CNS targeting complexes and uses thereof

Abstract

The present application relates to complexes comprising a central nervous system (CNS)-targeting agent covalently linked to a molecular payload (e.g., an oligonucleotide, polypeptide, small molecule, or gene therapy pay load) for delivery to cells (e.g., cells of the CNS) and uses thereof, particularly uses relating to treatment of disease.

Description

CNS TARGETING COMPLEXES AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No.63 / 367,814, entitled “BRAIN TARGETING COMPLEXES AND USES THEREOF,” filed on July 6, 2022, and of U.S. Provisional Application Serial No. 63 / 496,184, entitled “CNS TARGETING COMPLEXES AND USES THEREOF,” filed on April 14, 2023, the entire contents of each of which are incorporated herein by reference. FIELD OF THE INVENTION

[0002] 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 uses relating to treatment of disease. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The contents of the electronic sequence listing (D082470081WO00-SEQ-COB.xml; Size: 3,883,598 bytes; and Date of Creation: July 5, 2023) are herein incorporated by reference in their entirety. BACKGROUND

[0004] Neurological diseases and disorders, affecting the central nervous system (CNS), affect millions of people around the world, and many have few or no treatment options. Therapeutic compounds with potential efficacy in various neurological conditions often fail to achieve their intended effects or are limited in their efficacy because of limitations in their biodistribution, including inability to efficiently cross the blood-brain barrier. SUMMARY

[0005] According to some aspects, the present disclosure provides complexes comprising central nervous system (CNS)-targeting agent covalently linked to molecular payloads, compositions comprising such complexes, and methods of their use. The CNS-targeting agents of the complexes described herein comprises an anti-transferrin receptor 1 (TfR1) antibody that is demonstrated to be able to transport the molecular payloads across the blood-brain barrier(e.g., via receptor mediated transcytosis), resulting in delivery of the molecular payloads to cells of the CNS. In some embodiments, the molecular payloads of the complexes described herein modulate the expression or activity of genes associated with disease or disorder of the central nervous system (CNS) and / or have therapeutic effect to a disease or disorder of the CNS.

[0006] According to some aspects, complexes are provided herein, wherein a complex comprises an anti-TfR1 antibody covalently linked to a molecular payload for treating a central nervous system (CNS) disease or disorder, wherein the anti-TfR1 antibody comprises: (i) a heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) of SEQ ID NO: 2, a heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 3, a light chain complementarity determining region 1 (CDR-L1) of SEQ ID NO: 4, a light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 5, and a light chain complementarity determining region 3 (CDR-L3) of SEQ ID NO: 6; (ii) a CDR-H1 of SEQ ID NO: 7, a CDR-H2 of SEQ ID NO: 8, a CDR-H3 of SEQ ID NO: 9, a CDR-L1 of SEQ ID NO: 10, a CDR-L2 of SEQ ID NO: 11, and a CDR-L3 of SEQ ID NO: 6; or (iii) a CDR-H1 of SEQ ID NO: 12, a CDR-H2 of SEQ ID NO: 13, a CDR-H3 of SEQ ID NO: 14, a CDR-L1 of SEQ ID NO: 15, a CDR-L2 of SEQ ID NO: 5, and a CDR-L3 of SEQ ID NO: 16; wherein the complex delivers the molecular payload to a cell of the CNS.

[0007] In some embodiments, the anti-TfR1 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 17 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 18.

[0008] In some embodiments, the anti-TfR1 antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 19 and a light chain comprising an amino acid sequence of SEQ ID NO: 20.

[0009] In some embodiments, the anti-TfR1 antibody is a Fab.

[0010] In some embodiments, the molecular payload is configured to modulate expression of a gene associated with the CNS disease or disorder.

[0011] In some embodiments, the molecular payload comprises an oligonucleotide, a polypeptide, a small molecule, or a gene therapy payload. In some embodiments, the gene therapy payload comprises a messenger RNA (mRNA) molecule.

[0012] In some embodiments, the anti-TfR1 antibody is covalently linked to the molecular payload via a linker comprising a structure of formula (I):wherein n is any number from 0-10, and wherein m is any number from 0-10; and wherein L1 is a spacer that is 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)2NRA-, -NRAS(O)2-, or a combination thereof, wherein each RAis independently hydrogen or substituted or unsubstituted alkyl. In some embodiments, n is 3 and / or m is 4.

[0013] In some embodiments, the complex comprises a structure of formula (J):wherein n is any number from 0-10, and wherein m is any number from 0-10. In some embodiments, n is 3 and / or m is 4.

[0014] In some embodiments, the complex delivers the molecular payload to the cell of the CNS across the blood-brain barrier. In some embodiments, the complex delivers the molecular payload to the cell of the CNS across the choroid plexus.

[0015] In some embodiments, the gene associated with a CNS disease or disorder is DMPK, DMD, SMN, or FXN.

[0016] In some embodiments, the gene associated with a CNS disease or disorder is SOD1, C9orf72, ATXN2, or FUS.

[0017] In some embodiments, the gene associated with a CNS disease or disorder is LRRK2 or SNCA.

[0018] In some embodiments, the gene associated with a CNS disease or disorder is HTT or MSH3.

[0019] In some embodiments, the gene associated with a CNS disease or disorder is TREM2, APOE, MAPT, or APP.

[0020] In some embodiments, the gene associated with a CNS disease or disorder is GYS1, PrP, VLA-4, GFAP, UBE3A, LSD, or SCN9A.

[0021] In some embodiments, the gene associated with a CNS disease or disorder is SCN1A, SCN2A, SCN8A, SCN9A, CLN3, GRIA1, or PCDH19.

[0022] In some embodiments, 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.

[0023] In some embodiments, the gene associated with a CNS disease or disorder is PIKFYVE, SYF2, or UNC13A.

[0024] In some embodiments, the gene associated with a CNS disease or disorder is GRIN2A.

[0025] In some embodiments, the gene associated with a CNS disease or disorder is ATXN1, ATXN2, ATXN3, or MSH3.

[0026] In some embodiments, the gene associated with a CNS disease or disorder is GRN, C9orf72, MAPT, PIKFYVE, SYF2, or UNC13A.

[0027] In some embodiments, the gene associated with a CNS disease or disorder is TPP1 or CLN3.

[0028] In some embodiments, the gene associated with a CNS disease or disorder is APOE, SCN1A, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, or MECP2.

[0029] In some embodiments, the molecular payload comprises an oligonucleotide comprising a region of complementarity to a transcript as set forth in any one of SEQ ID NOs: 392-702, or to a target sequence of an oligonucleotide listed in any one of Tables 5-19. In some embodiments, the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5-19.

[0030] In some embodiments, the molecular payload comprises an oligonucleotide comprising a region of complementarity to a transcript as set forth in any one of SEQ ID NOs: 705-803, or to a target sequence of an oligonucleotide listed in any one of Tables 5-19. In some embodiments, the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5-19.

[0031] In some embodiments, the molecular payload comprises an oligonucleotide comprising a region of complementarity to a transcript as set forth in any one of SEQ ID NOs: 143-148, 167-169, 810-875, and 1059-1068, or to a target sequence of an oligonucleotide listed in any one of Tables 5-19. In some embodiments, the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5-19.

[0032] 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.

[0033] In some embodiments, the CNS disease or disorder is amyotrophic lateral sclerosis.

[0034] In some embodiments, the CNS disease or disorder is Parkinson’s disease.

[0035] In some embodiments, the CNS disease or disorder is essential tremor.

[0036] In some embodiments, the CNS disease or disorder is Huntington’s disease.

[0037] In some embodiments, the CNS disease or disorder is Alzheimer’s disease.

[0038] In some embodiments, the CNS disease or disorder is hereditary dystonia.

[0039] In some embodiments, the CNS disease or disorder is epilepsy.

[0040] In some embodiments, the CNS disease or disorder is a pain disorder.

[0041] In some embodiments, the CNS disease or disorder is a glycogen synthesis disorder; neurodegeneration; small fiber neuropathy; a nociception-related phenotype; Alexander disease; Angelman Syndrome; an autism-spectrum disorder; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis.

[0042] In some embodiments, the CNS disease or disorder is spinocerebellar ataxia (SCA).

[0043] In some embodiments, the CNS disease or disorder is frontotemporal dementia (FTD).

[0044] In some embodiments, the CNS disease or disorder is motor neuron disease.

[0045] In some embodiments, the CNS disease or disorder is Dravet syndrome.

[0046] In some embodiments, the CNS disease or disorder is Batten disease.

[0047] In some embodiments, the CNS disease or disorder is GM1 gangliosidosis.

[0048] In some embodiments, the CNS disease or disorder is Niemann-Pick Type A.

[0049] In some embodiments, the CNS disease or disorder is metachromatic leukodystrophy.

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

[0051] In some embodiments, the CNS disease or disorder is Tay-Sachs.

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

[0053] In some embodiments, the CNS disease or disorder is Gaucher disease, type II or III.

[0054] In some embodiments, the CNS disease or disorder is Rett syndrome.

[0055] In some embodiments, the CNS disease or disorder is the molecular payload is a molecular payload disclosed in any one of paragraphs

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[0056] According to some aspects, methods of treating a CNS disease or disorder are provided herein, wherein the method comprises administering to a subject in need thereof a complex disclosed herein.

[0057] According to some aspects, methods of delivering a molecular payload to the CNS of a subject are provided herein, wherein the method comprises administering to the subject a complex disclosed herein.

[0058] In some embodiments, the complex is administered to the subject intravenously.

[0059] In some embodiments, the complex is detectable in the cortex of the subject following the administration.

[0060] In some embodiments, the complex is detectable in the cerebellum of the subject following the administration.

[0061] In some embodiments, the complex is detectable in deep brain tissue of the subject following the administration. In some embodiments, the deep brain tissue is of the thalamus, caudate nucleus and / or putamen of the subject.

[0062] In some embodiments, the complex is detectable in cortical neurons, motor neurons, cells of the cerebellum, and / or choroid plexus cells of the subject following the administration.

[0063] In some embodiments, the molecular payload comprises a protein. In some embodiments, the protein is an enzyme.

[0064] 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.

[0065] In some embodiments, the payload comprises an oligonucleotide.

[0066] In some embodiments, the subject has been diagnosed with or is suspected of having ALS, Angelman syndrome, Rett syndrome, Parkinson, lewy body dementia, 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

[0067] FIG.1 shows antisense oligonucleotide (ASO) concentration (ng ASO / g tissue) within brain tissue of mice administered PBS (“Vehicle”), ASO that was not covalently linked to an antibody (“Naked ASO”), complexes comprising a first anti-TfR1 Fab covalently linked to the ASO (“Anti-TfR1 Fab1-ASO Complex”), or complexes comprising a second anti-TfR1 Fab covalently linked to the ASO (“Anti-TfR1 Fab2-ASO Complex”) via intravenous injection. Bars show the average ASO concentration measured + / - standard deviation, and circles represent the values measured in tissues from individual mice (n = 4 mice per group).

