CNS targeting complexes and uses thereof

Abstract

The present application relates to complexes for delivery to cells (e.g., cells of CNS) comprising a central nervous system (CNS) targeting agent covalently linked to a molecular load (e.g., oligonucleotides, polypeptides, small molecules, or a gene therapy load) and uses thereof, in particular in connection with the treatment of disease.

Description

[0001] Related applications

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application Serial No. 63 / 367,814, filed on July 6, 2022, entitled “BRAIN TARGETING COMPLEXES AND USES THEREOF,” and U.S. Provisional Application Serial No. 63 / 496,184, filed on April 14, 2023, entitled “CNS TARGETING COMPLEXES AND USES THEREOF,” the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present application relates to targeting complexes for delivering molecular payloads across the blood-brain barrier and / or to cells of the central nervous system (CNS), formulations comprising such complexes, and uses thereof, particularly in connection with the treatment of diseases.

[0004] References to electronic sequence listings

[0005] The contents of the electronic sequence listing (D082470081WO00-SEQ-COB.xml; size: 3,883,598 bytes; and creation date: July 5, 2023) are incorporated herein by reference in their entirety. Background Art

[0006] Neurological diseases and disorders affecting the central nervous system (CNS) affect millions of people worldwide, and many have few or no treatment options. Potentially effective therapeutic compounds in a variety of neurological disorders often fail to achieve their intended effects or have their efficacy limited due to limitations in their biodistribution, including an inability to effectively cross the blood-brain barrier. Summary of the Invention

[0007] According to some aspects, the present disclosure provides a complex comprising a central nervous system (CNS) targeting agent covalently linked to a molecular payload, a composition comprising such a complex, and a method of using the same. The CNS targeting agent of the complex described herein comprises an anti-transferrin receptor 1 (TfR1) antibody that is shown to be capable of transporting a molecular payload across the blood-brain barrier (e.g., by receptor-mediated transcytosis), resulting in delivery of the molecular payload to cells of the CNS. In some embodiments, the molecular payload of the complex described herein regulates the expression or activity of a gene associated with a disease or condition of the central nervous system (CNS) and / or has a therapeutic effect on a disease or condition of the CNS.

[0008] According to some aspects, provided herein are complexes comprising an anti-TfR1 antibody covalently linked to a molecular payload for use in treating a central nervous system (CNS) disease or disorder, wherein the anti-TfR1 antibody comprises:

[0009] (i) heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 1, heavy chain complementarity determining region 2 (CDR-H2) of SEQ ID NO: 2, heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 3, light chain complementarity determining region 1 (CDR-L1) of SEQ ID NO: 4, light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 5, and light chain complementarity determining region 3 (CDR-L3) of SEQ ID NO: 6;

[0010] (ii) CDR-H1 of SEQ ID NO:7, CDR-H2 of SEQ ID NO:8, CDR-H3 of SEQ ID NO:9, CDR-L1 of SEQ ID NO:10, CDR-L2 of SEQ ID NO:11, and CDR-L3 of SEQ ID NO:6; or

[0011] (iii) CDR-H1 of SEQ ID NO: 12, CDR-H2 of SEQ ID NO: 13, CDR-H3 of SEQ ID NO: 14, CDR-L1 of SEQ ID NO: 15, CDR-L2 of SEQ ID NO: 5, and CDR-L3 of SEQ ID NO: 16;

[0012] The complex delivers a molecular payload to cells of the CNS.

[0013] In some embodiments, the anti-TfR1 antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 18.

[0014] In some embodiments, the anti-TfR1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0015] In some embodiments, the anti-TfR1 antibody is a Fab.

[0016] In some embodiments, the molecular cargo is configured to modulate expression of a gene associated with a CNS disease or disorder.

[0017] In some embodiments, the molecular cargo comprises an oligonucleotide, a polypeptide, a small molecule, or a gene therapy cargo. In some embodiments, the gene therapy cargo comprises a messenger RNA (mRNA) molecule.

[0018] In some embodiments, the anti-TfR1 antibody is covalently linked to the molecular payload via a linker comprising the structure of Formula (I):

[0019]

[0020] wherein n is any number from 0 to 10, and wherein m is any number from 0 to 10;

[0021] and wherein L1 is a spacer, said spacer being a substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -N(R A )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -,-NR A C(=O)-,-NR A C(=O)R A -,-C(=O)R A -,-NR A C(=O)O-,-NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-,-S(O)2NRA -,-NR A S(O)2-, or a combination thereof, wherein each R A In some embodiments, n is 3 and / or m is 4.

[0022] In some embodiments, the complex comprises a structure of Formula (J):

[0023]

[0024] wherein n is any number from 0 to 10, and wherein m is any number from 0 to 10. In some embodiments, n is 3 and / or m is 4.

[0025] In some embodiments, the complex delivers a molecular cargo across the blood-brain barrier to cells of the CNS. In some embodiments, the complex delivers a molecular cargo across the choroid plexus to cells of the CNS.

[0026] In some embodiments, the gene associated with a CNS disease or disorder is DMPK, DMD, SMN, or FXN.

[0027] In some embodiments, the gene associated with a CNS disease or disorder is SOD1, C9orf72, ATXN2, or FUS.

[0028] In some embodiments, the gene associated with a CNS disease or disorder is LRRK2 or SNCA.

[0029] In some embodiments, the gene associated with a CNS disease or disorder is HTT or MSH3.

[0030] In some embodiments, the gene associated with a CNS disease or disorder is TREM2, APOE, MAPT, or APP.

[0031] In some embodiments, the gene associated with a CNS disease or disorder is GYS1, PrP, VLA-4, GFAP, UBE3A, LSD, or SCN9A.

[0032] In some embodiments, the gene associated with a CNS disease or disorder is SCN1A, SCN2A, SCN8A, SCN9A, CLN3, GRIA1, or PCDH19.

[0033] In some embodiments, the gene associated with a CNS disease or disorder is:

[0034] TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, or ECHS1.

[0035] In some embodiments, the gene associated with a CNS disease or disorder is PIKFYVE, SYF2, or UNC13A.

[0036] In some embodiments, the gene associated with a CNS disease or disorder is GRIN2A.

[0037] In some embodiments, the gene associated with a CNS disease or disorder is ATXN1, ATXN2, ATXN3, or MSH3.

[0038] In some embodiments, the gene associated with a CNS disease or disorder is GRN, C90rf72, MAPT, PIKFYVE, SYF2, or UNC13A.

[0039] In some embodiments, the gene associated with a CNS disease or disorder is TPP1 or CLN3.

[0040] In some embodiments, the gene associated with a CNS disease or disorder is APOE, SCN1A, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, or MECP2.

[0041] In some embodiments, the molecular payload comprises an oligonucleotide comprising a complementary region to a transcript set forth in any one of SEQ ID NOs: 392 to 702, or an oligonucleotide comprising a complementary region to a target sequence comprising an oligonucleotide listed in any one of Tables 5 to 19. In some embodiments, the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5 to 19.

[0042] In some embodiments, the molecular payload comprises an oligonucleotide comprising a complementary region to a transcript set forth in any one of SEQ ID NOs: 705 to 803, or an oligonucleotide comprising a complementary region to a target sequence comprising an oligonucleotide listed in any one of Tables 5 to 19. In some embodiments, the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5 to 19.

[0043] In some embodiments, the molecular payload comprises an oligonucleotide comprising a complementary region to a transcript set forth in any one of SEQ ID NOs: 143 to 148, 167 to 169, 810 to 875, and 1059 to 1068, or an oligonucleotide comprising a complementary region to a target sequence comprising an oligonucleotide listed in any one of Tables 5 to 19. In some embodiments, the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5 to 19.

[0044] In some embodiments, the CNS disease or disorder is a neuromuscular disease or disorder. In some embodiments, the neuromuscular disease or disorder is Duchenne muscular dystrophy, myotonic dystrophy, Friedreich's ataxia, or spinal muscular atrophy.

[0045] In some embodiments, the CNS disease or disorder is amyotrophic lateral sclerosis.

[0046] In some embodiments, the CNS disease or disorder is Parkinson's disease.

[0047] In some embodiments, the CNS disease or disorder is essential tremor.

[0048] In some embodiments, the CNS disease or disorder is Huntington's disease.

[0049] In some embodiments, the CNS disease or disorder is Alzheimer's disease.

[0050] In some embodiments, the CNS disease or disorder is hereditary dystonia.

[0051] In some embodiments, the CNS disease or disorder is epilepsy.

[0052] In some embodiments, the CNS disease or disorder is a pain disorder.

[0053] In some embodiments, the CNS disease or disorder is a glycogen synthesis disorder; neurodegeneration; small fiber neuropathy; nociception-related phenotype; Alexander disease; Angelman syndrome; autism spectrum disorder; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis.

[0054] In some embodiments, the CNS disease or disorder is spinocerebellarataxia (SCA).

[0055] In some embodiments, the CNS disease or disorder is frontotemporal dementia (FTD).

[0056] In some embodiments, the CNS disease or disorder is motor neuron disease.

[0057] In some embodiments, the CNS disease or disorder is Dravet syndrome.

[0058] In some embodiments, the CNS disease or disorder is Batten disease.

[0059] In some embodiments, the CNS disease or disorder is GM1 gangliosidosis.

[0060] In some embodiments, the CNS disease or disorder is Niemann-Pick Type A.

[0061] In some embodiments, the CNS disease or disorder is metachromatic leukodystrophy.

[0062] In some embodiments, the CNS disease or disorder is Krabbe disease.

[0063] In some embodiments, the CNS disease or disorder is Tay-Sachs.

[0064] In some embodiments, the CNS disease or disorder is Sandhoff disease.

[0065] In some embodiments, the CNS disease or disorder is Gaucher disease type II or type III.

[0066] In some embodiments, the CNS disease or disorder is Rett syndrome.

[0067] In some embodiments, the CNS disease or disorder is a molecular payload disclosed in any one of paragraphs

[0216] to

[1208] . In some embodiments, the molecular payload is a molecular payload disclosed in any one of the following paragraphs:

