miRNA itself or to a DNA polynucleotide encoding the miRNA. An example of a miRNA scaffold is the miR-155 sequence (Lagos-Quintana, M. et al. (2002) Curr. Biol.12:735-9). Commercially available kits UR6-23082/161118-04901 for cloning a sequence into a miRNA scaffold are known in the art (e.g., the INVITROGEN BLOCK-IT Pol II miR RNAi expression vector kit from Life Technologies, Thermo Fisher Scientific; Waltham, Mass.). A functional variant or equivalent of a reference peptide, polypeptide, or protein refers to a polypeptide derivative of the reference peptide, polypeptide, or protein, e.g., a protein having one or more point mutations, insertions, deletions, truncations, a fusion protein, or a combination thereof. It retains substantially the activity to of the reference peptide, polypeptide, or protein. In general, the functional equivalent is at least 60% (e.g., any number between 60% and 100%, inclusive, e.g., 60%, 70 %, 80%, 85%, 90%, 95%, and 99%) identical to the reference peptide, polypeptide, or protein. In certain embodiments, a point mutation can be a conservative modification. As used herein, the term "conservative modification" refers to amino acid modifications that do not significantly affect or alter the biological characteristics of a polypeptide or protein. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into a polypeptide or protein by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include: amino acids with basic side chains (e.g., lysine, arginine, histidine); acidic side chains (e.g., aspartic acid, glutamic acid); uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan); nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine); beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Non-conservative substitutions will entail exchanging a member of one of these classes for another class. As used herein, the terms “treat,” “treating” or “treatment” refer to administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. The terms “decrease,” “reduce,” “reduced,” “reduction,” “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least UR6-23082/161118-04901 about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment. As used herein, the term “ameliorate” means a detectable or measurable improvement in a subject’s disease, disorder or condition, or symptom thereof, or an underlying cellular response. A detectable or measurable improvement includes a subjective or objective decrease, reduction, inhibition, suppression, limit or control in the occurrence, frequency, severity, progression or duration of, complication cause by or associated with, improvement in a symptom of, or a reversal of a disease, disorder or condition. As used herein, the term “associated with” refers to with one another, if the presence, level and/or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and/or form correlates with incidence of and/or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). As used herein, the term “prevent” or “prevention” refers to delay of onset, and/or reduction in frequency and/or severity of one or more sign or symptom of a particular disease, disorder or condition. In some embodiments, prevention is assessed on a population basis such that an agent is considered to “prevent” a particular disease, disorder or condition if a statistically significant decrease in the development, frequency and/or intensity of one or more sign or symptom of the disease, disorder or condition is observed in a population susceptible to the disease, disorder or condition. Prevention may be considered complete when onset of disease, disorder or condition has been delayed for a predefined period of time. The term “agent” as used herein means any compound or substance such as, but not limited to, a small molecule, nucleic acid, polypeptide, peptide, drug, ion, virus, cell, etc. An “agent” can be any chemical, entity or moiety, including without limitation synthetic and naturally-occurring proteinaceous and non-proteinaceous entities. In some embodiments, an agent is nucleic acid, nucleic acid analogues, proteins, antibodies, peptides, aptamers, oligomer of nucleic acids, amino acids, or carbohydrates including without limitation proteins, oligonucleotides, ribozymes, DNAzymes, glycoproteins, siRNAs, lipoproteins, aptamers, and modifications and combinations thereof etc. In some embodiments, the agent is selected from UR6-23082/161118-04901 the group consisting of a nucleic acid, a small molecule, a polypeptide, and a peptide. In some embodiments the agent is an oligonucleotide, protein, or a small molecule. In some embodiments the agent comprises one or more oligonucleotides. In some aspects the oligonucleotide is a splice-switching oligonucleotide. In certain aspects the oligonucleotide is an antisense oligonucleotide (ASO). In certain embodiments, agents are small molecule having a chemical moiety. For example, chemical moieties included unsubstituted or substituted alkyl, aromatic, or heterocyclyl moieties including macrolides, leptomycins and related natural products or analogues thereof. Compounds can be known to have a desired activity and/or property, or can be selected from a library of diverse compounds. In some embodiments, the agent is a genomic modification system (e.g., a CRISPR/Cas, Zinc Finger Nuclease, or TALEN systems). CRISPR/Cas systems can employ a variety of Cas proteins (Haft et al. PLoS Comput Biol. 2005; 1(6)e60). In some embodiments, the CRISPR/Cas system is a CRISPR type I system. In some embodiments, the CRISPR/Cas system is a CRISPR type II system. In some embodiments, the CRISPR/Cas system is a CRISPR type V system. A “small molecule” is defined as a molecule with a molecular weight that is less than 10 kD, typically less than 2 kD, and preferably less than 1 kD. Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing an inorganic component, molecules comprising a radioactive atom, synthetic molecules, peptide mimetics, and antibody mimetics. As a therapeutic, a small molecule may be more permeable to cells, less susceptible to degradation, and less apt to elicit an immune response than large molecules. As used herein, the term “polypeptide” or “protein” is used to designate a series of amino acid residues connected to the other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. The term “polypeptide” refers to a polymer of protein amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function. The term “peptide” is often used in reference to small polypeptides, but usage of this term in the art overlaps with “protein” or “polypeptide.” Exemplary polypeptides include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, as well as both naturally and non-naturally occurring variants, fragments, and analogs of the foregoing. As used herein, the term “subject” refers to an organism, for example, a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog). In some embodiments, a subject is a non-human disease model. In some embodiments, a human subject is an adult, adolescent, or pediatric UR6-23082/161118-04901 subject. In some embodiments, a subject is suffering from a disease, disorder or condition, e.g., a disease, disorder or condition that can be treated as provided herein. In some embodiments, a subject is suffering from a disease, disorder or condition associated with neuronal hyperexcitability. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a susceptible subject is predisposed to and/or shows an increased risk (as compared to the average risk observed in a reference subject or population) of developing a disease, disorder or condition. In some embodiments, a subject displays one or more symptoms of a disease, disorder or condition. In some embodiments, a subject does not display a particular symptom (e.g., clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a human patient. In some embodiments, a subject is an individual to whom diagnosis and/or therapy is and/or has been administered. As used herein, the term “pharmaceutically acceptable” refers to those agents, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, the term “pharmaceutically-acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and UR6-23082/161118-04901 aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; (22) C2-C12 alcohols, such as ethanol; and (23) other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservative and antioxidants can also be present in the formulation. The terms such as “excipient”, “carrier”, “pharmaceutically acceptable carrier” or the like are used interchangeably herein. As used herein, the term “therapeutically effective amount” refers to an amount that produces the desired therapeutic effect for which it is administered. In some embodiments, the term refers to an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. As used herein, the term “administer” refers to the placement of an agent or composition into a subject (e.g., a subject in need) by a method or route which results in at least partial localization of the agent or composition at a desired site such that desired effect is produced. Routes of administration suitable for the methods of the invention include both local and systemic routes of administration. Generally, local administration results in more of the administered agents being delivered to a specific location as compared to the entire body of the subject, whereas, systemic administration results in delivery of the agents to essentially the entire body of the subject. The compositions and agents disclosed herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, and topical (including buccal and sublingual) administration. Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, UR6-23082/161118-04901 intrathecal, intraventricular, intracranial, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion. In preferred embodiments of the aspects described herein, the compositions are administered by intravenous infusion or injection. As used herein, the term “glial cells” refers to a population of non-neuronal cells that provide support and nutrition, maintain homeostasis, either form myelin or promote myelination, and participate in signal transmission in the nervous system. “Glial cells” as used herein encompasses fully differentiated cells of the glial lineage, such as oligodendrocytes or astrocytes, and as well as glial progenitor cells. Glial progenitor cells are cells having the potential to differentiate into cells of the glial lineage such as oligodendrocytes and astrocytes. The glial progenitor cells described herein may be derived from any suitable source of pluripotent stem cells, such as, for example and without limitation, human induced pluripotent stem cells (iPSCs) and embryonic stem cells, as described in more detail below. In one example, glial progenitor cells can be cells rejuvenated from glial progenitor cells or progenies thereof as described herein. In some embodiments, to treat a subject in need thereof, glial progenitor cells or rejuvenated cells are young glial or glial progenitor cells, or are younger than the counterparts in the subject to be treated. As used herein, the term “about,” or “approximately” refers to a measurable value such as an amount of the biological activity, homology or length of a polynucleotide or polypeptide sequence, dose, time, temperature, and the like, and is meant to encompass variations