[0068] FIGs.2A and 2B show antisense oligonucleotide (ASO) concentration (ng ASO / g tissue) within brain tissue of mice administered vehicle control (25 mM Tris, 10 % sucrose, pH 7.4; “Vehicle”), ASO that was not covalently linked to an antibody (“Naked ASO”), complexes comprising a control Fab with no specificity for TfR1 covalently linked to the ASO (“Control Fab-ASO Complex”), or complexes comprising an anti-TfR1 Fab covalently linked to the ASO (“Anti-TfR1 Fab1-ASO Complex”) via intravenous injection. FIG.2A shows ASO concentration measured in the cortex. FIG.2B shows ASO concentration measured in the cerebellum. Bars show the average ASO concentration measured + standard deviation (n = 7 mice per group).

[0069] FIGs.3A and 3B show human mutant DMPK expression measured within brain tissue of mice administered vehicle control (25 mM Tris, 10 % sucrose, pH 7.4; “Vehicle”), ASO that was not covalently linked to an antibody (“Naked ASO”), complexes comprising a control Fab with no specificity for TfR1 covalently linked to the ASO (“Control Fab-ASO Complex”), or complexes comprising an anti-TfR1 Fab covalently linked to the ASO (“Anti-TfR1 Fab1-ASO Complex”) via intravenous injection. Values are shown relative to expression in vehicle-treated mice. FIG.3A shows human mutant DMPK expression measured in the cortex. FIG.3B shows human mutant DMPK expression measured in the cerebellum. Bars show the average ASO concentration measured + standard deviation (*, P < 0.05; ***, P < 0.001, calculated by one-way ANOVA with Dunnet’s multiple comparisons test; n = 7 mice per group).

[0070] FIG.4 shows quantification of human mutant DMPK foci in nuclei of brain cells of the cerebellum of mice administered vehicle control (25 mM Tris, 10 % sucrose, pH 7.4; “Vehicle”) or complexes comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO (“Anti-TfR1 Fab1-ASO Complex”) via intravenous injection, measured by counting of foci per mm2of nucleus area over hundreds of cells imaged. Data are shown as mean + standard deviation (*, P < 0.05, calculated by Welch’s t-test; n = 6-7 mice per group).

[0071] FIG.5 shows quantification of human mutant DMPK foci in nuclei of brain cells of the cortex of mice administered vehicle control or complexes comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO (“Anti-TfR1 Fab1-ASO Complex”) via intravenous injection, measured by counting of foci per mm2of nucleus area over hundreds of cells imaged. Data are shown as mean + standard deviation (**, P < 0.01; n = 4-5 mice per group).

[0072] FIG.6 shows human mutant DMPK expression measured within brain tissue of mice administered vehicle or complexes comprising anti-TfR1 Fab1 covalently linked to DMPK- targeting ASOs. DMPK expression was measured 8 weeks following a single intravenous administration of vehicle or the complexes. Bars show the average DMPK expression normalized to mice administered the vehicle control, + standard deviation (n = 3-5 mice per group).

[0073] FIG.7 shows human mutant DMPK expression measured within brain tissue of mice administered vehicle or complexes comprising anti-TfR1 Fab1 covalently linked to DMPK- targeting ASOs. DMPK expression was measured on day 56, following two intravenous administrations (on days 0 and 28, respectively) of vehicle or the complexes. Bars show the average DMPK expression normalized to mice administered the vehicle control, + standard deviation (n = 3-5 mice per group; *, P ≤ 0.05).

[0074] FIGs.8A-8C show quantification of ASO (in nM) within brain tissue of cynomolgus monkeys following administration of ASO not covalently linked to an antibody (“Naked ASO”; downward facing arrows) or an ASO-equivalent dose of anti-TfR1 Fab1-ASO complexes (upward facing arrows) via intravenous (IV) injection. ASO content over time was measured by hybridization-based ELISA in the cortex (FIG.8A), deep brain (FIG.8B) and cerebellum (FIG.8C). Values are shown as mean + / - standard error (N = 2 monkeys per group).

[0075] FIGs.9A-9C show ASO distribution in brain tissue of cynomolgus monkeys following administration of ASO not covalently linked to an antibody (“Naked ASO”) or an ASO- equivalent dose of anti-TfR1 Fab1-ASO complexes via intravenous (IV) or intrathecal (IT)administration. ASO distribution was measured by in situ hybridization, and is shown in the cortex and deep brain areas (FIG.9A) and cerebellum (FIG.9B) in monkeys intravenously (IV) administered either the naked ASO or the complexes, and in the cortex and deep brain of monkeys intrathecally (IT) administered naked ASO or IV administered the complexes (FIG. 9C). The deep brain area shown includes the caudate nucleus and putamen.

[0076] FIGs.10A-10D show ASO concentration (ng ASO / g tissue) within CNS tissue of mice administered vehicle control (25 mM Tris, 10 % sucrose, pH 7.4; “Vehicle”) or complexes comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO (“Anti-TfR1 Fab1- ASO Complexes”) at ASO-equivalent doses of 5 mg / kg or 10 mg / kg via intravenous injection at 0 and 28 days. ASO concentration was measured in the cortex (FIG.10A), cerebellum (FIG.10B), deep brain regions (FIG.10C), and spinal cord (FIG.10D) of treated mice. Bars show the average ASO concentration measured + standard deviation (n = 6-7 mice per group).

[0077] FIGs.11A-11E show human mutant DMPK expression measured within brain tissue of mice administered vehicle control (25 mM Tris, 10 % sucrose, pH 7.4; “Vehicle”) or complexes comprising an anti-TfR1 Fab covalently linked to the ASO (“Anti-TfR1 Fab1-ASO Complexes”) at ASO-equivalent doses of 5 mg / kg or 10 mg / kg via intravenous injection at 0 and 28 days. Values are shown relative to expression in vehicle-treated mice. Human mutant DMPK expression was measured in the cortex (FIG.11A), cerebellum (FIG.11B), deep brain regions (FIG.11C), brain stem (FIG.11D) and spinal cord (FIG.11E) of treated mice. Bars show the average ASO concentration measured + standard deviation (*, P < 0.05; **, P < 0.01; ***, P < 0.005, calculated by one-way ANOVA with Dunnet’s multiple comparisons test; n = 6-7 mice per group, or 2-3 mice per group for spinal cord analysis).

[0078] FIGs.12A-12C shows quantification of human mutant DMPK foci in nuclei of cortical neurons (FIG.12A), cells of the cerebellum (FIG.12B), and choroid plexus cells (FIG.12C), of mice administered vehicle control (25 mM Tris, 10 % sucrose, pH 7.4; “Vehicle”) or complexes comprising an anti-TfR1 Fab covalently linked to a DMPK-targeting ASO (“Anti- TfR1 Fab1-ASO Complexes”) at ASO-equivalent doses of 10 mg / kg via intravenous injection. Bars represent foci area per mm2of nuclear area in regions of interest imaged with an average total tissue area of 2 mm2. Data are shown as mean + standard deviation of μm2per mm2(*, P < 0.05; **, P < 0.01, calculated by Dunnet’s multiple comparisons test; n = 6-7 mice per group).DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0079] Aspects of the disclosure relate to a recognition that while certain molecular payloads (e.g., oligonucleotides, peptides, small molecules, gene therapies) can have beneficial effects in cells of the central nervous system (CNS), it has proven challenging for such molecular payloads to achieve their intended effects in the CNS because of limitations in their biodistribution, including inability to efficiently cross the blood-brain barrier. Accordingly, the present disclosure, in some aspects, provides complexes comprising CNS-targeting agents covalently linked to molecular payloads in order to overcome such challenges. The CNS-target agent of the present disclosure comprises an anti-transferrin receptor 1 (TfR1) antibody that is demonstrated to be able to transport molecular payloads to cells of the CNS. In some embodiments, such delivery is across the blood-brain barrier (e.g., via receptor mediated transcytosis), resulting in delivery of the molecular payloads to cells of the CNS. In some embodiments, such delivery is across the choroid plexus, resulting in delivery of the molecular payloads to cells of the CNS. In some embodiments, an anti-TfR1 antibody of the complexes described herein exhibits pH-dependent binding affinity to TfR1 (e.g., having different binding affinity under different pH conditions). In some embodiments, an anti-TfR1 antibody of the complexes described herein exhibits pH-independent binding affinity to TfR1 (e.g., having comparable binding affinity under different pH conditions).

[0080] In some embodiments, complexes provided herein may comprise molecular payloads that modulate (e.g., increase or reduce) expression and / or activity of genes associated with CNS diseases and disorders, such as by modulating transcription, translation, post- transcriptional modification (e.g., splicing), mRNA stability, and / or protein stability. In some embodiments, complexes provided herein may comprise molecular payloads that are synthetic nucleic acids (e.g., DNA or RNA) that may be used to express one or more proteins that modulate expression and activity of genes associated with CNS diseases and disorders. In some embodiments, complexes provided herein may comprise molecular payloads that have therapeutic effect in a CNS disease or disorder, but may or may not modulate the expression or activity of any genes associated with CNS diseases and disorders.

[0081] Neurological diseases and disorders, which affect the CNS, have varying etiologies and potential treatment modalities. Examples of such CNS diseases and disorders include, without limitation, 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, among others. Other examples of CNS diseases anddisorders include essential tremor and hereditary dystonia. Additional 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 types II and III, and Rett syndrome. Various genes are implicated in CNS diseases and disorders, including, without limitation, 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. Other genes implicated in CNS diseases and disorders include, without limitation, TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, and ECHS1. Additional genes implicated in CNS diseases and disorders include, without limitation, PIKFYVE, SYF2, UNC13A, ATXN1, ATXN3, GRN, GRIN2A, TPP1, GLB1, ASM, ARSA, GALC, HEXA, HEXB, GBA, and MECP2. Molecular payloads may be effective at treating CNS diseases and disorders upon their delivery to cells of the CNS, e.g., by crossing the blood-brain barrier, and / or by crossing the choroid plexus. Certain molecular payloads may alleviate signs or symptoms of CNS diseases and disorders, such as, in some embodiments, by modulating expression or activity of genes implicated in CNS diseases and disorders. Molecular payloads that alleviate signs or symptoms of CNS diseases and disorders without modulating expression or activity of any genes implicated in CNS diseases and disorders may also be used in accordance with the present disclosure. Delivery of molecular payloads to the CNS may also be useful for other purposes aside from treatment of CNS diseases and disorders.

[0082] Further aspects of the disclosure, including a description of defined terms, are provided below. I. Definitions

[0083] Administering: As used herein, the terms “administering” or “administration” means to provide a complex to a subject in a manner that is physiologically and / or (e.g., and) pharmacologically useful (e.g., to treat a condition in the subject).