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[1193] . According to some aspects, provided herein are methods of treating a CNS disease or disorder, wherein the method comprises administering to a subject in need thereof a complex disclosed herein. According to some aspects, provided herein are methods of delivering a molecular cargo to the CNS of a subject, wherein the method comprises administering to the subject a complex disclosed herein. In some embodiments, the complex is administered to the subject intravenously. In some embodiments, the complex is detectable in the cortex of a subject following administration. In some embodiments, the complex is detectable in the cerebellum of a subject following administration. In some embodiments, the complex is detectable in deep brain tissue of the subject following administration. In some embodiments, the deep brain tissue is the thalamus, caudate nucleus, and / or putamen of the subject. In some embodiments, the complex is detectable in cortical neurons, motor neurons, cells of the cerebellum, and / or choroid plexus cells of a subject following administration. In some embodiments, the molecular cargo comprises a protein. In some embodiments, the protein is an enzyme. In some embodiments, the subject has been diagnosed with or is suspected of having Batten disease, GM1 gangliosidosis, Niemann-Pick type A, metachromatic leukodystrophy, Krabbe disease, Tay-Sachs, Sandhoff disease, or Gaucher disease. In some embodiments, the payload comprises an oligonucleotide. In some embodiments, the subject has been diagnosed with or is suspected of having ALS, Angelman syndrome, Rett syndrome, Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease (which may or may not be associated with cerebral amyloid angiopathy (CAA) or frontotemporal dementia), epilepsy, Alexander disease, spinal muscular atrophy, Batten disease, Huntington's disease, spinocerebellar ataxia, motor neuron disease, or Dravet syndrome. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Shown are the antisense oligonucleotide (ASO) concentrations (ng ASO / g tissue) in brain tissue of mice administered intravenously: PBS ("vehicle"), ASO not covalently linked to an antibody ("naked ASO"), a complex comprising a first anti-TfR1 Fab covalently linked to an ASO ("anti-TfR1 Fab1-ASO complex"), or a complex comprising a second anti-TfR1 Fab covalently linked to an ASO ("anti-TfR1 Fab2-ASO complex"). Bars show the mean ASO concentration measured + / - standard deviation, and circles represent values ​​measured in tissue from individual mice (n=4 mice / group). Figure 2A and 2B Shown are the antisense oligonucleotide (ASO) concentrations (ng ASO / g tissue) in brain tissue of mice administered intravenously: vehicle control (25 mM Tris, 10% sucrose, pH 7.4; “Vehicle”), ASO not covalently linked to an antibody (“naked ASO”), a complex comprising a control Fab not specific for TfR1 covalently linked to the ASO (“control Fab-ASO complex”), or a complex comprising an anti-TfR1 Fab covalently linked to the ASO (“anti-TfR1 Fab1-ASO complex”). Figure 2A Shown are ASO concentrations measured in the cortex. Figure 2B The ASO concentrations measured in the cerebellum are shown. The bars show the mean ASO concentrations measured + standard deviation (n=7 mice / group). Figure 3A and 3BShown is the expression of human mutant DMPK measured in brain tissue of mice administered by intravenous injection: vehicle control (25 mM Tris, 10% sucrose, pH 7.4; "Vehicle"), ASO not covalently linked to an antibody ("naked ASO"), a complex comprising a control Fab not specific for TfR1 covalently linked to an ASO ("control Fab-ASO complex"), or a complex comprising an anti-TfR1 Fab covalently linked to an ASO ("anti-TfR1 Fab1-ASO complex"). Values ​​are shown relative to expression in vehicle-treated mice. Figure 3A Shown is human mutant DMPK expression measured in the cortex. Figure 3B Shown is the expression of human mutant DMPK measured in the cerebellum. The bars show the mean ASO concentration measured + standard deviation (*, P < 0.05; ***, P < 0.001, calculated by one-way ANOVA and Dunnet's multiple comparison test; n = 7 mice / group). Figure 4 Figure 5 shows quantification of human mutant DMPK foci in the nuclei of cerebellar brain cells of mice administered intravenously with either a vehicle control (25 mM Tris, 10% sucrose, pH 7.4; “Vehicle”) or a complex comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO (“anti-TfR1 Fab1-ASO complex”), as measured by counting the number of human mutant DMPK foci per mm2 in hundreds of cells imaged. 2 The nuclear area of ​​the lesions was measured by counting. Data are shown as mean + standard deviation (*, P < 0.05, calculated by Welch's t-test; n = 6 to 7 mice / group). Figure 5 Figure 2 shows quantification of human mutant DMPK foci in the nuclei of cortical brain cells of mice administered intravenously with either a vehicle control or a complex comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO ("anti-TfR1 Fab1-ASO complex") by counting the number of human mutant DMPK foci per mm in hundreds of cells imaged. 2 The nuclear area of ​​the lesions was measured by counting. Data are shown as mean + standard deviation (**, P < 0.01; n = 4 to 5 mice / group). Figure 6 Shown is the expression of human mutant DMPK measured in brain tissue of mice administered vehicle or a complex comprising anti-TfR1 Fab1 covalently linked to a DMPK targeting ASO. DMPK expression was measured 8 weeks after a single intravenous administration of vehicle or complex. The bars show the average DMPK expression + standard deviation normalized relative to mice administered vehicle control (n = 3 to 5 mice / group). Figure 7Shown is the expression of human mutant DMPK measured in brain tissue of mice administered vehicle or a complex comprising anti-TfR1 Fab1 covalently linked to a DMPK targeting ASO. DMPK expression was measured on day 56 after two intravenous administrations of vehicle or complex (on days 0 and 28, respectively). The bars show the average DMPK expression + standard deviation normalized to mice administered vehicle control (n = 3 to 5 mice / group; *, P ≤ 0.05). Figures 8A to 8C Quantification of ASO (in nM) in brain tissue of cynomolgus monkeys following intravenous (IV) administration of ASO not covalently linked to an antibody ("naked ASO"; downward arrow) or an ASO equivalent dose of anti-TfR1 Fab1-ASO complex (upward arrow). Cortical ( Figure 8A ), deep brain ( Figure 8B ) and cerebellum ( Figure 8C ) over time. Values ​​are shown as mean + / - standard error (N = 2 monkeys / group). Figures 9A to 9C Figure 2 shows the distribution of ASO in brain tissue of cynomolgus monkeys after administration of an ASO not covalently linked to an antibody ("naked ASO") or an ASO equivalent dose of anti-TfR1 Fab1-ASO complex by intravenous (IV) or intrathecal (IT) administration. ASO distribution was measured by in situ hybridization and shows the distribution of ASO in cortical and deep brain regions ( Figure 9A ) and cerebellum ( Figure 9B ) and intrathecal (IT) administration of naked ASO or IV administration of complex ( Figure 9C Figure 3. Distribution of ASOs in the cortex and deep brain of monkeys with α-glucose β-glucose α ... Figures 10A to 10D Shown are ASO concentrations (ng ASO / g tissue) in CNS tissue of mice administered vehicle control (25 mM Tris, 10% sucrose, pH 7.4; “Vehicle”) or a complex comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO (“Anti-TfR1 Fab1-ASO Complex”) at an ASO equivalent dose of 5 mg / kg or 10 mg / kg by intravenous injection on days 0 and 28. The cortex ( Figure 10A ), cerebellum( Figure 10B ), deep brain regions ( Figure 10C ) and spinal cord ( Figure 10D). The bars show the mean ASO concentrations measured + standard deviation (n = 6 to 7 mice / group). Figures 11A to 11E Shown is the expression of human mutant DMPK measured in brain tissue of mice administered vehicle control (25 mMTris, 10% sucrose, pH 7.4; "Vehicle") or a complex comprising anti-TfR1 Fab covalently linked to an ASO ("Anti-TfR1 Fab1-ASO Complex") at an ASO equivalent dose of 5 mg / kg or 10 mg / kg by intravenous injection on days 0 and 28. Values ​​are shown relative to expression in vehicle-treated mice. The cortex of treated mice ( Figure 11A ), cerebellum( Figure 11B ), deep brain regions ( Figure 11C ), brainstem( Figure 11D ) and spinal cord ( Figure 11E ) in the human mutant DMPK expression. The bars show the mean ASO concentration measured + standard deviation (*, P < 0.05; **, P < 0.01; ***, P < 0.005, calculated by one-way ANOVA and Dunnet's multiple comparison test; n = 6 to 7 mice / group, or 2 to 3 mice / group for spinal cord analysis). Figures 12A to 12C Shown are cortical neurons of mice that were administered intravenously with either a vehicle control (25 mM Tris, 10% sucrose, pH 7.4; “Vehicle”) or a complex comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO (“Anti-TfR1 Fab1-ASO Complex”) at an ASO equivalent dose of 10 mg / kg. Figure 12A ), cells of the cerebellum ( Figure 12B ), and choroid plexus cells ( Figure 12C Quantification of human mutant DMPK foci in the nucleus of ). Bars represent 2 mm 2 Average total tissue area imaged per mm in the target area 2 The data are presented in μm. 2 / mm 2 The calculated values ​​are mean + standard deviation (*, P < 0.05; **, P < 0.01, calculated by Dunnet's multiple comparison test; n = 6 to 7 mice / group). DETAILED DESCRIPTION Some aspects of the present disclosure relate to the following recognition: although certain molecular payloads (e.g., oligonucleotides, peptides, small molecules, gene therapy) can have beneficial effects in cells of the central nervous system (CNS), it has been shown that such molecular payloads are challenging to achieve their intended effects in the CNS due to limitations in their biodistribution, including the inability to effectively cross the blood-brain barrier. Therefore, in some aspects, the present disclosure provides a complex comprising a CNS targeting agent covalently linked to a molecular payload to overcome such challenges. The CNS targeting agent of the present disclosure comprises an anti-transferrin receptor 1 (TfR1) antibody that is shown to be capable of transporting molecular payloads to cells of the CNS. In some embodiments, such delivery crosses the blood-brain barrier (e.g., by receptor-mediated transcytosis), resulting in delivery of the molecular payload to cells of the CNS. In some embodiments, such delivery crosses the choroid plexus, resulting in delivery of the molecular payload to cells of the CNS. In some embodiments, the anti-TfR1 antibody of the complex described herein exhibits pH-dependent binding affinity to TfR1 (e.g., having different binding affinities under different pH conditions). In some embodiments, the anti-TfR1 antibodies of the complexes described herein exhibit pH-independent binding affinity to TfR1 (eg, have comparable binding affinity under different pH conditions). In some embodiments, the complexes provided herein may include a molecular payload that regulates (e.g., increases or decreases) the expression and / or activity of a gene associated with a CNS disease and disorder, for example, by regulating transcription, translation, post-transcriptional modification (e.g., splicing), mRNA stability, and / or protein stability. In some embodiments, the complexes provided herein may include a molecular payload that is a synthetic nucleic acid (e.g., DNA or RNA) that can be used to express one or more proteins that regulate the expression and activity of a gene associated with a CNS disease and disorder. In some embodiments, the complexes provided herein may include a molecular payload that has a therapeutic effect in a CNS disease or disorder, but may or may not regulate the expression or activity of any gene associated with a CNS disease and disorder. Neurological diseases and disorders that affect CNS have different causes of disease and potential treatment modes. Some examples of such CNS diseases and disorders include, but are not limited to, neuromuscular disorders (e.g., myotonic dystrophy, Duchenne muscular dystrophy, Friedreich's ataxia and spinal muscular atrophy), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, Alzheimer's disease, epilepsy and pain disorders, etc. Other examples of CNS diseases and disorders include essential tremor and hereditary dystonia. Other examples of CNS diseases and disorders include spinocerebellar ataxia, motor neuron disease, Dravet syndrome, Batten disease, GM1 gangliosidosis, Niemann-Pick type A, metachromatic leukodystrophy, Krabbe disease, Tay-Sachs, Sandhoff disease, Gaucher disease type II and type III, and Rett syndrome. A variety of genes are associated with CNS diseases and disorders, including but not limited to DMPK, DMD, SMN, FXN, SOD1, C9orf72, ATXN2, FUS, LRRK2, SNCA, HTT, MSH3, TREM2, APOE, MAPT, APP, GYS1, PrP, VLA-4, UBE3A, GFAP, LSD, SCN9A, SCN1A, SCN2A, SCN8A, CLN3, GRIA1, and PCDH19, among others. Additional genes associated with CNS diseases and disorders include, but are not limited to, TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, and ECHS1. Additional genes associated with CNS diseases and disorders include, but are not limited to, PIKFYVE, SYF2, UNC13A, ATXN1, ATXN3, GRN, GRIN2A, TPP1, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, and MECP2. The molecular payload can be effectively used to treat CNS diseases and conditions after it is delivered to cells of the CNS (e.g., by crossing the blood-brain barrier, and / or by delivering through the choroid plexus). Certain molecular payloads can alleviate the signs or symptoms of CNS diseases and conditions, for example, in some embodiments, by regulating the expression or activity of genes associated with CNS diseases and conditions. Molecular payloads that alleviate the signs or symptoms of CNS diseases and conditions without regulating the expression or activity of any genes associated with CNS diseases and conditions can also be used according to the present disclosure. The delivery of molecular payloads to the CNS can also be used for other purposes besides treating CNS diseases and conditions. Additional aspects of the disclosure, including a description of defined terms, are provided below. I. Definition Administer: As used herein, the term "administer," "administer," or variations thereof, means providing a complex to a subject (eg, to treat a condition in a subject) in a physiologically and / or (eg, and) pharmacologically acceptable manner. Alzheimer's disease: The term "Alzheimer's disease" as used herein refers to a progressive neurological disorder characterized by atrophy of brain tissue and loss of neurons, particularly in advanced age. Alzheimer's disease is a common cause of dementia, including Alzheimer's disease. Symptoms of Alzheimer's disease include memory loss that worsens over time, difficulty concentrating, especially with respect to abstract concepts, difficulty multitasking, impaired decision-making, and changes in personality or behavior. Alzheimer's disease is also associated with the formation of beta-amyloid plaques and tau protein tangles (also known as neurofibrillary tangles) in brain tissue, which are cytotoxic, disrupt communication between cells, and lead to neuronal death. The cause of Alzheimer's disease is not yet fully understood, however, the development of Alzheimer's disease may be influenced by the inheritance of certain genetic risk factors. For example, genes involved in the pathophysiology of Alzheimer's disease include, but are not limited to, TREM2, APOE, MAPT, and APP (see, e.g., Neuner SM, et al. "Genetic architecture of Alzheimer's disease." Neurobiol Dis. 2020; 143: 104976; and Ibanez L, et al. "Advances in Genetic and Molecular Understanding of Alzheimer's Disease." Genes (Basel). 2021; 12(8): 1247). Alzheimer's disease may be associated with or unassociated with cerebral amyloid angiopathy (CAA) or frontotemporal dementia. Amyotrophic lateral sclerosis (ALS): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the central nervous system. ALS causes the degeneration of motor neurons that control muscle movement, ultimately leading to loss of control of the muscles needed to move, speak, eat, and breathe. Approximately 90% of ALS cases are considered sporadic, occurring in patients with no known family history of the disease, and 5% to 10% of all cases are familial (i.e., hereditary). Genes associated with the development of ALS include, for example, SOD1 (associated with approximately 12% to 20% of familial ALS cases), C9orf72 (associated with approximately 25% to 40% of familial ALS cases), ATXN2, and FUS. In some embodiments, accumulation of TDP-43 aggregates is associated with ALS. PIKFYVE, SYF2, and UNC13A are also associated with the pathophysiology of ALS. In some embodiments, single nucleotide polymorphisms and / or other changes in PIKFYVE, SYF2, and UNC13A are associated with ALS. ANO3: As used herein, ANO3 refers to a gene encoding Anoctamin 3 (also known as DYT23; DYT24; TMEM16C; C11orf25; or GENX-3947), which is a protein belonging to the TMEM16 family of predicted membrane proteins. In some embodiments, ANO3 can be a human gene (Gene ID: 63982), a non-human primate gene (e.g., Gene ID: 101865236), or a rodent gene (e.g., Gene ID: 228432, Gene ID: 311287). In humans, mutations in the gene encoding ANO3 are associated with the occurrence of hereditary dystonia. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_001313726.2; NM_031418.4; XM_047427399.1; XM_017018118.3; NM_001313727.2; Antibody: The term "antibody" as used herein refers to a polypeptide comprising at least one immunoglobulin variable domain or at least one antigenic determinant (e.g., a paratope that specifically binds to an antigen). In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, an Fv fragment, or a scFv fragment. In some embodiments, the antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, the antibody is a diabody. In some embodiments, the antibody comprises a framework with a human germline sequence. In another embodiment, the antibody comprises a heavy chain constant domain selected from IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, the antibody comprises a heavy (H) chain variable region (abbreviated herein as VH) and / or (e.g., and) a light (L) chain variable region (abbreviated herein as VL). In some embodiments, the antibody comprises a constant domain, such as an Fc region. An immunoglobulin constant domain refers to a heavy chain constant domain or a light chain constant domain. The amino acid sequences of human IgG heavy and light chain constant domains and their functional variations are known. With regard to the heavy chain, in some embodiments, the heavy chain of the antibody described herein may be an alpha (α), delta (Δ), epsilon (ε), gamma (γ) or mu (μ) heavy chain. In some embodiments, the heavy chain of the antibody described herein may comprise a human alpha (α), delta (Δ), epsilon (ε), gamma (γ) or mu (μ) heavy chain. In a specific embodiment, the antibody described herein comprises a human γ1CH1, CH2, and / or (e.g., and) CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (γ) heavy chain constant region, such as any known in the art. Non-limiting examples of human constant region sequences have been described in the art, for example, see U.S. Patent No. 5,693,780 and Kabat EA et al., (1991) supra. In some embodiments, the VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or at least 99% identical to any variable chain constant region provided herein. In some embodiments, the antibody is modified, for example, by glycosylation, phosphorylation, sumoylation and / or (for example, and) methylation.In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody by N-glycosylation, O-glycosylation, C-glycosylation, glycosylphosphatidylinositolization (GPI anchor attachment) and / or (e.g., and) phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides or polysaccharides. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched polysaccharides. In some embodiments, one or more sugar or carbohydrate molecules comprise mannose units, glucose units, N-acetylglucosamine units, N-acetylgalactosamine units, galactose units, fucose units or phospholipid units. In some embodiments, the antibody is a construct comprising a polypeptide comprising one or more antigen-binding fragments of the present disclosure connected to a linker polypeptide or an immunoglobulin constant domain. The linker polypeptide comprises two or more amino acid residues connected by a peptide bond and is used to connect one or more antigen-binding portions. Some examples of linker polypeptides have been reported (see, e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448; Poljak, RJ, et al. (1994) Structure 2: 1121-1123). In addition, an antibody can be part of a larger immunoadhesion molecule formed by covalent or non-covalent association of the antibody or antibody portion with one or more other proteins or peptides. Some examples of such immunoadhesion molecules include the use of a streptavidin core region to prepare tetrameric scFv molecules (Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6:93-101), and the use of cysteine ​​residues, a marker peptide, and a C-terminal polyhistidine tag to prepare bivalent and biotinylated scFv molecules (Kipriyanov, SM, et al. (1994) Mol. Immunol. 31:1047-1058). APP: The term "APP" as used herein refers to a gene encoding an amyloid beta precursor protein (also known as AAA, ABETA, ABPP, AD1, APPI, CTFγ, CVAP, PN-II, PN2, α-sAPP, and pre-A4), which is a protein involved in synapse formation and neural plasticity. In some embodiments, APP can be a human gene (Gene ID: 351), a non-human primate gene (e.g., Gene ID: 100427716), or a rodent gene (e.g., Gene ID: 11820, Gene ID: 54226). In humans, mutations in the APP gene are associated with the occurrence of Alzheimer's disease. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000484.4 and NM_201413.3). APOE: APOE as used herein refers to the gene encoding apolipoprotein E (also known as AD2, ApoE4, LDLCQ5 and LPG), which is a protein involved in the formation of lipoprotein particles and the transport of lipids through the circulatory system. In some embodiments, APOE can be a human gene (Gene ID: 348), a non-human primate gene (e.g., Gene ID: 714623), or a rodent gene (e.g., Gene ID: 11816, Gene ID: 25728). In humans, mutations in the gene encoding APOE are associated with the occurrence of Alzheimer's disease. In some embodiments, the APOE4 allele is associated with the occurrence of Alzheimer's disease. In some embodiments, the APOE4 allele is associated with the occurrence of motor neuron disease. Therefore, in some embodiments, allele-specific regulation (e.g., inhibition) of APOE (e.g., APOE4) can be used to treat CNS diseases or disorders such as Alzheimer's disease or motor neuron disease. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_000041.4 and NM_001302688.2). Approximately: As used herein, the terms "approximately" or "about" when applied to one or more values ​​of interest refer to a value that is similar to the reference value. In certain embodiments, the terms "approximately" or "about" refer to a range of values ​​that falls within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) the reference value, unless otherwise specified or otherwise apparent from the context (unless such a number exceeds 100% of the possible values). ARSA:ARSA used in this article refers to the gene encoding arylsulfatase A (also known as sulfatase, epididymal secretory sperm binding protein, MLD, ASA or sulfatase), which is an enzyme that decomposes sulfatide. In some embodiments, ARSA can be a human gene (e.g., Gene ID: 410), a non-human primate gene (e.g., Gene ID: 458946, Gene ID: 716500) or a rodent gene (e.g., Gene ID: 11883, Gene ID: 315222). In humans, mutations in the gene encoding ARSA are associated with the occurrence of metachromatic leukodystrophy. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000487.6; NM_001085425.3; NM_001085426.3; NM_001085427.3; NM_001085 428.3;NM_001362782.2;XM_047441363.1;XM_024452241.2;XM_011530691.4). ASM: The term "ASM" as used herein refers to the gene encoding acid sphingomyelinase (also known as SCMPD 1, ASMASE and NPD). Wild-type acid sphingomyelinase is a lysosomal enzyme involved in the conversion of lipids to ceramides. Mutations in ASM typically result in a shortage or complete loss of function of acid sphingomyelinase, leading to the accumulation of fat in cells of multiple organs and tissues (including the central nervous system). In some embodiments, ASM can be a human gene (Gene ID: 6609), a non-human primate gene (Gene ID: 711248) or a rodent gene (Gene ID: 20597; Gene ID: 308909). In humans, mutations in ASM are associated with the occurrence of Niemann-Pick type A. ATP1A3: As used herein, ATP 1A3 refers to the gene encoding ATPase Na+ / K+ transporting subunit α3 (also known as RDP; AHC2; CAPOS; DEE99; DYT12; or ATP1A1), which is a protein belonging to the P-type cation transporting ATPase family and the Na+ / K+ ATPase family. In some embodiments, ATP1A3 can be a human gene (Gene ID: 478), a non-human primate gene (e.g., Gene ID: 102122869), or a rodent gene (e.g., Gene ID: 232975, Gene ID: 24213). In humans, mutations in the gene encoding ATP1A3 are associated with the development of hereditary dystonia. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_152296.5; NM_001256213.2; NM_001256214.2; and XM_047438862.1). ATXN1: ATXN1 as used herein refers to the gene encoding ataxia-1. Ataxia-1 is expressed throughout the body and is thought to be involved in regulating protein production, including transcription and RNA processing. Ataxia-1 binds RNA and associates with large protein complexes. It is thought to be involved in transcriptional repression and is thought to regulate developmental processes controlled by Notch and Capicua. Human ATXN1 (Gene ID: 6310) contains a CAG repeat region that typically contains 6 to 39 repeats. Longer expansions of the CAG repeat region in ATXN1 (typically 40 to 83 or more) can lead to neurodegenerative diseases, including spinocerebellar ataxia 1 (SCA1). The expanded CAG repeat region leads to incorrect protein folding and the production of non-functional ataxia-1. The abnormal protein forms aggregates in the cell nucleus, causing cell damage. There is evidence that ataxia protein-1 aggregates are found only or primarily in cells of the CNS, and in particular in Purkinje cells of the cerebellum. The accumulation of protein aggregates leads to cell death; the loss of these cells over time leads to the cerebellar defects characteristic of SCA1. See Banfi, et al. “Identification and characterization of the gene causing type 1 spinocerebellar ataxia” Nature Genet. 7: 513-520 (1994); and Orr, et al. “Expansion of an unstable trinucleotide CAGrepeat in spinocerebellar ataxia type 1” Nature Genet. 4: 221-226 (1993). Allele-specific inhibition of ATXN1 may be effective in treating SCA1. See Miller, et al. “Allele-specific silencing of dominant disease genes” Proc. Nat. Acad. Sci. 100: 7195-7200 (2003). ATXN2: ATXN2 as used herein refers to the gene encoding ataxin-2. It is ubiquitously expressed in a variety of tissues, and ataxin-2 is localized to the Golgi apparatus and stress granules in normal cells. Ataxia-2 ​​is involved in regulating mRNA translation through its interaction with poly(A) binding protein, and is also involved in the formation of stress granules and P bodies, both of which are also involved in RNA regulation. Human ATXN2 contains a CAG repeat region that typically contains 22 or 23 repeats, but can contain up to 31 repeats. Longer expansions of the CAG repeat region in ATXN2 can lead to neurodegenerative diseases, including spinocerebellar ataxia 2 (SCA2) and amyotrophic lateral sclerosis (ALS). The interaction between ataxin-2 and the protein TDP-43 is believed to be involved in the occurrence of ALS in some patients. See, e.g., Elden, et al. "Ataxin-2 intermediate-length polyglutamine expansions are associated withincreased risk for ALS" Nature 466:1069-1075 (2010). Disease-associated ATXN2 alleles typically contain 34 to 52 CAG repeats, but can contain as few as 32 or more than 100, and their size can expand as the allele is passed to successive generations. In some embodiments, as described in Elden, et al, as few as 27 CAG repeats can be associated with ALS. Allele-specific inhibition of ATXN2 can be effective in treating SCA2. See Miller, et al. "Allele-specific silencing of dominant disease genes" Proc. Nat. Acad. Sci. 100:7195-7200 (2003). ATXN3: ATXN3 as used herein refers to the gene encoding ataxia-3 (also known as AT3, ATX3, JOS, MJD, MJD1 and SCA3). Ataxia-3 is expressed throughout the body and is thought to be involved in the proteasome processing system. Ataxia-3 removes ubiquitin from proteins to be degraded so that the ubiquitin can be recycled. Ataxia-3 may also be involved in regulating the first stage of transcription. Human ATXN2 (Gene ID: 4287) contains a CAG repeat region that typically contains 13 to 36 repeats. Longer expansions of the CAG repeat region in ATXN3 (typically 50 or more) can lead to neurodegenerative diseases, including spinocerebellar ataxia 3 (SCA3). The expanded CAG repeat region leads to incorrect protein folding and the production of non-functional ataxia-3. This nonfunctional ataxin-3 is unable to remove ubiquitin from proteins, causing such proteins to aggregate in the nucleus along with ubiquitin and ataxin-3. These protein aggregates can lead to cell death, including cell death in neurons as well as in other cells of the CNS. Neurons are generally the cell type most affected by mutations in ATXN3. See Kawaguchi, et al. "CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1" Nature Genet. 8: 221-228 (1994). Allele-specific inhibition of ATXN3 may be effective in treating SCA3. See Miller, et al. "Allele-specific silencing of dominant disease genes" Proc. Nat. Acad. Sci. 100: 7195-7200 (2003). Batten disease: The term "Batten disease" as used herein refers to a class of lysosomal diseases also known as neuronal ceroid lipofuscinosis (NCL). Batten disease is a neurological disorder caused by multiple mutations in 13 genes and is usually inherited in a recessive manner. In some embodiments, Batten disease is caused by mutations in CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, CLN8, CLN10, CLN11, CLN12, CLN13, or CLN14. In particular, in connection with the present disclosure, in some embodiments, Batten disease is caused by mutations in CLN2 or CLN3. Symptoms of Batten disease include seizures, visual impairment, cognitive and behavioral decline, motor decline, developmental defects, and premature death. Batten disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity, and neuronal loss. The genetic cause of Batten disease is well known and is attributed to mutations in one of thirteen different genes encoding lysosomal and extralysosomal proteins. Genes involved in the pathophysiology of Batten disease include PPT1(CLN1), TPP1(CLN2), CLN3(CLN3), DNAJC5(CLN4), CLN5(CLN5), CLN6(CLN6), MFSD8(CLN 7), CLN8 (CLN8), CTSD (CLN10), GRN (CLN11), ATP13A2 (CLN12), CTSF (CLN13), and KCTD7 (CLN14). In some embodiments, the subject in need of treatment for Batten disease exhibits seizure activity. In some embodiments, seizure activity includes myoclonic jerks, grand mal seizures, and tonic-clonic seizures. In some embodiments, the subject in need of treatment for Batten disease exhibits symptoms of visual impairment. In some embodiments, visual impairment includes optic atrophy, progressive vision loss, pigmentary retinopathy, macular degeneration, visual decline, retinopathy, decreased pupillary light reflex, loss of central vision, and blindness. In some embodiments, the subject in need of treatment for Batten disease exhibits symptoms of cognitive and behavioral decline. In some embodiments, cognitive and behavioral decline includes irritability, overexcitement, anxiety, agitation, depression, inappropriate laughter, mood disorders, intellectual disability, dementia, and personality disorders. In some embodiments, the subject in need of treatment for Batten disease exhibits symptoms of motor decline. In some embodiments, motor decline includes loss of motor coordination; choreoathetosis; stereotypic movements; myoclonus ataxia; motor decline; spasticity; dystonic features; hypotonia; rigidity; impaired balance; myoclonus; ataxia; facial movement disorders; clumsiness; loss of motor coordination; dysarthria; severe respiratory distress; central, axial and / or limb hypotonia; appendicitis; tremor; parkinsonism; hyperreflexia; apraxia of speech; echolalia; delayed speech; and dysarthric speech. In some embodiments, the subject in need of treatment for Batten disease exhibits symptoms of developmental defects. In some embodiments, developmental defects include slowed head growth, premature death, microcephaly, overriding sutures, halt in developmental milestones, developmental regression, and developmental arrest. Blood-brain barrier: As used herein, the term "blood-brain barrier" refers to the highly selective semipermeable boundary of endothelial cells that prevents the non-selective passage of various molecules in the blood into the extracellular fluid of the CNS. It allows the passage of some small molecules by diffusion and actively transports various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are essential for neural function, but blocks the non-specific transport of other molecules. C9orf72: As used herein, C9orf72 refers to the gene encoding the chromosome 9 open reading frame 72 protein. This protein is present in many areas of the brain, including the cytoplasm of neurons and in presynaptic terminals. Pathogenic mutations in the C9orf72 gene, particularly hexanucleotide repeat expansions, are associated with ALS. In some embodiments, mutations in C9orf72 are associated with familial forms of ALS. In some embodiments, mutations in C9orf72 are associated with frontotemporal dementia (e.g., C9FTD). CDR: The term "CDR" as used herein refers to the complementary determining region within an antibody variable sequence. A typical antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), which are generally involved in antigen binding. The VH and VL regions can be further subdivided into hypervariable regions, also known as "complementarity determining regions" (CDRs), interspersed with more conserved regions known as "framework regions" (FRs). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework regions and CDRs can be precisely identified using methods known in the art, such as by the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or (e.g., and) contact definitions, all of which are well known in the art. See, for example, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIHPublication No. 91-3242; the international ImMunoGeneTics information imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27: 209-212 (1999); Ruiz, M. et al., Nucleic Acids Res., 28: 219-221 (2000); Lefranc, M.-P., Nucleic Acids Res., 29: 207-209 (2001); Lefranc, M.-P., Nucleic Acids Res., 31: 307-310 (2003); Lefranc, M.-P. et al., In Silico Biol., 5, 0006 (2004) [Epub], 5: 45-60 (2005); al., Nucleic Acids Res., 33: D593-597 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 37: D1006-1012 (2009); Lefranc, M.-P. et al., Nucleic Acids Res., 43: D413-422 (2015); Chothia et al., (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol. 196: 901-917, A1-1azikani et al (1997) J. Molec. Biol. 273: 927-948; and Almagro, J. Mol. Recognit. 17: 132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. The CDR used herein may refer to a CDR defined by any method known in the art. Two antibodies having the same CDR means that the amino acid sequence of the CDR of the two antibodies is the same, as determined by the same method (eg, IMGT definition). There are three CDRs in each variable region of the heavy and light chains, referred to as CDR1, CDR2, and CDR3 for each variable region. As used herein, the term "CDR set" refers to the group of three CDRs that appear within a single variable region and are capable of binding an antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries that define the three CDRs. These CDRs may be referred to as Kabat CDRs. Subportions of the CDRs may be designated L1, L2, and L3 or H1, H2, and H3, where "L" and "H" designate light and heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with the Kabat CDRs. Padlan (FASEB J. 9: 133-139 (1995)) and MacCallum (J Mol Biol 262(5): 732-45 (1996)) have described other boundaries that define CDRs that overlap with the Kabat CDRs. Other CDR boundary definitions may not strictly follow one of the above systems but still be consistent with the Kabat CDRs. CDRs overlap, although they can be shortened or lengthened based on predictions or based on experimental findings that specific residues or groups of residues or even entire CDRs do not significantly affect antigen binding. The methods used herein can utilize CDRs defined according to any one of these systems. Some examples of CDR definition systems are provided in Table 1. Table 1. CDR definitions <![CDATA[IMGT 1 ]]> <![CDATA[Kabat 2 ]]> <![CDATA[Chothia 3 ]]> CDR-H1 27-38 31-35 26-32 CDR-H2 56-65 50-65 53-55 CDR-H3 105-116 / 117 95-102 96-101 CDR-L1 27-38 24-34 26-32 CDR-L2 56-65 50-56 50-52 CDR-L3 105-116 / 117 89-97 91-96 1 the international ImMunoGeneTics information imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res. 27: 209-212 (1999) 2Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242 3 Chothia et al., J. Mol. Biol. 196: 901-917 (1987)) CDR-grafted antibody: The term "CDR-grafted antibody" refers to an antibody comprising a heavy chain variable region sequence and a light chain variable region sequence from one species but in which the sequence of one or more CDR regions of VH and / or (e.g., and) VL is replaced by a CDR sequence of another species, such as an antibody having a murine heavy chain variable region and a light chain variable region in which one or more murine CDRs (e.g., CDR3) have been replaced by a human CDR sequence. Central nervous system (CNS): The term "central nervous system" (CNS) as used herein refers to the brain and spinal cord and includes neurons and non-neural support cells (e.g., glial cells) as well as blood-brain barrier cells. The blood-brain barrier prevents a variety of molecules from the circulation from non-selectively passing into the extracellular fluid of the CNS. The CNS also includes cells of the blood-cerebrospinal fluid barrier, such as cells of the choroid plexus. CNS disease or condition: As used herein, "CNS disease or condition" refers to a disease or condition that affects the CNS (e.g., CNS structure or function) and / or has an etiology in the CNS. CNS diseases and conditions are also referred to as neurological diseases or conditions. Some examples of CNS diseases or conditions include, but are not limited to, neuromuscular diseases and conditions (e.g., muscular dystrophy, myotonic dystrophy, spinal muscular atrophy, and Friedreich's ataxia), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Alzheimer's disease, epilepsy, and pain disorders. Other examples of CNS diseases or conditions include essential tremor and hereditary dystonia. Certain lysosomal storage diseases are also examples of CNS diseases or conditions. CNS targeting agent: The term "CNS targeting agent" as used herein refers to a molecule that specifically binds to an antigen expressed on cells of the CNS (e.g., neurons, supporting cells, and / or cells of the blood-brain barrier). The antigen in or on a CNS cell can be a membrane protein, such as an integral membrane protein or a peripheral membrane protein. Generally speaking, a CNS targeting agent specifically binds to an antigen on a CNS cell, which helps transport the molecular payload across the blood-brain barrier and / or helps internalize the CNS targeting agent (and any associated molecular payload) into the CNS cell. In some embodiments, a CNS targeting agent specifically binds to an internalized cell surface receptor (e.g., transferrin receptor 1) on a cell of the CNS and can be internalized into a CNS cell by receptor-mediated internalization. In some embodiments, a CNS targeting agent is a small molecule, protein, peptide, nucleic acid (e.g., aptamer) or antibody. In some embodiments, a CNS targeting agent is connected to a molecular payload. CNS targeting antibodies: The term "CNS targeting antibody" as used herein refers to a CNS targeting agent, which is an antibody that specifically binds to an antigen present in or on a CNS cell. In some embodiments, a CNS targeting antibody specifically binds to an antigen on a CNS cell (e.g., a neuron, a supporting cell, and / or a cell of the blood-brain barrier), which helps transport a molecular payload across the blood-brain barrier and / or helps internalize the CNS targeting antibody (and any associated molecular payload) into a CNS cell. In some embodiments, a CNS targeting antibody specifically binds to an internalizing cell surface receptor present on a CNS cell. In some embodiments, a CNS targeting antibody helps transcytosis of cells (e.g., endothelial cells) across the blood-brain barrier. In some embodiments, a CNS targeting antibody is an antibody that specifically binds to a transferrin receptor (e.g., transferrin receptor 1). Chimeric antibody: The term "chimeric antibody" refers to an antibody that comprises heavy and light chain variable region sequences from one species and constant region sequences from another species, for example, an antibody having murine heavy and light chain variable regions linked to human constant regions. CLN2: See “TPP1”. CLN3: The term "CLN3" as used herein refers to a gene encoding a CLN3 lysosomal / endosomal transmembrane protein (also known as battenin, BTN1, BTS, and JNCL), which is a protein involved in lysosomal function. In some embodiments, CLN3 can be a human gene (Gene ID: 1201), a non-human primate gene (e.g., Gene ID: 705815), or a rodent gene (e.g., Gene ID: 12752, Gene ID: 293485). In humans, mutations in the gene encoding CLN3 are associated with epilepsy and seizures, as well as CLN3 Batten disease. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000086.2 and NM_001286104.2). Complementary: The term "complementary" as used herein refers to the ability to accurately pair between two nucleosides or two groups of nucleosides. In particular, complementarity is a term that characterizes the degree of hydrogen bond pairing that causes binding between two nucleosides or two groups of nucleosides. For example, if the base at one position of an oligonucleotide can hydrogen bond with the base at the corresponding position of a target nucleic acid (e.g., mRNA), it is considered that the bases at that position are complementary to each other. Base pairing can include both standard Watson-Crick (Watson-Crick) base pairing and non-Watson-Crick base pairing (e.g., Wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairing, adenosine base (A) is complementary to thymidine base (T) or uracil base (U), cytosine base (C) is complementary to guanosine base (G), and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize with any A, C, U or T and are considered to be complementary thereto. Inosine (I) is also considered in the art to be a universal base and is considered complementary to any A, C, U, or T. Conservative amino acid substitution: As used herein, "conservative amino acid substitution" refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared using methods known to those of ordinary skill in the art for altering polypeptide sequences, such as those found in references compiling such methods, e.g., Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protoco1s in Mo1ecu1ar Biology, FMAusubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include substitutions between amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D. Covalently linked: As used herein, the term "covalently linked" refers to the characteristic of two or more molecules being linked together by at least one covalent bond. In some embodiments, two molecules can be covalently linked together by a single bond (e.g., a disulfide bond or a disulfide bridge) that acts as a linker between the molecules. However, in some embodiments, two or more molecules can be covalently linked together by a molecule that acts as a linker, which links the two or more molecules together by multiple covalent bonds. In some embodiments, the linker can be a cleavable linker. However, in some embodiments, the linker can be a non-cleavable linker. Cross-reactivity: The term "cross-reactivity" as used herein and in the context of a targeting agent (e.g., a CNS targeting agent, such as an antibody) refers to the property that the substance can specifically bind to more than one antigen (e.g., antigens of multiple homologs, paralogs, or orthologs) of a similar type or class with similar affinity or avidity. For example, in some embodiments, antibodies with cross-reactivity for similar types or classes of human and non-human primate antigens (e.g., human transferrin receptor and non-human primate transferrin receptor) can bind to human antigens and non-human primate antigens with similar affinity or avidity. In some embodiments, antibodies have cross-reactivity for similar types or classes of human antigens and rodent antigens. In some embodiments, antibodies have cross-reactivity for similar types or classes of rodent antigens and non-human primate antigens. In some embodiments, antibodies have cross-reactivity for similar types or classes of human antigens, non-human primate antigens, and rodent antigens. DMD: As used herein, the term "DMD" refers to the gene encoding dystrophin, a key component of the dystrophin-glycoprotein complex that bridges the internal cytoskeleton and the extracellular matrix in muscle cells, particularly in myofibers. Deletions, duplications, and point mutations in DMD can cause dystrophinopathies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, or cardiomyopathy. The use of alternative promoters and alternative splicing produce a large number of different transcript variants and protein isoforms of this gene. In some embodiments, the dystrophin gene can be a human gene (Gene ID: 1756), a non-human primate gene (e.g., Gene ID: 465559), or a rodent gene (e.g., Gene ID: 13405; Gene ID: 24907). In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000109.3, NM_004006.2, NM_004009.3, NM_004010.3 and NM_004011.3). DMD allele: As used herein, the term "DMD allele" refers to any of the alternative forms (e.g., wild-type or mutant forms) of the DMD gene. In some embodiments, the DMD allele may encode a dystrophin protein that retains its normal and typical function. In some embodiments, the DMD allele may comprise one or more mutations that cause muscular dystrophy. Common mutations that cause Duchenne muscular dystrophy involve frameshifts, deletions, substitutions, and duplications of one or more of the 79 exons present in the dystrophin allele (e.g., exon 8, exon 23, exon 41, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55). Additional examples of DMD mutations are disclosed in, e.g., Flanigan KM, et al., Mutational spectrum of DMD mutations indystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat. 2009 Dec; 30(12): 1657-66, the contents of which are incorporated herein by reference in their entirety. DMPK: The term "DMPK" as used herein refers to the gene encoding myotonic kinase (also known as myotonic dystrophy kinase or dystrophic myotonic kinase), a serine / threonine protein kinase. Substrates of the enzyme may include myogenin, the beta subunit of the L-type calcium channel, and phospholemman. In some embodiments, DMPK may be a human gene (Gene ID: 1760), a non-human primate gene (e.g., Gene ID: 456139, Gene ID: 715328), or a rodent gene (e.g., Gene ID: 13400). In humans, a CTG repeat expansion in the 3' noncoding, untranslated region of DMPK is associated with myotonic dystrophy type 1 (DM1). In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_001081563.2, NM_004409.4.NM_001081560.2, NM_001081562.2, NM_001288764.1, NM_001288765.1, and NM_001288766.1). DMPK Allele: As used herein, the term "DMPK allele" refers to any of the alternative forms (e.g., wild-type or mutant forms) of the DMPK gene. In some embodiments, a DMPK allele may encode a wild-type myotonic kinase protein kinase that retains its normal and typical function. In some embodiments, a DMPK allele may comprise one or more disease-associated repeat expansions. In some embodiments, a normal subject has two DMPK alleles comprising 5 to 37 repeat units. In some embodiments, the number of CTG repeat units in subjects with DM1 ranges from about 50 to about 3,000 or more, with higher repeat numbers resulting in greater disease severity. In some embodiments, mildly affected subjects with DM1 have at least one DMPK allele comprising 50 to 150 repeat units. In some embodiments, subjects with classic DM1 have at least one DMPK allele comprising 100 to 1,000 or more repeat units. In some embodiments, subjects with congenital onset DM1 may have at least one DMPK allele comprising more than 2,000 repeat units. Dravet syndrome: The term "Drawer syndrome," as used herein, is also known as severe myoclonic epilepsy of infancy (SMEI), and refers to the most severe condition in the genetic epilepsy with febrile seizures plus (GEFS+) spectrum. Dravet syndrome is usually caused by de novo mutations, but cases caused by familial mutations also occur. Symptoms of Dravet syndrome include epileptic seizures, cognitive decline, developmental regression, intellectual disability, and ataxia. More than 80% of cases of Dravet syndrome are attributed to mutations in SCN1A, of which more than 900 different mutations have been reported. In some embodiments, a subject in need of treatment for Dravet syndrome has symptoms selected from the following: epileptic seizures (e.g., febrile seizures, afebrile seizures, myoclonic seizures, and absence seizures), cognitive decline, developmental regression, intellectual disability, and ataxia. Dystrophinopathy: The term "dystrophinopathy" as used herein refers to a muscle disease or neurological disease caused by one or more mutant DMD alleles. Dystrophinopathy includes a spectrum of illness (from mild to severe) including Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). In some embodiments, at one end of the spectrum, dystrophinopathy is phenotypically associated with an asymptomatic increase in serum concentration of creatine phosphokinase (CK) and / or (e.g., and) muscle cramps associated with myoglobinuria. In some embodiments, at the other end of the spectrum, dystrophinopathy is phenotypically associated with a progressive muscle disease that is typically classified as Duchenne or Becker muscular dystrophy when skeletal muscle is initially affected, and as DMD-associated dilated cardiomyopathy (DCM) when the heart is initially affected. Symptoms of Duchenne muscular dystrophy include muscle loss or degeneration, decreased muscle function, pseudohypertrophy of the tongue and calf muscles, a higher risk of neurologic abnormalities, and a shortened lifespan. Duchenne muscular dystrophy is associated with Online Mendelian Inheritance in Man (OMIM) Entry #310200. Becker muscular dystrophy is associated with OMIM Entry #300376. Dilated cardiomyopathy is associated with OMIM Entry X#302045. ECHS1: ECHS1 as used herein refers to the gene encoding enoyl-CoA hydratase short chain 1 (also known as SCEH; mECH; mECH1; or ECHS1D), which is a protein that functions in the second step of the mitochondrial fatty acid β-oxidation pathway. In some embodiments, ECHS1 can be a human gene (Gene ID: 1892), a non-human primate gene (e.g., Gene ID: 101925228), or a rodent gene (e.g., Gene ID: 93747, Gene ID: 140547). In humans, mutations in the gene encoding ECHS1 are associated with the occurrence of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with GenBank RefSeq accession number NM_004092.4). Epilepsy: The term "epilepsy" as used herein refers to a neurological disorder characterized by abnormal activity in neurons of the brain, which can cause sporadic epileptic seizures and can be accompanied by loss of consciousness. Symptoms of an epileptic seizure can include sudden confusion or anxiety, dizziness, loss of recognition, loss of consciousness, staring spells, muscle rigidity, and involuntary movements of the limbs. Epileptic seizures usually occur in the absence of external stimulation. Epileptic seizures can occur because of abnormal neural activity in only one area of ​​the brain (focal seizures), or because of abnormal neural activity in the entire brain (generalized seizures). Focal seizures can occur with or without loss of consciousness and can cause changes in muscle movement and / or sensory perception. Generalized seizures are also characterized by absence seizures (i.e., petit mal seizures, which occur briefly and cause loss of awareness and repetitive body movements), clonic seizures (repetitive involuntary muscle movements), myoclonic seizures (sudden involuntary muscle movements), tonic seizures (muscle stiffness), atonic seizures (loss of muscle control, but not stiffness), and tonic-clonic seizures (i.e., grand mal seizures, which cause loss of consciousness, muscle stiffness, and sudden involuntary muscle movements). Epilepsy can cause death due to damage sustained during a seizure, status epilepticus, or sudden unexpected death in epilepsy (SUDEP). Only about half of epilepsy cases have an identifiable cause, such as a developmental disorder, a brain abnormality (e.g., brain cancer, traumatic brain injury, or a vascular disorder, e.g., stroke), an infection that infects the brain, or the inheritance of genetic risk factors. For example, genes involved in the pathophysiology of epilepsy include, but are not limited to, SCN1A, SCN2A, SCN8A, CLN3, GRIA1, and PCDH19 (see, e.g., Wang J, et al. "Epilepsy-associated genes." Seizure. 2017; 44: 11-20; Abdennadher M, et al. "Seizure phenotype in CLN3 disease and its relation to other neurologic outcome measures." J Inherit Metab Dis. 2021; 44(4): 1013-1020; and Samanta D "PCDH19-Related Epilepsy Syndrome: A Comprehensive Clinical Review." Pediatr Neurol. 2020; 105: 3-9). GRIN2A is also involved in the pathophysiology of epilepsy in some embodiments. Essential tremor: The term "essential tremor" as used herein refers to a neurological condition characterized by involuntary shaking movements. It is sometimes also called familial tremor or benign essential tremor. Essential tremor affects both men and women and is most common in people 40 years of age and older. The tremor is most likely to be noticed in the forearms and hands, and the upper arms, head, eyelids and other muscles may also be affected. People with essential tremor may have difficulty grasping or using small objects (such as silverware or writing utensils). The tremors associated with essential tremor most often include small, rapid movements that occur 4 to 12 times a second. Specific symptoms may include nodding, trembling, or trembling of the voice (if the tremor affects the voice box); and problems with writing, drawing, drinking from a cup, or using tools (for example, if the tremor affects the hands and / or forearms). Essential tremor usually worsens over time and can be severe in some patients. The exact cause of essential tremor is unknown, but many cases of essential tremor are genetic and inherited in an autosomal dominant manner. Mutated genes associated with essential tremor can affect multiple brain regions, including the deep brain (such as the thalamus) and the cerebellum. Framework: The term "framework" or "framework sequence" as used herein refers to the remaining sequence of the variable region minus the CDRs. Since the exact definition of CDR sequences can be determined by different systems, the meaning of framework sequences has correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2 and CDR-L3 of the light chain and CDR-H1, CDR-H2 and CDR-H3 of the heavy chain) also divide the framework regions on the light and heavy chains into four subregions (FR1, FR2, FR3 and FR4) on each chain, wherein CDR1 is located between FR1 and FR2, CDR2 is located between FR2 and FR3, and CDR3 is located between FR3 and FR4. Where a specific subregion is not designated as FR1, FR2, FR3 or FR4, the framework region mentioned by others represents the combined FRs within the variable region of a single naturally occurring immunoglobulin chain. FR as used herein represents one of the four subregions, and FRs represents two or more of the four subregions that constitute the framework region. Human heavy and light chain linker sequences are known in the art. In one embodiment, acceptor sequences known in the art can be used in the antibodies disclosed herein. Friedreich's Ataxia: As used herein, the term "Friedreich's Ataxia" refers to an autosomal recessive disorder caused by mutations in the FXN gene and characterized by progressive damage to muscle tissue and the nervous system. Friedreich's Ataxia is a neurological disorder associated with an expansion of a GAA trinucleotide repeat in the FXN gene, which leads to decreased FXN expression. The expanded GAA trinucleotide repeat, located within the first intron, forms an R-loop that interferes with normal transcription, reducing FXN gene expression. FXN alleles in healthy individuals contain <36 GAA repeats, whereas in FRDA patients, GAA expansions ranging from 70 to 1700 GAA repeats result in a lack of FXN mRNA and subsequent decreased levels of frataxin, a nuclear-encoded mitochondrial protein essential for life (see, e.g., Silva et al., “Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear laminain single cells.” Hum. Molec. Genet., 2015, Vol. 24, No. 12 3457-3471). Friedreich's ataxia, its genetic basis, and associated symptoms are described in the art (see, e.g., Montemini, L. et al. "The Friedreich's ataxia GAA triplet repeat: premutation and normal alleles." Hum. Molec. Genet., 1997, 6: 1261-1266.; Filla, A. et al. "The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich's ataxia." Am. J. Hum. Genet. 1996, 59: 554-560.; Pandolfo, M. Friedreich's ataxia: the clinical picture. J. Neurol. 2009, 256, 3-8.). Friedreich's ataxia is associated with Online Mendelian Inheritance in Man (OMIM) Entry #229300. Frontotemporal dementia: As used herein, the term "frontotemporal dementia" or "FTD" refers to a disease in which there is progressive degeneration of the frontal and / or temporal lobes of the brain. FTD causes progressive deficits in behavior, executive function, and / or language, with symptoms including changes in social and personal behavior, apathy, blunted emotions, deficits in expressive language, and deficits in processing language. FTD is considered one of the most common forms of dementia, accounting for 10% to 20% of all dementia cases. FTD can generally be classified as: (i) behavioral variant FTD (bvFTD), (ii) primary progressive aphasia (PPA), (iii) progressive supranuclear palsy (PSP), and (iv) corticobasal syndrome (CBS). Many cases of FTD are associated with mutations in C9orf72, granulin (GRN), and MAPT. In addition, pathologically, three major protein deposits are found in the brains of FTD patients: TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS), and tau. In some embodiments, the subject in need of treatment for FTD has a mutation in the GRN gene, C9orf72 gene, and / or MAPT gene. In some embodiments, the subject in need of treatment for FTD suffers from progressive degeneration of the frontal and / or temporal lobes of the brain. In some embodiments, the subject in need of treatment for FTD has TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS), and / or tau deposits in the brain. In some embodiments, the subject in need of treatment for FTD has behavioral, executive function, and / or language defects. In some embodiments, the subject in need of treatment for FTD has one or more of the following symptoms: changes in social and personal behavior, apathy, emotional blunting, defects in expressive language, and defects in processing language. FUS: As used herein, FUS refers to the gene encoding the RNA-binding protein FUS / TLS (also known as heterogeneous nuclear ribonucleoprotein P2). This protein is a subunit of a complex involved in the maturation of precursor mRNA (pre-mRNA) and has also been shown to be involved in DNA repair responses. Loss of function of the protein encoded by FUS leads to increased DNA damage in neurons, and certain mutations in FUS repair the PARP-dependent DNA damage response, leading to neurodegeneration and the formation of aggregates of the RNA-binding protein FUS / TSL. Several mutations in FUS have been identified in ALS patients. See, for example, Kwiatkowski, et al., "Mutations in the FUS / TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis" Science 323(5918):1205-1205 (2009); and Vance, et al., "Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6" Science 323(5918):1208-1211 (2009). The mechanism by which FUS mutations cause ALS is unknown, but it is believed that toxicity may be caused by toxic cytoplasmic gain of function, because many ALS-associated FUS mutations are located in its nuclear localization signal, and mouse models that do not express FUS, and therefore completely lose nuclear FUS localization, do not develop obvious ALS-like symptoms. FXN: As used herein, the term "FXN" refers to a gene encoding a frataxin, a protein associated with iron homeostasis. In some embodiments, FXN may be a human gene (Gene ID: 2395), a non-human primate gene (e.g., Gene ID: 737660), or a rodent gene (e.g., Gene ID: 14297, Gene ID: 499335). In humans, a GAA repeat expansion in the first intron of FXN is associated with Friedreich's ataxia (a neurological disorder). In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000144.4 and NM_181425.2). GALC: GALC as used herein refers to the gene encoding galactosylceramidase (also referred to as GALC and entrez: 2581), which is a lysosomal protein. Galactosylceramidase degrades galactolipids involved in myelin production. In some embodiments, GALC can be a human gene (e.g., Gene ID: 2581), a non-human primate gene (e.g., Gene ID: 693322, Gene ID: 736519), or a rodent gene (e.g., Gene ID: 14420, Gene ID: 314360). In humans, mutations in the GALC gene are associated with the occurrence of Krabbe disease. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000153.4;NM_001201401.2;NM_001201402.2;XM_011536618.3;XM_047431198.1; XM_047431199.1). Gaucher disease type II and type III: The term "Gaucher disease" or "GD" as used herein refers to Gaucher disease type II and type III, which are inherited disorders in which fatty substances (e.g., glucocerebroside) accumulate in cells and certain organs (e.g., spleen and liver). The accumulation of these fatty substances can cause organ enlargement, negatively affecting organ function. If the bones are affected, it can weaken the bones, and if the bone marrow is affected, it can interfere with blood clotting. Type II Gaucher disease is a form of Gaucher disease that affects the central nervous system, spleen, liver, lungs, and bones. Type II Gaucher disease (also known as Gaucher type II and acute infantile neuronopathic Gaucher disease) develops symptoms within the first year of life. Symptoms of Gaucher type II include poor development, abnormal eye movements, hypertonia, laryngospasm, seizures, prolonged chest infections, enlarged spleen, and enlarged liver. Current enzyme replacement therapies for Gaucher type I and Gaucher type III are ineffective for Gaucher type II. Gaucher type II is a fatal disease, with death usually occurring within the first two years of life. Gaucher type III (also known as chronic neuronopathic Gaucher disease) develops during childhood. The initial symptoms of Gaucher type III are an enlarged liver and spleen, poor diet, and less than normal weight gain. Other symptoms include seizures, skeletal irregularities, eye movement disorders, cognitive problems, poor coordination, respiratory problems, and blood disorders. Both Gaucher types II and III are neuropathic. Furthermore, both are associated with mutations in the GBA gene. In some embodiments, a subject in need of treatment for Gaucher disease has a mutation in the GBA gene. In some embodiments, a subject in need of treatment for Gaucher disease has accumulated glucocerebroside in cells and / or organs. In some embodiments, a subject in need of treatment for Gaucher disease has an enlarged liver and / or an enlarged spleen. In some embodiments, a subject in need of treatment for Gaucher disease has one or more of the following symptoms: abnormal eye movements, hypertonia, laryngospasm, seizures, chronic chest infections, an enlarged spleen, or an enlarged liver. In some embodiments, the subject in need of treatment for Gaucher disease has one or more of the following symptoms: poor diet, less than normal weight gain, skeletal irregularities, eye movement disorders, cognitive problems, poor coordination, breathing problems, and blood disorders. GBA: As used herein, the term "GBA" refers to the gene (also known as GBA1, GCB, GLUC) encoding β-glucocerebrosidase (also known as acid β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, glucosylceramidase β, glucocerebrosidase, or GCase), which is a lysosomal membrane protein. β-glucocerebrosidase cleaves β-glucosidic linkages. In some embodiments, GBA can be a human gene (e.g., Gene ID: 2629), a non-human primate gene (e.g., Gene ID: 719103), or a rodent gene (e.g., Gene ID: 14466, Gene ID: 684536). In humans, mutations in the GBA gene are associated with the development of Gaucher disease types II and III. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000157.4; NM_001005741.3; NM_001005742.3; NM_001171811.2; NM_001171812.2). GCH1: As used herein, GCH1 refers to the gene encoding GTP cyclohydrolase 1 (also known as GCH; DYT5; DYT14; DYT5a; GTPCH1; HPABH4B; GTP-CH-1), which is a protein that is a member of the GTP cyclohydrolase family and is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP to 7,8-dihydroneopterin triphosphate. In some embodiments, GCH1 can be a human gene (Gene ID: 2643), a non-human primate gene (e.g., Gene ID: 695675), or a rodent gene (e.g., Gene ID: 14528, Gene ID: 29244). In humans, mutations in the gene encoding GCH1 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_001024071.2; NM_001024070.2; NM_001024024.2; NM_000161.3; XM_017021218.2; and XM_047431261.1). GFAP: The term "GFAP" as used herein refers to a gene encoding glial fibrillary acidic protein (also known as ALXDRD), a protein involved in cell communication in the CNS. In some embodiments, GFAP can be a human gene (Gene ID: 2670), a non-human primate gene (e.g., Gene ID: 712941), or a rodent gene (e.g., Gene ID: 14580, Gene ID: 24387). In humans, mutations in the GFAP gene are associated with Alexander disease. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_002055.5 and NM_001131019.3). GLB1: The term "GLB1" as used herein refers to the gene encoding galactosidase β1 (also known as EBP, ELNR1 or MPS4B), which is a lysosomal enzyme that mediates the catabolism of several molecules, including GM1 ganglioside. GM1 ganglioside is an important factor in neuronal plasticity, neuronal repair, and the release of neurotrophic factors in the brain. When mutated, GLB1 produces galactosidase β1 with reduced or eliminated function, leading to the accumulation of GM1 ganglioside in the brain and ultimately neuronal death. GLB1 mutations are associated with GM1 gangliosidosis and Morquio syndrome B. In some embodiments, GLB1 can be a human gene (Gene ID: 2720), a non-human primate gene (Gene ID: 709355) or a rodent gene (Gene ID: 12091; Gene ID: 316033). GM1 gangliosidosis: As used herein, the term "GM1 gangliosidosis" refers to a lysosomal storage disorder caused by a defect in the enzyme β-galactosidase. GM1 gangliosidosis is a neurological disorder inherited in an autosomal recessive manner and is associated with mutations in the GLB1 gene. Symptoms of GM1 gangliosidosis include cognitive impairment, developmental delay, skeletal abnormalities, seizures, movement disorders, and visual impairment. GM1 gangliosidosis is characterized by neuronal cell death and demyelination, inflammatory responses, autophagy, and mitochondrial dysfunction. The genetic basis of GM1 gangliosidosis is attributed to mutations in GLB1, of which there are 102 reported mutations. See Brunetti-Pierri, et al. "GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects" Mol Gen Metabolism 94(4): 391-396 (2008). GM1 gangliosidosis is closely related to both Tay-Sachs and Sandhoff diseases; therefore, treatments for Tay-Sachs and / or Sandhoff disease may also be effective in treating GM1 gangliosidosis (and vice versa). GNAL: GNAL as used herein refers to the gene encoding G protein subunit αL (also known as HG10 and DYT25), which is a protein that is a stimulatory G protein α subunit that mediates odor signaling in the olfactory epithelium. The G protein subunit αL protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. In some embodiments, GNAL can be a human gene (Gene ID: 2774), a non-human primate gene (e.g., Gene ID: 102137826), or a rodent gene (e.g., Gene ID: 14680, Gene ID: 24611). In humans, mutations in the gene encoding GNAL are associated with the development of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_182978.4; NM_001142339.3; NM_001261443.2; NM_001261444.2; NM_001369387.1; and XM_006722324.4). GRIA1: The term "GRIA1" as used herein refers to the gene encoding the glutamate ion channel receptor AMPA-type subunit 1 (also known as GLUH1, GLUR1, GLURA, GluA1, and HBGR1), which is a protein associated with neuronal signaling through the glutamate neurotransmitter. In some embodiments, GRIA1 can be a human gene (Gene ID: 2890), a non-human primate gene (e.g., Gene ID: 714117), or a rodent gene (e.g., Gene ID: 14799, Gene ID: 50592). In humans, mutations in the GRIA1 gene are associated with epilepsy and seizures, as well as nociception-related phenotypes (e.g., pain disorders). In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000827.4 and NM_001114183.2). GRIN2A: The term GRIN2A used herein refers to a gene (also known as LKS; EPND; FESD; NR2A; GluN2A; NMDAR2A) encoding a glutamate ion channel receptor NMDA subunit 2A (gluN2A), which is a protein that is a component of a subset of NMDA receptors. In some embodiments, GRIN2A can be a human gene (Gene ID: 2903), a non-human primate gene (e.g., Gene ID: 102123126), or a rodent gene (e.g., Gene ID: 14811, Gene ID: 24409). In humans, mutations in the GRIN2A gene are associated with epilepsy and epileptic seizures. More than 50 mutations in GRIN2A have been identified in patients with epilepsy. Many GRIN2A mutations result in the production of non-functional gluN2A proteins or prevent the production of gluN2A proteins, potentially leading to a reduction in the number of functional NMDA receptors. Signaling therefore occurs more through other types of NMDA receptors that are more easily stimulated, leading to excessive signaling in the brain. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000833.5; NM_001134407.3; NM_001134408.2). GRN: As used herein, GRN refers to the gene (also known as GEP; GP88; PEPI; PGRN; CLN11; PCDGF) encoding progranulin (also known as granulin precursor, proepithelin, and PC cell-derived growth factor), a protein that is active in many tissues throughout the body. The function of progranulin in the brain is not well understood, but it has been shown to play an important role in the survival of neurons. In humans, mutations in GRN are associated with frontotemporal dementia (FTD). FTD associated with GRN mutations (sometimes referred to as "GRN-FTD" or "GRN-associated FTD") has been shown to involve the accumulation of TAR DNA binding protein 43 into aggregates in certain cells of the central nervous system, including neurons in the brain. These protein aggregates interfere with cell function and can lead to cell death. See, for example, Baker, et al., "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17" Nature 442:916-919 (2006); Cruts, et al., "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21" Nature 442:920-924(2006); Borroni, et al. “Progranulin genetic variations in frontotemporal lobardegeneration: evidence for low mutation frequency in an Italian clinicalseries” Neurogenetics 9: 197-205 (2008); and Chen-Plotkin, et al. “Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration” Arch. Neurol. 68: 488-497 (2011); the entire contents of each of which are incorporated herein by reference.See also Hsiung, et al. "GRN Frontotemporal Dementia" 2007Sep 7 [Updated 2020Feb 6]. In: Adam MP, et al., editors. [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from ncbi.nlm.nih.gov / books / NB K1371 / . Mutations in granulin that cause defects may play a role in lysosomal dysfunction. In some embodiments, GRN can be a human gene (e.g., Gene ID: 2896), a non-human primate gene (e.g., Gene ID: 454728, Gene ID: 714851), or a rodent gene (e.g., Gene ID: 14824, Gene ID: 29143). In humans, mutations in the gene encoding GRN are associated with the occurrence of FTD, such as heterozygous mutations, resulting in insufficient production of progranulin. A human transcript variant encoding progranulin annotated with GenBank RefSeq accession number NM_002087.4 has been characterized. GYS1: As used herein, the term "GYS1" refers to the gene encoding glycogen synthase, a protein that plays a role in the synthesis of glycogen. In some embodiments, GYS1 can be a human gene (Gene ID: 2997), a non-human primate gene (e.g., Gene ID: 574233, Gene ID: 456196, Gene ID: 102134439), or a rodent gene (e.g., Gene ID: 14936, Gene ID: 690987). In humans, expression of mutant glycogen synthase proteins (e.g., from mutant GYS1 genes) results in reduced glycogen synthesis. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_001161587.1 and NM_002103.5). Hereditary Dystonia: As used herein, the term "hereditary dystonia" refers to movement disorders characterized by sustained or intermittent muscle contractions that result in abnormal, often repetitive movements and / or postures. Dystonic movements are often patterned and distorted and may be associated with tremor. Some forms of hereditary dystonia are associated with neurodegeneration and gradually worsen over time, while other forms are not associated with neurodegeneration and typically reach a period of symptom stability after an initial period of worsening. Hereditary dystonias can be characterized by the body parts affected and are generally classified as focal, affecting 1 body part (e.g., eyelid, mouth, throat, neck, or hand and arm); segmental, affecting 2 or more contiguous body parts (e.g., axial—neck and trunk; brachial—1 arm and trunk or 2 arms + / - neck + / - trunk; or crural—1 leg and trunk or 2 legs + / - trunk); multifocal—2 or more non-contiguous body parts (e.g., faciobrachial—blepharospasm and hand / arm); hemidystonia—2 or more body parts (e.g., ipsilateral arm and leg); or generalized—3 or more body parts (e.g., trunk and 2 or more other parts + / - legs). Many genes have been associated with hereditary dystonia, including TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, and ECHS1. Hereditary dystonia, the genetic basis of the disease, and associated symptoms are described in the art (see, e.g., Klein, et al., “Hereditary Dystonia Overview” 2003 Oct 28 (Updated 2017 Jun 22) In: Adam, et al., editors, Gene Reviews [Internet], Seattle (WA): University of Washington, Seattle, 1993-2023, NCBI Bookshelf ID: NBK1155, PMID 20301334). HEXA: As used herein, "HEXA" refers to the gene (also known as TSD and hexosaminidase subunit alpha) encoding the alpha subunit of β-hexosaminidase A (also known as hexosaminidase A), an enzyme that breaks down GM2 ganglioside and molecules containing N-acetylhexosamine. Mutations in HEXA reduce or eliminate the activity of β-hexosaminidase A, leading to the accumulation of GM2 ganglioside in neuronal cells, which can lead to cell death. In some embodiments, HEXA can be a human gene (e.g., Gene ID: 3073), a non-human primate gene (e.g., Gene ID: 698251, Gene ID: 748732), or a rodent gene (e.g., Gene ID: 15211, Gene ID: 300757). In humans, mutations in the gene encoding HEXA are associated with the occurrence of Tay-Sachs. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_000520.6; NM_001318825.2). HEXB: "HEXB" as used herein refers to the gene encoding the β subunit of β-hexosaminidase A (also known as hexosaminidase A) (also known as ENC-1AS, HEL-248, and HEL-S-111). Wild-type HEXB is a subunit of β-hexosaminidase A that is involved in the degradation of ganglioside GM2 and other molecules. Mutations in HEXB reduce or eliminate the activity of β-hexosaminidase A, leading to the accumulation of GM2 ganglioside in neuronal cells, which can lead to cell death. In some embodiments, HEXB can be a human gene (Gene ID: 3074), a non-human primate gene (Gene ID: 704464), or a rodent gene (Gene ID: 15212; Gene ID: 294673). Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_000521.4; NM_001292004.2).In humans, mutations in HEXB are associated with the development of Sandhoff disease. Human antibody: The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example, in CDRs, and particularly in CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (e.g., a mouse) have been grafted onto human framework sequences. Humanized antibody: The term "humanized antibody" refers to an antibody that comprises a heavy chain variable region sequence and a light chain variable region sequence from a non-human species (e.g., a mouse) but in which at least a portion of the VH and / or (e.g., and) VL sequence has been altered to be more "human-like" (i.e., more similar to human germline variable sequences). One type of humanized antibody is a CDR-grafted antibody in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, humanized anti-TfR1 antibodies and antigen-binding portions are provided. Such antibodies can be produced by obtaining murine anti-TfR1 monoclonal antibodies using conventional hybridoma technology followed by humanization using in vitro genetic engineering, such as those disclosed in PCT Publication No. WO 2005 / 123126A2 by Kasaian et al. HTT: As used herein, HTT refers to the gene encoding the huntingtin protein. HTT is widely expressed and is essential for normal development. The precise function of the huntingtin protein encoded by HTT is unknown, but it plays an important role in nerve cells and is involved in axonal transport. HTT is expressed in many tissues throughout the body, with the highest expression levels in the brain. Huntingtin has been found to directly interact with many other proteins, including several involved in transcription, transport, and cell signaling. Certain mutations in HTT lead to the development of Huntington's disease. HTT contains a CAG trinucleotide repeat region. CAG trinucleotide repeat expansion is associated with Huntington's disease. In some embodiments, a normal subject has two HTT alleles containing about 10 to about 35 CAG repeats. In some embodiments, a subject suffering from Huntington's disease or a subject expected to develop Huntington's disease has an HTT allele containing 40 or more CAG repeats. In some embodiments, a subject with one or two HTT alleles containing 36 to 40 CAG repeats may or may not develop symptoms of Huntington's disease. Mutant HTT is also known as mHTT. Huntington's Disease: Huntington's disease is a neurological disorder characterized by the degeneration of neurons in the striatum. It results in the progressive degeneration of nerve cells in the brain, which has a wide-ranging impact on the patient's functional abilities and often leads to motor, cognitive, and psychiatric impairments. Huntington's disease affects the entire brain, however, certain areas of the brain are more highly affected than others. The striatum, which plays a key role in the control of movement, mood, and behavior, is often the part of the brain most affected by Huntington's disease. Huntington's disease is associated with the expansion of the CAG trinucleotide repeat in HTT. Internalized cell surface receptor: The term "internalized cell surface receptor" as used herein refers to a cell surface receptor that is internalized by a cell, for example, under external stimulation (e.g., ligand binding to a receptor). In some embodiments, the internalized cell surface receptor is internalized by endocytosis. In some embodiments, the internalized cell surface receptor is internalized by clathrin-mediated endocytosis. However, in some embodiments, the internalized cell surface receptor is internalized by a clathrin-independent pathway, such as phagocytosis, macropinocytosis, pits and raft-mediated uptake or constitutive clathrin-independent endocytosis. In some embodiments, the internalized cell surface receptor comprises an intracellular domain, a transmembrane domain and / or (e.g., and) an extracellular domain, which may optionally further comprise a ligand binding domain. In some embodiments, the cell surface receptor becomes internalized by the cell after ligand binding. In some embodiments, the ligand may be a CNS targeting agent or a CNS targeting antibody. In some embodiments, the internalized cell surface receptor is a transferrin receptor. Isolated antibody: As used herein, "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to transferrin receptor is substantially free of antibodies that specifically bind to antigens other than transferrin receptor). However, an isolated antibody that specifically binds to the transferrin receptor complex may have cross-reactivity with other antigens (e.g., transferrin receptor molecules from other species). Furthermore, an isolated antibody may be substantially free of other cellular material and / or (e.g., and) chemical substances. Kabat numbering: The terms "Kabat numbering," "Kabat definition," and "Kabat notation" are used interchangeably herein. These terms, recognized in the art, refer to a system for numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 5501068). No. 91-3242). For the heavy chain variable region, the hypervariable region of CDR1 is from amino acids 31 to 35, the hypervariable region of CDR2 is from amino acids 50 to 65, and the hypervariable region of CDR3 is from amino acids 95 to 102. For the light chain variable region, the hypervariable region of CDR1 is from amino acids 24 to 34, the hypervariable region of CDR2 is from amino acids 50 to 56, and the hypervariable region of CDR3 is from amino acids 89 to 97. KMT2B: As used herein, KMT2B refers to the gene encoding lysine methyltransferase 2B (also known as HRX2; MLL2; MLL4; TRX2; WBP7; DYT28; MLL1B; MRD68; WBP-7; and CXXC10), which is a protein comprising multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET domain. In some embodiments, KMT2B can be a human gene (Gene ID: 9757), a non-human primate gene (e.g., Gene ID: 102115861), or a rodent gene (e.g., Gene ID: 75410, Gene ID: 102550344). In humans, mutations in the gene encoding KMT2B are associated with the development of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_014727.3; XM_011527561.3; XM_011527562.3; Krabbe disease: As used herein, the terms "Krabbe disease," "KD," "KRD," "globoid cell leukodystrophy," or "galactosylceramide lipidosis" refer to a metabolic disorder in which lipids accumulate to harmful levels in various tissues throughout the body, including the nervous system, leading to the death of cells of the central nervous system, including the brain. Krabbe disease is characterized by cells with more than one nucleus (globoid cells), which lead to the breakdown of the myelin sheath that coats the nerves. Krabbe disease is caused by a mutation in the GALC gene, which results in a deficiency of the enzyme galactosylceramidase. Galactosylceramidase is an essential enzyme in myelin metabolism. Symptoms of Krabbe disease include irritability, rigid posture, delayed mental development, delayed physical development, deterioration of motor skills, muscle weakness, hypertonia, myoclonic seizures, spasms, fever, blindness, difficulty swallowing, and deafness. Krabbe disease is most commonly seen in infants (infantile form), usually beginning before the age of one year. 10% to 15% of Krabbe disease patients have a late onset of the disease, which occurs in adolescent or adult form. In some embodiments, the subject has a mutation in the GALC gene. In some embodiments, the subject has an accumulation of lipids in the central nervous system (e.g., brain). In some embodiments, the subject has spherical cells in the central nervous system (e.g., brain). In some embodiments, the subject has a defect in galactosylceramidase. In some embodiments, the subject has one or more of the following symptoms: irritability, stiff posture, delayed mental development, delayed physiological development, degeneration of motor skills, muscle weakness, hypertonia, myoclonic seizures, spasms, fever, blindness, dysphagia, and deafness. LRRK2: As used herein, LRRK2 refers to the gene that encodes the dardarin protein, also known as leucine-rich repeat kinase 2 and PARK8. Variants of LRRK2 are associated with an increased risk of Parkinson's disease. Mutations in LRRK2, the G2019S mutant of the dardarin protein, have been shown to cause Parkinson's disease and are a relatively common cause of familial Parkinson's disease. This G2019S mutation results in increased kinase activity of the protein. Mutations in LRRK2 are the most common known cause of both familial and sporadic Parkinson's disease. LSD: As used herein, the term "LSD" refers to a gene encoding a lysine-specific demethylase, a protein associated with neuronal differentiation and physiology. An example of an LSD is LSD1 (also known as KDM1A, AOF2, BHCl10, CPRF, and KDM1). In some embodiments, the LSD can be a human gene (Gene ID: 23028), a non-human primate gene (e.g., Gene ID: 718609), or a rodent gene (e.g., Gene ID: 99982, Gene ID: 500569). In humans, mutations in genes encoding LSDs are associated with neurodegeneration (e.g., Alzheimer's disease, tauopathy, and / or frontotemporal dementia). Additionally, multiple human transcript variants of LSD (eg, LSD1) encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_015013.4 and NM_001009999.3). MAPT: The term "MAPT" as used herein refers to a gene encoding the microtubule-associated protein tau (also known as tau, tau-40, DDPAC, FTDP-17, MAPTL, MSTD, MTBT1, MTBT2, PPND, and PPP1R1 03), which is a protein involved in the stabilization of axonal microtubules. In some embodiments, MAPT can be a human gene (Gene ID: 4137), a non-human primate gene (e.g., Gene ID: 574327), or a rodent gene (e.g., Gene ID: 17762, Gene ID: 29477). In humans, mutations in the MAPT gene may be associated with the occurrence of Alzheimer's disease. Mutations in the MAPT gene may also be associated with certain tau diseases, including frontotemporal dementia. Aggregates formed by hyperphosphorylated tau proteins contribute to the pathological conditions of Alzheimer's disease. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_016835.5, NM_005910.6, and NM_001377265.1). MECP2: The term MECP2 as used herein refers to the gene encoding methyl-CpG binding protein 2 (also known as RS; RTS; RTT; PPMX; MRX16; MRX79; MRXSL; AUTSX3; MRXS13), which is a protein that binds to methylated DNA and plays an important role in mammalian development. In some embodiments, MECP2 can be a human gene (Gene ID: 4204), a non-human primate gene (e.g., Gene ID: 102135563), or a rodent gene (e.g., Gene ID: 17257, Gene ID: 29386). In humans, mutations in the MECP2 gene are responsible for most cases of Rett syndrome. Multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_004992.4; NM_001110792.2; NM_001316337.2; NM_001369391.2; NM_001369392.2; NM_001369393.2; NM_001369394.2; NM_001386137.1; NM_001386138.1; NM_001386139.1). Inhibition of MECP2 (eg, a mutant form thereof) may be effective in treating Rett syndrome. Increasing the level and / or activity of methyl-CpG binding protein 2 or a functional fragment thereof may also be effective in treating Rett syndrome. Metachromatic leukodystrophy (MLD): The term "metachromatic leukodystrophy" or "MLD" as used herein refers to a lysosomal storage disease (LSD) characterized by defects in the lysosomal enzyme arylsulfatase A (ARSA) or its sphingolipid activator protein B (SapB), resulting in dysfunction and destruction of myelin in the central and peripheral nervous systems. This leads to progressive degeneration of neurodevelopmental and neurocognitive functions. Metachromatic leukodystrophy is associated with mutations in the arylsulfatase A gene (ARSA) and / or the prosaposin gene (PSAP). There is currently no effective treatment for metachromatic leukodystrophy. In some embodiments, a subject (e.g., a subject diagnosed with MLD) suffers from deterioration of the myelin sheath. In some embodiments, a subject (eg, a subject diagnosed with MLD) suffers from a deterioration in neurodevelopmental and / or neurocognitive function. Molecular payload: The term "molecular payload" as used herein refers to a molecule or substance that plays a role in regulating biological outcomes. In some embodiments, the molecular payload is connected to or otherwise associated with a CNS targeting agent. In some embodiments, the molecular payload is a small molecule, a polypeptide (e.g., a protein, a peptide, an antibody), a gene therapy payload (e.g., a nucleic acid), or an oligonucleotide. In some embodiments, the molecular payload plays a role in regulating the transcription of a DNA sequence, regulating the expression of a protein, or regulating the activity of a protein. In some embodiments, the molecular payload is an oligonucleotide comprising a chain having a complementary region to a target gene. In some embodiments, the molecular payload is a polypeptide that is biologically active in a specific disease context (e.g., a CNS disease or disorder). In some embodiments, the molecular payload is a small molecule that is biologically active in a specific disease context (e.g., a CNS disease or disorder). In some embodiments, the molecular payload is a gene therapy payload that encodes a biologically active compound (e.g., a polypeptide). Motor neuron disease: The term "motor neuron disease" as used herein refers to a group of progressive neurological disorders that destroy motor neurons, which control skeletal muscle activity. Motor neuron diseases include diseases such as ALS, progressive bulbar palsy, primary lateral sclerosis, progressive muscular atrophy, spinal muscular atrophy, Kennedy's disease, and post-polio syndrome. A variety of genes and mutations therein are associated with the occurrence of motor neuron disease. For example, APOE (e.g., APOE4 allele) is associated with the occurrence of certain types of motor neuron disease. Therefore, in some embodiments allele-specific regulation of APOE (e.g., APOE4) can be used to treat motor neuron disease. In some embodiments, the subject in need of treating motor neuron disease has one or more symptoms associated therewith. MSH3: MSH3 as used herein refers to the gene encoding MutS homolog 3 protein. This protein is involved in the mismatch repair system. MSH3 plays a significant role in tumor suppression in cancer by repairing somatic mutations in DNA, and both loss of expression and overexpression of MSH3 can cause carcinogenesis. It has been shown that overexpression of MSH3 reduces the ability of mismatch repair, and increased expression of MSH3 is associated with the progression of Huntington's disease. See, for example, Flower, et al. "MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1" Brain 142(7): 1876-1888(2019). Evidence also suggests that mutations in MSH3 may be associated with the occurrence of spinocerebellar ataxia. Niemann-Pick Type A: The term "Niemann-Pick Type A" as used herein refers to Niemann-Pick Type A (NPA), also known as infantile neurovisceral acid sphingomyelinase deficiency, a fatal lysosomal neurodegenerative disorder associated with a deficiency in the activity of acid sphingomyelinase. NPA is inherited in an autosomal recessive pattern. Symptoms of NPA include developmental delay, hepatosplenomegaly, lung damage, visual abnormalities, neurodegeneration, and premature death. NPA disease is characterized by accumulation of sphingomyelin in lysosomes, dysfunction of the autophagy-lysosomal pathway, and astrogliosis. The genetic cause of NPA disease has been identified as a mutation in the ASM gene. See, for example, Marín, et al. “c-Ablactivation linked to autophagy-lysosomal dysfunction contributes toneurological impairment in Niemann-Pick type A disease” Front Cell Devel Biol. 10:844297 (2022). Oligonucleotide: The term "oligonucleotide" as used herein refers to an oligomeric nucleic acid compound up to 200 nucleotides in length. Some examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (e.g., siRNA, shRNA), microRNA, spacer polymers, mixed polymers, phosphorodiamidate morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNA), etc. Oligonucleotides can be single-stranded or double-stranded. In some embodiments, the oligonucleotide may comprise one or more modified nucleosides (e.g., 2'-O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, the oligonucleotide may comprise one or more modified internucleoside linkages. In some embodiments, the oligonucleotide may comprise one or more phosphorothioate linkages, which may be Rp or Sp stereochemical configurations. Parkinson's disease: Parkinson's disease is a neurological disorder that primarily affects the motor system and is a form of synucleinopathy because it is associated with the abnormal accumulation of alpha-synuclein in the brain. The motor symptoms of the disease are caused by the death of cells in the substantia nigra region of the midbrain, resulting in dopamine deficiency. The cause of cell death is poorly understood but involves the accumulation of misfolded proteins in Lewy bodies within neurons. At least 11 autosomal dominant and 9 autosomal recessive gene mutations have been associated with the development of Parkinson's disease, including mutations in: SNCA, LRRK2, PARK3, UCHL1, GIGYF2, HTRA2, EIF4G1, TMEM230, CHCHD2, RIC3, ​​VPS35 (autosomal dominant); and PRKN, PINK2, PARK7, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, and VPS13C (autosomal recessive). Mutations in SNCA and LRRK2 have been found to be risk factors for sporadic Parkinson's disease. PCDH19: The term "PCDH19" as used herein refers to the gene encoding protocadherin 19 (also known as DEE9, EFMR, and EIEE9), a protein involved in cell adhesion. In some embodiments, PCDH19 can be a human gene (Gene ID: 57526), ​​a non-human primate gene (e.g., Gene ID: 703042), or a rodent gene (e.g., Gene ID: 279653, Gene ID: 317183). In humans, mutations in the gene encoding PCDH1 9 are associated with epilepsy and seizures. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_020766.3 and NM_001184880.2). PIKFYVE: As used herein, PIKFYVE refers to the gene encoding the type III phosphatidylinositol 3-phosphate 5-kinase protein (PIPKIII) (also known as CFD; FAB1; HEL37; PIP5K; PIP5K3; ZFYVE29), which phosphorylates certain phosphatidylinositols (e.g., PtdIns and PtdIns3P). In some embodiments, PIKFYVE can be a human gene (Gene ID: 200576), a non-human primate gene (e.g., Gene ID: 710115), or a rodent gene (e.g., Gene ID: 18711, Gene ID: 316457). PIKFYVE and mutations therein are associated with ALS and frontotemporal dementia (FTD). Multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_015040.4; NM_152671.4; NM_001178000.2). PNKD: As used herein, PNKD refers to a gene encoding a metallo-β-lactamase domain-containing PNKD (also known as R1; MR1; PDC; DYT8; FPD1; MR-1; BRP17; MR-1S; PKND1; PNKD1; FKSG19; TAHCCP2; KIPP1184), which is a protein believed to play a role in the regulation of myofibrillogenesis. In some embodiments, PNKD can be a human gene (Gene ID: 25953), a non-human primate gene (e.g., Gene ID: 101867223), or a rodent gene (e.g., Gene ID: 56695, Gene ID: 100188944). In humans, mutations in the gene encoding PNKD are associated with the development of hereditary dystonia. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_015488.5; NM_022572.4; NM_001077399.3; XM_017003771.2; and XM_017003772.2). PRKRA: As used herein, PRKRA refers to the gene encoding the protein activator of the interferon-induced protein kinase EIF2AK2 (also known as RAX; PACT; DYT16; HSD14), which is a protein kinase activated by double-stranded RNA that mediates the effects of interferon in response to viral infection. In some embodiments, PRKRA can be a human gene (Gene ID: 8575), a non-human primate gene (e.g., Gene ID: 102116511), or a rodent gene (e.g., Gene ID: 23992, Gene ID: 311130). In humans, mutations in the gene encoding PRKRA are associated with the development of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_003690.5; NM_001139517.1; NM_001139518.1; NM_001316362.2; XM_011512063.3; and XM_047446138.1). PrP:The term "PrP" as used herein refers to a gene encoding a prion protein (also known as PRNP, PRIP, CD230, and CJD), which is a protein involved in the neural function that can form cytotoxic prions. In some embodiments, PrP can be a human gene (Gene ID: 5621), a non-human primate gene (e.g., Gene ID: 717859), or a rodent gene (e.g., Gene ID: 19122, Gene ID: 24686). In humans, mutations in the PrP gene are associated with neurodegeneration. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000311.5 and NM_183079.4). In some embodiments, PrP is associated with small fiber neuropathy, nociception-related phenotypes, Alexander disease, Angelman syndrome, autism spectrum disorder, retinitis pigmentosa, isolated macular dystrophy, and / or multiple sclerosis. PRRT2: As used herein, PRRT2 refers to the gene encoding proline-rich transmembrane protein 2 (also known as PKC; EKD1; ICCA; BFIC2; BFIS2; DSPB3; DYT10; FICCA; IFITMD1), which is a transmembrane protein containing a proline-rich domain in its N-terminal half. In some embodiments, PRRT2 can be a human gene (Gene ID: 112476), a non-human primate gene (e.g., Gene ID: 102124815), or a rodent gene (e.g., Gene ID: 69017, Gene ID: 361651). In humans, mutations in the gene encoding PRRT2 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_145239.3; NM_001256442.2; NM_001256443.2; XM_011545715.4; XM_017022887.3; Recombinant antibody: As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, generated or isolated by recombinant means, e.g., antibodies expressed using recombinant expression vectors transfected into host cells (described in more detail in this disclosure), antibodies isolated from recombinant, combinatorial human antibody libraries (Hoogenboom HR, (1997) TIB Tech. 15: 62-70; Azzazy H., and Highsmith WE, (2002) Clin. Biochem. 35: 425-445; Gavilondo JV, and Larrick JW (2002) BioTechniques 29: 128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21: 371-378), antibodies isolated from animals (e.g., mice) transgenic for human immunoglobulin genes (see, e.g., Taylor, LD, et al. (1992) Nucl. Acids Res. 20: 6287-6295; Kellermann SA., and Green LL (2002) Current Opinion in Biotechnology 13: 593-597; Little M. et al (2000) Immunology Today 21: 364-370), or antibodies prepared, expressed, produced, or isolated by any other means involving splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis), and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. One embodiment of the present disclosure provides fully human antibodies capable of binding to human transferrin receptor, which can be generated using techniques well known in the art, such as, but not limited to, using human Ig phage libraries, such as those disclosed in PCT Publication No. WO 2005 / 007699A2 to Jermutus et al. Complementary region: As used herein, the term "complementary region" refers to a nucleotide sequence, such as an oligonucleotide, that is sufficiently complementary to a homologous nucleotide sequence, such as a target nucleic acid, such that the two nucleotide sequences can anneal to each other under physiological conditions (e.g., in a cell). In some embodiments, the complementary region is fully complementary to the homologous nucleotide sequence of the target nucleic acid. However, in some embodiments, the complementary region is partially complementary to the homologous nucleotide sequence of the target nucleic acid (e.g., at least 80%, 90%, 95%, or 99% complementary). In some embodiments, the complementary region comprises 1, 2, 3, or 4 mismatches compared to the homologous nucleotide sequence of the target nucleic acid. Rett syndrome: The term "Rett syndrome" as used herein refers to a spectrum of conditions associated with mutations in MECP2. Rett syndrome is a brain disorder that occurs almost exclusively in girls. Subjects with Rett syndrome begin to experience severe problems with language and communication, learning, coordination, and other brain functions at approximately 6 to 18 months of age. In early childhood, affected subjects lose the purposeful use of their hands and begin to make repetitive hand-wringing, hand-washing, or hand-clapping motions. They tend to grow more slowly than other children, and approximately 75% have microcephaly. Other signs and symptoms that may occur include abnormal breathing, spitting or drooling, unusual eye movements such as fixed staring or excessive blinking, cold hands and feet, irritability, sleep disorders, seizures, and scoliosis. More than 99% of subjects with Rett syndrome do not have a family history of the condition, and many of these cases are caused by new mutations in MECP2. Inhibition of mutant forms of MECP2 (e.g., by antisense oligonucleotide therapy) can, in some embodiments, be effective in treating Rett syndrome or its symptoms. Increasing the level and / or activity of the protein encoded by MECP2 or a functional fragment thereof (eg, by delivery of a gene therapy payload) may also be effective in treating Rett syndrome or its symptoms. Sandhoff disease: The term "Sandhoff disease," sometimes referred to as GM2 gangliosidosis, as used herein refers to a continuum of conditions that gradually destroy neurons in the central nervous system. Sandhoff disease is inherited in an autosomal recessive manner. Symptoms of Sandhoff disease include progressive weakness, seizures, developmental defects, neurological impairment, cognitive impairment, and premature death. Sandhoff disease is characterized by cortical atrophy, cerebellar atrophy, and spinal cord atrophy. The genetic cause of Sandhoff disease has been identified as approximately 30 mutations in the HEXB gene. See Xiao, et al. "Sandhoff Disease," April 14, 2022, in: Adam MP, Mirzaa GM, Pagon RA, et al., editors. [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. In some embodiments, the subject in need of treatment for Sandhoff disease exhibits progressive weakness. In some embodiments, progressive weakness includes lower limb weakness. In some embodiments, the subject in need of treatment for Sandhoff disease exhibits epileptic seizures. In some embodiments, the subject in need of treatment for Sandhoff disease exhibits developmental defects. In some embodiments, developmental defects include developmental arrest and developmental regression. In some embodiments, the subject in need of treatment for Sandhoff disease exhibits neurological damage. In some embodiments, neurological damage includes loss of motor skills, exaggerated startle response, hypotonia, hyperreflexia, neuropathy, neuronopathy, atrophy, fasciculations, balance problems, tremors, dysarthria, dysphagia, and spasticity. In some embodiments, the subject in need of treatment for Sandhoff disease exhibits cognitive impairment. In some embodiments, cognitive impairment includes decreased attention, cognitive decline, executive function deficits, and memory deficits. In some embodiments, the subject in need of treatment for Sandhoff disease does not exhibit hepatosplenomegaly. Sandhoff disease is very similar to Tay-Sachs; therefore, treatments for Tay-Sachs may also be effective in treating Sandhoff disease (and vice versa). Sandhoff disease is also closely related to GM1 gangliosidosis, and therefore, treatments for GM1 gangliosidosis may be effective in treating Sandhoff disease. SCA1: As used herein, "SCA1" refers to spinocerebellar ataxia type 1, which is associated with a CAG repeat expansion in ATXN1. See "Spinocerebellar ataxias." SCA2: As used herein, "SCA2" refers to spinocerebellar ataxia type 2, which is associated with a CAG repeat expansion in ATXN2. See "Spinocerebellar ataxia." SCA3: As used herein, "SCA3" refers to spinocerebellar ataxia type 3, which is associated with a CAG repeat expansion in ATXN3. See "Spinocerebellar ataxias." SCN1A: As used herein, the term "SCN1A" refers to the gene encoding the sodium voltage-gated channel alpha subunit 1 (also known as DEE6, DEE6A, DEE6B, DRVT, EIEE6, FEB3, FEB3A, FHM3, GEFSP2, HBSCI, NAC1, Nav1.1, SCN1, and SMEI). The sodium voltage-gated channel alpha subunit 1 is a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN1A can be a human gene (Gene ID: 6323), a non-human primate gene (e.g., Gene ID: 704086), or a rodent gene (e.g., Gene ID: 20265, Gene ID: 81574). In humans, mutations in the SCN1A gene (e.g., loss-of-function mutations in SCN1A) are associated with epilepsy and seizures and are accompanied by Dravet syndrome (severe myoclonic epilepsy of infancy (SEMI)). Gain-of-function mutations in SCN1A are associated with other neurological disorders such as familial hemiplegic migraine, epileptic encephalopathy, and joint contractures. See, for example, Brunklaus, et al. “The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications” Brain 145(11): 3816-3831 (2022); and Ding, et al. “SCN1A Mutation-Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis” Front Neurol. 12: 743726 (2021). The most common mutations in the SCN1A gene include Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, and Asp1866Tyr. Mutations in SCN1A typically result in reduced function of the encoded protein or no protein expression. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_006920.6 and NM_001165963.4). In some embodiments, SCN1A or its mutant form is associated with pain disorders. SCN2A: The term "SCN2A" as used herein refers to the gene encoding the sodium voltage-gated channel alpha subunit 2 (also known as BFIC3, BFIS3, BFNIS, DEE11, EA9, EIEE11, HBA, HBSCI, HBSCII, NAC2, Nav1.2, SCN2A1, and SCN2A2), The sodium voltage-gated channel alpha subunit 2 is a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN2A can be a human gene (Gene ID: 6326), a non-human primate gene (e.g., Gene ID: 703298), or a rodent gene (e.g., Gene ID: 110876, Gene ID: 24766). In humans, mutations in the SCN2A gene (e.g., gain-of-function mutations in SCN2A) are associated with epilepsy and epileptic seizures. Loss-of-function mutations in SCN2A are associated with other neurological disorders including autism spectrum disorders (with or without epilepsy). See, for example, Zeng, et al. "SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis" Front Mol Neurosci. 15: 809951 (2022) doi: 10.3389 / fnmo1.2022.809951. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_021007.3 and NM_001040142.2).In some embodiments, SCN2A or a mutant form thereof is associated with a pain disorder. SCN8A: The term "SCN8A" as used herein refers to a gene encoding sodium voltage-gated channel alpha subunit 8 (also known as BFIS5, CERIII, CIAT, DEE13, EIEE13, MED, MYOCL2, NaCh6, Nav1.6, and PN4), which is a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN8A can be a human gene (Gene ID: 6334), a non-human primate gene (e.g., Gene ID: 695972), or a rodent gene (e.g., Gene ID: 20273, Gene ID: 29710). In humans, mutations in the SCN8A gene (e.g., gain-of-function mutations in SCN8A) are associated with epilepsy and seizures. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_0 14191.4 and NM_001330260.2). In some embodiments, SCN8A or a mutant form thereof is associated with a pain disorder. SCN9A: The term "SCN9A" as used herein refers to a gene encoding sodium voltage-gated channel alpha subunit 9 (also known as ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA, Nav1.7, PN1, and SFNP), which is a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN9A can be a human gene (Gene ID: 6335), a non-human primate gene (e.g., Gene ID: 574119), or a rodent gene (e.g., Gene ID: 20274, Gene ID: 78956). In humans, mutations in the SCN9A gene are associated with a variety of pain disorders. In some embodiments, mutations in SCN9A are associated with small fiber neuropathy and nociceptive-related phenotypes. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_002977.3 and NM_001365536.1). SGCE: As used herein, SGCE refers to the gene encoding sarcoglycan ε (also known as ESG; DYT11; e-SG), which is a member of the sarcoglycan family. Sarcoglycans are transmembrane proteins that are components of the dystrophin-glycoprotein complex, connecting the actin cytoskeleton to the extracellular matrix. Unlike other family members that are primarily expressed in striated muscle, ε sarcoglycan is more widely expressed. In some embodiments, SGCE can be a human gene (Gene ID: 8910), a non-human primate gene (e.g., Gene ID: 101865326), or a rodent gene (e.g., Gene ID: 20392, Gene ID: 432360). In humans, mutations in the gene encoding SGCE are associated with the development of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_003919.3; NM_001099400.2; NM_001099401.2; NM_001301139.2; NM_001346713.2; NM_001346715.2; NM_001346717.2; NM_001346719.2; NM_0()1346720.2; NM_001362807.2; NM_()01362808.2; and NM_001362809.2). SLC2A1: As used herein, SLC2A1 refers to the gene encoding solute carrier family 2 member 1 (also known as CSE; PED; DYT9; GLUT; DYT17; DYT18; EIG12; GLUT1; HTLVR; GLUT-1; SDCHCN; GLUTlDS), The solute carrier family 2 member 1 is the major glucose transporter in the mammalian blood-brain barrier. In some embodiments, SLC2A1 can be a human gene (Gene ID: 6513), a non-human primate gene (e.g., Gene ID: 102144217), or a rodent gene (e.g., Gene ID: 20525, Gene ID: 24778). In humans, mutations in the gene encoding SLC2A1 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with GenBank RefSeq accession number: NM_006516.4). SMN: As used herein, SMN refers to the gene encoding survival motor neuron protein. Survival motor neuron protein participates in transcriptional splicing by participating in the assembly of ribonucleoproteins that bind to pre-mRNA to form the spliceosome. Deficiency in survival motor neuron protein activity leads to widespread splicing defects (especially in spinal motor neurons) and degeneration of lower spinal motor neurons. Survival motor neuron protein is encoded by the genes SMN1 and SMN2, mutations in each of which are associated with spinal muscular atrophy, and both may be referred to as "SMN." Molecular payloads that can be used to modulate SMN1 can also be used to modulate SMN2, and vice versa, and can be used to treat CNS diseases and disorders. SNCA: As used herein, SNCA refers to the gene encoding α-synuclein. α-Synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release and is abundant in the brain. SNCA is primarily expressed in neural tissue (e.g., neurons) but can also be found in glial cells. α-Synuclein is primarily present in presynaptic terminals in two forms: free and membrane-bound, with approximately 15% of the protein in neurons being membrane-bound at a given time. Alternative splicing of the SNCA transcript results in the production of at least three α-synuclein isoforms. In pathological conditions characterized by the presence of Lewy bodies, including Parkinson's disease, α-synuclein aggregates to form insoluble fibrils. These pathological conditions are known as synucleinopathies. The mechanism of α-synuclein aggregation is uncertain. Several mutations in SNCA are associated with Parkinson's disease, including mutations that result in α-synuclein with the following amino acid substitutions: A53T, A30P, E46K, H50Q, G51D, A18T, A29S, A53E, A53V, E57A, V15A, T72M, L8I, V15D, M127I, P117S, M5T, G93A, E83Q, and A30G. Alpha-synuclein has been shown to interact with the dopamine transporter, parkin (ligase), phospholipase D1, SNCAIP, tau protein, and amyloid-β. SOD1: The term "SOD1" refers to superoxide dismutase 1 and the gene that encodes it. SOD1 is an enzyme associated with apoptosis, amyotrophic lateral sclerosis, and Parkinson's disease. The SOD1 protein is a 32 kDa homodimer containing a binuclear Cu / Zn site in each subunit. The Cu / Zn site is responsible for destroying free superoxide radicals in the body by catalyzing the dismutation of superoxide to hydrogen peroxide and molecular oxygen. Wild-type SOD1 protein has been shown to have anti-apoptotic properties in neural cultures, while mutant SOD1 proteins have been shown to promote apoptosis in neural cells. Mutations in the SOD1 gene are associated with familial ALS, but wild-type SOD1 is also associated with the majority of sporadic ALS cases, representing 90% of ALS patients. The most common SOD1 mutations are A4V, H46R, and G93S. Virtually all known ALS-associated SOD1 mutations act in a dominant manner, making a single mutant copy of the SOD1 gene sufficient to cause disease. The precise mechanism by which mutations in SOD1 cause ALS is unknown, but some evidence suggests that it is the result of a toxic gain of function, as many disease-associated SOD1 mutations, including A4V and G93A, retain enzymatic activity and Sod1-deficient mice do not develop ALS. The DNA oxidation product 8-OHdG, a well-established marker of oxidative DNA damage, accumulates in the mitochondria of motor neurons in ALS patients, suggesting that oxidative damage to motor neuron DNA (e.g., mitochondrial DNA) caused by mutant SOD1 may contribute significantly to the etiology of ALS. Specific binding: As used herein, the term "specific binding" refers to the ability of a molecule to bind to a binding partner with a degree of affinity or avidity that enables the molecule to be used to distinguish the binding partner from a suitable control in a binding assay or other binding context. With respect to antibodies, the term "specific binding" refers to the ability of an antibody to bind to a specific antigen with a degree of affinity or avidity compared to an appropriate reference antigen or antigens that enables the antibody to be used to distinguish the specific antigen from other antigens, e.g., to a degree that allows for preferential targeting of certain cells (e.g., CNS cells) by binding to an antigen as described herein. In some embodiments, an antibody may be present if it has at least about 10 -4 M, 10 -5 M, 10 -6M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 K of binding to target is M or less D , the antibody specifically binds to the target. In some embodiments, the antibody specifically binds to the transferrin receptor (e.g., an epitope of the apical domain of the transferrin receptor). Spinocerebellar ataxia: The term "spinocerebellar ataxia" or "SCA" as used herein refers to a class of CNS disorders characterized by coordination problems, usually due to effects on the cerebellum and spinal cord (also known as "autosomal dominant cerebellar ataxia"). SCA is typically characterized by a slowly progressive disorder of coordinated movement in gait and is often associated with poor coordination of the hands, speech, and eye movements. SCA is a progressive neurodegenerative disorder that is inherited in an autosomal dominant pattern. There are more than 40 types of SCA, each with similar causes and symptoms. The most common form of SCA is SCA3, also known as Machado-Joseph disease. Most genetic mutations associated with SCA result in significant damage to the Purkinje neurons of the cerebellum with continuous cerebellar atrophy. In addition, other parts of the CNS, such as the spinal cord, basal ganglia, and pontine nuclei in the brainstem, may be involved. See, e.g., Klockgether, et al. "Spinocerebellar ataxia" Nat Rev Dis Primers 5:24 (2019) doi:10.1038 / s41572-019-0074-3; and Bhandari, et al. "Spinocerebellar Ataxia." [Updated 2022 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; available at ncbi.nlm.nih.gov / books / NBK557816 / . Of particular relevance to the present disclosure are SCAs associated with MSH3 and SCA1, SCA2, and SCA3. Many forms of SCA are associated with expansions of trinucleotide repeats within the ataxia protein (ATXN) gene. SCA1 is associated with a CAG repeat expansion in ATXN1, SCA2 is associated with a CAG repeat expansion in ATXN2, and SCA3 is associated with a CAG repeat expansion in ATXN3. Currently, there is no treatment available for SCA; therefore, clinical intervention focuses primarily on symptom management through physical therapy, occupational therapy, and speech therapy. SPR: As used herein, SPR refers to the gene encoding septopterin reductase (also known as SDR3 8C 1), which is an aldehyde-ketone reductase that catalyzes the NADPH-dependent reduction of pteridine derivatives. SPR is important in the biosynthesis of tetrahydrobiopterin (BH4). Due to septopterin reductase deficiency, mutations in this gene lead to DOPA-responsive dystonia. In some embodiments, SPR can be a human gene (Gene ID: 6697), a non-human primate gene (e.g., Gene ID: 102128831), or a rodent gene (e.g., Gene ID: 20751, Gene ID: 29270). In humans, mutations in the gene encoding SPR are associated with the occurrence of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with GenBank RefSeq accession number: NM_003124.5). Subject: As used herein, the term "subject" refers to a mammal. In some embodiments, the subject is a non-human primate or rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient, such as a human patient having or suspected of having a disease. In some embodiments, the subject is a human patient having or suspected of having a CNS disease or condition. In some embodiments, the subject is a human patient having one or more symptoms associated with a CNS disease or condition, such as one or more symptoms disclosed herein. SYF2: SYF2 as used herein refers to a gene encoding the pre-mRNA splicing factor SYF2 (also known as P29; CBPIN; NTC31; fSAP29), which is primarily located in the nucleus. In some embodiments, SYF2 can be a human gene (Gene ID: 25949), a non-human primate gene (e.g., Gene ID: 102139055), or a rodent gene (e.g., Gene ID: 68592, Gene ID: 170933). SYF2 and mutations therein are associated with ALS and frontotemporal dementia (FTD). Multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_207170.4; NM_015484.5). TAF1: TAF1 as used herein refers to the gene encoding TATA box binding protein-associated factor 1 (also known as OF; XDP; BA2R; CCG1; CCGS; DYT3; KAT4; P250; NSCL2; TAF2A; MRXS33; N-TAF1; TAFII250; DYT3 / TAF1; TAFII-250; TAF(II)250), the TATA box binding protein-associated factor 1 is a member of a group of evolutionarily conserved proteins known as TBP-associated factors. TAF1 encodes the largest subunit of the basal transcription factor TFIID, which binds to the core promoter sequence containing the transcription start site and also binds to activators and other transcriptional regulators. In some embodiments, TAF1 can be a human gene (Gene ID: 6872), a non-human primate gene (e.g., Gene ID: 102118965), or a rodent gene (e.g., Gene ID: 270627, Gene ID: 317256). In humans, mutations in the gene encoding TAF1 are associated with the development of hereditary dystonia. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_004606.5; NM_138923.4; NM_001286074.2; NR_104387.2; NR_104388.2; NR_104389.2; NR_104390.2; NR_104391.2; NR_10439 2.2; NR_104393.2; NR_104394.2; NR_104395.2; NR_104396.2; XM_005262300.3; 2.1; ;XM_047442400.1; Tay-Sachs: As used herein, the term "Tay-Sachs" refers to a genetic disorder characterized by the destruction of nerve cells in the central nervous system. Tay-Sachs is also known as GM2 gangliosidosis. Tay-Sachs is associated with mutations in the enzyme hexosaminidase A (HEXA), which leads to the accumulation of GM2 ganglioside in lysosomes and nerve cells. Tay-Sachs primarily affects young children (infantile form) but can occur during adolescence (juvenile form) and in adulthood. Tay-Sachs is characterized by neurodegeneration, and its symptoms include: slowed development, progressive loss of mental abilities, dementia, blindness, increased startle reflex to noise, progressive loss of hearing, swallowing problems, seizures, cherry-red spots in the eyes, muscle weakness, and ataxia. Conventional treatment for Tay-Sachs focuses on relieving symptoms and delaying progression. In some embodiments, the subject in need of treatment for Tay-Sachs has a mutation in the HEXA gene. In some embodiments, the subject in need of treatment for Tay-Sachs suffers from neurodegeneration. In some embodiments, the subject in need of treatment for Tay-Sachs has one or more of the following symptoms: developmental delay, progressive loss of mental abilities, dementia, blindness, increased startle reflex to noise, progressive loss of hearing, swallowing problems, seizures, cherry-red spots in the eyes, muscle weakness, and ataxia. Tay-Sachs is very similar to Sandhoff disease; therefore, treatments for Sandhoff disease may also be effective in treating Tay-Sachs (and vice versa). Tay-Sachs is also closely related to GM1 gangliosidosis, and therefore, treatments for GM1 gangliosidosis may be effective in treating Tay-Sachs (and vice versa). TH: TH as used herein refers to the gene encoding tyrosine hydroxylase (also known as TYH; DYT14; DYT5b), which is a protein involved in the conversion of tyrosine to dopamine. Tyrosine hydroxylase protein is the rate-limiting enzyme in the synthesis of catecholamines and thus plays a key role in the physiology of adrenergic neurons. In some embodiments, TH can be a human gene (Gene ID: 7054), a non-human primate gene (e.g., Gene ID: 102134074), or a rodent gene (e.g., Gene ID: 21823, Gene ID: 25085). In humans, mutations in the gene encoding TH are associated with the occurrence of hereditary dystonia. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000360.4; NM_199292.3; NM_199293.3; and XM_011520335.3). THAP1: THAP1 as used herein refers to a gene encoding THAP domain-containing 1 (also known as DYT6), which is a protein containing a THAP domain (conserved DNA binding domain). This protein co-localizes with the apoptosis response protein PAWR / PAR-4 in promyelocytic leukemia (PML) nuclear bodies and acts as a pro-apoptotic factor, connecting PAWR to PML nuclear bodies. In some embodiments, THAP1 can be a human gene (Gene ID: 55145), a non-human primate gene (e.g., Gene ID: 101926823), or a rodent gene (e.g., Gene ID: 73754, Gene ID: 306547). In humans, mutations in the gene encoding THAP1 are associated with the occurrence of hereditary dystonia. Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (eg, as annotated with the following GenBank RefSeq accession numbers: NM_018105.3 and NM_199003.2). TOR1A: TOR1A as used herein refers to a gene encoding torsin family 1 member A (also known as DQ2; AMC5; DYT1), which is a member of the AAA family of adenosine triphosphatases (ATPases). In some embodiments, TOR1A can be a human gene (Gene ID: 1861), a non-human primate gene (e.g., Gene ID: 102124758), or a rodent gene (e.g., Gene ID: 30931, Gene ID: 266606). In humans, mutations in the gene encoding TOR1A are associated with the occurrence of hereditary dystonia. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with GenBank RefSeq accession number: NM_000113.3). TPP1: "TPP1" as used herein refers to the gene encoding tripeptidyl peptidase 1 (also known as GIG1, LPIC, SCAR7 and CLN2). Tripeptidyl peptidase 1 is associated with CLN2 Batten disease. Wild-type tripeptidyl peptidase 1 mediates the cleavage of N-terminal tripeptides from substrates. In CLN2 Batten disease, mutations in tripeptidyl peptidase 1 severely reduce its enzymatic activity, leading to incomplete breakdown and subsequent accumulation of proteins in lysosomes. The most common tripeptidyl peptidase 1 mutation is a single amino acid change. The inheritance of CLN2 Batten disease is autosomal recessive. In some embodiments, CLN2 can be a human gene (Gene ID: 1200), a non-human primate gene (Gene ID: 709838) or a rodent gene (Gene ID: 12751; Gene ID: 83534). Transferrin receptor: The term "transferrin receptor" as used herein (also referred to as TFRC, CD71, p90, TFR or TFR1) refers to an internalized cell surface receptor that binds transferrin to promote iron uptake by endocytosis. In some embodiments, the transferrin receptor can be of human origin (NCBI Gene ID 7037), non-human primate origin (e.g., NCBI Gene ID 711568 or NCBI Gene ID 102136007), or rodent origin (e.g., NCBI Gene ID 22042). In addition, a variety of human transcript variants encoding different receptor isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1). TREM2: TREM2 as used herein refers to a gene encoding triggering receptor 2 expressed on myeloid cells (also known as PLOSL2, Trem2a, Trem2b, and Trem2c), which is a protein involved in inflammation, synaptic pruning, and neuronal cell survival. In the brain, TREM2 is expressed in microglia. In some embodiments, TREM2 can be a human gene (Gene ID: 54209), a non-human primate gene (e.g., Gene ID: 719740), or a rodent gene (e.g., Gene ID: 83433, Gene ID: 301227). In humans, mutations in the TREM2 gene are associated with the occurrence of Alzheimer's disease. In some embodiments, mutations in TREM2 are associated with an increased risk of Alzheimer's disease. Genetic variants of TREM2 are associated with an increased risk of multiple neurodegenerative diseases, including frontotemporal dementia and Alzheimer's disease. See, e.g., Carmona, et al. "The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders" Lancet Neurology 17(8): 721-730 (2018). In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_018965.4 and NM_001271821.2). UBE3A: The term "UBE3A" as used herein refers to the gene encoding the ubiquitin protein ligase E3A (also known as E6AP, ANCR, AS, EPVE6AP, HPVE6A, and PIX1), which is a protein associated with ubiquitination and proteolysis. In some embodiments, UBE3A can be a human gene (Gene ID: 7337), a non-human primate gene (e.g., Gene ID: 711270), or a rodent gene (e.g., Gene ID: 22215, Gene ID: 361585). In humans, mutations in the UBE3A gene are associated with Angelman syndrome and autism spectrum disorder. In addition, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_130838.4, NM_000462.5, and NM_130839.5). UNC13A: The term "UNC13A" as used herein refers to a gene encoding Unc-13 homolog A (also known as Munc13-1 and unc-13 homolog A (C. elegans)), which is a member of the UNC13 family of proteins involved in calcium-triggered synaptic vesicle release (see, e.g., J.S. Dittman "Unc13: a multifunctional synaptic marvel" Curr Opin Neurobiol. 57: 17-25 (2019)). In some embodiments, UNC13A can be a human gene (Gene ID: 23025), a non-human primate gene (e.g., Gene ID: 720000, Gene ID: 102123626), or a rodent gene (e.g., Gene ID: 382018, Gene ID: 64829). Additionally, multiple human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_001080421.3, NM_001387021.1, NM_001387022.1, NM_001387023.1, XM_011527810.3, XM_01 1527811.3, XM_017026502.2, XM_054320277.1, XM_054320278.1, and UNC13A contains cryptic exons that promote nonsense-mediated decay. Certain single nucleotide polymorphisms in UNC13A are associated with an increased risk of cryptic exon inclusion in UNC13A transcripts. Such polymorphisms in UNC13A are associated with neurodegenerative diseases such as ALS and frontotemporal dementia (see, e.g., Brown, et al. "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A" Nature 603: 131-137 (2022); and Ma, et al. "TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC 13A" Nature 603: 124-130 (2022)). VLA-4: As used herein, the term "VLA-4" refers to the gene encoding late-appearing antigen 4 (also known as ITGA4, CD49D, and IA4). The late-appearing antigen 4 is a protein involved in cell adhesion and signal transduction. In some embodiments, VLA-4 can be a human gene (Gene ID: 3676), a non-human primate gene (e.g., Gene ID: 704745), or a rodent gene (e.g., Gene ID: 16401, Gene ID: 311144). In humans, mutations in the VLA-4 gene are associated with retinitis pigmentosa 26, isolated macular dystrophy, and multiple sclerosis. In addition, a variety of human transcript variants encoding different protein isoforms have been characterized (e.g., as annotated with the following GenBank RefSeq accession numbers: NM_000885.6 and NM_001316312.2). 