of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% 1%, 0.5% or even 0.1%, in either direction (greater than or less than) of the specified amount unless otherwise stated, otherwise evident from the context, or except where such number would exceed 100% of a possible value. As used herein, the term “homologous,” or “homology,” refers to two or more reference entities (e.g., a nucleic acid or polypeptide sequence) that share at least partial identity over a given region or portion. For example, when an amino acid position in two peptides is occupied by identical amino acids, the peptides are homologous at that position. Notably, a homologous peptide will retain activity or function associated with the unmodified or reference peptide and the modified peptide will generally have an amino acid sequence “substantially homologous” with the amino acid sequence of the unmodified sequence. When referring to a polypeptide, nucleic acid or fragment thereof, “substantial homology” or “substantial similarity,” means that UR6-23082/161118-04901 when optimally aligned with appropriate insertions or deletions with another polypeptide, nucleic acid (or its complementary strand) or fragment thereof, there is sequence identity in at least about 70% to 99% of the sequence. The extent of homology (identity) between two sequences can be ascertained using computer program or mathematical algorithm known in the art. Such algorithms that calculate percent sequence homology (or identity) generally account for sequence gaps and mismatches over the comparison region or area. EXAMPLES Example 1 Meta‐analysis was carried out to identify astrocytic genes that are dysregulated in neurodegenerative disease‐derived astrocytes, but not in otherwise healthy aged astrocytes. The analysis was carried out using a large set of databases covering gene expression by both murine and human astrocytes, as derived from both wild‐type and aged cells and compared to age‐matched cells sourced from patients with a variety of neurodegenerative disorders. More specifically, six transcriptomic datasets were collected from published studies investigating the effects of aging (Boisvert, M.M., Erikson, G.A., Shokhirev, M.N. & Allen, N.J. The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell Rep. 22, 269-285 (2018)), Alzheimer's Disease (Zeng, H., et al. Integrative in situ mapping of single- cell transcriptional states and tissue histopathology in a mouse model of Alzheimer's disease. Nat. Neurosci.26, 430-446 (2023); Habib, N., et al. Disease-associated astrocytes in Alzheimer's disease and aging. Nat. Neurosci.23, 701-706 (2020); and Park, H., et al. Single- cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice. Nat Commun 14, 802 (2023)), ALS (Liu, W., et al. Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis. Neurobiol. Dis. 141, 104877 (2020)), or Huntington's disease (Benraiss, A., et al. Cell-intrinsic glial pathology is conserved across human and murine models of Huntington's disease. Cell Rep.36, 109308 (2021)). These six datasets allowed the inventors to complete the comparisons of disease condition with wildtype differential expression. The focus was specifically on astrocytic cells, and it was ensured that all included datasets were derived from mice. These datasets encompassed both bulk and single-cell resolution RNA sequencing experiments. With the given datasets the inventors were able to access or complete six different condition/wildtype crosses. When available, published lists of differentially expressed genes (DEGs) were utilized. In cases where such lists were not available, the inventors aligned the published FastQ files UR6-23082/161118-04901 against a GRCm39 ens106 reference using STAR, and utilized RNA-Seq by Expectation Maximization (RSEM) (Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. Aug 42011;12:323. doi:10.1186/1471-2105-12-323) for bulk RNA and STARsolo (Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. Jan 1 2013;29(1):15-21. doi:10.1093/bioinformatics/bts635) for cellular resolution datasets. The cellular resolution datasets were then restricted to clusters expressing GFAP and AQP4, so as to enrich for astrocytes. DEG lists were generated by comparing the condition to the wildtype using Wilcoxon rank sum, requiring an adjusted p-value of 0.05 or lower. These DEG lists were then filtered to include only genes that were included in a list of 280 genes associated with any of the 61 potassium-related Gene Ontology (GO) terms or pathways found in the Enrichr databases (Chen EY, Tan CM, Kou Y, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. Apr 15 2013;14:128. doi:10.1186/1471-2105-14-128; Kuleshov MV, Jones MR, Rouillard AD, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. Jul 8 2016;44(W1):W90-7. doi:10.1093/nar/gkw377; and Xie Z, Bailey A, Kuleshov MV, et al. Gene Set Knowledge Discovery with Enrichr. Curr Protoc. Mar 2021;1(3):e90. doi:10.1002/cpz1.90) . Finally, the inventors identified those genes that appeared in at least three out of the six datasets, resulting in a concise list of genes commonly and significantly dysregulated in astrocytes of mice with our targeted neurodegenerative conditions. The consistent changes of cortical [K⁺]e across disease models suggested that there might be common molecular pathways mediating the dysregulated potassium homeostasis. On that basis, the inventors mined six published transcriptomic databases covering astrocytic gene expression in the AD, ALS and HD mouse models that we studied (FIGs.1-2). Using published differential expression gene (DEG) lists, if available, or creating their own if not, the inventors identified the intersection of DEGs present