[0084] Alzheimer’s Disease: As used herein, the term “Alzheimer’s disease” refers to a progressive neurological disorder that is characterized by atrophy of brain tissue and loss of neurons, particularly with advanced age. Alzheimer’s disease is a frequent cause of dementia, including pre-senile dementia. Symptoms of Alzheimer’s disease include memory loss that worsens over time, difficulty with concentration, especially in regard to abstract concepts, difficulty with multitasking, impaired decision-making, and changes in personality or behavior.Alzheimer’s disease is also associated with the formation of beta-amyloid protein plaques and tau protein tangles (also known as neurofibrillary tangles) in brain tissue, which are cytotoxic, disrupt communication between cells, and contribute to neuronal death. The cause of Alzheimer’s disease is incompletely understood, however, development of Alzheimer’s disease can be influenced by 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 or may not be associated with cerebral amyloid angiopathy (CAA) or Frontotemporal dementia.

[0085] Amyotrophic lateral sclerosis (ALS): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells of the central nervous system. ALS results in degeneration of motor neurons which control muscle movement, ultimately resulting in loss of control of the muscles needed to move, speak, eat, and breathe. Approximately 90% of ALS cases are considered sporadic, occurring in patients without a known family history of the disease, and 5-10% of all cases are familial (i.e., inherited). Genes associated with the development of ALS include, for example, SOD1 (associated with about 12-20% of familial ALS cases), C9orf72 (associated with about 25-40% of familial ALS cases), ATXN2, and FUS. In some embodiments, accumulation of TDP-43 aggregates is associated with ALS. PIKFYVE, SYF2, and UNC13A have also been implicated in the pathophysiology of ALS. In some embodiments, single nucleotide polymorphism(s) and / or other alterations in PIKFYVE, SYF2, and UNC13A are associated with ALS.

[0086] ANO3: As used herein, ANO3 refers to the gene encoding Anoctamin 3 (also referred to as DYT23; DYT24; TMEM16C; C11orf25; or GENX-3947), a protein that belongs to the TMEM16 family of predicted membrane proteins. In some embodiments, ANO3 may be a human (Gene ID: 63982), non-human primate (e.g., Gene ID: 101865236), or rodent gene (e.g., Gene ID: 228432, Gene ID: 311287). In humans, mutations in a gene encoding ANO3 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_001313726.2; NM_031418.4; XM_047427399.1; XM_017018118.3; NM_001313727.2; XM_017018119.3; and XM_011520282.4) have been characterized that encode different protein isoforms.

[0087] Antibody: As used herein, the term “antibody” refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one antigenic determinant, e.g., paratope that specifically binds to an antigen. In some embodiments, an antibody is a full-length antibody. In some embodiments, an antibody is a chimeric antibody. In some embodiments, an antibody is a humanized antibody. However, in some embodiments, an antibody is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment or a scFv fragment. In some embodiments, an antibody is a nanobody derived from a camelid antibody or a nanobody derived from shark antibody. In some embodiments, an antibody is a diabody. In some embodiments, an antibody comprises a framework having a human germline sequence. In another embodiment, an antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, an 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, an antibody comprises a constant domain, e.g., an Fc region. An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of an antibody described herein can be an alpha (α), delta (∆), epsilon (ε), gamma (γ) or mu (µ) heavy chain. In some embodiments, the heavy chain of an antibody described herein can comprise a human alpha (α), delta (∆), epsilon (ε), gamma (γ) or mu (µ) heavy chain. In a particular embodiment, an antibody described herein comprises a human gamma 1 CH1, 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, e.g., see U.S. Pat. No.5,693,780 and Kabat E A 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 of the variable chain constant regions provided herein. In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecule are conjugated to the antibody via N-glycosylation, O- glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or (e.g., and) phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate moleculeare monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecule is a branched oligosaccharide or a branched glycan. In some embodiments, the one or more sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, an antibody is a construct that comprises a polypeptide comprising one or more antigen binding fragments of the disclosure linked to a linker polypeptide or an immunoglobulin constant domain. Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen binding portions. Examples of linker polypeptides have been reported (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123). Still further, an antibody may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058).

[0088] APP: As used herein, the term “APP” refers to the gene encoding amyloid beta precursor protein (also referred to as AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II, PN2, alpha-sAPP, and pre-A4), a protein involved in synapse formation and neural plasticity. In some embodiments, APP may be a human (Gene ID: 351), non-human primate (e.g., Gene ID: 100427716), or rodent gene (e.g., Gene ID: 11820, Gene ID: 54226). In humans, mutations in an APP gene are associated with the development of Alzheimer’s disease. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000484.4 and NM_201413.3) have been characterized that encode different protein isoforms.

[0089] APOE: As used herein, APOE refers to the gene encoding apolipoprotein E (also referred to as AD2, ApoE4, LDLCQ5, and LPG), a protein involved in the formation of lipoprotein particles and the transport of lipids through the circulatory system. In some embodiments, APOE may be a human (Gene ID: 348), non-human primate (e.g., Gene ID: 714623), or rodent gene (e.g., Gene ID: 11816, Gene ID: 25728). In humans, mutations in a gene encoding APOE are associated with the development of Alzheimer’s disease. In some embodiments, APOE4 allele is associated with the development of Alzheimer’s disease. Insome embodiments, APOE4 allele is associated with the development of motor neuron disease. Accordingly, in some embodiments, allele-specific modulation (e.g., suppression) of APOE (e.g., APOE4) is useful in the treatment of CNS disease or disorders such as Alzheimer’s disease or motor neuron disease. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000041.4 and NM_001302688.2) have been characterized that encode different protein isoforms.

[0090] Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall 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) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0091] ARSA: As used herein, ARSA refers to a gene encoding arylsulfatase A (also referred to as, Cerebroside-Sulfatase, Epididymis Secretory Sperm Binding Protein, MLD, ASA, or sulfatidase) an enzyme that breaks down sulfatides. In some embodiments ARSA may be a human (e.g., Gene ID: 410), non-human primate (e.g., Gene ID: 458946 , Gene ID: 716500), or rodent (e.g., Gene ID: 11883, Gene ID: 315222) gene. In humans, mutations in a gene encoding ARSA are associated with the development of Metachromatic leukodystrophy. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000487.6; NM_001085425.3; NM_001085426.3; NM_001085427.3; NM_001085428.3; NM_001362782.2; XM_047441363.1; XM_024452241.2; XM_011530691.4) have been characterized that encode different protein isoforms.

[0092] ASM: As used herein, the term “ASM” refers to a gene (also known as SCMPD1, ASMASE, and NPD) encoding acid sphingomyelinase. Wildtype acid sphingomyelinase is a lysosomal enzyme involved in the conversion of lipids into ceramide. Mutations in ASM typically result in a shortage or complete loss-of-function of acid sphingomyelinase, leading to accumulation of fat in the cells of various organs and tissues, including the central nervous system. In some embodiments, ASM may 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 development of Niemann-Pick Type A.

[0093] ATP1A3: As used herein, ATP1A3 refers to the gene encoding ATPase Na+ / K+ transporting subunit alpha 3 (also referred to as RDP; AHC2; CAPOS; DEE99; DYT12; orATP1A1), a protein that belongs to the family of P-type cation transport ATPases, and to the family of Na+ / K+ ATPases. In some embodiments, ATP1A3 may be a human (Gene ID: 478), non-human primate (e.g., Gene ID: 102122869), or rodent gene (e.g., Gene ID: 232975, Gene ID: 24213). In humans, mutations in a gene encoding ATP1A3 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_152296.5; NM_001256213.2; NM_001256214.2; and XM_047438862.1) have been characterized that encode different protein isoforms.

[0094] ATXN1: As used herein, ATXN1 refers to a gene that encodes the protein ataxin-1. Ataxin-1 protein is expressed throughout the body, and is thought to be involved in regulating protein production, including transcription and RNA processing. Ataxin-1 binds RNA and associates with large protein complexes. It is thought to be involved in transcriptional repression and to regulate Notch- and Capicua-controlled developmental processes. Human ATXN1 (Gene ID: 6310) includes a CAG repeat region, which normally includes 6-39 repeats. Longer expansions of the CAG repeat region (typically 40-83 or more) in ATXN1 can result in neurodegenerative disease, including spinocerebellar ataxia 1 (SCA1). The expanded CAG repeat region results in incorrect protein folding and a nonfunctional ataxin-1 protein. The abnormal protein forms aggregates within cell nuclei, resulting in cell damage. Evidence suggests that ataxin-1 aggregates are found only or primarily in cells of CNS, and particularly within Pukinje cells of the cerebellum. Accumulation of protein aggregates results in cell death; the loss of these cells over time results in the cerebellar deficiencies 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 CAG repeat in spinocerebellar ataxia type 1” Nature Genet.4: 221-226 (1993). Allele-specific inhibition of ATXN1 may be effective in treatment of SCA1. See Miller, et al. “Allele-specific silencing of dominant disease genes” Proc. Nat. Acad. Sci.100: 7195-7200 (2003).

[0095] ATXN2: As used herein, ATXN2 refers to the gene that encodes the protein ataxin-2. It is ubiquitously expressed in various tissues, and the ataxin-2 protein localizes to the Golgi apparatus and stress granules within normal cells. The ataxin-2 protein is involved in regulating mRNA translation through its interactions with the 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 includes a CAG repeat region, which normally includes 22 or 23 repeats, but can include up to 31 repeats. Longer expansions of the CAG repeat region inATXN2 can result in neurodegenerative disease, including spinocerebellar ataxia 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Interactions between ataxin-2 and the protein TDP-43 are thought to be involved in the development of ALS in certain patients. See, e.g., Elden, et al. “Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS” Nature 466:1069-1075 (2010). A disease-associated ATXN2 allele often contains 34-52 CAG repeats, but can contain as few as 32 or over 100, and can expand in size when the allele is transmitted to successive generations. In some embodiments, as few as 27 CAG repeats can be associated with ALS, as described in Elden, et al. Allele-specific inhibition of ATXN2 may be effective in treatment of SCA2. See Miller, et al. “Allele-specific silencing of dominant disease genes” Proc. Nat. Acad. Sci.100: 7195-7200 (2003).

[0096] ATXN3: As used herein, ATXN3 refers to a gene (also known as AT3, ATX3, JOS, MJD, MJD1, and SCA3) which encodes ataxin-3 protein. Ataxin-3 protein is expressed throughout the body, and is believed to be involved in the proteasome processing system. Ataxin-3 removes ubiquitin from proteins to be degraded so that the ubiquitin can be recycled. Ataxin-3 may also be involved in regulating the first stage of transcription. Human ATXN2 (Gene ID: 4287) includes a CAG repeat region, which normally includes 13-36 repeats. Longer expansions of the CAG repeat region (typically 50 or more) in ATXN3 can result in neurodegenerative disease, including spinocerebellar ataxia 3 (SCA3). The expanded CAG repeat region results in incorrect protein folding and a nonfunctional ataxin-3 protein. This nonfunctional ataxin-3 protein cannot remove ubiquitin from proteins, resulting in aggregation of such proteins, along with ubiquitin and ataxin-3, within the nucleus of cells. These protein aggregates can result in cell death, including in neurons and other cells of the CNS. Neurons are typically the cell types that are the 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 treatment of SCA3. See Miller, et al. “Allele-specific silencing of dominant disease genes” Proc. Nat. Acad. Sci.100: 7195-7200 (2003).