2'-modified nucleosides: As used herein, the terms "2'-modified nucleosides" and "2'-modified ribonucleosides" are used interchangeably and refer to nucleosides having a modified sugar moiety at the 2' position. In some embodiments, the 2'-modified nucleoside is a 2'-4' bicyclic nucleoside, wherein the 2' and 4' positions of the sugar are bridged (e.g., through a methylene, ethylene, or (S)-constrained ethyl bridge). In some embodiments, the 2'-modified nucleoside is a non-bicyclic 2'-modified nucleoside, e.g., wherein the 2' position of the sugar moiety is substituted. Some non-limiting examples of 2'-modified nucleosides include: 2'-deoxy, 2'-fluoro (2'-F), 2'-O-methyl (2'-O-Me), 2'-O-methoxyethyl (2'-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), 2'-O-N-methylacetamido (2'-O-NMA), locked nucleic acid (LNA, methylene-bridged nucleic acid), ethylene-bridged nucleic acid (ENA), and (S)-constrained ethyl-bridged nucleic acid (cEt). In some embodiments, the 2'-modified nucleosides described herein are high-affinity modified nucleosides and oligonucleotides comprising 2'-modified nucleosides that have increased affinity for the target sequence relative to unmodified oligonucleotides. Some examples of the structures of 2'-modified nucleosides are provided below: These examples are shown with phosphate groups, but any internucleoside linkage is contemplated between 2'-modified nucleosides. II. Complex Provided herein are complexes comprising a targeting agent (e.g., an antibody) covalently linked to a molecular payload. In some embodiments, the complex comprises a central nervous system (CNS) targeting antibody covalently linked to an oligonucleotide. The complex can comprise an antibody that specifically binds to a single antigenic site or to at least two antigenic sites that may be present on the same or different antigens. The complex can be used to modulate the activity or function of at least one gene, protein, and / or (e.g., and) nucleic acid in a CNS cell, or to alleviate the symptoms of a CNS disease condition. In some embodiments, the molecular payload present in the complex is responsible for the regulation of the gene, protein, and / or (e.g., and) nucleic acid. The molecular payload can be a small molecule, protein, nucleic acid, oligonucleotide, or any molecular entity that can modulate the activity or function of a gene, protein, and / or (e.g., and) nucleic acid in a cell. In some embodiments, the CNS targeting agent of the complex described herein comprises an anti-transferrin receptor 1 (TfR1) antibody covalently linked to a molecular cargo, such as an oligonucleotide, polypeptide, small molecule, or gene therapy cargo. Antibody In some embodiments, the complexes described herein comprise an antibody that binds to human transferrin receptor 1 (TfR1). An exemplary human TfR1 amino acid sequence corresponding to NCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens) is as follows: Table 2 provides some examples of anti-TfR1 antibody sequences that can be used in the complexes provided herein. Table 2. Some examples of anti-TfR1 antibody sequences In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain complementary determining region 1 (CDR-H1) of SEQ ID NO: 1 (according to the IMGT definition system), a heavy chain complementary determining region 2 (CDR-H2) of SEQ ID NO: 2 (according to the IMGT definition system), a heavy chain complementary determining region 3 (CDR-H3) of SEQ ID NO: 3 (according to the IMGT definition system), a light chain complementary determining region 1 (CDR-L1) of SEQ ID NO: 4 (according to the IMGT definition system), a light chain complementary determining region 2 (CDR-L2) of SEQ ID NO: 5 (according to the IMGT definition system) and a light chain complementary determining region 3 (CDR-L3) of SEQ ID NO: 6 (according to the IMGT definition system). In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain complementary determining region 1 (CDR-H1) of SEQ ID NO:7 (according to the Kabat definition system), a heavy chain complementary determining region 2 (CDR-H2) of SEQ ID NO:8 (according to the Kabat definition system), a heavy chain complementary determining region 3 (CDR-H3) of SEQ ID NO:9 (according to the Kabat definition system), a light chain complementary determining region 1 (CDR-L1) of SEQ ID NO:10 (according to the Kabat definition system), a light chain complementary determining region 2 (CDR-L2) of SEQ ID NO:11 (according to the Kabat definition system) and a light chain complementary determining region 3 (CDR-L3) of SEQ ID NO:6 (according to the Kabat definition system). In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain complementary determining region 1 (CDR-H1) of SEQ ID NO: 12 (according to the Chothia definition system), a heavy chain complementary determining region 2 (CDR-H2) of SEQ ID NO: 13 (according to the Chothia definition system), a heavy chain complementary determining region 3 (CDR-H3) of SEQ ID NO: 14 (according to the Chothia definition system), a light chain complementary determining region 1 (CDR-L1) of SEQ ID NO: 15 (according to the Chothia definition system), a light chain complementary determining region 2 (CDR-L2) of SEQ ID NO: 5 (according to the Chothia definition system) and a light chain complementary determining region 3 (CDR-L3) of SEQ ID NO: 16 (according to the Chothia definition system). In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain variable region (VH), which comprises no more than 25 amino acid variations in the framework region (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid variations) compared to the VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or in addition (e.g., supplementally), the anti-TfR1 antibody of the present disclosure comprises a light chain variable region (VL), which comprises no more than 25 amino acid variations in the framework region (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid variations) compared to the VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TfR1 antibody of the present disclosure comprises a VH comprising in the framework region an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or additionally (e.g., supplementally), in some embodiments, an anti-TfR1 antibody of the present disclosure comprises a VL comprising in the framework region an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or additionally (e.g., supplementally), in some embodiments, an anti-TfR1 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO:18. In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98% or 99%) identical to the amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (e.g., supplementally), the anti-TfR1 antibody of the present disclosure comprises a light chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98% or 99%) identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-TfR1 antibody of the present disclosure is a Fab comprising a heavy chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98% or 99%) identical to the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally (e.g., supplementally), the anti-TfR1 antibody of the present disclosure is a Fab comprising a light chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98% or 99%) identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (e.g., supplement), the anti-TfR1 antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-TfR1 antibody of the present disclosure is a Fab comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (e.g., supplement), the anti-TfR1 antibody of the present disclosure is a Fab comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-TfR1 antibodies provided herein may have one or more post-translational modifications. In some embodiments, N-terminal cyclization, also known as pyroglutamate (pyro-Glu) formation, may occur at the N-terminal glutamic acid (Glu) and / or glutamine (Gln) residues of the antibody during production. Therefore, it should be understood that antibodies designated as having a sequence comprising an N-terminal glutamic acid or glutamine residue encompass antibodies that have undergone pyroglutamate formation caused by post-translational modification. In some embodiments, pyroglutamate formation occurs in the heavy chain sequence. In some embodiments, pyroglutamate formation occurs in the light chain sequence. Molecular payload Some aspects of the present disclosure provide molecular payloads, e.g., for modulating biological outcomes, e.g., transcription of a DNA sequence, processing of a pre-mRNA transcript, stability of a pre-mRNA or mRNA transcript, expression of a protein (e.g., translation of an mRNA), or activity of a protein, which can be linked to an anti-TfR1 antibody described herein (e.g., an anti-TfR1 antibody in Table 2). In some embodiments, such molecular payloads are targeted to CNS cells, e.g., by specifically binding to a nucleic acid or protein in or on a CNS cell after delivery to the CNS cell via the linked anti-TfR1 antibody. It should be understood that various types of molecular payloads can be used in accordance with the present disclosure. For example, a molecular payload can comprise or consist of an oligonucleotide (e.g., an antisense oligonucleotide or an RNA interference oligonucleotide), a polypeptide (e.g., a peptide, a protein, or an antibody that binds to a nucleic acid or protein in a CNS cell), a small molecule (e.g., a small molecule that modulates the function of a nucleic acid or protein in a CNS cell), or a gene therapy payload (e.g., a nucleic acid encoding a polypeptide having biological activity in a CNS cell). In some embodiments, the molecular cargo is an oligonucleotide comprising a strand having a complementary region to a gene (eg, a gene transcript) provided in Table 3. Table 3. List of central nervous system diseases and corresponding genes. In some embodiments, the molecular cargo is an oligonucleotide comprising a strand having a complementary region to a gene (eg, a gene transcript) provided in Table 4. Table 4. List of central nervous system diseases and corresponding genes. Oligonucleotide loading In some embodiments, oligonucleotides can be used to treat a variety of CNS diseases and disorders.For example, oligonucleotides can be used to regulate the expression or activity of a variety of genes involved in CNS diseases and disorders, such as by regulating the transcription of genes, regulating the stability of mRNA molecules encoded by genes, regulating the translation of mRNA molecules encoded by genes, and regulating the splicing of precursor mRNA transcripts encoded by genes. Oligonucleotides can be used to treat a variety of CNS diseases and disorders, for example, by promoting oligonucleotide delivery to cells in CNS. In some embodiments, oligonucleotides disclosed herein can be delivered to cells in CNS using complexes disclosed herein (for example, anti-TfR1 antibody complexes comprising the oligonucleotides). In some embodiments, the oligonucleotides can be used to treat a neuromuscular disease or disorder (e.g., Duchenne muscular dystrophy, myotonic dystrophy, Friedreich's ataxia, or spinal muscular atrophy); amyotrophic lateral sclerosis; Parkinson's disease; Huntington's disease; Alzheimer's disease; epilepsy; pain disorders; glycogen synthesis disorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman syndrome; autism spectrum disorder; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis. In some embodiments, oligonucleotides can be used to treat essential tremor and / or hereditary dystonia. In some embodiments, the oligonucleotides can be used to modulate one or more genes associated with a CNS disease or condition. In some embodiments, the one or more genes associated with a CNS disease or condition are DMPK, DMD, SMN, FXN, SOD1, C9orf72, ATXN2, FUS, LRRK2, SNCA, HTT, MSH3, TREM2, APOE, MAPT, APP, GYS1, PrP, VLA-4, GFAP, UBE3A, LSD, SCN9A, SCN1A, SCN2A, SCN8A, CLN3, GRIA1, or PCDH19. In some embodiments, the one or more genes associated with a CNS disease or disorder are TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, or ECHS1. In some embodiments, the one or more genes associated with a CNS disease or disorder is PIKFYVE, SYF2, UNC13A, ATXN1, ATXN3, GRN, GRIN2A, TPP1, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, or MECP2. In some embodiments, the 5' or 3' nucleoside (e.g., terminal nucleoside) of any one of the oligonucleotides described herein is optionally conjugated to an amine group via a spacer. In some embodiments, the spacer comprises an aliphatic moiety. In some embodiments, the spacer comprises a polyethylene glycol moiety. In some embodiments, there is a phosphodiester linkage between the spacer and the 5' or 3' nucleoside of the oligonucleotide. In some embodiments, the 5' or 3' nucleoside (e.g., terminal nucleoside) of any one of the oligonucleotides described herein is conjugated to a spacer, wherein the spacer is a substituted or unsubstituted aliphatic, a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, -O-,-N(R A )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -,-NR A C(=O)-,-NR A C(=O)R A -,-C(=O)R A -,-NR A C(=O)O-,-NR A C(=O)N(R A)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-,-S(O)2NR A -,-NR A S(O)2-, or a combination thereof; each RA is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, the spacer is substituted or unsubstituted alkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, -O-, -N(R A )-, or -C(=O)N(R A )2, or a combination thereof. In some embodiments, the 5' or 3' nucleoside of any of the oligonucleotides described herein is in the form of -NH2-(CH2) n -, wherein n is an integer from 1 to 12. In some embodiments, n is 6, 7, 8, 9, 10, 11 or 12. In some embodiments, in the formula NH2-(CH2) n - A phosphodiester linkage exists between the compound and the 5' or 3' nucleoside of the oligonucleotide. In some embodiments, the compound of formula NH2-(CH2)6- is conjugated to the oligonucleotide via a reaction between 6-amino-1-hexanol (NH2-(CH2)6-OH) and the 5' phosphate of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to a targeting agent, eg, a CNS targeting agent such as an anti-TfRl antibody, eg, via an amine group. a. Oligonucleotide size / sequence Oligonucleotides can have a variety of different lengths, for example, depending on the format. In some embodiments, the length of the oligonucleotide is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75 or more nucleotides. In some embodiments, the oligonucleotide is 8 to 50 nucleotides in length, 8 to 40 nucleotides in length, 8 to 30 nucleotides in length, 10 to 15 nucleotides in length, 10 to 20 nucleotides in length, 15 to 25 nucleotides in length, 21 to 23 nucleotides in length, 20 to 25 nucleotides in length, etc. In some embodiments, the nucleic acid sequence of an oligonucleotide used for the purposes of the present disclosure is "complementary" to a target nucleic acid when it can specifically hybridize to the target nucleic acid. In some embodiments, an oligonucleotide that hybridizes to a target nucleic acid (e.g., provided in Table 3, e.g., a transcript provided by any one of SEQ ID NOs: 392 to 702) results in modulation of the activity or expression of the target (e.g., decreased mRNA translation, altered pre-mRNA splicing, exon skipping, target mRNA degradation, etc.). In some embodiments, an oligonucleotide that hybridizes to a target nucleic acid (e.g., provided in Table 4, e.g., a transcript provided by any one of SEQ ID NOs: 705 to 803) results in modulation of the activity or expression of the target (e.g., decreased mRNA translation, altered pre-mRNA splicing, exon skipping, target mRNA degradation, etc.). In some embodiments, an oligonucleotide that hybridizes to a target nucleic acid (e.g., provided in Table 3 or Table 4, e.g., a transcript provided by any one of SEQ ID NOs: 143 to 148, 167 to 169, 810 to 875, and 1059 to 1068) results in modulation of the activity or expression of the target (e.g., decreased mRNA translation, altered pre-mRNA splicing, exon skipping, target mRNA degradation, etc.). In some embodiments, an oligonucleotide that hybridizes to a target nucleic acid results in increased activity or expression of the target (e.g., increased mRNA translation, e.g., increased mRNA translation of a wild-type form of an mRNA; altered pre-mRNA splicing; exon skipping; target mRNA stabilization, etc.). In some embodiments, the nucleic acid sequence of the oligonucleotide has a sufficient degree of complementarity to its target nucleic acid such that it does not hybridize to non-target sequences under conditions where it is desirable to avoid non-specific binding, e.g., under physiological conditions. Therefore, in some embodiments, oligonucleotide can be complementary to the continuous nucleotides of target nucleic acid at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%. In some embodiments, complementary nucleotide sequence does not need to be 100% complementary to the nucleotide sequence targeted thereto to specifically hybridize with target nucleic acid or have specificity to target nucleic acid. In certain embodiments, oligonucleotide comprises one or more core bases relative to target nucleic acid mispairing. In certain embodiments, the activity associated with the target is reduced due to such mispairing, but the activity associated with non-target is reduced with a larger amount (that is, the selectivity of target nucleic acid is improved and the off-target effect is reduced). In some embodiments, the oligonucleotide comprises a complementary region to the target nucleic acid that is 8 to 15, 8 to 30, 8 to 40, or 10 to 50, or 5 to 50, 15 to 20, 20 to 25, or 5 to 40 nucleotides in length. In some embodiments, the complementary region to the target nucleic acid of the oligonucleotide is 8 to 15, 8 to 30, 8 to 40, or 10 to 50, or 5 to 50, 15 to 20, 20 to 25, or 5 to 40 nucleotides in length. 47, 48, 49, or 50 nucleotides. In some embodiments, the complementary region is complementary to at least 8 continuous nucleotides of the target nucleic acid. In some embodiments, the oligonucleotide can comprise 1, 2, or 3 base mispairings compared to the portion of continuous nucleotides of the target nucleic acid. In some embodiments, the oligonucleotide can have up to 3 mispairings on 15 bases, or up to 2 mispairings on 10 bases. In some embodiments, the oligonucleotide is complementary (e.g., at least 85%, at least 90%, at least 95%, or 100% complementary) to the target sequence of any one of the oligonucleotides described herein (e.g., the oligonucleotides listed in Tables 5 to 19). In some embodiments, the oligonucleotide is complementary (e.g., at least 85%, at least 90%, at least 95%, or 100% complementary) to the target sequence provided herein (e.g., listed in Table 3, e.g., the transcript provided by any one of SEQ ID NOs: 392 to 702). In some embodiments, the oligonucleotide is complementary (e.g., at least 85%, at least 90%, at least 95%, or 100% complementary) to the target sequence provided herein (e.g., listed in Table 4, e.g., the transcript provided by any one of SEQ ID NOs: 705 to 803). In some embodiments, the oligonucleotide is complementary (e.g., at least 85%, at least 90%, at least 95%, or 100% complementary) to a target sequence provided herein (e.g., listed in Table 3 or Table 4, e.g., a transcript provided by any one of SEQ ID NOs: 143 to 148, 167 to 169, 810 to 875, and 1059 to 1068). In some embodiments, oligonucleotides useful for targeting the transcripts provided herein comprise a sequence comprising at least 8 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more) consecutive nucleobases of an oligonucleotide sequence provided herein (e.g., an oligonucleotide sequence listed in any one of Tables 5 to 19). In some embodiments, oligonucleotides useful for targeting the transcripts provided herein comprise a sequence comprising a complementary region of at least 8 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more) consecutive nucleobases that is complementary to a target sequence of an oligonucleotide sequence provided herein (e.g., an oligonucleotide sequence listed in any one of Tables 5 to 19). In some embodiments, it is understood that methylation of the nucleobase uracil at the C5 position forms thymine. Thus, in some embodiments, a nucleotide or nucleoside having a C5 methylated uracil (or 5-methyl-uracil) can be equivalently identified as a thymine nucleotide or nucleoside. In some embodiments, any one or more thymine bases (T) in any of the oligonucleotides provided herein (e.g., the oligonucleotides listed in any of Tables 5 to 19) can independently and optionally be a uracil base (U), and / or any one or more U in the oligonucleotides provided herein can independently and optionally be T. b. Oligonucleotide modification: The oligonucleotides described herein may be modified, for example, to comprise a modified sugar moiety, a modified internucleoside linkage, a modified nucleotide or nucleoside, and / or (e.g., and) a combination thereof. Additionally, in some embodiments, the oligonucleotide may exhibit one or more of the following properties: not mediating alternative splicing; not being immunostimulatory; having nuclease resistance; having increased cellular uptake compared to unmodified oligonucleotides; being non-toxic to cells or mammals; having increased internalization out of endosomes in cells; minimizing TLR stimulation; or avoiding pattern recognition receptors. Any modified chemical composition (chemistry) or form of the oligonucleotides described herein may be combined with one another. For example, one, two, three, four, five or more different types of modifications may be included in the same oligonucleotide. In some embodiments, certain nucleotide or nucleoside modifications can be used that render the oligonucleotides into which they are incorporated more resistant to nuclease digestion than native oligodeoxynucleotide or oligoribonucleotide molecules; these modified oligonucleotides survive intact for longer periods of time than unmodified oligonucleotides. Some specific examples of modified oligonucleotides include those containing modified backbones, such as modified internucleoside linkages, such as phosphorothioate linkages, phosphotriester linkages, methylphosphonate linkages, short-chain alkyl linkages or cycloalkyl sugar inter-linkages, or short-chain heteroatom linkages or heterocyclic sugar inter-linkages. Thus, the oligonucleotides of the present disclosure can be stabilized to resist nucleolytic degradation, for example, by incorporating modifications such as nucleotide or nucleoside modifications. In some embodiments, the length of the oligonucleotide can be as many as 50 or as many as 100 nucleotides, wherein 2 to 10, 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 40, 2 to 45 or more nucleotides or nucleosides of the oligonucleotide are modified nucleotides / nucleosides. The length of the oligonucleotide can be 8 to 30 nucleotides, wherein 2 to 10, 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30 nucleotides or nucleosides of the oligonucleotide are modified nucleotides / nucleosides. The length of the oligonucleotide can be 8 to 15 nucleotides, wherein 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 2 to 13, 2 to 14 nucleotides or nucleosides of the oligonucleotide are modified nucleotides / nucleosides. Optionally, the oligonucleotide can have each nucleotide or nucleoside except 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 modified nucleotides / nucleosides. Oligonucleotide modifications are further described in this article. c. Modified nucleosides In some embodiments, the oligonucleotides described herein comprise at least one nucleoside modified at the 2' position of the sugar. In some embodiments, the oligonucleotides comprise at least one 2'-modified nucleoside. In some embodiments, all nucleosides in the oligonucleotides are 2'-modified nucleosides. In some embodiments, the oligonucleotides described herein comprise one or more non-bicyclic 2'-modified nucleosides, such as 2'-deoxy, 2'-fluoro (2'-F), 2'-O-methyl (2'-O-Me), 2'-O-methoxyethyl (2'-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA) modified nucleosides. In some embodiments, the oligonucleotides described herein comprise one or more 2'-4' bicyclic nucleosides in which the ribose ring comprises a bridging moiety connecting two atoms in the ring, for example, a 2'-O atom connected to a 4'-C atom by a methylene (LNA) bridge, an ethylene (ENA) bridge, or an (S)-constrained ethyl (cEt) bridge. Some examples of LNAs are described in International Patent Application Publication No. WO / 2008 / 043753, published April 17, 2008, and entitled "RNA Antagonist Compounds For The Modulation Of PCSK9," the contents of which are incorporated herein by reference in their entirety. Some examples of ENAs are provided in International Patent Publication No. WO 2005 / 042777, published May 12, 2005, and entitled "APP / ENA Antisense"; Morita et al., Nucleic Acid Res., Suppl 1:241-242, 2001; Surono et al., Hum. Gene Ther., 15:749-757, 2004; Koizumi, Curr. Opin. Mol. Ther., 8:144-149, 2006; and Horie et al., Nucleic Acids Symp. Ser (Oxf), 49:171-172, 2005; the disclosures of which are incorporated herein by reference in their entirety. Some examples of cEt are provided in: US Patents 7,101,993, 7,399,845, and 7,569,686, each of which is incorporated herein by reference in its entirety. In some embodiments, the oligonucleotide comprises a modified nucleoside disclosed in one of the following U.S. patents or patent application publications: U.S. Patent 7,399,845, which issued on July 15, 2008, and is entitled “6-Modified Bicyclic Nucleic Acid Analogs”; U.S. Patent 7,741,457, which issued on June 22, 2010, and is entitled “6-Modified Bicyclic Nucleic Acid Analogs”; U.S. Patent 8,022,193, which issued on September 20, 2011, and is entitled “6-Modified Bicyclic Nucleic Acid Analogs”; U.S. Patent 7,569,686, which issued on August 4, 2009, and is entitled “Compounds And Methods For Synthesis Of Bicyclic Nucleic Acid Analogs”; U.S. Patent 7,335,765, which issued on February 26, 2008, and is entitled “Novel Nucleoside And Oligonucleotide Analogues”; U.S. Patent 7,314,923, issued on January 1, 2008, and entitled “Novel Nucleoside And Oligonucleotide Analogues”; U.S. Patent 7,816,333, issued on October 19, 2010, and entitled “Oligonucleotide Analogues And Methods Utilizing The Same”; and U.S. Publication No. 2011 / 0009471, now U.S. Patent 8,957,201, issued on February 17, 2015, and entitled “Oligonucleotide Analogues And Methods Utilizing The Same,” the entire contents of each of which are incorporated herein by reference for all purposes. In some embodiments, an oligonucleotide comprises at least one modified nucleoside that results in an increase in the Tm of the oligonucleotide by 1° C., 2° C., 3° ​​C., 4° C., or 5° C. compared to an oligonucleotide that does not have at least one modified nucleoside. An oligonucleotide may have a plurality of modified nucleosides that result in an overall increase in the Tm of the oligonucleotide by 2° C., 3° ​​C., 4° C., 5° C., 6° C., 7° C., 8° C., 9° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., or more compared to an oligonucleotide that does not have modified nucleosides. Oligonucleotides may comprise a mixture of different types of nucleosides. For example, an oligonucleotide may comprise a mixture of 2'-deoxyribonucleosides or ribonucleosides and 2'-fluoro modified nucleosides. An oligonucleotide may comprise a mixture of deoxyribonucleosides or ribonucleosides and 2'-O-Me modified nucleosides. An oligonucleotide may comprise a mixture of 2'-fluoro modified nucleosides and 2'-O-Me modified nucleosides. An oligonucleotide may comprise a mixture of 2'-4' bicyclic nucleosides and 2'-MOE, 2'-fluoro or 2'-O-Me modified nucleosides. An oligonucleotide may comprise a mixture of non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE, 2'-fluoro or 2'-O-Me) and 2'-4' bicyclic nucleosides (e.g., LNA, ENA, cEt). Oligonucleotides may comprise different types of alternative nucleosides. For example, an oligonucleotide may comprise alternative 2'-deoxyribonucleosides or ribonucleosides and 2'-fluoro modified nucleosides. An oligonucleotide may comprise alternative deoxyribonucleosides or ribonucleosides and 2'-O-Me modified nucleosides. An oligonucleotide may comprise alternative 2'-fluoro modified nucleosides and 2'-O-Me modified nucleosides. An oligonucleotide may comprise alternative 2'-4' bicyclic nucleosides and 2'-MOE, 2'-fluoro or 2'-O-Me modified nucleosides. An oligonucleotide may comprise alternative non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE, 2'-fluoro or 2'-O-Me) and 2'-4' bicyclic nucleosides (e.g., LNA, ENA, cEt). In some embodiments, an oligonucleotide described herein comprises a 5'-vinylphosphonate modification, one or more abasic residues, and / or one or more inverted abasic residues. d. Internucleoside linkages / backbone In some embodiments, the oligonucleotide may comprise a phosphorothioate linkage or other modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a phosphorothioate internucleoside linkage. In some embodiments, the oligonucleotide comprises a phosphorothioate internucleoside linkage between at least two nucleosides. In some embodiments, the oligonucleotide comprises a phosphorothioate internucleoside linkage between all nucleosides. For example, in some embodiments, the oligonucleotide comprises a modified internucleoside linkage at the first, second, and / or (e.g., and) third internucleoside linkage at the 5' or 3' end of the nucleotide sequence. Phosphorus-containing linkages that can be used include, but are not limited to, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methylphosphonates and other alkylphosphonates including 3' alkylenephosphonates, as well as chiral phosphonates, phosphinates, phosphoramidates including 3'-aminophosphoramidates and aminoalkylphosphoramidates, thionylphosphoramidates, thionylalkylphosphonates, thionylalkylphosphotriesters and boranophosphates with normal 3'-5' linkages, 2'-5' linked analogs of these, and those in which adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2' with opposite polarity; see U.S. Patent No. 3,687,808 ; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050. In some embodiments, the oligonucleotide may have a heteroatom backbone, such as a methylene (methylimino) or MMI backbone; an amide backbone (see De Mesmaeker et al. Ace. Chem. Res. 1995, 28: 366-374); a morpholino backbone (see Summerton and Weller, U.S. Patent No. 5,034,506); or a peptide nucleic acid (PNA) backbone (in which the phosphodiester backbone of the oligonucleotide is replaced by a polyamide backbone, with the nucleotides being bound directly or indirectly to aza nitrogen atoms of the polyamide backbone; see Nielsen et al., Science 1991, 254, 1497). e. Stereospecific oligonucleotides In some embodiments, the internucleotidic phosphorus atom of the oligonucleotide is chiral, and the properties of the oligonucleotide are adjusted by the configuration based on the chiral phosphorus atom. In some embodiments, an appropriate method can be used to synthesize P-chiral oligonucleotide analogs in a stereo controlled manner (e.g., as described in Oka N, Wada T, Stereocontrolled synthesis of oligonucleotide analogs containing chiral internucleotidic phosphorusatoms. Chem Soc Rev. 2011 Dec; 40 (12): 5829-43.). In some embodiments, a thiophosphate-containing oligonucleotide is provided, which comprises nucleoside units linked together by substantially all Sp or substantially all Rp thiophosphate sugar interlinkages. In some embodiments, such thiophosphate oligonucleotides having substantially chiral pure sugar interlinkages are prepared by enzymatic synthesis or chemical synthesis, as described, for example, in U.S. Pat. No. 5,587,261, issued on December 12, 1996, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the chirality-controlled oligonucleotide provides a selective cleavage pattern of the target nucleic acid. For example, in some embodiments, the chirality-controlled oligonucleotide provides a single-site cleavage within the complementary sequence of the nucleic acid, as described, for example, in U.S. Patent Application Publication No. 20170037399A1, published on February 2, 2017, entitled "CHIRAL DESIGN," the contents of which are incorporated herein by reference in their entirety. f. Morpholino In some embodiments, the oligonucleotide can be a morpholino-based compound. Morpholino-based oligomeric compounds are described in Dwaine A. Braasch and David R. Corey, Biochemistry, 2002, 41(14), 4503-4510); Genesis, volume 30, issue 3, 2001; Heasman, J., Dev. Biol., 2002, 243, 209-214; Nasevicius et al., Nat. Genet., 2000, 26, 216-220; Lacerra et al., Proc. Natl. Acad. Sci., 2000, 97, 9591-9596; and U.S. Patent No. 5,034,506, issued July 23, 1991. In some embodiments, the morpholino-based oligomeric compound is a phosphorodiamidate morpholino oligomer (PMO) (e.g., as described in Iverson, Curr. Opin. Mol. Ther., 3:235-238, 2001; and Wang et al., J. Gene Med., 12:354-364, 2010; the disclosures of which are herein incorporated by reference in their entireties). g. Peptide nucleic acid (PNA) In some embodiments, both the sugar and internucleoside linkages (main chain) of the nucleotide units of the oligonucleotide are replaced by new groups. In some embodiments, the base unit is maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound (an oligonucleotide mimic that has been shown to have excellent hybridization properties) is referred to as peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of the oligonucleotide is replaced by a main chain containing amides (e.g., an aminoethylglycine main chain). The core base is retained and is directly or indirectly bound to the nitrogen atom of the amide portion of the main chain. Representative publications reporting the preparation of PNA compounds include, but are not limited to, U.S. Patents no. 5,539,082; 5,714,331; and 5,719,262, each of which is incorporated herein by reference. Further teachings of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500. h. Mixed polymers In some embodiments, oligonucleotide described herein can be mixed polymer or comprise mixed polymer sequence pattern.Generally speaking, mixed polymer is the oligonucleotide that comprises natural and non-naturally occurring nucleosides or comprises two different types of non-naturally occurring nucleosides with alternative pattern usually.Mixed polymer has higher binding affinity than unmodified oligonucleotide usually, and can be used for specific binding target molecule, for example, to block the binding site on the target molecule.Generally speaking, mixed polymer does not raise RNA enzyme to target molecule and therefore does not promote the cutting of target molecule.Described such oligonucleotide that can not raise RNA enzyme H, for example, referring to WO2007 / 112754 or WO2007 / 112753. In some embodiments, the mixed polymer comprises or consists of a repeating pattern of nucleoside analogs and naturally occurring nucleosides, or one type of nucleoside analogs and a second type of nucleoside analogs. However, the mixed polymer does not need to comprise a repeating pattern, and may alternatively comprise any arrangement of modified nucleosides and naturally occurring nucleosides, or one type of modified nucleosides and a second type of modified nucleosides. The repeating pattern can be, for example, wherein every second or every third nucleoside is a modified nucleoside (e.g., LNA), and the remaining nucleosides are naturally occurring nucleosides, such as DNA, or 2' substituted nucleoside analogs, such as 2'-MOE or 2' fluoro analogs, or any other modified nucleosides described herein. It is recognized that the repeating pattern of modified nucleosides, such as LNA units, can be combined with modified nucleosides in a fixed position, for example, at the 5' or 3' end. In some embodiments, the mixed polymer does not comprise a region of more than 5, more than 4, more than 3, or more than 2 consecutive naturally occurring nucleosides (e.g., DNA nucleosides). In some embodiments, the mixed polymer comprises at least one region consisting of at least two consecutive modified nucleosides, e.g., at least two consecutive LNAs. In some embodiments, the mixed polymer comprises at least one region consisting of at least three consecutive modified nucleoside units, e.g., at least three consecutive LNAs. In some embodiments, the mixed polymer does not contain regions of more than 7, more than 6, more than 5, more than 4, more than 3, or more than 2 consecutive nucleoside analogs (e.g., LNA). In some embodiments, LNA units may be replaced by other nucleoside analogs (e.g., those mentioned herein). Mixed polymers can be designed to contain a mixture of modified nucleosides with enhanced affinity (e.g., LNA nucleosides and 2'-O-Me nucleosides in a non-limiting example). In some embodiments, the mixed polymer comprises modified internucleoside linkages (e.g., phosphorothioate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five, or more nucleosides. Any suitable method can be used to produce mixed polymers. Representative U.S. patents, U.S. patent publications, and PCT publications that teach the preparation of mixed polymers include U.S. Patent Publication Nos. US20060128646, US20090209748, US20090298916, US20110077288, and US20120322851, and U.S. Patent No. 7,687,617. In some embodiments, the mixed polymer comprises one or more morpholino nucleosides. For example, in some embodiments, the mixed polymer can comprise morpholino nucleosides mixed (e.g., in an alternating manner) with one or more other nucleosides (e.g., DNA, RNA nucleosides) or modified nucleosides (e.g., LNA, 2'-O-Me nucleosides). In some embodiments, mixed-mers can be used for splice correction or exon skipping, e.g., as reported in: Touznik A., et al.. LNA / DNA mixmer-based antisense oligonucleotidescorrect alternative splicing of the SMN2 gene and restore SMNproteinexpression in type 1SMAfibroblasts Scientific Reports, volume 7, Article number: 3672 (2017), Chen S. et al., Synthesis of a Morpholino Nucleic Acid(MNA)-Uridine Phosphoramidite, and Exon Skipping Using MNA / 2′-O-MethylMixmerAntisense Oligonucleotide, Molecules 2016, 21, 1582, The contents of each of which are incorporated herein by reference. i. Polymers In some embodiments, the molecular payload can comprise a polymer (e.g., a concatemer) of two or more oligonucleotides connected by a linker. In some embodiments, in this way, the oligonucleotide loading of the complex can be increased to exceed the available attachment sites on the targeting agent (e.g., available thiol sites on an antibody), or otherwise adjusted to achieve a specific payload loading. The oligonucleotides in the polymer can be the same or different (e.g., targeting different genes or different sites on the same gene or its product). In some embodiments, the polymer comprises two or more oligonucleotides linked together by a cleavable linker. However, in some embodiments, the polymer comprises two or more oligonucleotides linked together by a non-cleavable linker. In some embodiments, the polymer comprises two, three, four, five, six, seven, eight, nine, ten or more oligonucleotides linked together. In some embodiments, the polymer comprises two to five, two to ten, or four to twenty oligonucleotides linked together. In some embodiments, the polymer comprises 2 or more oligonucleotides connected end to end (in a linear arrangement). In some embodiments, the polymer comprises 2 or more oligonucleotides connected end to end by an oligonucleotide-based joint (e.g., a poly-dT joint, a base-free joint). In some embodiments, the polymer comprises the 5' end of an oligonucleotide, which is connected to the 3' end of another oligonucleotide. In some embodiments, the polymer comprises the 3' end of an oligonucleotide, which is connected to the 3' end of another oligonucleotide. In some embodiments, the polymer comprises the 5' end of an oligonucleotide, which is connected to the 5' end of another oligonucleotide. Nevertheless, in some embodiments, the polymer may comprise a branched structure comprising a plurality of oligonucleotides connected together by a branched joint. Other examples of multimers that can be used in the complexes provided herein are disclosed in, for example, U.S. Patent Application No. 2015 / 0315588A1, entitled Methods of delivering multiple targeting oligonucleotides to a cell using cleavable linkers, published on November 5, 2015; U.S. Patent Application No. 2015 / 0247141A1, entitled Multimeric Oligonucleotide Compounds, published on September 3, 2015; U.S. Patent Application No. US 2011 / 0158937A1, entitled Immunostimulatory Oligonucleotide Multimers, published on June 30, 2011; and U.S. Patent Application No. US 2011 / 0158937A1, entitled Triplex-Forming Antisense Oligonucleotides Having Abasic Linkers Targeting Nucleic Acids Comprising Mixed Sequences Of Purines And No. 5,693,773 for Pyrimidines, the contents of each of which are incorporated herein by reference in their entirety. j. Gap polymers In some embodiments, the oligonucleotides described herein are spacer polymers. Spacer polymer oligonucleotides generally have the formula 5'-XYZ-3', wherein X and Z serve as the flanking regions around spacer Y. In some embodiments, the flanking region X of formula 5'-XYZ-3' is also referred to as X district, flanking sequence X, 5' wing region X, or 5' wing segment. In some embodiments, the flanking region Z of formula 5'-XYZ-3' is also referred to as Z district, flanking sequence Z, 3' wing region Z, or 3' wing segment. In some embodiments, the spacer Y of formula 5'-XYZ-3' is also referred to as Y district, Y segment, or spacer segment Y. In some embodiments, each nucleoside in spacer Y is a 2'-deoxyribonucleoside, and 5' wing region X or 3' wing region Z do not contain any 2'-deoxyribonucleoside. In some embodiments, the gapmer oligonucleotide comprises a complementary region of at least 15 consecutive nucleosides (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, or 20 consecutive nucleosides) of a target nucleic acid sequence provided herein (e.g., listed in Table 3, e.g., a transcript provided by any one of SEQ ID NOs: 392 to 702, or the target sequence of any one of the oligonucleotides listed in Tables 5 to 19) and / or at least 15 consecutive nucleosides (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, or 20 consecutive nucleosides) of a nucleotide sequence comprising an oligonucleotide sequence in any one of Tables 5 to 19, wherein each thymine base (T) can be independently and optionally replaced with a uracil base (U), and each U can be independently and optionally replaced with a T. In some embodiments, the gapmer oligonucleotide comprises a complementary region of at least 15 consecutive nucleosides (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, or 20 consecutive nucleosides) of a target nucleic acid sequence provided herein (e.g., listed in Table 4, e.g., a transcript provided by any one of SEQ ID NOs: 705 to 803). In some embodiments, the gapmer oligonucleotide comprises a complementary region of at least 15 consecutive nucleosides (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, or 20 consecutive nucleosides) of a target nucleic acid sequence provided herein (e.g., listed in Table 3 or Table 4, e.g., a transcript provided by any one of SEQ ID NOs: 143 to 148, 167 to 169, 810 to 875, and 1059 to 1068). In some embodiments, the Y region is a continuous segment of nucleotides, for example, a region of 6 or more DNA nucleotides, which can recruit RNA enzymes (e.g., RNAse H). In some embodiments, the spacer binds to the target nucleic acid, at which point the RNAse is recruited and can subsequently cut the target nucleic acid. In some embodiments, the flanks of the Y region 5' and 3' are X and Z regions comprising high-affinity modified nucleosides, for example, one to six high-affinity modified nucleosides. Some examples of high-affinity modified nucleosides include, but are not limited to, 2'-modified nucleosides (e.g., 2'-MOE, 2'O-Me, 2'-F) or 2'-4' bicyclic nucleosides (e.g., LNA, cEt, ENA). In some embodiments, the length of the flanking sequences X and Z can be 1 to 20 nucleotides, 1 to 8 nucleotides, or 1 to 5 nucleotides. The flanking sequences X and Z can have similar lengths or different lengths. In some embodiments, the spacer segment Y can be a nucleotide sequence that is 5 to 20 nucleotides, 5 to 15 nucleotides, 5 to 12 nucleotides, or 6 to 10 nucleotides in length. In some embodiments, in addition to DNA nucleosides, the spacer of the spacer oligonucleotide may include modified nucleosides known to be acceptable for effective RNase H action, such as C4'-substituted nucleosides, acyclic nucleosides, and nucleosides of arabino configuration. In some embodiments, the spacer includes one or more unmodified internucleosides. In some embodiments, one or two flanking regions each independently include one or more thiophosphate internucleoside linkages (e.g., thiophosphate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. In some embodiments, the spacer and two flanking regions each independently include modified internucleoside linkages (e.g., thiophosphate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. Suitable methods can be used to generate gapmers. Representative U.S. patents, U.S. patent publications, and PCT publications that teach the preparation of gapmers include, but are not limited to: U.S. Patents No. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; 5,700,922; 5,898,031; 7,015,315; 7,101,993; 7,399,845; 7,432,250; 7,569,686; 7,683,036; 7,750,131; 8,580,756; 9,045,75 4; 9,428,534; 9,695,418; 10,017,764; 10,260,069; 9,428,534; 8,580,756; U.S. Patent Publication Nos. US20050074801, US20090221685; US20090286969, US20100197762, and US20110112170; PCT Publication Nos. WO2004069991; WO2005023825; WO2008049085 and WO2009090182; and EP Patent No. EP2,149,605, Each of which is incorporated herein by reference in its entirety. In some embodiments, the length of the gapmer is 10 to 40 nucleosides. For example, the length of the gapmer can be 10 to 40, 10 to 35, 10 to 30, 10 to 25, 10 to 20, 10 to 15, 15 to 40, 15 to 35, 15 to 30, 15 to 25, 15 to 20, 20 to 40, 20 to 35, 20 to 30, 20 to 25, 25 to 40, 25 to 35, 25 to 30, 30 to 40, 30 to 35, or 35 to 40 nucleosides. In some embodiments, the length of the gapmer is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleosides. In some embodiments, the length of the spacer Y in the spacer polymer is 5 to 20 nucleosides. For example, the length of the spacer Y can be 5 to 20, 5 to 15, 5 to 10, 10 to 20, 10 to 15 or 15 to 20 nucleosides. In some embodiments, the length of the spacer Y is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 nucleosides. In some embodiments, each nucleoside in the spacer Y is a 2'-deoxyribonucleoside. In some embodiments, all nucleosides in the spacer Y are 2'-deoxyribonucleosides. In some embodiments, one or more nucleosides in the spacer Y are modified nucleosides (for example, 2' modified nucleosides, such as those described herein). In some embodiments, one or more cytosines in the spacer Y are optionally 5-methyl-cytosine. In some embodiments, each cytosine in spacer Y is 5-methyl-cytosine. In some embodiments, the 5'-wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3'-wing of the gapmer (Z in the 5'-XYZ-3' formula) are independently 1 to 20 nucleosides in length. For example, the 5'-wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3'-wing of the gapmer (Z in the 5'-XYZ-3' formula) can independently be 1 to 20, 1 to 15, 1 to 10, 1 to 7, 1 to 5, 1 to 3, 1 to 2, 2 to 5, 2 to 7, 3 to 5, 3 to 7, 5 to 20, 5 to 15, 5 to 10, 10 to 20, 10 to 15, or 15 to 20 nucleosides in length. In some embodiments, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula) are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleosides in length. In some embodiments, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula) are the same length. In some embodiments, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula) are different lengths. In some embodiments, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) is longer than the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula). In some embodiments, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) is shorter than the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula). In some embodiments, the gapmer comprises the following 5'-XYZ-3': 5-10-5，4-12-4，3-14-3，2-16-2，1-18-1，3-10-3，2-10-2，1-10-1，2-8-2，4-6-4，3-6-3，2-6-2，4-7-4，3-7-3，2-7-2，4-8-4，3-8-3，2-8-2，1-8-1，2-9-2，1-9-1，2-10-2，1-10-1，1-12-1，1-16-1，2-15-1，1-15-2，1-14-3，3-14-1，2-14-2，1-13-4，4-13-1，2-13-3，3-13-2，1-12-5，5-12-1，2-12-4，4-12-2，3-12-3，1-11-6，6-11-1，2-11-5，5-11-2，3-11-4，4-11-3，1-17-1，2-16-1，1-16-2，1-15-3，3-15-1，2-15-2，1-14-4，4-14-1，2-14-3，3-14-2，1-13-5，5-13-1，2-13-4，4-13-2，3-13-3，1-12-6，6-12-1，2-12-5，5-12-2，3-12-4，4-12-3，1-11-7，7-11-1，2-11-6，6-11-2，3-11-5，5-11-3，4-11-4，1-18-1，1-17-2，2-17-1，1-16-3，1-16-3，2-16-2，1-15-4，4-15-1，2-15-3，3-15-2，1-14-5，5-14-1，2-14-4，4-14-2，3-14-3，1-13-6，6-13-1，2-13-5，5-13-2，3-13-4，4-13-3，1-12-7，7-12-1，2-12-6，6-12-2，3-12-5，5-12-3，1-11-8，8-11-1，2-11-7，7-11-2，3-11-6，6-11-3，4-11-5，5-11-4，1-18-1，1-17-2，2-17-1，1-16-3，3-16-1，2-16-2，1-15-4，4-15-1，2-15-3，3-15-2，1-14-5，2-14-4，4-14-2，3-14-3，1-13-6，6-13-1，2-13-5，5-13-2，3-13-4，4-13-3，1-12-7，7-12-1，2-12-6，6-12-2，3-12-5，5-12-3，1-11-8，8-11-1，2-11-7，7-11-2，3-11-6，6-11-3，4-11-5，5-11-4，1-19-1，1-18-2，2-18-1，1-17-3，3-17-1，2-17-2，1-16-4，4-16-1，2-16-3，3-16-2，1-15-5，2-15-4，4-15-2，3-15-3，1-14-6，6-14-1，2-14-5，5-14-2，3-14-4，4-14-3，1-13-7，7-13-1，2-13-6，6-13-2，3-13-5，5-13-3，4-13-4，1-12-8，8-12-1，2-12-7，7-12-2，3-12-6，6-12-3，4-12-5，5-12-4，2-11-8，8-11-2，3-11-7，7-11-3，4-11-6，6-11-4，5-11-5，1-20-1，1-19-2，2-19-1，1-18-3，3-18-1，2-18-2，1-17-4，4-17-1，2-17-3，3-17-2，1-16-5，2-16-4，4-16-2，3-16-3，1-15-6，6-15-1，2-15-5，5-15-2，3-15-4，4-15-3，1-14-7，7-14-1，2-14-6，6-14-2，3-14-5，5-14-3，4-14-4，1-13-8，8-13-1，2-13-7，7-13-2，3-13-6，6-13-3，4-13-5，5-13-4，2-12-8，8-12-2，3-12-7，7-12-3，4-12-6，6-12-4，5-12-5，3-11-8，8-11-3，4-11-7，7-11-4，5-11-6，6-11-5，1-21-1，1-20-2，2-20-1，1-20-3，3-19-1，2-19-2，1-18-4，4-18-1，2-18-3，3-18-2，1-17-5，2-17-4，4-17-2，3-17-3，1-16-6，6-16-1，2-16-5，5-16-2，3-16-4，4-16-3，1-15-7，7-15-1，2-15-6，6-15-2，3-15-5，5-15-3，4-15-4，1-14-8，8-14-1，2-14-7，7-14-2，3-14-6，6-14-3，4-14-5，5-14-4，2-13-8，8-13-2，3-13-7，7-13-3，4-13-6，6-13-4，5-13-5，1-12-10，10-12-1，2-12-9，9-12-2，3-12-8，8-12-3，4-12-7，7-12-4，5-12-6，6-12-5，4-11-8，8-11-4，5-11-7, 7-11-5, 6-11-6, 1-22-1, 1-21-2, 2-21-1, 1-21-3, 3-20-1, 2-20-2, 1-19-4, 4-19-1, 2-19-3, 3-19-2, 1-18-5, 2-18-4, 4-18-2, 3-18-3, 1-17-6, 6-17-1, 2-17-5, 5-17-2, 3-17-4, 4-17-3, 1-16-7, 7-16-1, 2-16-6, 6-16-2, 3-16-5, 5-16-3, 4-16-4, 1-15-8, 8-15-1, 2-15-7, 7-15-2, 3-15-6, 6-15-3, 4-15-5, 5-15-4, 2-14-8, 8-14-2, 3-14-7, 7-14-3, 4-14-6, 6-14-4, 5-14-5, 3-13-8, 8-13-3, 4-13-7, 7-13-4, 5-13-6, 6-13-5, 4-12-8, 8-12-4, 5-12-7, 7-12-5, 6-12-6, 5-11-8, 8-11-5, 6-11-7, or 7-11-6. , These numbers indicate the number of nucleosides in the X, Y, and Z regions of the 5'-XYZ-3' gapmer. In some embodiments, one or more nucleosides in the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) or the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula) are modified nucleosides (e.g., high affinity modified nucleosides). In some embodiments, the modified nucleosides (e.g., high affinity modified nucleosides) are 2'-modified nucleosides. In some embodiments, the 2'-modified nucleosides are 2'-4' bicyclic nucleosides or non-bicyclic 2'-modified nucleosides. In some embodiments, the high affinity modified nucleoside is a 2'-4' bicyclic nucleoside (e.g., LNA, cEt, or ENA) or a non-bicyclic 2'-modified nucleoside (e.g., 2'-fluoro (2'-F), 2'-O-methyl (2'-O-Me), 2'-O-methoxyethyl (2'-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-ON-methylacetamido (2'-O-NMA)). In some embodiments, one or more nucleosides in the 5' wing (X in the 5'-XYZ-3' formula) of a gapmer are high-affinity modified nucleosides. In some embodiments, each nucleoside in the 5' wing (X in the 5'-XYZ-3' formula) of a gapmer is a high-affinity modified nucleoside. In some embodiments, one or more nucleosides in the 3' wing (Z in the 5'-XYZ-3' formula) of a gapmer are high-affinity modified nucleosides. In some embodiments, each nucleoside in the 3' wing (Z in the 5'-XYZ-3' formula) of a gapmer is a high-affinity modified nucleoside. In some embodiments, one or more nucleosides in the 5' wing (X in the 5'-XYZ-3' formula) of a gapmer are high-affinity modified nucleosides, and one or more nucleosides in the 3' wing (Z in the 5'-XYZ-3' formula) of a gapmer are high-affinity modified nucleosides. In some embodiments, each nucleoside in the 5'-wing (X in the 5'-XYZ-3' formula) of the gapmer is a high affinity modified nucleoside, and each nucleoside in the 3'-wing (Z in the 5'-XYZ-3' formula) of the gapmer is a high affinity modified nucleoside. In some embodiments, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) comprises the same high-affinity nucleoside as the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula). For example, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula) can comprise one or more non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE or 2'-O-Me). In another example, the 5' wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3' wing of the gapmer (Z in the 5'-XYZ-3' formula) can comprise one or more 2'-4' bicyclic nucleosides (e.g., LNA or cEt). In some embodiments, each nucleoside in the 5'-wing (X in the 5'-XYZ-3' formula) of the gapmer and the 3'-wing (Z in the 5'-XYZ-3' formula) of the gapmer is a non-bicyclic 2'-modified nucleoside (e.g., 2'-MOE or 2'-O-Me). In some embodiments, each nucleoside in the 5'-wing (X in the 5'-XYZ-3' formula) of the gapmer and the 3'-wing (Z in the 5'-XYZ-3' formula) of the gapmer is a 2'-4' bicyclic nucleoside (e.g., LNA or cEt). In some embodiments, the gapmer comprises a 5'-XYZ-3' configuration, wherein X and Z are independently 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length, and Y is 6 to 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein each nucleoside of X and Z is a non-bicyclic 2'-modified nucleoside (e.g., 2'-MOE or 2'-O-Me) and each nucleoside of Y is a 2'-deoxyribonucleoside. In some embodiments, the gapmer comprises a 5'-XYZ-3' configuration, wherein X and Z are independently 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length, and Y is 6 to 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein each nucleoside of X and Z is a 2'-4' bicyclic nucleoside (e.g., LNA or cEt), and each nucleoside of Y is a 2'-deoxyribonucleoside. In some embodiments, the 5'-wing of the gapmer (X in the 5'-XYZ-3' formula) comprises a different high-affinity nucleoside than the 3'-wing of the gapmer (Z in the 5'-XYZ-3' formula). For example, the 5'-wing of the gapmer (X in the 5'-XYZ-3' formula) can comprise one or more non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE or 2'-O-Me), and the 3'-wing of the gapmer (Z in the 5'-XYZ-3' formula) can comprise one or more 2'-4' bicyclic nucleosides (e.g., LNA or cEt). In another example, the 3'-wing of the gapmer (Z in the 5'-XYZ-3' formula) can comprise one or more non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE or 2'-O-Me), and the 5'-wing of the gapmer (X in the 5'-XYZ-3' formula) can comprise one or more 2'-4' bicyclic nucleosides (e.g., LNA or cEt). In some embodiments, the gapmer comprises a 5'-XYZ-3' configuration, wherein X and Z are independently 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length, and Y is 6 to 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein each nucleoside in X is a non-bicyclic 2'-modified nucleoside (e.g., 2'-MOE or 2'-O-Me), each nucleoside in Z is a 2'-4' bicyclic nucleoside (e.g., LNA or cEt), and each nucleoside in Y is a 2'-deoxyribonucleoside. In some embodiments, the gapmer comprises a 5'-XYZ-3' configuration, wherein X and Z are independently 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length, and Y is 6 to 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein each nucleoside in X is a 2'-4' bicyclic nucleoside (e.g., LNA or cEt), each nucleoside in Z is a non-bicyclic 2'-modified nucleoside (e.g., 2'-MOE or 2'-O-Me), and each nucleoside in Y is a 2'-deoxyribonucleoside. In some embodiments, the 5'-wing of the gapmer (X in the 5'-XYZ-3' formula) comprises one or more non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE or 2'-O-Me) and one or more 2'-4' bicyclic nucleosides (e.g., LNA or cEt). In some embodiments, the 3'-wing of the gapmer (Z in the 5'-XYZ-3' formula) comprises one or more non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE or 2'-O-Me) and one or more 2'-4' bicyclic nucleosides (e.g., LNA or cEt). In some embodiments, both the 5'-wing of the gapmer (X in the 5'-XYZ-3' formula) and the 3'-wing of the gapmer (Z in the 5'-XYZ-3' formula) comprise one or more non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE or 2'-O-Me) and one or more 2'-4' bicyclic nucleosides (e.g., LNA or cEt). In some embodiments, the gapmer comprises a 5'-XYZ-3' configuration, wherein X and Z are independently 2 to 7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6 to 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein at least one, but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 (the 5'-most position being position 1) of X is a non-bicyclic 2'-modified nucleoside (e.g., 2'-MOE or 2'-O-Me), wherein the remaining nucleosides in both X and Z are 2'-4' bicyclic nucleosides (e.g., LNA or cEt), and wherein each nucleoside in Y is a 2' deoxyribonucleoside. In some embodiments, the gapmer comprises a 5'-XYZ-3' configuration, wherein X and Z are independently 2 to 7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6 to 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein at least one, but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 (the 5'-most position being position 1) of Z is a non-bicyclic 2'-modified nucleoside (e.g., 2'-MOE or 2'-O-Me), wherein the remaining nucleosides in both X and Z are 2'-4' bicyclic nucleosides (e.g., LNA or cEt), and wherein each nucleoside in Y is a 2' deoxyribonucleoside. In some embodiments, the gapmer comprises a 5'-XYZ-3' configuration, wherein X and Z are independently 2 to 7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6 to 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein at least one, but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 of X and at least one, but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 (the 5'-most position being position 1) of Z is a non-bicyclic 2'-modified nucleoside (e.g., 2'-MOE or 2'-O-Me), wherein the remaining nucleosides in both X and Z are 2'-4' bicyclic nucleosides (e.g., LNA or cEt), and wherein each nucleoside in Y is a 2' deoxyribonucleoside. Some non-limiting examples of gapmer configurations having a mixture of non-bicyclic 2'-modified nucleosides (e.g., 2'-MOE or 2'-O-Me) and 2'-4' bicyclic nucleosides (e.g., LNA or cEt) in the 5'-wing (X in the 5'-XYZ-3' formula) and / or the 3'-wing (Z in the 5'-XYZ-3' formula) of the gapmer include: BBB-(D)n-BBBAA;KKK-(D)n-KKKAA;LLL-(D)n-LLLAA;BBB-(D)n-BBBEE;KK K-(D)n-KKKEE;LLL-(D)n-LLLEE;BBB-(D)n-BBBAA;KKK-(D)n-KKKAA;LLL- (D)n-LLLAA;BBB-(D)n-BBBEE;KKK-(D)n-KKKEE;LLL-(D)n-LLLEE;BBB-(D )n-BBBAAA;KKK-(D)n-KKKAAA;LLL-(D)n-LLLAAA;BBB-(D)n-BBBEEE;KKK- (D)n-KKKEEE;LLL-(D)n-LLLEEE;BBB-(D)n-BBBAAA;KKK-(D)n-KKKAAA;LLL-(D)n-LLLAAA;BBB-(D)n-BBBEEE;KKK-(D)n-KKKEE-LLLEE-LEED); FATHER-(D)n-FATHER;BROTHER-(D)n-BROTHER;LALA-(D)n-ALAL;BEBE-(D)n-EBEB;KEKE-(D)n-EKEK;LELE-(D)n-ELEL;BABA-(D)n-ABAB;UNBROTHER-(D)n-ALAK; -(D)n-ALAL;BEBE-(D)n-EBEB;CAKE-(D)n-EKEK;LELE-(D)n-ELEL;ABAB-(D)n-ABAB;AKAK-(D)n-AKAK;ALAL-(D)n-ALAL;EBEB-(D)n-EKEB-(D)EB-(D) n-EKEK;ELEL-(D)n-ELEL;ABAB-(D)n-ABAB;AKAK-(D)n-AKAC;ALAL-(D)n-ALAL;EBEB-(D)n-EBEB;EKEK-(D)n-EKEK;ELEL-(D)n-ELEL;AABB-D) AA;BBAA-(D)n-AABB;AAKK-(D)n-KKAA;AALL-(D)n-LLAA;EEBB-(D)n-BBEE;EEKK-(D)n-KKEE;EELL-(D)n-LLEE;AABB-(D)n-BBAAK-AKAK-Ad) ALL-(D)n-LLAA;EEBB-(D)n-BBEE;EEKK-(D)n-KKEE;EELL-(D)n-LLEE;BBB -(D)n-BBA;KKK-(D)n-KKA;LLL-(D)n-LLA;BBB-(D)n-BBE;KKK-(D)n-KKE;LLL-(D)n-LLE;BBB-(D)n-BBA;KKK-(D)n-KKA;LLL-(D)n-LLA;BBB-(D)n-B BE;KKK-(D)n-KKE;LLL-(D)n-LLE;BBB-(D)n-BBA;KKK-(D)n-KKA;LLL-(D) n-LLA;BBB-(D)n-BBE;KKK-(D)n-KKE;LLL-(D)n-LLE;ABBB-(D)n-BBBA;AK KK-(D)n-KKKA;ALLL-(D)n-LLLA;EBBB-(D)n-BBBE;EKKK-(D)n-KKKE;ELLL -(D)n-LLLE;ABBB-(D)n-BBBA;AKKK-(D)n-KKKA;ALLL-(D)n-LLLA;EBBB-(D)n-BBBE;EKKK-(D)n-KKKE;ELLL-(D)n-LLLE;ABBB-(D)n-AKK-A )n-KKKAA;ALLL-(D)n-LLLAA;EBBB-(D)n-BBBEE;EKKK-(D)n-KKKEE;ELLL-(D)n-LLLEE;ABBB-(D)n-BBBAA;AKKK-(D)n-KKKAA;ALLL-LLLAA(ABBLA) -(D)n-BBBEE;EKKK-(D)n-KKKEE;ELLL-(D)n-LLLEE;AABBB-(D)n-BBB;AAK KK-(D)n-KKK;AALLL-(D)n-LLL;EEBBB-(D)n-BBB;EEKKK-(D)n-KKK;EELLL -(D)n-LLL;AABBB-(D)n-BBB;AACCK-(D)n-KKK;AALLL-(D)n-LLL;EEBBB-( D)n-BBB;EEKKK-(D)n-KKK;EELLL-(D)n-LLL;AABBB-(D)n-BBBA;AAKKK-(D )n-KKKA;AALLL-(D)n-LLLA;EEBBB-(D)n-BBBE;EEKKK-(D)n-KKKE;EELLL-(D)n-LLLE;AABBB-(D)n-BBBA;AAKKK-(D)n-KKKA;ALLLL-(D)LL-LLA) B-(D)n-BBBE?AKKAAKK-(D)n-BBB ;ALLALLL-(D)n-LLL;EBBEBB-(D)n-BBB;EKKEKK-(D)n-KKK;ELLELL-(D)n-LLL;ABBABB-(D)n-BBB;AKKAKK-(D)n-KKK;ALLALL-(D)n-LLL;EBBEBB-(D)n-BBB;EKKEKK-(D)n-KK K; ELLELL-(D)n-LLL; EEEK-(D)n-EEEEEEEE; EEK-(D)n-EEEEEEEE; EK-(D)n-EEEEEEEEEE; EK-(D)n-EEEKK; K-(D)n-EEEKEKE; K-(D)n-EEEKEKEE; K-(D)n-EEKEK; EEKEKE;EK-(D)n-EEEKEK;EEK-(D)n-KEEKE;EK-(D)n-EEKEK;EK-(D)n-KEEK;EEK-(D)n -EEEKEK; EK-(D)n-KEEEKEE; EK-(D)n-EEKEKE; EK-(D)n-EEEKEKE; and EK-(D)n-EEEEKEK; wherein "A" represents a 2'-modified nucleoside; "B" represents a 2'-4' bicyclic nucleoside; "K" represents a constrained ethyl nucleoside (cEt); "L" represents an LNA nucleoside; and "E" represents a 2'-MOE modified ribonucleoside; "D" represents a 2'-deoxyribonucleoside; and "n" represents the length of the spacer segment (Y in the 5'-XYZ-3' configuration) and is an integer from 1 to 20. In some embodiments, any of the gap polymers described herein comprises one or more modified nucleoside linkages (e.g., phosphorothioate linkages) in each of regions X, Y, and Z. In some embodiments, each internucleoside linkage in any of the gap polymers described herein is a phosphorothioate linkage. In some embodiments, regions X, Y, and Z each independently comprise a mixture of phosphorothioate linkages and phosphodiester linkages. In some embodiments, each internucleoside linkage in spacer Y is a phosphorothioate linkage, 5' wing region X comprises a mixture of phosphorothioate linkages and phosphodiester linkages, and 3' wing region Z comprises a mixture of phosphorothioate linkages and phosphodiester linkages. Peptide loading In some embodiments, polypeptides (e.g., peptides, proteins, including but not limited to enzymes, antibodies, etc.) can be used to treat a variety of CNS diseases and disorders. For example, polypeptides can be used to regulate the expression or activity of a variety of genes involved in CNS diseases and disorders, for example, by regulating the expression or activity of proteins involved in CNS diseases or disorders. In a non-limiting example, enzymes that modify, degrade, or otherwise affect a specific biomolecule (e.g., protein or nucleic acid) can be used to treat a CNS disease or disorder involving the specific biomolecule. Polypeptides can be used to treat a variety of CNS diseases and disorders, for example, by promoting polypeptide delivery into cells of the CNS. In some embodiments, the polypeptides disclosed herein can be delivered to cells of the CNS using a complex disclosed herein (e.g., an anti-TfR1 antibody complex comprising the polypeptide). In some embodiments, the polypeptides can be used to treat a neuromuscular disease or disorder (e.g., Duchenne muscular dystrophy, myotonic dystrophy, Friedreich's ataxia, or spinal muscular atrophy); amyotrophic lateral sclerosis; Parkinson's disease; Huntington's disease; Alzheimer's disease; epilepsy; pain disorders; glycogen synthesis disorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman syndrome; autism spectrum disorder; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis. In some embodiments, the polypeptides can be used to treat essential tremor and / or hereditary dystonia. In some embodiments, the polypeptides can be used to treat spinocerebellar ataxia, motor neuron disease, Dravet syndrome, Batten disease, GM1 gangliosidosis, Niemann-Pick type A, metachromatic leukodystrophy, Krabbe disease, Tay-Sachs, Sandhoff disease, Gaucher disease types II and III, and / or Rett syndrome. In some embodiments, the polypeptides can be used to regulate one or more genes associated with a CNS disease or condition. In some embodiments, the one or more genes associated with a CNS disease or condition are DMPK, DMD, SMN, FXN, SOD1, C9orf72, ATXN2, FUS, LRRK2, SNCA, HTT, MSH3, TREM2, APOE, MAPT, APP, GYS1, PrP, VLA-4, GFAP, UBE3A, LSD, SCN9A, SCN1A, SCN2A, SCN8A, CLN3, GRIA1, or PCDH19. In some embodiments, the one or more genes associated with a CNS disease or disorder are TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, or ECHS1. In some embodiments, the one or more genes associated with a CNS disease or disorder is PIKFYVE, SYF2, UNC13A, ATXN1, ATXN3, GRN, GRIN2A, TPP1, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, or MECP2. Small molecule payload In some embodiments, small molecules can be used to treat a variety of CNS diseases and disorders. For example, small molecules can be used to regulate the expression or activity of a variety of genes involved in CNS diseases and disorders, such as by regulating the expression or activity of proteins involved in CNS diseases or disorders. In a non-limiting example, small molecules that increase, decrease, or otherwise affect the expression of a specific biomolecule (e.g., protein or nucleic acid) can be used to treat a CNS disease or disorder involving the specific biomolecule. Small molecules can be used to treat a variety of CNS diseases and disorders, for example, by promoting the delivery of small molecules into the cells of the CNS. In some embodiments, the small molecules disclosed herein can be delivered into the cells of the CNS using a complex disclosed herein (e.g., an anti-TfR1 antibody complex comprising the small molecule). In some embodiments, the small molecules can be used to treat neuromuscular diseases or disorders (e.g., Duchenne muscular dystrophy, myotonic dystrophy, Friedreich's ataxia, or spinal muscular atrophy); amyotrophic lateral sclerosis; Parkinson's disease; Huntington's disease; Alzheimer's disease; epilepsy; pain disorders; glycogen synthesis disorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman syndrome; autism spectrum disorder; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis. In some embodiments, small molecules can be used to treat essential tremor and / or hereditary dystonia. In some embodiments, the small molecules can be used to treat spinocerebellar ataxia, motor neuron disease, Dravet syndrome, Batten disease, GM1 gangliosidosis, Niemann-Pick type A, metachromatic leukodystrophy, Krabbe disease, Tay-Sachs, Sandhoff disease, Gaucher disease types II and III, and / or Rett syndrome. In some embodiments, small molecules can be used to modulate one or more genes associated with a CNS disease or condition. In some embodiments, one or more genes associated with a CNS disease or condition is DMPK, DMD, SMN, FXN, SOD1, C9orf72, ATXN2, FUS, LRRK2, SNCA, HTT, MSH3, TREM2, APOE, MAPT, APP, GYS1, PrP, VLA-4, GFAP, UBE3A, LSD, SCN9A, SCN1A, SCN2A, SCN8A, CLN3, GRIA1, or PCDH19. In some embodiments, the one or more genes associated with a CNS disease or disorder are TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, or ECHS1. In some embodiments, the one or more genes associated with a CNS disease or disorder are PIKFYVE, SYF2, UNC13A, ATXN1, ATXN3, GRN, GRIN2A, TPP1, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, or MECP2. The compounds described herein (e.g., small molecule payloads) may contain one or more asymmetric centers and may therefore exist in multiple stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers. Gene therapy payload In some embodiments, gene therapy payloads (e.g., nucleic acids encoding bioactive molecules or otherwise therapeutic molecules) can be used to treat a variety of CNS diseases and disorders. For example, gene therapy can be used to regulate the expression or activity of a variety of genes involved in CNS diseases and disorders, for example, by encoding proteins involved in CNS diseases or disorders. In a non-limiting example, a gene therapy payload encoding a specific biomolecule (e.g., a protein or nucleic acid) can be used to treat a CNS disease or disorder (e.g., a disease or disorder whose cause of disease involves abnormally low expression of a biomolecule or expression of an inactive form of a biomolecule) to which the specific biomolecule is related. Gene therapy can be used to treat a variety of CNS diseases and disorders, for example, by promoting the delivery of gene therapy payloads to cells in the CNS. In some embodiments, the gene therapy disclosed herein can be delivered to cells in the CNS using a complex disclosed herein (e.g., an anti-TfR1 antibody complex comprising the gene therapy payload). In some embodiments, gene therapy can be used to treat neuromuscular diseases or disorders (e.g., Duchenne muscular dystrophy, myotonic dystrophy, Friedreich's ataxia, or spinal muscular atrophy); amyotrophic lateral sclerosis; Parkinson's disease; Huntington's disease; Alzheimer's disease; epilepsy; pain disorders; glycogen synthesis disorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman syndrome; autism spectrum disorder; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis. In some embodiments, gene therapy can be used to treat essential tremor and / or hereditary dystonia. In some embodiments, gene therapy can be used to treat spinocerebellar ataxia, motor neuron disease, Dravet syndrome, Batten disease, GM1 gangliosidosis, Niemann-Pick type A, metachromatic leukodystrophy, Krabbe disease, Tay-Sachs, Sandhoff disease, Gaucher disease types II and III, and / or Rett syndrome. In some embodiments, gene therapy can be used to modulate one or more genes associated with a CNS disease or condition. In some embodiments, the one or more genes associated with a CNS disease or condition are DMPK, DMD, SMN, FXN, SOD1, C9orf72, ATXN2, FUS, LRRK2, SNCA, HTT, MSH3, TREM2, APOE, MAPT, APP, GYS1, PrP, VLA-4, GFAP, UBE3A, LSD, SCN9A, SCN1A, SCN2A, SCN8A, CLN3, GRIA1, or PCDH19. In some embodiments, the one or more genes associated with a CNS disease or disorder are TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, or ECHS1. In some embodiments, the one or more genes associated with a CNS disease or disorder are PIKFYVE, SYF2, UNC13A, ATXN1, ATXN3, GRN, GRIN2A, TPP1, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, or MECP2. Molecular payloads for treating ALS A variety of molecular payloads can be used to treat ALS, including oligonucleotides, polypeptides (e.g., peptides, proteins, enzymes, antibodies, etc.), small molecules (e.g., small molecule inhibitors, etc.), and gene therapy (e.g., nucleic acids and / or nucleic acid vectors encoding therapeutic molecules (e.g., therapeutic proteins)). In some embodiments, molecular payloads that can be used to treat ALS may include molecular payloads that modulate (e.g., increase or decrease) the expression or activity of SOD1, ATXN2, C9orf72, and / or FUS. Some examples of oligonucleotides that can be used to treat ALS (e.g., oligonucleotides that target genes associated with ALS (e.g., SOD1, ATXN2, C9orf72, FUS, etc.) (e.g., directly or indirectly regulate the expression or activity of the gene)) include those listed below in Table 5. Each oligonucleotide provided in Table 5 can have any modification pattern disclosed herein. Table 5. Oligonucleotides for the treatment of ALS Abbreviations used in Table 5: A = adenine; mC = 5-methylcytosine; G = guanine; T = thymine; e = 2'-O-methoxyethyl ribose modified sugar; d = 2'-deoxyribose; s = phosphorothioate internucleoside linkage; o = phosphodiester internucleoside linkage; k = cEt modified sugar. In each sequence listed in Table 5, each T can be optionally and independently replaced by U. Some examples of oligonucleotides that can be used to treat ALS (e.g., oligonucleotides that target genes associated with ALS (e.g., PIKFYVE, SYF2, UNC13A, etc.) (e.g., directly or indirectly regulate the expression or activity of the gene)) include those listed below in Table 6. Each oligonucleotide provided in Table 6 can have any modification pattern disclosed herein. Table 6. Oligonucleotides for the treatment of ALS *e = 2'-MOE modified sugar; L = locked nucleic acid (LNA) nucleoside; d = deoxyribonucleoside; m = 2'-O-methylribonucleoside; s = phosphorothioate internucleoside linkage. In each sequence listed in Table 6, each T can be optionally and independently replaced by U, and each U can be optionally and independently replaced by T. Some examples of small molecules that can be used to treat ALS include: and pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof. Other examples of small molecules that can be used to treat ALS include: Apilimod, APY0201, YM-201636, and pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof. Some examples of polypeptides that can be used to treat ALS include (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4- oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide. Molecular payload targeting SOD1 The superoxide dismutase 1 (SOD1) gene and mutations therein are associated with ALS, which primarily affects upper and lower motor neurons. Therefore, in some embodiments, modulation of SOD1 expression and activity (e.g., by inhibiting the expression and / or activity of mutant SOD1 proteins) can have a therapeutic effect on subjects with ALS. Oligonucleotides In some embodiments, SOD1 expression and / or activity can be modulated by using oligonucleotides targeted to SOD1 sequences. In some embodiments, an oligonucleotide useful for treating ALS (e.g., targeting SOD1 (e.g., directly or indirectly modulating the expression or activity of SOD1)) comprises a complementary region to a SOD1 transcript provided in Table 3 (e.g., provided by SEQ ID NO: 392). In some embodiments, some examples of oligonucleotides that can be used to treat ALS (e.g., targeting SOD1 (e.g., directly or indirectly regulating the expression or activity of SOD1)) are provided in: Smith, et al., "Antisense oligonucleotide therapy for neurodegenerative disease" J. Clin. Invest. (2006) 116(8):2290-96 doi:10.1172 / JCI25424; van Zundert, et al., "Silencing strategies for therapy of SOD1-mediated ALS" Neurosis. Lett. (2017) 636:32-39 doi:10.1016 / j.neulet.2016.07.059; and the publication entitled "Antisense Modulation of Superoxide Dismutase 1, Soluble and U.S. Patent Application Publication No. 20040091919A1, entitled “Compounds and methods for modulating expression of PCSK9”, published on December 10, 2009; U.S. Patent Application Publication No. 20140378533A1, entitled “Modulation of RNA by repeat targeting”, published on December 25, 2014; U.S. Patent Application Publication No. 20150184154A1, entitled “New Treatment for Neurodegenerative Diseases”, published on July 2, 2015; U.S. Patent Application Publication No. 20160272976A1, entitled “Products and Methods for Treatment of Familial Amyotrophic Lateral Sclerosis”, published on September 22, 2016; and U.S. Patent Application Publication No. 20160272976A1, entitled “Products and Methods for Treatment of Familial Amyotrophic Lateral Sclerosis”, published on August 4, 2016. Amyotrophic Lateral Sclerosis”; U.S. Patent Application Publication No. 20160222391A1, entitled “Chiral Design,” published on February 9, 2017;20170037399A1; U.S. Patent Application Publication No. 20170037410A1, entitled “Compositions for Modulating SOD-1 Expression,” published on February 9, 2017; U.S. Patent Application Publication No. 20170152517A1, entitled “Treatment of Amyotrophic Lateral Sclerosis,” published on June 1, 2017; U.S. Patent Application Publication No. 20160089453A1, entitled “RNA-Modulating Agents,” published on March 31, 2016; U.S. Patent Application Publication No. 20180282732A1, entitled “Compositions and Methods of Treating Amyotrophic Lateral Sclerosis (ALS),” published on October 4, 2018; and U.S. Patent Application Publication No. 20180282732A1, entitled “Improved Treatments Using International Patent Application Publication No. WO2016180784A1 entitled “MiR-155 Inhibitors for Treating Amyotrophic Lateral Sclerosis (ALS)” published on June 14, 2018; U.S. Patent Application Publication No. 20180161357A1 entitled “Nucleic acid molecules targeting superoxide dismutase 1 (sod1)” published on July 12, 2018; U.S. Patent Application Publication No. 20180195072A1 entitled “Oligonucleotide compositions and methods thereof” published on August 2, 2018; U.S. Patent Application Publication No. 20180216107A1 entitled “Oligonucleotide compositions and methods thereof” published on July 29, 2021 thereof”; U.S. Patent Application Publication No. 20210228615A1 entitled “Methods and compositions for the treatment of rare diseases” published on June 6, 2019;20190167815A1; U.S. Patent Application Publication No. 20210054383A1, entitled “Oligonucleotides for modulating tmem106b expression,” published on February 25, 2021; U.S. Patent Application Publication No. 20210269881A1, entitled “Long non-coding RNAs (lncRNAs) for the diagnosis and therapeutics of brain disorders, in particular cognitive disorders,” published on September 2, 2021; U.S. Patent Application Publication No. 10808247B2, entitled “Methods for treating neurological disorders using a synergistic small molecule and nucleic acids therapeutic approach,” published on October 20, 2020; and U.S. Patent Application Publication No. 10808247B2, entitled “Mixed tricyclo-DNA, 2'-modified RNA oligonucleotide compositions and uses” published on September 14, 2021. thereof”; International Patent Application Publication No. WO2020198270A1, entitled “Compositions and methods for treating neurodegenerative disorders”, published on October 1, 2020; U.S. Patent Application Publication No. 20220170025A1, entitled “Compositions and methods for inhibiting gene expression in the central nervous system”, published on June 2, 2022; U.S. Patent Application Publication No. 10174328B2, entitled “Compositions and methods for treating amyotrophic lateral sclerosis”, published on January 8, 2019; International Patent Application Publication No. WO2020198270A1, entitled “Compositions and methods for treating neurodegenerative disorders”, published on November 5, 2020;WO2020222182A1; International Patent Application Publication No. WO2020247419A2 entitled “Oligonucleotides and methods of use for treating neurological diseases” published on December 10, 2020; International Patent Application Publication No. WO2021029896A1 entitled “Splice modulating oligonucleotides targeting receptor for advanced glycation end products and methods of use” published on February 18, 2021; U.S. Patent Application Publication No. 20220090036A1 entitled “Compositions and methods for the targeting of SOD1” published on March 24, 2022; International Patent Application Publication No. WO2021108602A1 entitled “Methods and compositions for neuroprotection” published on November 25, 2020; and International Patent Application Publication No. WO2021108602A1 entitled “Use of International Patent Application Publication No. WO2021156832A1, entitled “miRNA-485 inhibitors for treating amyotrophic lateral sclerosis (ALS)”; and U.S. Patent Application Publication No. 20220073930A1, published on March 10, 2022, entitled “Compositions and methods for treating and preventing amyotrophic lateral sclerosis”; the entire contents of each of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat ALS by modulating the activity of genes and / or gene products other than the SOD1 gene / gene product (e.g., C9orf72, ATXN2, and / or FUS gene / gene product). peptides In some embodiments, SOD1 expression and / or activity can be modulated by administering a SOD1 polypeptide or a polypeptide that interacts with SOD1 (eg, to modulate its enzymatic activity). In some embodiments, some examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat ALS are provided in: Martin, et al. “GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis” Front. Cell Neurosci. 8: article 433 (2014); doi: 10.3389 / fncel.2014.00433; U.S. Patent Application Publication No. 20090124993A1, entitled “Treating neurological disorders”, published on May 14, 2009; U.S. Patent Application Publication No. 20140044722A1, entitled “Anti-SOD1 Antibodies and Uses Thereof”, published on February 13, 2014; U.S. Patent Application Publication No. 20140044722A1, entitled “Human and U.S. Patent Application Publication No. 20140301945, entitled “Anti-SOD1 Antibodies”; International Patent Application Publication No. WO2013106672A1, entitled “Methods and Compositions for the Treatment of Neurodegenerative Disease”, published on July 18, 2013; U.S. Patent Application Publication No. 20150184154A1, entitled “New Treatment for Neurodegenerative Diseases”, published on July 2, 2015; U.S. Patent Application Publication No. 20150259391A1, entitled “Treatment of Amyotrophic Lateral Sclerosis”, published on September 17, 2015; U.S. Patent Application Publication No. 20160115245A1, entitled “Single Domain Antibodies Against SOD1 and Their Use in Medicine”, published on April 28, 2016; and U.S. Patent Application Publication No. 20160115245A1, entitled “Composition and method for treating leukemia”, published on January 24, 2019. for treating amyotrophic lateralsclerosis” U.S. Patent Application Publication No.20190022179A1; U.S. Patent Application Publication No. 20200247854A1, entitled “Pharmaceutical composition for preventing or treating neurodegenerative disease comprising nckap1 protein or gene encoding same,” published on August 6, 2020; U.S. Patent Application Publication No. 20210206876A1, entitled “DPP3 binder directed to and binding to specific DPP3-epitopes and its use in the prevention or treatment of diseases / acute conditions that are associated with oxidative stress,” published on July 8, 2021; International Patent Application Publication No. WO2019104311A1, entitled “Compositions and methods for suppressing neurological disease,” published on May 31, 2019; and International Patent Application Publication No. WO2019104311A1, entitled “Compositions and methods of using same for treating amyotrophic lateral sclerosis,” published on April 8, 2021. U.S. Patent Application Publication No. 20210100869A1, entitled “Methods of treating neurological diseases” published on June 4, 2020; U.S. Patent Application Publication No. 20210162002A1, entitled “Regenerating functional neurons for treatment of spinal cord injury and ALS” published on June 3, 2021; U.S. Patent Application Publication No. 20210100869A1, entitled “Methods for treating neurological disorders using a synergistic small molecule and nucleic acids therapeutic approach” published on October 20, 2020.10808247B2; U.S. Patent Application Publication No. 20210284702A1, entitled “Fusion proteins comprising progranulin,” published on September 16, 2021; U.S. Patent Application Publication No. 20220017634A1, entitled “Engineered bispecific proteins,” published on January 20, 2022; U.S. Patent Application Publication No. 20220034907A1, entitled “Neurofilament protein for guiding therapeutic intervention in amyotrophic lateral sclerosis,” published on February 3, 2022; the entire contents of each of which are incorporated herein by reference. Certain polypeptides provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the SOD1 gene / gene product (e.g., the C9orf72, ATXN2, and / or FUS gene / gene product). Small molecules In some embodiments, SOD1 expression and / or activity can be modulated by using small molecules that can modulate SOD1 (e.g., to modulate its enzymatic activity or its expression). In some embodiments, some examples of small molecules that can be used to treat ALS are provided in the following: U.S. Patent Application Publication No. 20040219552A1, entitled “Novel Molecular Target for Neurotoxicity,” published on November 4, 2004; U.S. Patent Application Publication No. 20030130357A1, entitled “Use of Polyamine Analogs for Amyotrophic Lateral Sclerosis,” published on July 10, 2003; U.S. Patent Application Publication No. 20100152125A1, entitled “Compositions and Methods for the Diagnosis, Treatment, and Prevention of Amyotrophic Lateral Sclerosis and Related Neurological Diseases,” published on June 17, 2010; and U.S. Patent Application Publication No. 20100152125A1, entitled “Treatment of Neural Diseases or Related Neurological Diseases,” published on December 30, 2010. Conditions”; U.S. Patent Application Publication No. 201100331417A1, entitled “Compositions and Methods of Treatment Using Modulators of Motoneuron Diseases”, published on March 31, 2011; U.S. Patent Application Publication No. 20110166115A1, entitled “Use of Mifepristone for the Treatment of Amyotrophic Lateral Sclerosis”, published on July 7, 2011; U.S. Patent Application Publication No. 20150164901A1, entitled “Compounds, Compositions and Methods for Treating or Preventing Neurodegenerative Disorders”, published on June 18, 2015; and U.S. Patent Application Publication No. 20160164901A1, entitled “Methods, Compositions and Kits for Promoting Motor Neuron Survival and Treating and Diagnosing Neurodegenerative Disorders” U.S. Patent Application Publication No.20160082015A1; U.S. Patent Application Publication No. 20160287549A1, entitled “Novel Methods for Treating Neurodegenerative Diseases,” published on October 6, 2016; U.S. Patent Application Publication No. 20150210679A1, entitled “Small Molecule Inhibitors of Superoxide Dismutase Expression,” published on July 30, 2015; International PCT Application Publication No. WO2021174167A1, entitled “Compounds and methods for modulating splicing,” published on September 2, 2021; U.S. Patent Application Publication No. 20180028520A1, entitled “Methods and Pharmaceutical Compositions for Treatment of Amyotrophic Lateral Sclerosis,” published on February 1, 2018; and U.S. Patent Application Publication No. 20180028520A1, entitled “Treating neuromuscular International Patent Application Publication No. WO2016114655A1, entitled “Methods of Using GM604 in Modulating ALSDisease Biomarkers Leading to Prognosis and Therapeutic Treatment for ALSDisease,” published on June 8, 2017; and U.S. Patent Application Publication No. 20170157197A1, entitled “Diterpenoid derivatives and methods of use thereof,” published on December 14, 2017.20170354639A1; U.S. Patent Application Publication No. 20180289655A1, entitled “Methods and Compositions for the Intravenous Administration of Fumarates for the Treatment of Neurological Diseases,” published on October 11, 2018; U.S. Patent Application Publication No. 20170226127A1, entitled “Compounds, compositions, and methods,” published on August 10, 2017; U.S. Patent Application Publication No. 20170362206A1, entitled “Compounds, compositions, and methods,” published on June 15, 2017; U.S. Patent Application Publication No. 20180327391A1, entitled “Compounds, compositions, and methods,” published on November 15, 2018; and U.S. Patent Application Publication No. 20180327391A1, entitled “Compounds, compositions, and methods,” published on October 3, 2019. methods”; U.S. Patent Application Publication No. 20190300537A1, entitled “Polymorphs and solid forms of a pyrimidinylamino-pyrazole compound, and methods of production”, published on June 27, 2019; U.S. Patent Application Publication No. 9669014B2, entitled “Smallmolecule inhibitors of superoxide dismutase expression”, published on June 6, 2017; U.S. Patent Application Publication No. 20210130308A1, entitled “Modulators of eukaryotic initiation factor 2”, published on May 6, 2021; U.S. Patent Application Publication No. 20190300537A1, entitled “Polymorphs and solid forms of a pyrimidinylamino-pyrazole compound, and methods of production”, published on June 27, 2019; U.S. Patent Application Publication No. 9669014B2, entitled “Smallmolecule inhibitors of superoxide dismutase expression”, published on June 6, 2017; U.S. Patent Application Publication No. 20210130308A1, entitled “Modulators of eukaryotic initiation factor 2”, published on May 6, 2021; and U.S. Patent Application Publication No. 20190194170A1, entitled “Isoxazolidine derived inhibitors of receptor interacting protein kinase 1(RIPK1)”; U.S. Patent Application Publication No. 20180353480A1 entitled “Compounds, compositions, and methods” published on March 12, 2020;20200079784A1; U.S. Patent Application Publication No. 20200331900A1, titled “Compounds, compositions, and methods,” published on October 22, 2020; U.S. Patent Application Publication No. 20210147435A1, titled “Compounds, compositions, and methods,” published on May 20, 2021; U.S. Patent Application Publication No. 20210292311A1, titled “Compounds, compositions, and methods,” published on September 23, 2021; U.S. Patent Application Publication No. 20220177456A1, titled “Compounds, compositions, and methods,” published on June 9, 2022; and U.S. Patent Application Publication No. 20220177456A1, titled “Kinase Inhibitors and U.S. Patent Application Publication No. 20200087319A1, titled “ASK1 inhibiting agents”, published on November 28, 2019; U.S. Patent Application Publication No. 20190359634A1, titled “ASK1 inhibiting agents”, published on November 26, 2020; U.S. Patent Application Publication No. 20200368267A1, titled “Prophylactic and / or therapeutic agent for amyotrophic lateralsclerosis”, published on November 26, 2020; U.S. Patent Application Publication No. 20210115020A1, titled “ASK1 inhibiting agents”, published on April 22, 2021; U.S. Patent Application Publication No. 20210317103A1, titled “ASK1 inhibiting agents”, published on October 14, 2021; and U.S. Patent Application Publication No. 20210317103A1, titled “Pyridine macrocycle compounds as ASK1 inhibiting agents”, published on September 30, 2021. agents”; U.S. Patent Application Publication No. 20210300946A1, entitled “Methods of treating amyotrophic lateral sclerosis” published on November 18, 2021;20210353611A1; U.S. Patent Application Publication No. US20210023062A1, entitled “Compositions and Methods for the Treatment of Amyotrophic Lateral Sclerosis, Parkinson's Disease, Parkinson's Disease with Dementia, Dementia with Lewy Bodies, and Multiple System Atrophy,” published on January 28, 2021; International Patent Application Publication No. WO2021040627A1, entitled “A method of promoting survival and / or function of a motor neuron and related agents, uses and methods,” published on March 4, 2021; the entire contents of each of which are incorporated herein by reference. In some embodiments, the small molecule is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein. Certain small molecules provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the SOD1 gene / gene product (e.g., C9orf72, ATXN2, and / or FUS gene / gene product). Gene therapy In some embodiments, SOD1 expression and / or activity can be modulated using gene therapy that modulates SOD1 (e.g., by delivering nucleic acid encoding SOD1 or other molecules that interact with SOD1). In some embodiments, gene therapies useful for treating ALS, such as those involving administration of compounds encoding useful therapeutic agents, are provided in: U.S. Patent Application Publication No. 20030161814A1, entitled “Adeno-Associated Virus-Mediated Delivery of GDNF to Skeletal Muscles,” published on August 28, 2003; U.S. Patent Application Publication No. 20130287736A1, entitled “Gene Therapy for Neurodegenerative Disorders,” published on October 31, 2013; U.S. Patent Application Publication No. 20150182637A1, entitled “Widespread Gene Delivery of Gene Therapy Vectors,” published on July 2, 2015; and U.S. Patent Application Publication No. 20150182637A1, entitled “Treatment of Amyotrophic LateralSclerosis”; U.S. Patent Application Publication No. 20160272976A1, entitled “Products and Methods for Treatment of Familial Amyotrophic LateralSclerosis”, published on September 22, 2016; U.S. Patent Application Publication No. 20160130567A1, entitled “Messenger UNAMolecules and Uses Thereof”, published on May 12, 2016; U.S. Patent Application Publication No. 20180021364A1, entitled “Central Nervous System Targeting Polynucleotides”, published on January 25, 2018; U.S. Patent Application Publication No. 20180021364A1, entitled “Central Nervous System Targeting Polynucleotides”, published on September 24, 2020; ALS”; U.S. Patent Application Publication No. 20200297868A1, entitled “Translatable molecules and synthesis