in at least three out of the six datasets. Remarkably, while there were numerous shared DEGs among the disease states, none were shared by astrocytes in normal aging. It was found that, Fxyd1, a negative regulator of Na⁺/K⁺-ATPase activity, was selectively upregulated in all 3 AD models, and the ALS model, but unchanged in normal aging. In contrast, its expression fell in Huntington disease (HD) model mice, likely in a compensatory fashion to the previously described (Osipovitch et al., 2019) down-regulation of K channel expression in HD glia. Fxyd1 is of particular interest due to the common positive expression. Fxyd1 (FXYD Domain Containing Ion Transport Regulator-1) regulates the activity of the sodium/potassium- UR6-23082/161118-04901 transporting ATPase (NKA) which transports Na⁺ out of the cell and K⁺ into the cell. Since it typically serves to down-regulate Na⁺/K⁺-ATPase activity, Fxyd1’s relative over-expression suggests its disruption of astrocytic [K⁺]_e uptake and buffering in AD and ALS, leading to the high extracellular K⁺ of these conditions. Of note, Fxyd1 has been reported to inhibit Na⁺/K⁺- ATPase activity only in its unphosphorylated state; its activities in the CNS if phosphorylated remain unclear. As such, the overexpression of Fxyd1 would have effect of raising extracellular K+. Astrocytes are traditionally regarded as the major cell type responsible for K⁺ buffering (Verkhratsky, A., Nedergaard, M. & Hertz, L. Why are astrocytes important? Neurochem. Res. 40, 389-401 (2015); Parpura, V., et al. Glial cells in (patho)physiology. J Neurochem 121, 4- 27 (2012); and Walz, W. Role of astrocytes in the clearance of excess extracellular potassium. Neurochemistry international 36, 291-300 (2000)). Na⁺/K⁺-ATPase contributes to the clearance of extracellular K⁺ after neuronal activity (Larsen, B.R., et al. Glia 62, 608-622 (2014)), so that its negative regulation by Fxyd1 may raise [K⁺]e, hence yielding both the elevated cortical [K⁺]e and potentiated startle-induced [K⁺]e of both the ALS and AD models. The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the present disclosure as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present disclosure as set forth in the claims. Such variations are not regarded as a departure from the scope of the disclosure, and all such variations are intended to be included within the scope of the following claims. All references cited herein are incorporated by reference in their entireties.

Claims

UR6-23082/161118-04901 CLAIMS WHAT IS CLAIMED IS: 1. A method of (i) reducing brain hyperexcitability or (ii) treating a condition mediated by brain hyperexcitability in a subject in need thereof, comprising increasing the level or activity of Na⁺, K⁺ ATPase in a glial cell of the subject. 2. A method of lowering the brain interstitial potassium level in a subject in need thereof, comprising increasing the level or activity of Na⁺, K⁺ ATPase in a glial cell of the subject. 3. The method of claim 1 or 2, wherein the subject has a condition mediated by neuronal hyperexcitability. 4. The method of claim 2 or 3, wherein the brain interstitial potassium level is restored to ±30% of that of normal healthy adult human brain. 5. The method of any one of the proceeding claims, wherein said increasing comprises reducing the expression level of a FXYD1 gene in the glial cell. 6. The method of claim 5, wherein said reducing comprises administering to the subject an agent that reduces the expression level of the FXYD1 gene in the glial cell. 7. The method of claim 6, wherein the agent comprises or encodes an inhibitory nucleic acid or a CRISPR/Cas system. 8. The method of claim 7, wherein the inhibitory nucleic acid comprises an RNA molecule (small interfering RNA (siRNA), short hammerhead RNA (shRNA), or microRNA (miRNA). 9. The method of claim 7, wherein the agent is an expression cassette or a vector comprising a sequence encoding the inhibitory nucleic acid or encoding one or more components of the CRISPR/Cas system. 10. The method of claim 9, wherein the sequence is operably linked to a cell-type selective or cell type-specific regulatory sequence. UR6-23082/161118-04901 11. The method of claim 10, wherein the cell-type selective or cell type-specific regulatory sequence comprises a promoter or an enhancer or both. 12. The method of claim 11, wherein the promoter is a glial cell-specific promoter or a regulatable promoter. 13. The method of any one of claims 9-12, wherein the vector is a viral vector. 14. The method of any one of the proceeding claims, wherein the glial cell is an astrocyte. 15. The method of any one of the proceeding claims, wherein the glial cell is glial progenitor cell. 16. The method of any one of claims 1 and 3-15, wherein the condition is a neurodegenerative disease. 17. The method of any one of claims 1 and 3-15, wherein the condition is amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, Huntington's disease, or schizophrenia. 18. The method of any one of claims 7-17, wherein the inhibitory nucleic acid or siRNA molecule comprises or encodes a sequence that is at least 75% complementary to a segment of the FXYD1 gene or RNA. 19. The method of any one of claims 7-17, wherein the CRISPR/Cas system comprises or encodes a guide RNA (gRNA) sequence that is at least 75% complementary to a segment of the FXYD1 gene or RNA. 20. An inhibitory nucleic acid or siRNA molecule comprises or encodes a sequence that is at least 75% complementary to a segment of the FXYD1 gene or RNA. 21. A pharmaceutical composition comprising (i) the inhibitory nucleic acid or siRNA molecule of claim 20 and (ii) a pharmaceutically acceptable carrier or excipient.