[0097] Batten disease: As used herein, the term “Batten disease” refers to a family of lysosomal disorders also known as neuronal ceroid lipofuscinoses (NCLs). Batten diseases are nervous system disorders caused by various mutations to 13 genes, usually inherited in a recessive pattern. In some embodiments, Batten disease results from mutations in CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, CLN8, CLN10, CLN11, CLN12, CLN13, or CLN14. In particular, as relevant to the present disclosure, in some embodiments Batten disease results from mutations in CLN2 or CLN3. Symptoms of Batten disease includeseizures, visual impairment, cognitive and behavioral decline, motor decline, developmental impairment, and premature death. Batten disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity, and neuronal loss. The genetic causes of Batten disease are well known and are attributed to mutations in one of thirteen different genes encoding lyososomal 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 (CLN7), CLN8 (CLN8), CTSD (CLN10), GRN (CLN11), ATP13A2 (CLN12), CTSF (CLN13), and KCTD7 (CLN14). In some embodiments, a subject in need of treatment for Batten disease presents with seizure activity. In some embodiments, seizure activity comprises myoclonic jerks, grand mal seizures, and tonic-clonic seizures. In some embodiments, a subject in need of treatment for Batten disease exhibits symptoms of visual impairment. In some embodiments, visual impairment comprises optic nerve atrophy, progressive vision loss, pigmentary retinopathy, macular degeneration, visual failure, retinopathy, diminished pupillary light reflex, central vision loss, and blindness. In some embodiments, a subject in need of treatment for Batten disease exhibits symptoms of cognitive and behavioral decline. In some embodiments, cognitive and behavioral decline comprises irritability, hyperexcitability, anxiety, agitation, depression, inappropriate laughter, mood disturbances, intellectual disability, dementia, and personality abnormalities. In some embodiments, a subject in need of treatment for Batten disease exhibits symptoms of motor decline. In some embodiments, motor decline comprises loss of motor coordination, choreoathetosis, stereotypic movements, myoclonus ataxia, motor decline, spasticity, dystonic features, hypotonia, rigidity, impaired balance, myoclonus, ataxia, facial dyskinesia, clumsiness, motor coordination loss, dysarthria, severe respiratory distress, central, axial and / or limb hypotonia, appendicular spasticity, tremor, parkinsonism, hyperreflexia, speech apraxia, echolalia, delayed speech, and dysarthric speech. In some embodiments, a subject in need of treatment for Batten disease exhibits symptoms of developmental impairment. In some embodiments, developmental impairment comprises decelerated head growth, premature death, microcephaly, overriding sutures, halt in developmental milestones, developmental regression, and developmental arrest.

[0098] Blood-brain barrier: as used herein, the term “blood-brain barrier” refers to a highly selective semipermeable border of endothelial cells that prevents various molecules in the blood from non-selectively crossing into the extracellular fluid of the CNS. It allows passage of some small molecules by diffusion, and active transport of various nutrients, ions, organicanions, and macromolecules such as glucose and amino acids that are crucial to neural function, but blocks non-specific transport of other molecules.

[0099] C9orf72: As used herein, C9orf72 refers to the gene which encodes the chromosome 9 open reading frame 72 protein. The protein is found in many regions of the brain, including within the cytoplasm of neurons and in presynaptic terminals. Disease-causing mutations, particularly hexanucleotide repeat expansions, in the C9orf72 gene 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).

[0100] CDR: As used herein, the term "CDR" refers to the complementarity determining region within antibody variable sequences. A typical antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into regions of hypervariability, also known as “complementarity determining regions” (“CDR”), interspersed with regions that are more conserved, which are known as “framework regions” (“FR”). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework region and CDRs can be precisely identified using methodology known in the art, for example, by the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or (e.g., and) the contact definition, all of which are well known in the art. See, e.g., Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; IMGT®, the international ImMunoGeneTics information system® 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); Lefranc, M.-P. et 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, Al-lazikani 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. As used herein, a CDR may refer to the CDR defined by any method known in the art. Two antibodies having the same CDR means that the two antibodies have the sameamino acid sequence of that CDR as determined by the same method, for example, the IMGT definition.

[0101] There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. The term "CDR set" as used herein refers to a group of three CDRs that occur in a single variable region capable of binding the 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 defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Sub-portions of CDRs may be designated as L1, L2 and L3 or H1, H2 and H3 where the "L" and the "H" designates the light chain and the heavy chains regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (FASEB J.9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems. Examples of CDR definition systems are provided in Table 1. Table 1. CDR Definitions

[0102] CDR-grafted antibody: The term "CDR-grafted antibody" refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and / or (e.g., and) VL are replaced withCDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.

[0103] Central nervous system (CNS): as used herein, the term “central nervous system” (CNS) refers to the brain and spinal cord, and includes neurons and non-nervous supporting cells (e.g., glia) as well as the blood-brain barrier cells. The blood-brain barrier prevents various molecules from non-selectively crossing into the extracellular fluid of the CNS from the circulation. The CNS also includes cells of the blood-cerebrospinal fluid barrier, such as the cells of the choroid plexus.

[0104] CNS disease or disorder: as used herein, a “CNS disease or disorder” refers to a disease or disorder which affects the CNS (e.g., CNS structure or function) and / or which has an etiology in the CNS. CNS diseases and disorders are also known as neurological disease or disorders. Examples of CNS diseases or disorders include, but are not limited to, neuromuscular diseases and disorders (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, amongst others. Other examples of CNS diseases or disorders include essential tremor and hereditary dystonia. Certain lysosomal storage disorders are also examples of CNS diseases or disorders.

[0105] CNS-targeting agent: As used herein, the term, “CNS-targeting agent,” 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 CNS cells may be a membrane protein, for example an integral membrane protein or a peripheral membrane protein. Typically, a CNS-targeting agent specifically binds to an antigen on CNS cells that facilitates transport of the molecular payload across the blood-brain barrier and / or internalization of the CNS-targeting agent (and any associated molecular payload) into the CNS cells. In some embodiments, a CNS-targeting agent specifically binds to an internalizing, cell surface receptor (e.g., transferrin receptor 1) on cells of the CNS and is capable of being internalized into CNS cells through receptor mediated internalization. In some embodiments, a CNS-targeting agent is a small molecule, a protein, a peptide, a nucleic acid (e.g., an aptamer), or an antibody. In some embodiments, a CNS-targeting agent is linked to a molecular payload.

[0106] CNS-targeting antibody: As used herein, the term “CNS-targeting antibody” refers to a CNS-targeting agent that is an antibody that specifically binds to an antigen found in or on CNS cells. In some embodiments, a CNS-targeting antibody specifically binds to an antigenon CNS cells (e.g., neurons, supporting cells, and / or cells of the blood-brain barrier) that facilitates transport of the molecular payload across the blood-brain barrier and / or internalization of the CNS-targeting antibody (and any associated molecular payment) into the CNS cells. In some embodiments, the CNS-targeting antibody specifically binds to an internalizing, cell surface receptor present on CNS cells. In some embodiments, the CNS- targeting antibody facilitates transcytosis across cells (e.g., endothelial cells) of the blood-brain barrier. In some embodiments, the CNS-targeting antibody is an antibody that specifically binds to a transferrin receptor (e.g., transferrin receptor 1).

[0107] Chimeric antibody: The term "chimeric antibody" refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.

[0108] CLN2: See “TPP1”.

[0109] CLN3: As used herein, the term “CLN3” refers to the gene encoding CLN3 lysosomal / endosomal transmembrane protein (also referred to as battenin, BTN1, BTS, and JNCL), a protein involved in lysosomal function. In some embodiments, CLN3 may be a human (Gene ID: 1201), non-human primate (e.g., Gene ID: 705815), or rodent gene (e.g., Gene ID: 12752, Gene ID: 293485). In humans, mutation in a gene encoding CLN3 is associated with epilepsy and seizures, as well as CLN3 Batten disease. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000086.2 and NM_001286104.2) have been characterized that encode different protein isoforms.

[0110] Complementary: As used herein, the term “complementary” refers to the capacity for precise pairing between two nucleosides or two sets of nucleosides. In particular, complementary is a term that characterizes an extent of hydrogen bond pairing that brings about binding between two nucleosides or two sets of nucleosides. For example, if a base at one position of an oligonucleotide is capable of hydrogen bonding with a base at the corresponding position of a target nucleic acid (e.g., an mRNA), then the bases are considered to be complementary to each other at that position. Base pairings may include both canonical 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 pairings, adenosine-type bases (A) are complementary to thymidine-type bases (T) or uracil- type bases (U), that cytosine-type bases (C) are complementary to guanosine-type bases (G), and that universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to and areconsidered complementary to any A, C, U, or T. Inosine (I) has also been considered in the art to be a universal base and is considered complementary to any A, C, U or T.

[0111] Conservative amino acid substitution: As used herein, a “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 according to methods for altering polypeptide sequence known to one of ordinary skill in the art such as are found in references which compile 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 Protocols in Molecular Biology, F.M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include substitutions made amongst 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.

[0112] Covalently linked: As used herein, the term “covalently linked” refers to a characteristic of two or more molecules being linked together via 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 disulfide bridge, that serves as a linker between the molecules. However, in some embodiments, two or more molecules can be covalently linked together via a molecule that serves as a linker that joins the two or more molecules together through multiple covalent bonds. In some embodiments, a linker may be a cleavable linker. However, in some embodiments, a linker may be a non-cleavable linker.

[0113] Cross-reactive: As used herein and in the context of a targeting agent (e.g., a CNS- targeting agent, such as an antibody), the term “cross-reactive,” refers to a property of the agent being capable of specifically binding to more than one antigen of a similar type or class (e.g., antigens of multiple homologs, paralogs, or orthologs) with similar affinity or avidity. For example, in some embodiments, an antibody that is cross-reactive against human and non- human primate antigens of a similar type or class (e.g., a human transferrin receptor and non- human primate transferrin receptor) is capable of binding to the human antigen and non- human primate antigens with a similar affinity or avidity. In some embodiments, an antibody is cross-reactive against a human antigen and a rodent antigen of a similar type or class. In some embodiments, an antibody is cross-reactive against a rodent antigen and a non-human primate antigen of a similar type or class. In some embodiments, an antibody is cross-reactive against a human antigen, a non-human primate antigen, and a rodent antigen of a similar type or class.

[0114] DMD: As used herein, the term “DMD” refers to a gene that encodes dystrophin protein, a key component of the dystrophin-glycoprotein complex, which bridges the inner cytoskeleton and the extracellular matrix in muscle cells, particularly muscle fibers. Deletions, duplications, and point mutations in DMD may cause dystrophinopathies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. In some embodiments, a dystrophin gene may be a human (Gene ID: 1756), non-human primate (e.g., Gene ID: 465559), or rodent gene (e.g., Gene ID: 13405; Gene ID: 24907). In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000109.3, NM_004006.2, NM_004009.3, NM_004010.3 and NM_004011.3) have been characterized that encode different protein isoforms.