thereof,” published on November 15, 2018;20180327471A1; U.S. Patent Application Publication No. 20200247854A1, entitled “Pharmaceutical composition for preventing or treating neurodegenerative disease comprising nckap1 protein or gene encoding same,” published on August 6, 2020; U.S. Patent Application Publication No. 20210024907A1, entitled “Nucleic acid-based therapeutics,” published on January 28, 2021; U.S. Patent Application Publication No. 20210254103A1, entitled “Treatment of amyotrophic lateral sclerosis and disorders associated with the spinal cord,” published on August 19, 2021; U.S. Patent Application Publication No. 20200172590A1, entitled “Methods of treating neurological diseases,” published on June 4, 2020; and U.S. Patent Application Publication No. 20200172590A1, entitled “Compositions and methods for the U.S. Patent Application Publication No. 20220090036A1, entitled “Nucleic acids encoding human FUS protein and use in the treatment of amyotrophic lateral sclerosis (ALS)”, published on October 14, 2021; and International Patent Application Publication No. WO2022060857A1, entitled “Compositions and methods for treating amyotrophic lateral sclerosis (ALS) with aav-miR-SOD1”, published on March 24, 2022; the entire contents of each of which are incorporated herein by reference. Certain gene therapies provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the SOD1 gene / gene product (e.g., C9orf72, ATXN2, and / or FUS gene / gene product). Molecular payload targeting ATXN2 The ATXN2 gene, which encodes the ataxin-2 protein, and mutations therein are associated with ALS, which primarily affects upper and lower motor neurons. Thus, in some embodiments, modulation of ATXN2 expression and activity (e.g., by inhibiting the expression and / or activity of mutant ATXN2 proteins and / or their interactions with other proteins) can have a therapeutic effect on subjects with ALS. Oligonucleotides In some embodiments, ATXN2 (and / or the ataxin-2 protein encoded by ATXN2) expression and / or activity can be modulated by using oligonucleotides targeted to the ATXN2 sequence. In some embodiments, oligonucleotides useful for treating ALS, e.g., targeting ATXN2 (e.g., directly or indirectly modulating the expression or activity of ATXN2), comprise a region complementary to an ATXN2 transcript provided in Table 3 (e.g., provided by any one of SEQ ID NOs: 396 to 400). In some embodiments, some examples of oligonucleotides that can be used to treat ALS, e.g., targeting ATXN2 (e.g., directly or indirectly regulating the expression or activity of ATXN2), are provided in: Becker et al. (2017) “Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice” Nature 544:367-371; Scoles et al. (2017) “Antisense oligonucleotide therapy for spinocerebellar ataxia type 2” Nature 544:362-366; U.S. Patent Application Publication No. 20110142789A1, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis,” published on June 16, 2011; and U.S. Patent Application Publication No. 20130142789A1, entitled “Modulation of nuclear-retained U.S. Patent Application Publication No. 20130225659A1, entitled “Compounds and methods for reducing ATXN2 expression,” published on August 3, 2021; U.S. Patent Application Publication No. 20220064639A1, entitled “Compounds and methods for reducing ATXN2 expression,” published on March 3, 2022; U.S. Patent Application Publication No. 10533178B2, entitled “Methods for modulating Ataxin 2 expression,” published on January 14, 2020; U.S. Patent Application No. 10006027B2, entitled “Methods for modulating Ataxin2 expression,” published on June 26, 2018; U.S. Patent Application No. 20190064639A1, entitled “Compounds and methods for reducing ATXN2 expression,” published on March 3, 2022;10308934B2; U.S. Patent Application No. 11111494B2, entitled “Compositions for modulating Ataxin 2 expression,” published on September 7, 2021; U.S. Patent Application No. 11345915B2, entitled “RNA modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders,” published on May 31, 2022; U.S. Patent Application Publication No. 20140378533A1, entitled “Modulation of RNA by repeat targeting,” published on December 25, 2014; U.S. Patent Application Publication No. 20150148404A1, entitled “RNA Modulating Oligonucleotides with Improved Characteristics for the Treatment of Neuromuscular Disorders,” published on May 28, 2015; U.S. Patent Application Publication No. 20150148404A1, entitled “Nucleic acids and nucleic acid analogs for treating, preventing, and U.S. Patent Application Publication No. 20210169914A1, entitled “Disrupting Pathological Polynucleotide-Binding Protein Inclusions”; U.S. Patent Application Publication No. 20160040163A1, entitled “DNA for the Modulation of Genes,” published on February 11, 2016; U.S. Patent Application Publication No. 10174328B2, entitled “Compositions and Methods for Treating Amyotrophic Lateral Sclerosis,” published on January 8, 2019; and U.S. Patent Application Publication No. 20220162615A1, entitled “Methods for Reducing Ataxin-2 Expression,” published on May 26, 2022; the entire contents of each of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat ALS by modulating the activity of genes and / or gene products other than the ATXN2 gene / gene product (e.g., C9orf72, SOD1, and / or FUS gene / gene product). peptides In some embodiments, ATXN2 expression and / or activity can be modulated by administering an ataxin-2 polypeptide or a polypeptide that interacts with ataxin-2 (e.g., to modulate its biological activity and / or its interaction with other biomolecules). In some embodiments, some examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat ALS are provided in the following: U.S. Patent Application Publication No. 20110142789A1, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis,” published on June 16, 2011; U.S. Patent Application No. 10066007B2, entitled “Dipeptide-repeat proteins as therapeutic target in neurodegenerative diseases with hexanucleotide repeat expansion,” published on September 4, 2019; U.S. Patent Application No. 11273149B2, entitled “Compositions and methods for the treatment of amyotrophic lateral sclerosis, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, and multiple system atrophy,” published on March 15, 2022; and U.S. Patent Application No. 11273149B2, entitled “Methods of treating neuronal disorders using MNTF peptides and analogs thereof”; International PCT application publication No. WO2021222168A2, published on November 4, 2021, entitled “Compositions and methods for the treatment of tdp-43 proteinopathies”; the entire contents of each of which are incorporated herein by reference. Certain polypeptides provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the ATXN2 gene / gene product (eg, C9orf72, SOD1, and / or FUS gene / gene product). Small molecules In some embodiments, ATXN2 expression and / or activity can be modulated by using small molecules that can modulate ATXN2 (eg, to modulate its biological activity, its expression, and / or its interactions with other biomolecules). In some embodiments, some examples of small molecules that can be used to treat ALS are provided in the following: U.S. Patent Application Publication No. 20110142789A1, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis,” published on June 16, 2011; U.S. Patent Application Publication No. 20130303562A1, entitled “Chemical and RNAi suppressors of neurotoxicity in Huntington's disease,” published on November 14, 2013; U.S. Patent Application Publication No. 20140228333A1, entitled “Methods for inhibiting muscle atrophy,” published on March 29, 2016; International PCT Application Publication No. WO2021174167A1, entitled “Compounds and methods for modulating splicing,” published on September 2, 2021; and U.S. Patent Application Publication No. WO20210142789A1, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis,” published on March 28, 2013. compositions for the treatment of Alzheimer's disease and polyglutamine expansion disorder”; U.S. Patent Publication No. 10159670B2, entitled “Methods of diagnosing and treating motor neurondiseases and other cellular stress-related diseases”, published on December 25, 2018; and U.S. Patent Publication No. 9790188B2, entitled “Benzimidazole derivatives and uses thereof”, published on October 17, 2017; the entire contents of each of which are incorporated herein by reference. In some embodiments, the small molecule is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein. Certain small molecules provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the ATXN2 gene / gene product (e.g., C9orf72, SOD1, and / or FUS gene / gene product). Gene therapy In some embodiments, ATXN2 expression and / or activity can be modulated using gene therapy that modulates ATXN2 (eg, by delivering nucleic acid encoding ATXN2 or other molecules that interact with ATXN2). In some embodiments, gene therapies useful for treating ALS, such as those involving administration of compounds encoding useful therapeutic agents, are provided in: U.S. Patent Application Publication No. 20110142789A1, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis,” published on June 16, 2011; U.S. Patent Application Publication No. 20100047261A1, entitled “Base-modified RNA for increasing the expression of a protein,” published on February 25, 2010; U.S. Patent Application Publication No. 20100203076A1, entitled “Complexes of RNA and cationic peptides for transfection and for immunostimulation,” published on August 12, 2010; and U.S. Patent Application Publication No. 20100203076A1, entitled “Messenger RNA molecules and uses” published on October 27, 2020. thereof”; U.S. Patent Publication No. 10815463B2, titled “Therapeutic for treatment of diseases including the central nervous system”, published on October 26, 2021; U.S. Patent Application Publication No. 20180327471A1, titled “Translatable molecules and synthesis thereof”, published on November 15, 2018; the entire contents of each of which are incorporated herein by reference. Certain gene therapies provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the ATXN2 gene / gene product (e.g., C9orf72, SOD1, and / or FUS genes / gene products). Molecular payload targeting C9orf72 The C9orf72 gene, encoding the chromosome 9 open reading frame 72 protein, and mutations therein are associated with ALS, which primarily affects upper and lower motor neurons. Thus, in some embodiments, modulation of C9orf72 expression and activity (e.g., by inhibiting the expression of mutant C9orf72 and / or the activity of the protein encoded thereby) can have a therapeutic effect on subjects with ALS. Oligonucleotides In some embodiments, C9orf72 expression and / or activity can be modulated by using oligonucleotides that target the C9orf72 sequence. In some embodiments, an oligonucleotide useful for treating ALS, e.g., targeting C9orf72 (e.g., directly or indirectly modulating the expression or activity of C9orf72), comprises a region complementary to a C9orf72 transcript provided in Table 3 (e.g., provided by any one of SEQ ID NOs: 393 to 395). In some embodiments, some examples of oligonucleotides that can be used to treat ALS, for example, targeting C9orf72 (e.g., directly or indirectly modulating the expression or activity of C9orf72), are provided in the following: U.S. Patent Publication No. 10577604B2, entitled “Methods for monitoring C9ORF72 expression,” published on March 3, 2020; U.S. Patent Publication No. 10443052B2, entitled “Compositions for modulating C9ORF72 expression,” published on October 15, 2019; U.S. Patent Publication No. 10793855B2, entitled “Compositions for modulating expression of C9ORF72 antisense transcript,” published on October 6, 2020; U.S. Patent Publication No. 10793855B2, entitled “Compositions for modulating expression of C9ORF72 antisense transcript,” published on October 27, 2020; U.S. Patent Publication No. 10815483B2, entitled “expression”; U.S. Patent Publication No. 11260073B2, entitled “Compositions and methods for modulating C9ORF72”, published on March 1, 2022; U.S. Patent Publication No. 10407678B2, entitled “Compositions for modulating expression of C9ORF72 antisense transcript”, published on October 9, 2019; U.S. Patent Publication No. 11162096B2, entitled “Compositions for modulating expression of C9ORF72 antisense transcript”, published on November 2, 2021; U.S. Patent Publication No. US10066228B2, entitled “Oligonucleotides for treating expanded repeat diseases”, published on September 4, 2018; U.S. Patent Publication No. 10066228B2, entitled “RNA modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders”, published on May 31, 2022.11345915B2; U.S. Patent Publication No. 9963699B2, entitled “Methods for modulating C9ORF72 expression,” published on May 8, 2018; U.S. Patent Publication No. 10221414B2, entitled “Compositions for modulating C9ORF72 expression,” published on May 5, 2019; U.S. Patent Application Publication No. 20160108396A1, entitled “Oligomers targeting hexanucleotide repeat expansion in human C9ORF72 gene,” published on April 21, 2016; U.S. Patent Publication No. 10538762, entitled “Allele selective inhibition of mutant C9orf72 fociexpression by duplex RNAS targeting the expanded hexanucleotide repeat,” published on January 21, 2020; U.S. Patent Application Publication No. 10538762, entitled “Compositions and methods of treating amyotrophic lateral fibrosis by duplex RNAs targeting the expanded hexanucleotide repeat,” published on March 24, 2020 sclerosis (ALS)”; U.S. Patent Publication No. 10597660B2, entitled “Mixed tricyclo-DNA, 2′-modified RNA oligonucleotide compositions and uses thereof”, published on September 14, 2021; U.S. Patent Application Publication No. 20210284629A1, entitled “Methods and compounds for the treatment of genetic disease”, published on September 16, 2021; U.S. Patent Application Publication No. 20210269825A1, entitled “Compositions and methods for reducing spliceopathy and treating RNA dominance disorders”, published on September 2, 2021; U.S. Patent Application Publication No. 20210269825A1, entitled “Oligonucleotide-Based Modulation of C9orf72”, published on December 10, 2020.20200385737A1; U.S. Patent Application Publication No. 20200385723A1, entitled “Anti-c9orf72 oligonucleotides and related methods,” published on December 10, 2020; U.S. Patent Application Publication No. 20220145300A1, entitled “Oligonucleotide compositions and methods of use thereof,” published on May 12, 2022; U.S. Patent Application Publication No. 20210032620A1, entitled “Oligonucleotide compositions and methods thereof,” published on February 4, 2021; International PCT Application Publication No. WO2021119226A1, entitled “Human chromosome 9 open reading frame 72 (c9orf72) irna agent compositions and methods of use thereof,” published on December 10, 2020; and International PCT Application Publication No. WO2021119226A1, entitled “DUAL-ACTING U.S. Patent Application Publication No. 20210340535A1, entitled “siRNA BASEDMODULATION OF C9orf72”; International PCT Application Publication No. WO2021205005A2, published on October 14, 2021, entitled “Antisense sequences for treating amyotrophic lateral sclerosis”; the entire contents of each of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat ALS by modulating the activity of genes and / or gene products other than the C9orf72 gene / gene product (eg, the ATXN2, SOD1, and / or FUS gene / gene product). peptides In some embodiments, the expression of C9orf72 and / or the activity of the protein encoded thereby can be modulated by using a polypeptide, e.g., a polypeptide that can interact with C9orf72 and / or the protein encoded thereby (e.g., to modulate its biological activity and / or its interaction with other biomolecules). In some embodiments, some examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat ALS are provided in the following: U.S. Patent Publication No. 10295547B2, entitled “Use and treatment of di-aminoacid repeat-containing proteins associated with ALS,” published on May 21, 2019; U.S. Patent Publication No. 11197911B2, entitled “Peptidylic inhibitors targeting C9ORF72 hexanucleotide repeat-mediated neurodegeneration,” published on December 14, 2021; U.S. Patent Application Publication No. 20220153874A1, entitled “Human-derived anti-(poly-ga) dipeptiderepeat (dpr) antibody,” published on May 19, 2022; and U.S. Patent Application Publication No. 20220153874A1, entitled “Method of treating motor neuron disease with an antibody that agonizes MuSK"; the entire contents of each of which are incorporated herein by reference. Certain polypeptides provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the C9orf72 gene / gene product (eg, the ATXN2, SOD1, and / or FUS gene / gene product). Small molecules In some embodiments, C9orf72 expression and / or the activity of the protein it encodes can be modulated by using small molecules that can modulate C9orf72 (e.g., to modulate its biological activity, its expression, and / or its interactions with other biomolecules). In some embodiments, some examples of small molecules that can be used to treat ALS are provided in the following: U.S. Patent Publication No. 10675293B2, entitled “Nucleoside agents for the reduction of the deleterious activity of extended nucleotide repeat containing genes,” published on June 9, 2020; International PCT Application Publication No. WO2021174167A1, entitled “Compounds and methods for modulating splicing,” published on September 2, 2021; U.S. Patent Publication No. 11241417B2, entitled “Compositions and methods for the treatment and prevention of neurological disorders,” published on February 8, 2022; the entire contents of each of which are incorporated herein by reference. In some embodiments, the small molecule is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein. Certain small molecules provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the C9orf72 gene / gene product (eg, the ATXN2, SOD1, and / or FUS gene / gene product). Gene therapy In some embodiments, C9orf72 expression and / or activity can be modulated using gene therapy that modulates C9orf72 (e.g., by delivering nucleic acid encoding C9orf72 or other molecules that interact with the protein it encodes). In some embodiments, gene therapies that can be used to treat ALS, such as those involving the administration of compounds encoding useful therapeutic agents, are provided in the following: U.S. Patent Publication No. 10597660B2, entitled “Compositions and methods of treating amyotrophic lateral sclerosis (ALS)” published on March 24, 2020; U.S. Patent Application Publication No. 20210269825A1, entitled “Compositions and methods for reducing spliceopathy and treating RNA dominance disorders” published on September 2, 2021; U.S. Patent Publication No. 10801027B2, entitled “Inhibitors of SRSF1 to treat neurodegenerative disorders” published on October 13, 2020; International PCT Application Publication No. WO2021160464A1, entitled “Gene therapy” published on August 19, 2021; the entire contents of each of which are incorporated herein by reference. Certain gene therapies provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the C9orf72 gene / gene product (e.g., the ATXN2, SOD1, and / or FUS gene / gene product). Molecular payload targeting FUS The FUS gene, which encodes the RNA-binding protein FUS / TLS, and mutations therein are associated with ALS, which primarily affects upper and lower motor neurons. Thus, in some embodiments, modulation of FUS expression and activity (e.g., by inhibiting the expression of mutant FUS and / or the activity of the protein encoded thereby) may have a therapeutic effect on subjects with ALS. Oligonucleotides In some embodiments, FUS expression and / or activity can be modulated by using oligonucleotides targeted to the FUS sequence. In some embodiments, oligonucleotides useful for treating ALS, e.g., targeting FUS (e.g., directly or indirectly modulating the expression or activity of FUS), comprise a region complementary to a FUS transcript provided in Table 3 (e.g., provided by any one of SEQ ID NOs: 401 to 404). In some embodiments, some examples of oligonucleotides that can be used to treat ALS, such as targeting FUS (e.g., directly or indirectly modulating the expression or activity of FUS), are provided in: International PCT Application Publication No. WO2020243292A1, entitled “Compounds and methods for reducing fus expression,” published on December 3, 2020; U.S. Patent Publication No. 11332733B2, entitled “Modified compounds and uses thereof,” published on May 17, 2022; U.S. Patent Application Publication No. 20100256223A1, entitled “Oligonucleotides for modulating target RNA activity,” published on October 7, 2010; and U.S. Patent Application Publication No. 20150256223A1, entitled “FUS / TLS-based compounds and methods for diagnosis, treatment and prevention of amyotrophic lateral sclerosis and related motor U.S. Patent Application Publication No. 9150860B2, entitled “Methods and compositions for treating diseases, disorders or injury of the CNS”, published on October 4, 2012; U.S. Patent Application Publication No. 10781445B2, entitled “Decoy oligonucleotides for the treatment of diseases”, published on September 22, 2020; U.S. Patent Application Publication No. 20190127733A1, entitled “Oligonucleotide compositions and methods thereof”, published on May 2, 2019; U.S. Patent Application Publication No. 20190127733A1, entitled “Inhibition of stress granuleformation through manipulation of UBAP2L”, published on December 14, 2021.11197883B2; U.S. Patent Application Publication No. 20210169914A1, entitled “Nucleic acids and nucleic acid analogs for treating, preventing, and disrupting pathological polynucleotide-binding protein inclusions,” published on June 10, 2021; International PCT Application Publication No. WO2021203043A2, entitled “Targeted inhibition using engineered oligonucleotides,” published on October 7, 2021; International PCT Application Publication No. WO2021207854A1, entitled “Compositions and methods for inhibiting TDP-43 and FUS aggregation,” published on October 21, 2021; the entire contents of each of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat ALS by modulating the activity of genes and / or gene products other than the FUS gene / gene product (eg, the ATXN2, SOD1, and / or C9orf72 gene / gene product). peptides In some embodiments, FUS expression and / or the activity of the protein encoded thereby can be modulated by using polypeptides, e.g., polypeptides that can interact with FUS nucleic acid and / or the protein encoded thereby (e.g., to modulate its biological activity, its intracellular localization, and / or its interactions with other biomolecules). In some embodiments, some examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat ALS are provided in: U.S. Patent Publication No. 1132504B2, entitled “Methods of reducing FUS / TLS-or TDP-43-mediated neuronal cytotoxicity by UPF1,” published on May 17, 2022; U.S. Patent Application Publication No. 20180360925A1, entitled “Extracellular DNA as a therapeutic target inneurodegeneration,” published on December 20, 2018; the entire contents of each of which are incorporated herein by reference. Certain polypeptides provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the FUS gene / gene product (eg, the ATXN2, SOD1, and / or C9orf72 gene / gene product). Small molecules In some embodiments, FUS expression and / or the activity of its encoded protein can be modulated by using small molecules that can modulate FUS (e.g., to modulate its biological activity, its expression, its localization, and / or its interactions with other biomolecules). In some embodiments, some examples of small molecules that can be used to treat ALS are provided in the following: U.S. Patent Application Publication No. 20120272345A1, entitled “Diagnosis marker, diagnosis method and therapeutic agent for amyotrophic lateral sclerosis, and animal model and cell model developing amyotrophic lateral sclerosis,” published on October 25, 2012; U.S. Patent Application Publication No. 10159670B2, entitled “Methods of diagnosing and treating motor neuron diseases and other cellular stress-related diseases,” published on December 25, 2018; U.S. Patent Application Publication No. 20200216563A1, entitled “Hdac6 and protein aggregation,” published on July 9, 2020; and U.S. Patent Application Publication No. 20200216563A1, entitled “Compounds and methods for modulating splicing”; U.S. patent application publication No. 20200368267A1, titled “Prophylactic and / or therapeutic agent for amyotrophic lateral sclerosis” published on November 26, 2020; U.S. patent application publication No. 20220071955A1, titled “Methods of Treatment, Prevention and Diagnosis” published on March 10, 2022; the entire contents of each of which are incorporated herein by reference. In some embodiments, the small molecule is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein. Certain small molecules provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the FUS gene / gene product (eg, the ATXN2, SOD1, and / or C9orf72 gene / gene product). Gene therapy In some embodiments, FUS expression and / or activity can be modulated using gene therapy that modulates FUS (e.g., by delivering nucleic acid encoding FUS or other molecules that interact with FUS transcripts or proteins encoded by FUS). In some embodiments, gene therapies useful for treating ALS, such as those involving administration of compounds encoding useful therapeutic agents, are provided in: International PCT Application Publication No. WO2021205010A1, published on October 14, 2021, entitled “Nucleic acids encoding human FUS protein and use in the treatment of amyotrophic lateral sclerosis (ALS)”; the entire contents of each of which are incorporated herein by reference. Certain gene therapies provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the FUS gene / gene product (e.g., the ATXN2, SOD1, and / or C9orf72 gene / gene product). Targeting PIKFYVE's molecular payload The PIKFYVE gene, encoding phosphatidylinositol-3-phosphate 5-kinase type III (PIPKIII), and mutations therein are associated with ALS. Thus, in some embodiments, modulation of PIKFYVE expression and activity (e.g., by inhibiting the expression and / or activity of mutant PIPKIII proteins and / or their interactions with other proteins) can have a therapeutic effect on subjects with ALS. Oligonucleotides In some embodiments, PIKFYVE (and / or the PIPKIII protein encoded by PIKFYVE) expression and / or activity can be modulated by using oligonucleotides targeted to the PIKFYVE sequence. In some embodiments, oligonucleotides useful for treating ALS, e.g., targeting PIKFYVE (e.g., directly or indirectly modulating the expression or activity of PIKFYVE), comprise a region complementary to a PIKFYVE transcript provided in Table 3 (e.g., provided by any one of SEQ ID NOs: 143 to 148). In some embodiments, some examples of oligonucleotides that can be used to treat ALS, such as targeting PIKFYVE (e.g., directly or indirectly regulating the expression or activity of PIKFYVE), are provided below: US20220411804A1, entitled "Pikfyve antisense oligonucleotides," published on December 29, 2022; the entire contents of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat ALS by modulating the activity of genes and / or gene products other than the PIKFYVE gene / gene product (e.g., other genes / gene products associated with ALS). peptides In some embodiments, PIKFYVE expression and / or activity can be modulated by using a PIPKIII polypeptide or a polypeptide that can interact with PIPKIII (eg, to modulate its biological activity and / or its interaction with other biomolecules). In some embodiments, some examples of polypeptides (eg, peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat ALS include PIPKIII protein and functional fragments thereof. Certain polypeptides provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the PIKFYVE gene / gene product (e.g., other genes / gene products associated with ALS). Small molecules In some embodiments, PIKFYVE expression and / or activity can be modulated by using small molecules that can modulate PIPKIII (e.g., to modulate its biological activity, its expression, and / or its interactions with other biomolecules). In some embodiments, some examples of small molecules that can be used to treat ALS are provided in the following: US20190192527A1, entitled “Compositions comprising pikfyve inhibitors and methods related to inhibition of rank signaling”, published on June 27, 2019; WO2017040971A1, entitled “Methods of using inhibitors of pikfyve for the treatment of lysosomal storage disorders and neurodegenerative diseases”, published on March 9, 2017; WO2022086993A1, entitled “Novel inhibitors of pikfyve and methods using same”, published on April 28, 2022; US20210139505A1, entitled “PIKfyve Inhibitors”, published on May 13, 2021; and US20190192527A1, entitled “Compositions comprising pikfyve inhibitors and methods related to inhibition of rank signaling”, published on September 1, 2020. neurological diseases”; US10758545B2, entitled “Fused triazolo-pyrimidine compounds having useful pharmaceutical application”, published on July 20, 2021; the entire contents of each of which are incorporated herein by reference. In some embodiments, the small molecule is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein. Certain small molecules provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the PIKFYVE gene / gene product (e.g., other genes / gene products associated with ALS). Gene therapy In some embodiments, PIKFYVE expression and / or activity can be modulated using gene therapy that modulates PIKFYVE (eg, by delivering nucleic acids encoding PIKFYVE or other molecules that interact with PIKFYVE). In some embodiments, gene therapies useful for treating ALS, such as those involving administration of a compound encoding a useful therapeutic agent, include a cargo encoding PIPKIII or a functional fragment thereof. Certain gene therapies provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the PIKFYVE gene / gene product (e.g., other genes / gene products associated with ALS). Molecular payload targeting SYF2 The SYF2 gene, encoding the pre-mRNA splicing factor SYF2 protein, and mutations therein are associated with ALS. Thus, in some embodiments, modulation of SYF2 expression and activity (e.g., by inhibiting the expression and / or activity of the mutant pre-mRNA splicing factor SYF2 protein and / or its interactions with other proteins) can have a therapeutic effect on subjects with ALS. Oligonucleotides In some embodiments, SYF2 (and / or the pre-mRNA splicing factor SYF2 protein encoded by SYF2) expression and / or activity can be modulated by using oligonucleotides targeted to the SYF2 sequence. In some embodiments, oligonucleotides useful for treating ALS, e.g., targeting SYF2 (e.g., directly or indirectly modulating the expression or activity of SYF2), comprise a region complementary to a SYF2 transcript provided in Table 3 (e.g., provided by any one of SEQ ID NOs: 167 to 168). In some embodiments, some examples of oligonucleotides that can be used to treat ALS, such as targeting SYF2 (e.g., directly or indirectly regulating the expression or activity of SYF2), are provided below: US20230066380A1, entitled "Antagonism as a therapy for tdp-43 proteinopathies," published on March 2, 2023; the entire contents of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat ALS by modulating the activity of genes and / or gene products other than the SYF2 gene / gene product (eg, other genes / gene products associated with ALS). peptides In some embodiments, SYF2 expression and / or activity can be modulated by using a pre-mRNA splicing factor SYF2 polypeptide or a polypeptide that can interact with pre-mRNA splicing factor SYF2 (e.g., to modulate its biological activity and / or its interaction with other biomolecules). In some embodiments, some examples of polypeptides (eg, peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat ALS include pre-mRNA splicing factor SYF2 protein and functional fragments thereof. Certain polypeptides provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the SYF2 gene / gene product, eg, other genes / gene products associated with ALS. Small molecules In some embodiments, SYF2 expression and / or activity can be modulated by using small molecules that can modulate the pre-mRNA splicing factor SYF2 protein (e.g., to modulate its biological activity, its expression, and / or its interactions with other biomolecules). In some embodiments, some examples of small molecules that can be used to treat ALS are small molecules that increase or decrease the expression of SYF2, and / or small molecules that increase or decrease the level or activity of the pre-mRNA splicing factor SYF2 protein. Certain small molecules provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the SYF2 gene / gene product, such as other genes / gene products associated with ALS. Gene therapy In some embodiments, SYF2 expression and / or activity can be modulated using gene therapy that modulates SYF2 (eg, by delivering nucleic acid encoding SYF2 or other molecules that interact with SYF2). In some embodiments, gene therapies useful for treating ALS, such as those involving administration of a compound encoding a useful therapeutic agent, include a cargo encoding the pre-mRNA splicing factor SYF2 protein or a functional fragment thereof. Certain gene therapies provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the SYF2 gene / gene product, such as other genes / gene products associated with ALS. Molecular payloads targeting UNC13A The UNC13A gene, encoding the unc-13 homolog A protein, and mutations therein are associated with ALS. Thus, in some embodiments, modulation of UCN13A expression and activity (e.g., by inhibiting the expression and / or activity of mutant unc-13 homolog A proteins and / or their interactions with other proteins) can have a therapeutic effect on subjects with ALS. Oligonucleotides In some embodiments, UNC13A (and / or the unc-13 homolog A protein encoded by UNC13A) expression and / or activity can be modulated by using oligonucleotides that target the UNC13A sequence. In some embodiments, oligonucleotides useful for treating ALS, e.g., targeting UNC13A (e.g., directly or indirectly modulating the expression or activity of UNC13A), comprise a region complementary to a UNC13A transcript provided in Table 3 (e.g., provided by any one of SEQ ID NOs: 169 and 810 to 818). In some embodiments, some examples of oligonucleotides that can be used to treat ALS, such as targeting UNC13A (e.g., directly or indirectly modulating the expression or activity of UNC13A), are provided in the following: WO2022246251A2, entitled “Compounds for modulating unc13a expression”, published on November 24, 2022; WO2023102225, entitled “Treatment of neurological diseases using modulators of unc13a gene transcripts”, published on December 2, 2022; US20230125137, entitled “Unc13a antisense oligonucleotides”, published on April 27, 2023; WO2022122872, entitled “Therapeutics for the treatment of neurodegenerative disorders”, published on June 16, 2022; and US20230125137, entitled “Splice switcher antisense oligonucleotides with WO2023102242 entitled “modified backbone chemistries”; WO2023104964 entitled “Therapeutics for the treatment of neurodegenerative disorders” published on June 15, 2023; and US20220033818A1 entitled “Oligonucleotides targeting rna binding protein sites” published on February 3, 2023; the entire contents of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat ALS by modulating the activity of genes and / or gene products other than the UNC13A gene / gene product (eg, other genes / gene products associated with ALS). peptides In some embodiments, UNC13A expression and / or activity can be modulated using an unc-13 homolog A polypeptide or a polypeptide that interacts with unc-13 homolog A (e.g., to modulate its biological activity and / or its interaction with other biomolecules). In some embodiments, some examples of polypeptides (eg, peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat ALS include unc-13 homolog A protein and functional fragments thereof. Certain polypeptides provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the UNC13A gene / gene product (eg, other genes / gene products associated with ALS). Small molecules In some embodiments, UNC13A expression and / or activity can be modulated by using small molecules that can modulate the unc-13 homolog A protein (e.g., to modulate its biological activity, its expression, and / or its interactions with other biomolecules). In some embodiments, some examples of small molecules that can be used to treat ALS are small molecules that increase or decrease the expression of UNC13A, and / or small molecules that increase or decrease the level or activity of unc-13 homolog A protein. Certain small molecules provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the UNC13A gene / gene product, such as other genes / gene products associated with ALS. Gene therapy In some embodiments, UNC13A expression and / or activity can be modulated using gene therapy that modulates UNC13A (eg, by delivering nucleic acid encoding UNC13A or other molecules that interact with UNC13A). In some embodiments, gene therapies useful for treating ALS, such as those involving administration of a compound encoding a useful therapeutic agent, include a cargo encoding the unc-13 homolog A protein or a functional fragment thereof. Certain gene therapies provided in this section can be used to treat ALS by modulating the activity of genes and gene products other than the UNC13A gene / gene product, such as other genes / gene products associated with ALS. Molecular payloads for the treatment of spinocerebellar ataxias A variety of molecular payloads can be used to treat spinocerebellar ataxias (e.g., SCA1, SCA2, SCA3, and / or other types of SCA), including oligonucleotides, polypeptides (e.g., peptides, proteins, enzymes, antibodies, etc.), small molecules (e.g., small molecule inhibitors, etc.), and gene therapy (e.g., nucleic acids and / or nucleic acid vectors encoding therapeutic molecules (e.g., therapeutic proteins)). In some embodiments, molecular payloads that can be used to treat spinocerebellar ataxias can include molecular payloads that modulate (e.g., increase or decrease) the expression or activity of ATXN1, ATXN2, ATXN3, and / or MSH3. Some examples of oligonucleotides that can be used to treat spinocerebellar ataxia, for example, oligonucleotides that target genes associated with cerebellar ataxia (e.g., ATXN1, ATXN2, ATXN3, MSH3, etc.) (e.g., directly or indirectly modulate their expression or activity) include those listed below in Table 7. Each oligonucleotide provided in Table 7 can have any modification pattern disclosed herein. Table 7. Oligonucleotides for the treatment of spinocerebellar ataxias In each sequence listed in Table 7, each T can be optionally and independently replaced by U, and each U can be optionally and independently replaced by T. Some examples of small molecules that can be used to treat spinocerebellar ataxias (e.g., SCA1, SCA2, SCA3, and / or other types of SCA) include: baclofen, chlorzoxazone, A71623, and pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof. Some examples of polypeptides that can be used to treat spinocerebellar ataxias (e.g., SCA1, SCA2, SCA3, and / or other types of SCA) include antibodies, proteins, peptides, and enzymes. In some embodiments, polypeptides that can be used to treat SCA include: A71623 (Boc-Trp-Lys(Tac)-Asp-N-methyl-Phe-NH2) (SEQ ID NO: 807). Molecular payload targeting ATXN1 The ATXN1 gene, which encodes the ataxia-1 protein, and mutations therein are associated with SCA type 1 (SCA1). Thus, in some embodiments, modulation of ATXN1 expression and activity (e.g., by inhibiting the expression and / or activity of mutant ATXN1 proteins and / or their interactions with other proteins) can have a therapeutic effect on subjects with SCA1. Oligonucleotides In some embodiments, ATXN1 (and / or the ataxia 1 protein encoded by ATXN1) expression and / or activity can be modulated by using oligonucleotides targeted to the ATXN1 sequence. In some embodiments, oligonucleotides useful for treating SCA, eg, targeting ATXN1 (eg, directly or indirectly modulating the expression or activity of ATXN1), comprise a region complementary to an ATXN1 transcript provided in Table 3 (eg, provided by any one of SEQ ID NOs: 819-820). In some embodiments, some examples of oligonucleotides that can be used to treat SCA1, e.g., targeting ATXN1 (e.g., directly or indirectly modulating the expression or activity of ATXN1), are provided in: US11542504B2, entitled “Compounds and methods for modulating ATXN1,” published on January 3, 2023; and US11345915B2, entitled “RNA modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders,” published on May 31, 2022; the entire contents of each of which are incorporated herein by reference. Certain oligonucleotides provided in this section can be used to treat SCA1 by modulating the activity of genes and / or gene products other than the ATXN1 gene / gene product (eg, other genes / gene products associated with SCA and / or SCA1). peptides In some embodiments, ATXN1 expression and / or activity can be modulated by administering an Ataxin 1 polypeptide or a polypeptide that interacts with Ataxin 1 (eg, to modulate its biological activity and / or its interaction with other biomolecules). In some embodiments, some examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies, etc.) that can be used to treat SCA1 are provided in: US10989719B2, entitled “Methods for treating spinocerebellar ataxia type I using RPA1,” published on April 27, 2021; US10973812B2, entitled “Ataxia therapeutic compositions and methods,” published on April 13, 2021; the entire contents of each of which are incorporated herein by reference. Certain polypeptides provided in this section can be used to treat SCA1 by modulating the activity of genes and gene products other than the ATXN1 gene / gene product, such as other genes / gene products associated with SCA and / or SCA1. Small molecules In some embodiments, ATXN1 expression and / or activity can be modulated by using small molecules that can modulate ATXN1 (eg, to modulate its biological activity, its expression, and / or its interactions with other biomolecules). In some embodiments, some examples of small molecules that can be used to treat SCA1 are provided in US11382897B2, published on July 12, 2022, entitled "Therapeutic combination for treatment of cerebellar ataxia"; the entire contents of each of which are incorporated herein by reference. In some embodiments, the small molecule is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein. Certain small molecules provided in this section can be used to treat SCA1 by modulating the activity of genes and gene products other than the ATXN1 gene / gene product, such as other genes / gene products associated with SCA and / or SCA1. Gene therapy In some embodiments, ATXN1 expression and / or activity can be modulated using gene therapy that modulates ATXN1 (eg, by delivering nucleic acid encoding ATXN1 or other molecules that interact with ATXN1). In some embodiments, gene therapies useful for treating SCA1, such as those involving administration of compounds encoding useful therapeutic agents, are provided in: US20110016540A1, entitled “Genome editing of genes associated with trinucleotide repeat expansion disorders in animals,” published on January 20, 2011; US10989719B2, entitled “Methods for treating spinocerebellar ataxia type I using RPA1,” published on April 27, 2021; US11027024B2, entitled “Methods of delivery of transgenes for treating brain diseases,” published on June 8, 2021; and US20210238226A1, entitled “Methods and compounds for the treatment of genetic disease,” published on August 5, 2021; the entire contents of each of which are incorporated herein by reference. Certain gene therapies provided in this section can be used to treat SCA1 by modulating the activity of genes and gene products other than the ATXN1 gene / gene product, such as other genes / gene products associated with SCA and / or SCA1. Molecular payload targeting ATXN2 The ATXN2 gene, which encodes the atax...