[0115] DMD allele: As used herein, the term “DMD allele” refers to any one of alternative forms (e.g., wild-type or mutant forms) of a DMD gene. In some embodiments, a DMD allele may encode for dystrophin that retains its normal and typical functions. In some embodiments, a DMD allele may comprise one or more mutations that results in muscular dystrophy. Common mutations that lead to Duchenne muscular dystrophy involve frameshift, deletion, substitution, and duplicative mutations of one or more of 79 exons present in a 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. Further examples of DMD mutations are disclosed, for example, in Flanigan KM, et al., Mutational spectrum of DMD mutations in dystrophinopathy 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 its entirety.

[0116] DMPK: As used herein, the term “DMPK” refers to a gene that encodes myotonin- protein kinase (also known as myotonic dystrophy protein kinase or dystrophia myotonica protein kinase), a serine / threonine protein kinase. Substrates for this enzyme may include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. In some embodiments, DMPK may be a human (Gene ID: 1760), non-human primate (e.g., Gene ID: 456139, Gene ID: 715328), or rodent gene (e.g., Gene ID: 13400). In humans, a CTG repeat expansion in the 3' non-coding, untranslated region of DMPK is associated with myotonic dystrophy type I (DM1). In addition, multiple human transcript variants (e.g., as annotated under 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) have been characterized that encode different protein isoforms.

[0117] DMPK allele: As used herein, the term “DMPK allele” refers to any one of alternative forms (e.g., wild-type or mutant forms) of a DMPK gene. In some embodiments, a DMPK allele may encode for wild-type myotonin-protein kinase that retains its normal and typical functions. In some embodiments, a DMPK allele may comprise one or more disease- associated-repeat expansions. In some embodiments, normal subjects have two DMPK alleles comprising in the range of 5 to 37 repeat units. In some embodiments, the number of CTG repeat units in subjects having DM1 is in the range of about 50 to about 3,000 or more with higher numbers of repeats leading to an increased severity of disease. In some embodiments, mildly affected DM1 subjects have at least one DMPK allele having in the range of 50 to 150 repeat units. In some embodiments, subjects with classic DM1 have at least one DMPK allele having in the range of 100 to 1,000 or more repeat units. In some embodiments, subjects having DM1 with congenital onset may have at least one DMPK allele comprising more than 2,000 repeat units.

[0118] Dravet syndrome: As used herein, the term “Dravet syndrome”, also known as severe myoclonic epilepsy of infancy (SMEI), refers to the most severe disorder in the genetic epilepsy with febrile seizures plus (GEFS+) spectrum. Dravet syndrome is typically caused by de novo mutations, but cases arising from familial mutations also occur. Symptoms of Dravet syndrome include seizures, cognitive decline, developmental regression, intellectual disability, and ataxia. More than 80% of Dravet syndrome cases are attributed to mutations in SCN1A, in which over 900 distinct mutations have been reported. In some embodiments, a subject in need of treatment for Dravet syndrome has symptoms selected from: seizures (e.g., febrile seizures, afebrile seizures, myoclonic seizures and absence seizures), cognitive decline, developmental regression, intellectual disability, and ataxia.

[0119] Dystrophinopathy: As used herein, the term “dystrophinopathy” refers to a muscle or neurological disease results from one or more mutated DMD alleles. Dystrophinopathies include a spectrum of conditions (ranging from mild to severe) that includes 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 with myoglobinuria. In some embodiments, at the other end of the spectrum, dystrophinopathy is phenotypically associated with progressive muscle diseases that are generally classified as Duchenne or Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when the heart is primarily affected. Symptoms of Duchennemuscular dystrophy include muscle loss or degeneration, diminished muscle function, pseudohypertrophy of the tongue and calf muscles, higher risk of neurological 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.

[0120] ECHS1: As used herein, ECHS1 refers to the gene encoding enoyl-CoA hydratase, short chain 1 (also referred to as SCEH; mECH; mECH1; or ECHS1D), a protein that functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. In some embodiments, ECHS1 may be a human (Gene ID: 1892), non-human primate (e.g., Gene ID: 101925228), or rodent gene (e.g., Gene ID: 93747, Gene ID: 140547). In humans, mutations in a gene encoding ECHS1 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Number NM_004092.4) have been characterized that encode different protein isoforms.

[0121] Epilepsy: As used herein, the term “epilepsy” refers to a neurological disorder that is characterized by abnormal activity in neurons of the brain, which can cause episodic seizures and may be accompanied by loss of consciousness. Symptoms of epileptic seizures may include sudden confusion or anxiety, dizziness, loss of awareness, loss of consciousness, staring spells, muscular stiffness, and involuntary movement of extremities. Epileptic seizure frequently occur in the absence of an external stimulus. Epileptic seizures can occur due to abnormal neurological activity in only brain region (focal seizure), or due to abnormal neurological activity throughout the brain (generalized seizure). Focal seizures may occur with or without loss of consciousness and may cause altered muscle movement and / or sensory perception. Generalized seizures are further characterized as 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, without stiffness), and tonic-clonic seizures (i.e., grand mal seizures, which cause loss of consciousness, muscle stiffness, and sudden involuntary muscle movements). Epilepsy may cause death due to injuries sustained during a seizure, status epilepticus, or sudden unexpected death in epilepsy (SUDEP). Only approximately 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 affecting the brain, or inheritance of a genetic risk factor. For example, genes involved in thepathophysiology 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.

[0122] Essential tremor: As used herein, the term “essential tremor” refers to a neurological condition characterized by involuntary shaking movements. It is sometimes also known as familial tremor or benign essential tremor. Essential tremor affects both men and women, and is most common in people 40 and older. Tremors are most likely to be noticed in the forearm and hands, and the upper arms, head, eyelids, and other muscles may also be affected. People with essential tremor may have trouble holding or using small objects such as silverware or writing utensils. The shaking associated with essential tremor most commonly involves small, rapid movements occurring 4 to 12 times a second. Specific symptoms may include head nodding, shaking or quivering sound to the voice (if the tremor affects the voice box), and problems with writing, drawing, drinking from a cup, or using tools (e.g., if the tremor affects the hands and / or forearms). Essential tremor typically worsens over time and can be severe in some patients. The exact cause of essential tremor is unknown, though many cases of essential tremor are genetic in origin and are inherited in an autosomal dominant manner. Mutated genes associated with essential tremor may affect various regions of the brain, including the deep brain, such as the thalamus, as well as the cerebellum.

[0123] Framework: As used herein, the term "framework" or "framework sequence" refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of light chain and CDR-H1, CDR-H2, and CDR-H3 of heavy chain) also divide the framework regions on the light chain and the heavy chain into four sub-regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred by others, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub-regions, and FRs represents two or more of the four sub-regions constituting a framework region. Human heavychain and light chain acceptor sequences are known in the art. In one embodiment, the acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0124] Friedreich’s ataxia: As used herein, the term “Friedreich’s ataxia” refers to an autosomal recessive genetic disease caused by mutations in the FXN gene and is characterized by progressive damage of muscle tissues and the nervous system. Friedreich’s ataxia is a neurological disorder associated with an expansion of a GAA trinucleotide repeat in the FXN gene that leads to a decrease in the expression of FXN. The expanded GAA trinucleotide repeat, located within the first intron, forms a R-loop which can interfere with normal transcriptional processes to reduce 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 lead to FXN mRNA deficiency and subsequent reduced 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 lamina in single cells.” Hum. Molec. Genet., 2015, Vol.24, No.123457–3471). Friedreich’s ataxia, the genetic basis for the disease, and related symptoms are described in the art (see, e.g., Montermini, 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.

[0125] Frontotemporal dementia: As used herein, the term “Frontotemporal dementia” or “FTD” refers to a disease in which there is progressive degradation of the frontal and / or temporal lobes of the brain. FTD results in progressive deficits in behavior, executive function, and / or language, symptoms include: changes in social and personal behavior, apathy, blunting of emotions, deficits in expressive language, and deficits in processing language. FTD is considered one of the most prevalent forms of dementia representing 10% to 20% of all dementia cases. FTD can generally be categorized as: (i) behavioral variant FTD (bVFTD), (ii) primary progressive aphasia (PPA), (iii) progressive supranuclear palsy (PSP), and (iv) corticobasal syndrome (CBS). Many FTD cases are linked with mutations occurring in C9orf72, granulin (GRN), and MAPT. Additionally, pathologically, there are three major protein deposits found in the brains of FTD patients, TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS) and tau. In some embodiments, a subject in need of treatment for FTD has a mutation in a GRN gene, a C9orf72 gene, and / or a MAPT gene. In some embodiments, asubject in need of treatment for FTD has progressive degradation of the frontal and / or temporal lobes of the brain. In some embodiments, a 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, a subject in need of treatment for FTD has deficits in behavior, executive function, and / or language. In some embodiments, a subject in need of treatment for FTD has one or more of the following symptoms: changes in social and personal behavior, apathy, blunting of emotions, deficits in expressive language, and deficits in processing language.

[0126] FUS: As used herein, FUS refers to the gene which encodes 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 pre-mRNA, and also has been shown to be involved in a DNA repair response. Loss of function of the protein encoded by FUS results in increased DNA damage in neurons, and certain mutations in FUS impair the PARP-dependent DNA damage response, leading to neurodegeneration and RNA-binding protein FUS / TSL aggregate formation. Several mutations in FUS have been identified in ALS patients. See, e.g., 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 not known, however it is believed that the toxicity likely results from a toxic gain of cytoplasmic function, as many ALS-linked FUS mutations are located in its nuclear localization signal, and mouse models that do not express FUS, and therefore have a complete loss of nuclear FUS localization, do not develop clear ALS-like symptoms.

[0127] FXN: As used herein, the term “FXN” refers to a gene that encodes frataxin, a protein implicated in iron homeostasis. In some embodiments, FXN may be a human (Gene ID: 2395), non-human primate (e.g., Gene ID: 737660), or 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 (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000144.4 and NM_181425.2) have been characterized that encode different protein isoforms.

[0128] GALC: As used herein, GALC refers to a 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 may be human (e.g., Gene ID: 2581), non-human primate (e.g., Gene ID: 693322, Gene ID: 736519), or rodent (e.g., Gene ID: 14420, Gene ID: 314360). In humans, mutations in a GALC gene areassociated with the development of Krabbe disease. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000153.4; NM_001201401.2; NM_001201402.2; XM_011536618.3; XM_047431198.1; XM_047431199.1) have been characterized that encode different protein isoforms.

[0129] Gaucher disease, type II and III: As used herein, the term “Gaucher Disease” or “GD”, refers to Gaucher disease types II and III, genetic disorders in which fatty substances (e.g., glucocerebroside) accumulate in cells and certain organs (e.g., spleen and liver). The buildup of these fatty substances can cause the organ to enlarge, negatively affecting organ function. If the bones are affected, it can weaken the bone, and if bone marrow is affected it can interfere with 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 movement, hypertonia, laryngeal spasm, seizures, prolonged chest infections, enlarged spleen, and enlarged liver. Current enzyme replacement therapies for Gaucher type I and Gaucher type III are not effective in Goucher type II. Gaucher type II is a fatal disease with mortality usually within the first 2 years of life. Gaucher type III (also known as chronic neuronopathic Gaucher disease) develops during childhood. Initial symptoms of Gaucher type III are enlarged liver and spleen, poor eating, and less than normal weight gain. Other symptoms include, seizures, skeletal irregularities, eye movement disorders, cognitive problems, poor coordination, respiratory issues, and blood disorders. Both Gaucher type II and type III are neuropathic. Additionally, 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 an accumulation glucocerebroside in cells and / or in 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 movement, hypertonia, laryngeal spasm, seizures, prolonged chest infections, enlarged spleen, enlarged liver. In some embodiments, a subject in need of treatment for Gaucher disease has one or more of the following symptoms: poor eating, less than normal weight gain, skeletal irregularities, eye movement disorders, cognitive problems, poor coordination, respiratory issues, and blood disorders.

[0130] GBA: As used herein, the term “GBA” refers to a gene (also referred to as GBA1, GCB, GLUC) encoding β-glucocerebrosidase (also referred to as acid β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, glucosylceramidase beta, Glucocerebrosidase or GCase), which is a lysosomal membrane protein. β-glucocerebrosidase cleaves β-glucosidic linkages. In some embodiments, GBA may be human (e.g., Gene ID: 2629), non-human primate (e.g., Gene ID: 719103), or rodent (e.g., Gene ID: 14466, Gene ID: 684536). In humans, mutations in a GBA gene are associated with the development of Gaucher Disease type II and type III. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000157.4; NM_001005741.3; NM_001005742.3; NM_001171811.2; NM_001171812.2) have been characterized that encode different protein isoforms.

[0131] GCH1: As used herein, GCH1 refers to the gene encoding GTP cyclohydrolase 1 (also referred to as GCH; DYT5; DYT14; DYT5a; GTPCH1; HPABH4B; GTP-CH-1), a protein that is a member of the GTP cyclohydrolase family, and which is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8- dihydroneopterin triphosphate. In some embodiments, GCH1 may be a human (Gene ID: 2643), non-human primate (e.g., Gene ID: 695675), or rodent gene (e.g., Gene ID: 14528, Gene ID: 29244). In humans, mutations in a gene encoding GCH1 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_001024071.2; NM_001024070.2; NM_001024024.2; NM_000161.3; XM_017021218.2; and XM_047431261.1) have been characterized that encode different protein isoforms.

[0132] GFAP: As used herein, the term “GFAP” refers to a gene encoding glial fibrillary acidic protein (also referred to as ALXDRD), a protein involved in cell communication in the CNS. In some embodiments, GFAP may be a human (Gene ID: 2670), non-human primate (e.g., Gene ID: 712941), or rodent gene (e.g., Gene ID: 14580, Gene ID: 24387). In humans, mutations in a GFAP gene are associated with Alexander disease. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_002055.5 and NM_001131019.3) have been characterized that encode different protein isoforms.

[0133] GLB1: As used herein, the term “GLB1” refers to a gene (also known as EBP, ELNR1, or MPS4B) encoding galactosidase beta 1, a lysosomal enzyme which mediates catabolism of several molecules including GM1 ganglioside. GM1 ganglioside is an important factor in neuronal plasticity, neuronal repair, and release of neurotrophines in the brain. When mutated, GLB1 produces galactosidase beta 1 with reduced or eliminated function, leading to accumulation of GM1 ganglioside in the brain, ultimately resulting in neuronal death. GLB1mutations are associated with GM1 gangliosidosis and Morquio syndrome B. In some embodiments, GLB1 may 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).

[0134] GM1 gangliosidosis: As used herein, the term “GM1 gangliosidosis” refers to a lysosomal storage disorder caused by deficiencies in β-galactosidase enzyme. GM1 gangliosidosis is an nervous system disorder that is inherited in an autosomal recessive pattern, and is associated with mutations in the GLB1 gene. Symptoms of GM1 gangliosidosis include cognitive impairments, developmental delays, skeletal abnormalities, seizures, motor impairments, and visual impairments. 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 to Sandhoff disease; treatments for Tay-Sachs and / or Sandhoff disease therefore may also be effective in treating GM1 gangliosidosis (and vice versa).

[0135] GNAL: As used herein, GNAL refers to the gene encoding G protein subunit alpha L (also referred to as HG1O and DYT25), a protein that is a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. The G protein subunit alpha L protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. In some embodiments, GNAL may be a human (Gene ID: 2774), non-human primate (e.g., Gene ID: 102137826), or rodent gene (e.g., Gene ID: 14680, Gene ID: 24611). In humans, mutations in a gene encoding GNAL are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_182978.4; NM_001142339.3; NM_001261443.2; NM_001261444.2; NM_001369387.1; and XM_006722324.4) have been characterized that encode different protein isoforms.

[0136] GRIA1: As used herein, the term “GRIA1” refers to the gene encoding glutamate ionotropic receptor AMPA type subunit 1 (also referred to as GLUH1, GLUR1, GLURA, GluA1, and HBGR1), a protein implicated in neuronal signaling via glutamate neurotransmitters. In some embodiments, GRIA1 may be a human (Gene ID: 2890), non- human primate (e.g., Gene ID: 714117), or rodent gene (e.g., Gene ID: 14799, Gene ID: 50592). In humans, mutation in a GRIA1 gene is associated with epilepsy and seizures, as well as nociception-related phenotypes (e.g., pain disorders). In addition, multiple human transcriptvariants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000827.4 and NM_001114183.2) have been characterized that encode different protein isoforms.

[0137] GRIN2A: As used herein, the term GRIN2A refers to a gene (also known as LKS; EPND; FESD; NR2A; GluN2A; NMDAR2A) encoding glutamate ionotropic receptor NMDA type subunit 2A (gluN2A), a protein that is one component of a subset of NMDA receptors. In some embodiments, GRIN2A may be a human (Gene ID: 2903), non-human primate (e.g., Gene ID: 102123126), or rodent gene (e.g., Gene ID: 14811, Gene ID: 24409). In humans, mutations in a GRIN2A gene are associated with epilepsy and seizures. Over 50 mutations in GRIN2A have been identified in patients with epilepsy. Many GRIN2A mutations lead to production of non-functional gluN2A protein or prevent the production of gluN2A protein, likely 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, resulting in excessive signaling in the brain. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000833.5; NM_001134407.3; NM_001134408.2) have been characterized that encode different protein isoforms.

[0138] GRN: As used herein, GRN refers to a gene (also known as GEP; GP88; PEPI; PGRN; CLN11; PCDGF) that encodes progranulin (also known as granulin precursor, proepithelin, and PC cell-derived growth factor), a protein which is active in many tissues throughout the body. Progranulin’s function in the brain is not well understood, though it appears to play an important role in the survival of neurons. In humans, mutations in GRN are associated with frontotemporal dementia (FTD). FTD that is associated with GRN mutations (sometimes referred to as “GRN-FTD” or “GRN-related FTD”) has been suggested to involve 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, e.g., 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 lobar degeneration: evidence for low mutation frequency in an Italian clinical series” 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 herein incorporated by reference. See also Hsiung, et al. “GRN Frontotemporal Dementia” 2007 Sep 7 [Updated 2020 Feb 6]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): Universityof Washington, Seattle; 1993-2023. Available from: ncbi.nlm.nih.gov / books / NBK1371 / . Mutations in granulins that cause deficiencies may play a role in lysosome disfunction. In some embodiments ,GRN may be human (e.g., Gene ID: 2896), non-human primate (e.g., Gene ID: 454728, Gene ID: 714851), or rodent (e.g., Gene ID: 14824, Gene ID: 29143). In humans, mutations in a gene encoding GRN are associated with the development of FTD, such as a heterozygous mutation, causing inadequate production of progranulin. Human transcript variant annotated under GenBank RefSeq Accession Number NM_002087.4 has been characterized that encodes progranulin.

[0139] GYS1: As used herein, the term “GYS1” refers to a gene that encodes glycogen synthase, a protein which functions in the synthesis of glycogen. In some embodiments, GYS1 may be a human (Gene ID: 2997), non-human primate (e.g., Gene ID: 574233, Gene ID: 456196, Gene ID: 102134439), or rodent gene (e.g., Gene ID: 14936, Gene ID: 690987). In humans, expression of a mutant glycogen synthase protein (e.g., from a mutant GYS1 gene) results in decreased glycogen synthesis. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_001161587.1 and NM_002103.5) have been characterized that encode different protein isoforms.

[0140] Hereditary dystonia: As used herein, the term “hereditary dystonia” refers to a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements and / or postures. The dystonic movements are typically patterned and twisting, and may be associated with tremor. Some forms of hereditary dystonia are associated with neurodegeneration and progressively worsen over time, whereas other forms are independent of neurodegeneration and usually reach a plateau in symptoms after an initial period of worsening. Hereditary dystonia can be characterized by the body part(s) affected, and are typically classified as focal, affecting 1 body part (e.g., eyelids, mouth, larynx, 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 both arms + / - neck + / - trunk; or crural – 1 leg and trunk or both 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 sites, + / - leg involvement). A number of genes associated with hereditary dystonia include TOR1A, THAP1, ANO3, GNAL, KMT2B, GCH1, TH, SPR, TAF1, PRKRA, ATP1A3, SGCE, PNKD, PRRT2, SLC2A1, and ECHS1. Hereditary dystonia, the genetic basis for the disease, and related 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,GeneReviews [Internet], Seattle (WA): University of Washington, Seattle, 1993-2023, NCBI Bookshelf ID: NBK1155, PMID 20301334).

[0141] HEXA: As used herein, “HEXA” refers to a gene (also referred to as TSD and hexosaminidase subunit alpha) encoding the α subunit of the enzyme β-hexosaminidase A (also referred to as hexosaminidase A), an enzyme that breaks down GM2 gangliosides and molecules containing N-acetyl hexosamines. Mutations in HEXA reduce or eliminate the activity of β-hexaosaminidase A, resulting in the accumulation of GM2 gangliosides in neuronal cells, which can result in cell death. In some embodiments, HEXA may be human (e.g., Gene ID: 3073), non-human primate (e.g., Gene ID: 698251 , Gene ID: 748732), or rodent (e.g., Gene ID: 15211, Gene ID: 300757). In humans, mutations in a gene encoding HEXA are associated with the development of Tay-Sachs. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000520.6; NM_001318825.2) have been characterized that encode different protein isoforms.