Claims

1. A complex comprising an anti-TfR1 antibody covalently linked to a molecular payload for use in treating a central nervous system (CNS) disease or disorder, wherein the anti-TfR1 antibody comprises: (i) heavy chain complementary determining region 1 (CDR-H1) of SEQ ID NO: 1, heavy chain complementary determining region 2 (CDR-H2) of SEQ ID NO: 2, heavy chain complementary determining region 3 (CDR-H3) of SEQ ID NO: 3, light chain complementary determining region 1 (CDR-L1) of SEQ ID NO: 4, light chain complementary determining region 2 (CDR-L2) of SEQ ID NO: 5, and light chain complementary determining region 3 (CDR-L3) of SEQ ID NO: 6; (ii) CDR-H1 of SEQ ID NO:7, CDR-H2 of SEQ ID NO:8, CDR-H3 of SEQ ID NO:9, CDR-L1 of SEQ ID NO:10, CDR-L2 of SEQ ID NO:11, and CDR-L3 of SEQ ID NO:6; or (iii) CDR-H1 of SEQ ID NO: 12, CDR-H2 of SEQ ID NO: 13, CDR-H3 of SEQ ID NO: 14, CDR-L1 of SEQ ID NO: 15, CDR-L2 of SEQ ID NO: 5, and CDR-L3 of SEQ ID NO: 16; wherein said complex delivers said molecular cargo to cells of said CNS.

2. The complex of claim 1, wherein the anti-TfR1 antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

18.

3. The complex of claim 1 or claim 2, wherein the anti-TfR1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO:

20.

4. The complex of any one of claims 1 to 3, wherein the anti-TfR1 antibody is a Fab.

5. The complex of any one of claims 1 to 4, wherein the molecular cargo is configured to modulate expression of a gene associated with the CNS disease or disorder.

6. The complex of any one of claims 1 to 5, wherein the molecular cargo comprises an oligonucleotide, a polypeptide, a small molecule, or a gene therapy cargo, optionally wherein the gene therapy cargo comprises a messenger RNA (mRNA) molecule.

7. The complex of any one of claims 1 to 6, wherein the anti-TfR1 antibody is covalently linked to the molecular payload via a linker comprising the structure of the following formula (I): wherein n is any number from 0 to 10, and wherein m is any number from 0 to 10, optionally wherein n is 3 and / or m is 4; and wherein L1 is a spacer, the spacer being a substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-,-N(RA)-,-S-,-C(=O)-,-C(=O)O-,-C(=O)NRA -NRAC(=O)-,-NRAC(=O)RA,-C(=O)RA,-NRAC(=O)O-,-NRAC(=O)N(RA)-,-OC(=O)-OC(=O)O-,-OC(=O)N(RA),-S(O)2NR,-NRAS(O)2-, or a combination thereof, wherein each R A is independently hydrogen or substituted or unsubstituted alkyl.

8. The complex of any one of claims 1 to 7, wherein the complex comprises a structure of the following formula (J): wherein n is any number from 0 to 10, and wherein m is any number from 0 to 10, optionally wherein n is 3 and / or m is 4.

9. The complex of any one of claims 1 to 8, wherein the complex delivers the molecular cargo across the blood-brain barrier to cells of the CNS.

10. The complex of any one of claims 1 to 8, wherein the complex delivers the molecular cargo to cells of the CNS across the choroid plexus.

11. The complex of any one of claims 5 to 10, wherein the gene associated with a CNS disease or disorder is: (i) DMPK, DMD, SMN, or FXN; (ii) SOD1, C9orf72, ATXN2, or FUS; (iii) LRRK2 or SNCA; (iv) HTT or MSH3; (v) TREM2, APOE, MAPT, or APP; (vi) GYS1, PrP, VLA-4, GFAP, UBE3A, LSD, or SCN9A; or (vii) SCN1A, SCN2A, SCN8A, SCN9A, CLN3, GRIA1, or PCDH19.

12. The complex of any one of claims 5 to 10, wherein the gene associated with a CNS disease or disorder is: TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, or ECHS1.

13. The complex of any one of claims 5 to 10, wherein the gene associated with a CNS disease or disorder is: (i) PIKFYVE, SYF2, or UNC13A; (ii) GRIN2A; (iii) ATXN1, ATXN2, ATXN3, or MSH3; (iv) GRN, C9orf72, MAPT, PIKFYVE, SYF2, or UNC13A; (v) TPP1 or CLN3; or (vi) APOE, SCN1A, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, or MECP2.

14. The complex of any one of claims 1 to 13, wherein the molecular payload comprises an oligonucleotide comprising a complementary region to a transcript shown in any one of SEQ ID NOs: 392 to 702, or an oligonucleotide comprising a complementary region to a target sequence comprising an oligonucleotide listed in any one of Tables 5 to 19, optionally wherein the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5 to 19.

15. The complex of any one of claims 1 to 13, wherein the molecular payload comprises an oligonucleotide comprising a complementary region to a transcript shown in any one of SEQ ID NOs: 705 to 803, or an oligonucleotide comprising a complementary region to a target sequence comprising an oligonucleotide listed in any one of Tables 5 to 19, optionally wherein the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5 to 19.

16. The complex of any one of claims 1 to 13, wherein the molecular payload comprises an oligonucleotide comprising a complementary region to a transcript set forth in any one of SEQ ID NOs: 143 to 148, 167 to 169, 810 to 875, and 1059 to 1068, or an oligonucleotide comprising a complementary region to a target sequence comprising an oligonucleotide listed in any one of Tables 5 to 19, optionally wherein the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5 to 19.

17. The complex of any one of claims 1 to 16, wherein the CNS disease or disorder is a neuromuscular disease or disorder, optionally wherein the neuromuscular disease or disorder is: Duchenne muscular dystrophy, myotonic dystrophy, Friedreich's ataxia, or spinal muscular atrophy.

18. The complex of any one of claims 1 to 16, wherein the CNS disease or disorder is: (i) amyotrophic lateral sclerosis; (ii) Parkinson's disease; (iii) essential tremor; (iv) Huntington's disease; (v) Alzheimer's disease; (vi) hereditary dystonia; (vii) epilepsy; (viii) a pain disorder; or (ix) Glycogen synthesis disorder; neurodegeneration; Small fiber neuropathy; Nociception-related phenotypes; Alexander disease; Angelman syndrome; autism spectrum disorder; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis.

19. The complex of any one of claims 1 to 16, wherein the CNS disease or disorder is: (i) Spinocerebellar ataxia (SCA); (ii) frontotemporal dementia (FTD); (iii) motor neurone disease; (iv) Dravet syndrome; (v) Batten disease; (vi) GM1 gangliosidosis; (vii) Type A Niemann-Pick; (viii) metachromatic leukodystrophy; (ix) Krabbe disease; (x) Tay-Sachs; (xi) Sandhoff disease; (xii) Gaucher disease type II or III; or (xiii) Rett syndrome.

20. The complex of any one of claims 1 to 19, wherein the molecular payload is a molecular payload disclosed in any one of paragraphs [0216] to [1208], optionally wherein the molecular payload is a molecular payload disclosed in any one of the following paragraphs: [0296]-[0299], [0404]-[0406], [0468]-[0470], [0500]-[0502], [0535]-[0539], [0601]-[0604], [0666]-[0668], [0757]-[0759], [0779]-[0781], [0896]-[0901], [0916]-[0918], [0946]-[0948], [1049]-[1056], [1070]-[1078], [1092]-[1102], [1116]-[1124], [1138]-[1141], [1155]-[1158], [1172]-[1177], and [1191]-[1193].

21. A method of treating a CNS disease or disorder, the method comprising administering to a subject in need thereof a complex according to any one of claims 1 to 20.

22. A method of delivering a molecular cargo to the CNS of a subject, the method comprising administering to the subject the complex of any one of claims 1 to 20.

23. The method of claim 22, wherein the complex is administered to the subject intravenously.

24. The method of claim 22 or 23, wherein the complex is detectable in the cortex of the subject following the administering.

25. The method of any one of claims 22 to 24, wherein the complex is detectable in the cerebellum of the subject following the administering.

26. The method of any one of claims 22 to 25, wherein the complex is detectable in a deep brain tissue of the subject following the administration, optionally wherein the deep brain tissue is of the thalamus, caudate nucleus and / or putamen of the subject.

27. The method of any one of claims 22 to 26, wherein the complex is detectable in cortical neurons, motor neurons, cells of the cerebellum, and / or choroid plexus cells of the subject following the administering.

28. The method of any one of claims 22 to 27, wherein the molecular cargo comprises a protein, optionally wherein the protein is an enzyme.

29. The method of claim 28, wherein the subject has been diagnosed with or is suspected of having Batten disease, GM1 gangliosidosis, Niemann-Pick type A, metachromatic leukodystrophy, Krabbe disease, Tay-Sachs, Sandhoff disease, or Gaucher disease.

30. The method of any one of claims 22 to 27, wherein the payload comprises an oligonucleotide.

31. The method of claim 30, wherein the subject has been diagnosed with or is suspected of having ALS, Angelman syndrome, Rett syndrome, Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease (which may or may not be associated with cerebral amyloid angiopathy (CAA) or frontotemporal dementia), epilepsy, Alexander disease, spinal muscular atrophy, Batten disease, Huntington's disease, spinocerebellar ataxia, motor neuron disease, or Dravet syndrome.

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