[0142] HEXB: As used herein, “HEXB” refers to a gene (also referred to as ENC-1AS, HEL- 248, and HEL-S-111) encoding the β subunit of the enzyme β-hexosaminidase A (also referred to as hexosaminidase A). Wildtype HEXB is the subunit of β-hexosaminidase A, which is involved in the degradation of ganglioside GM2 and other molecules. Mutations in HEXB reduce or eliminate the activity of β-hexaosaminidase A, resulting in the accumulation of GM2 gangliosides in neuronal cells, which can result in cell death. In some embodiments, HEXB may 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). In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000521.4; NM_001292004.2) have been characterized that encode different protein isoforms. In humans, mutations in HEXB are associated with the development of Sandhoff disease.

[0143] 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 disclosure may include 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 the CDRs and in particular 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, such as a mouse, have been grafted onto human framework sequences.

[0144] Humanized antibody: The term "humanized antibody" refers to antibodies which comprise heavy and light chain variable region sequences 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 may be generated by obtaining murine anti-TfR1 monoclonal antibodies using traditional hybridoma technology followed by humanization using in vitro genetic engineering, such as those disclosed in Kasaian et al PCT publication No. WO 2005 / 123126 A2.

[0145] HTT: As used herein, HTT refers to the gene encoding huntingtin protein. HTT is widely expressed, and is required for normal development. The precise function of huntingtin protein encoded by HTT is not known, 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 interact directly with numerous other proteins, including several involved in transcription, transport, and cell signaling. Certain mutations in HTT result in the development of Huntington’s disease. HTT includes a CAG trinucleotide repeat region. CAG trinucleotide repeat expansion is associated with Huntington’s disease. In some embodiments, normal subjects have two HTT alleles comprising about 10 to about 35 CAG repeats. In some embodiments, subjects with Huntington’s disease, or who are expected to develop Huntington’s disease, have an HTT allele comprising 40 or more CAG repeats. In some embodiments, subjects with one or two HTT alleles comprising 36 to 40 CAG repeats may or may not develop symptoms of Huntington’s disease. Mutant HTT is also referred to as mHTT.

[0146] Huntington’s disease: Huntington’s disease is a neurological disease, characterized by degeneration of striatal neurons. It results in the progressive degeneration of nerve cells in the brain, having a wide impact on a patient’s functional abilities and usually results in movement, cognitive, and psychiatric disorders. Huntington’s disease affects the entire brain, however certain regions of the brain are more highly impacted than others. The striatum, which plays a key role in movement, mood, and behavioral control, is usually the portion of the brain most affected by Huntington’s disease. Huntington’s disease is associated with an expansion of a CAG trinucleotide repeat in HTT.

[0147] Internalizing cell surface receptor: As used herein, the term, “internalizing cell surface receptor” refers to a cell surface receptor that is internalized by cells, e.g., upon external stimulation, e.g., ligand binding to the receptor. In some embodiments, an internalizing cell surface receptor is internalized by endocytosis. In some embodiments, an internalizing cell surface receptor is internalized by clathrin-mediated endocytosis. However, in some embodiments, an internalizing cell surface receptor is internalized by a clathrin- independent pathway, such as, for example, phagocytosis, macropinocytosis, caveolae- and raft-mediated uptake or constitutive clathrin-independent endocytosis. In some embodiments, the internalizing 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, a cell surface receptor becomes internalized by a cell after ligand binding. In some embodiments, a ligand may be a CNS-targeting agent or a CNS-targeting antibody. In some embodiments, an internalizing cell surface receptor is a transferrin receptor.

[0148] Isolated antibody: An "isolated antibody", as used herein, 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 transferrin receptor is substantially free of antibodies that specifically bind antigens other than transferrin receptor). An isolated antibody that specifically binds transferrin receptor complex may, however, have cross-reactivity to other antigens, such as transferrin receptor molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and / or (e.g., and) chemicals.

[0149] Kabat numbering: The terms "Kabat numbering", "Kabat definitions and "Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci.190:382-391 and, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.

[0150] KMT2B: As used herein, KMT2B refers to the gene encoding lysine methyltransferase 2B (also referred to as HRX2; MLL2; MLL4; TRX2; WBP7; DYT28; MLL1B; MRD68; WBP-7; and CXXC10), a protein contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET domain. In some embodiments, KMT2B may be a human (Gene ID: 9757), non-human primate (e.g., Gene ID: 102115861), or rodent gene (e.g., Gene ID: 75410, Gene ID: 102550344). In humans, mutations in a gene encoding KMT2B are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_014727.3; XM_011527561.3; XM_011527562.3; XM_047439787.1; and XR_935878.3) have been characterized that encode different protein isoforms.

[0151] Krabbe disease: As used herein, the term “Krabbe disease”, “KD”, “KRD”, “globoid cell leukodystrophy”, or “galactosylceramide lipidosis” refers to a metabolic disorder in which lipids accumulate to harmful levels in different tissues throughout the body, including the nervous system, resulting in death of cells of the central nervous system including the brain. Krabbe disease is characterized by cells that have more than one nucleus (globoid cells), which results in the breaking down of the myelin coating on nerves. Krabbe disease results from a mutation in the GALC gene, which causes deficiency in the galactosylceramidase enzyme. Galactosylceramidase is an essential enzyme in myelin metabolism. Symptoms of Krabbe disease include irritability, stiff posture, delayed mental development, delayed physical development, deterioration of motor skills, muscle weakness, hypertonia, myoclonic seizures, spasticity, fever, blindness, difficulty swallowing, and deafness. Krabbe disease is most commonly found in infants (infantile form), usually beginning before the age of one.10%-15% of Krabbe disease patients have late onset of the disease, this occurs in a juvenile form or adult form. In some embodiments, a subject has a mutation in a GALC gene. In some embodiments, a subject has an accumulation of lipids in the central nervous system (e.g., brain). In some embodiments, a subject has globoid cells in the central nervous system (e.g., brain). In some embodiments, a subject has deficiency of a galactosylceramidase enzyme. In some embodiments, a subject has one or more of the following symptoms: irritability, stiff posture, delayed mental development, delayed physical development, deterioration of motor skills, muscle weakness, hypertonia, myoclonic seizures, spasticity, fever, blindness, difficulty swallowing, and deafness.

[0152] LRRK2: As used herein, LRRK2 refers to the gene encoding dardarin protein, which is also known as leucine-rich repeat kinase 2 and PARK8. Variants of LRRK2 are associated with an increased risk of Parkinson’s disease. A mutation in LRRK2 encoding a G2019Smutant of dardarin protein has been shown to cause Parkinson’s disease, and is a relatively common cause of familial Parkinson’s disease. This G2019S mutation results in enhanced kinase activity of the protein. Mutations in LRRK2 are the most common known cause of familial and sporadic Parkinson’s disease.

[0153] LSD: As used herein, the term “LSD” refers to genes encoding lysine-specific demethylases, proteins implicated in neuronal differentiation and physiology. One example of an LSD is LSD1 (also referred to as KDM1A, AOF2, BHC110, CPRF, and KDM1) In some embodiments, an LSD may be a human (Gene ID: 23028), non-human primate (e.g., Gene ID: 718609), or rodent gene (e.g., Gene ID: 99982, Gene ID: 500569). In humans, mutation in a gene encoding a LSD is associated with neurodegeneration, such as Alzheimer’s disease, tauopathy, and / or frontotemporal dementia. In addition, multiple human transcript variants of LSDs, such as LSD1 (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_015013.4 and NM_001009999.3), have been characterized that encode different protein isoforms.

[0154] MAPT: As used herein, the term “MAPT” refers to the gene encoding microtubule associated protein tau (also referred to as tau, tau-40, DDPAC, FTDP-17, MAPTL, MSTD, MTBT1, MTBT2, PPND, and PPP1R103), a protein involved in the stabilization of axonal microtubules. In some embodiments, MAPT may be a human (Gene ID: 4137), non-human primate (e.g., Gene ID: 574327), or rodent gene (e.g., Gene ID: 17762, Gene ID: 29477). In humans, mutation(s) in a MAPT gene may be associated with the development of Alzheimer’s disease. Mutation(s) in a MAPT gene may also be associated with certain tauopathies including frontotemporal dementia. Aggregates formed by hyperphosphorylated tau protein contribute to the pathology of Alzheimer’s disease. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_016835.5, NM_005910.6, and NM_001377265.1) have been characterized that encode different protein isoforms.

[0155] MECP2: As used herein, the term MECP2 refers to a gene (also known as RS; RTS; RTT; PPMX; MRX16; MRX79; MRXSL; AUTSX3; MRXS13) encoding methyl-CpG binding protein 2, a protein which binds to methylated DNA and has important roles in mammalian development. In some embodiments, MECP2 may be a human (Gene ID: 4204), non-human primate (e.g., Gene ID: 102135563), or rodent gene (e.g., Gene ID: 17257, Gene ID: 29386). In humans, mutation(s) in a MECP2 gene are the cause of most cases of Rett syndrome. Multiple human transcript variants (e.g., as annotated under 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) have been characterized that encode different protein isoforms. Suppression of MECP2 (e.g., mutant forms thereof) may be effective in treating Rett syndrome. Increasing levels and / or activity of methyl-CpG binding protein 2 or functional fragments thereof may also be effective in treating Rett syndrome.

[0156] Metachromatic leukodystrophy (MLD): As used herein, the term “Metachromatic leukodystrophy” or “MLD” refers to a lysosomal storage disease (LSD) that is characterized by deficiency in lysosomal enzyme arylsulfatase A (ARSA) or its sphingolipid activator protein B (SapB), causing dysfunction and destruction of myelin sheaths in the central nervous system and peripheral nervous system. This leads to progressive deterioration of neurodevelopment and neurocognitive functions. Metachromatic leukodystrophy is associated with mutations in the arylsulfatase A gene (ARSA) and / or in the prosaposin gene (PSAP). Presently there is no treatment that is effective against Metachromatic leukodystrophy. In some embodiments, a subject (e.g., a subject diagnosed as having MLD) has deterioration of myelin sheaths. In some embodiments, a subject (e.g., a subject diagnosed as having MLD) has deterioration of neurodevelopment and / or neurocognitive functions.

[0157] Molecular payload: As used herein, the term “molecular payload” refers to a molecule or species that functions to modulate a biological outcome. In some embodiments, a molecular payload is linked 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 functions to modulate the transcription of a DNA sequence, to modulate the expression of a protein, or to modulate the activity of a protein. In some embodiments, the molecular payload is an oligonucleotide that comprises a strand having a region of complementarity to a target gene. In some embodiments, the molecular payload is a polypeptide with biological activity in a particular disease context (e.g., a CNS disease or disorder). In some embodiments, the molecular payload is a small molecule with biological activity in a particular 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).

[0158] Motor neuron disease: As used herein, the term “motor neuron disease” refers to a group of progressive neurological disorders that destroy motor neurons, which control skeletal muscle activity. Motor neuron disease includes diseases such as ALS, progressive bulbar palsy, primary lateral sclerosis, progressive muscular atrophy, spinal muscular atrophy, Kennedy’s disease, and post-polio syndrome. Various genes and mutations therein are associated with thedevelopment of motor neuron disease. For example, APOE (e.g., APOE4 allele) is associated with the development of certain types of motor neuron disease. Accordingly, allele-specific modulation of APOE (e.g., APOE4) in some embodiments is useful in the treatment of motor neuron disease. In some embodiments, a subject in need of treatment for motor neuron disease has one or more symptoms associated therewith.

[0159] MSH3: As used herein, MSH3 refers to the gene encoding MutS Homolog 3 protein. The protein is involved in the mismatch repair system. MSH3 has a significant role in cancer in the suppression of tumors by repair of somatic mutations in DNA, and both loss of expression and over-expression of MSH3 can lead to oncogenic effects. Over-expression of MSH3 has been shown to decrease capacity for mismatch repair, and increased expression of MSH3 is associated with progression of Huntington’s disease. See, e.g., 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 development of spinocerebellar ataxia.

[0160] Niemann-Pick Type A: As used herein, the term “Niemann-Pick Type A” refers to Niemann-Pick Type A disease (NPA) a disease, also known as infantile neurovisceral acid sphingomyelinase deficiency, which is a fatal lysosomal neurodegenerative disorder associated with deficiencies 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 an accumulation of sphingomyelin in lysosomes, autophagy-lysosomal pathway dysfunction, and astrogliosis. The genetic cause of NPA disease has been identified as mutations in the ASM gene. See, e.g., Marín, et al. “c-Abl activation linked to autophagy- lysosomal dysfunction contributes to neurological impairment in Niemann-Pick type A disease” Front Cell Devel Biol.10: 844297 (2022).

[0161] Oligonucleotide: As used herein, the term “oligonucleotide” refers to an oligomeric nucleic acid compound of up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (e.g., siRNAs, shRNAs), microRNAs, gapmers, mixmers, phosphorodiamidate morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNAs), etc. Oligonucleotides may be single-stranded or double-stranded. In some embodiments, an oligonucleotide may comprise one or more modified nucleosides (e.g., 2′-O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, an oligonucleotide may comprise one or more modifiedinternucleoside linkages. In some embodiments, an oligonucleotide may comprise one or more phosphorothioate linkages, which may be in the Rp or Sp stereochemical conformation.

[0162] Parkinson’s disease: Parkinson’s disease is a neurological disease that primarily affects the motor system, and is one form of synucleinopathy, as it is associated with an abnormal accumulation of the protein alpha-synuclein in the brain. Motor symptoms of the disease result from the death of cells of the substantia nigra region of the midbrain, which leads to a dopamine deficit. The cause of cell death is poorly understood, but involves accumulation of misfolded proteins into Lewy bodies in the neurons. At least 11 autosomal dominant and 9 autosomal recessive gene mutations have been implicated in the development of Parkinson’s disease, including mutations in SNCA, LRRK2, PARK3, UCHL1, GIGYF2, HTRA2, EIF4G1, TMEM230, CHCHD2, RIC3, VPS35 (autosomal dominant); and in 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.

[0163] PCDH19: As used herein, the term “PCDH19” refers to the gene encoding protocadherin 19 (also referred to as DEE9, EFMR, and EIEE9), a protein involved in cell adhesion. In some embodiments, PCDH19 may be a human (Gene ID: 57526), non-human primate (e.g., Gene ID: 703042), or rodent gene (e.g., Gene ID: 279653, Gene ID: 317183). In humans, mutation in a gene encoding PCDH19 is associated with epilepsy and seizures. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_020766.3 and NM_001184880.2) have been characterized that encode different protein isoforms.

[0164] PIKFYVE: As used herein, PIKFYVE refers to a gene (also known as CFD; FAB1; HEL37; PIP5K; PIP5K3; ZFYVE29) encoding Phosphatidylinositol 3-Phosphate 5-Kinase Type III protein (PIPKIII), which phosphorylates certain phosphatidylinositols (e.g., PtdIns and PtdIns3P). In some embodiments, PIKFYVE may be a human (Gene ID: 200576), non- human primate (e.g., Gene ID: 710115), or rodent gene (e.g., Gene ID: 18711, Gene ID: 316457). PIKFYVE and mutations therein have been implicated in ALS and frontotemporal dementia (FTD). Multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Number: NM_015040.4; NM_152671.4; NM_001178000.2) have been characterized that encode different protein isoforms.

[0165] PNKD: As used herein, PNKD refers to the gene encoding PNKD metallo-beta- lactamase domain containing (also referred to as R1; MR1; PDC; DYT8; FPD1; MR-1; BRP17; MR-1S; PKND1; PNKD1; FKSG19; TAHCCP2; KIPP1184), a protein that is thoughtto play a role in the regulation of myofibrillogenesis. In some embodiments, PNKD may be a human (Gene ID: 25953), non-human primate (e.g., Gene ID: 101867223), or rodent gene (e.g., Gene ID: 56695, Gene ID: 100188944). In humans, mutations in a gene encoding PNKD are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_015488.5; NM_022572.4; NM_001077399.3; XM_017003771.2; and XM_017003772.2) have been characterized that encode different protein isoforms.

[0166] PRKRA: As used herein, PRKRA refers to the gene encoding protein activator of interferon induced protein kinase EIF2AK2 (also referred to as RAX; PACT; DYT16; HSD14), a protein kinase activated by double-stranded RNA which mediates the effects of interferon in response to viral infection. In some embodiments, PRKRA may be a human (Gene ID: 8575), non-human primate (e.g., Gene ID: 102116511), or rodent gene (e.g., Gene ID: 23992, Gene ID: 311130). In humans, mutations in a gene encoding PRKRA are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_003690.5; NM_001139517.1; NM_001139518.1; NM_001316362.2; XM_011512063.3; and XM_047446138.1) have been characterized that encode different protein isoforms.

[0167] PrP: As used herein, the term “PrP” refers to the gene encoding prion protein (also referred to as PRNP, PRIP, CD230, and CJD), a protein involved in neural function that can form cytotoxic prions. In some embodiments, PrP may be a human (Gene ID: 5621), non- human primate (e.g., Gene ID: 717859), or rodent gene (e.g., Gene ID: 19122, Gene ID: 24686). In humans, mutation in a PrP gene is associated with neurodegeneration. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000311.5 and NM_183079.4) have been characterized that encode different protein isoforms. In some embodiments, PrP is associated with small fiber neuropathy, nociception-related phenotypes, Alexander disease, Angelman Syndrome, autism-spectrum disorders, retinitis pigmentosa, isolated macular dystrophy, and / or multiple sclerosis.

[0168] PRRT2: As used herein, PRRT2 refers to the gene encoding proline rich transmembrane protein 2 (also referred to as PKC; EKD1; ICCA; BFIC2; BFIS2; DSPB3; DYT10; FICCA; IFITMD1), a transmembrane protein containing a proline-rich domain in its N-terminal half. In some embodiments, PRRT2 may be a human (Gene ID: 112476), non- human primate (e.g., Gene ID: 102124815), or rodent gene (e.g., Gene ID: 69017, Gene ID: 361651). In humans, mutations in a gene encoding PRRT2 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., asannotated under GenBank RefSeq Accession Numbers: NM_145239.3; NM_001256442.2; NM_001256443.2; XM_011545715.4; XM_017022887.3; XM_017022888.3; and XM_017022889.3) have been characterized that encode different protein isoforms.

[0169] Recombinant antibody: The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in more details in this disclosure), antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom H. R., (1997) TIB Tech.15:62-70; Azzazy H., and Highsmith W. E., (2002) Clin. Biochem.35:425-445; Gavilondo J. V., and Larrick J. W. (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L. D., et al. (1992) Nucl. Acids Res.20:6287-6295; Kellermann S-A., and Green L. L. (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, 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 disclosure provides fully human antibodies capable of binding 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 Jermutus et al., PCT publication No. WO 2005 / 007699 A2.

[0170] Region of complementarity: As used herein, the term “region of complementarity” refers to a nucleotide sequence, e.g., of an oligonucleotide, that is sufficiently complementary to a cognate nucleotide sequence, e.g., of a target nucleic acid, such that the two nucleotide sequences are capable of annealing to one another under physiological conditions (e.g., in a cell). In some embodiments, a region of complementarity is fully complementary to a cognate nucleotide sequence of target nucleic acid. However, in some embodiments, a region of complementarity is partially complementary to a cognate nucleotide sequence of target nucleic acid (e.g., at least 80%, 90%, 95% or 99% complementarity). In some embodiments, a regionof complementarity contains 1, 2, 3, or 4 mismatches compared with a cognate nucleotide sequence of a target nucleic acid.

[0171] Rett syndrome: As used herein, the term “Rett syndrome” refers to a spectrum of disorders associated with mutations in MECP2. Rett syndrome is a brain disorder that occurs almost exclusively in girls. Around 6 to 18 months of of age, subjects with Rett syndrome begin developing severe problems with language and communication, learning, coordination, and other brain functions. Early in childhood, affected subjects lose purposeful use of their hands and begin making repeated hand wringing, washing, or clapping motions. They tend to grow more slowly than other children and about 75% have microcephaly. Other signs and symptoms that can develop include breathing abnormalities, spitting or drooling, unusual eye movements such as intense staring or excessive blinking, cold hands and feet, irritability, sleep disturbances, seizures, and scoliosis. More than 99% of subjects with Rett syndrome have no family history of the disorder; many of these cases result from new mutations in MECP2. Suppression of mutant forms of MECP2, e.g., by antisense oligonucleotide therapy, may in some embodiments be effective in treating Rett syndrome or symptoms thereof. Increasing levels and / or activity of proteins or functional fragments thereof encoded by MECP2 (e.g., by delivery of gene therapy payloads) may also be effective in treating Rett syndrome or symptoms thereof.

[0172] Sandhoff disease: As used herein, the term “Sandhoff disease,” sometimes referred to as GM2 gangliosidosis, refers to a continuum of disorders that progressively destroy neurons in the central nervous system. Sandhoff disease is inherited in an autosomal recessive pattern. Symptoms of Sandhoff disease include progressive weakness, seizures, developmental deficits, neurological impairment, cognitive impairments, and premature death. Sandhoff disease is characterized by cortical, cerebellar, and spinal cord atrophy. The genetic cause of Sandhoff disease has been identified as about 30 mutations in the HEXB gene. See Xiao, et al. “Sandhoff Disease” 2022 Apr 14, in: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. In some embodiments, a subject in need of treatment for Sandhoff disease presents with progressive weakness. In some embodiments, progressive weakness comprises lower-extremity weakness. In some embodiments, a subject in need of treatment for Sandhoff disease presents with seizures. In some embodiments, a subject in need of treatment for Sandhoff disease presents with developmental deficits. In some embodiments, developmental deficits comprise developmental plateauing and developmental regression. In some embodiments, a subject in need of treatment for Sandhoff disease presents with neurological impairments. In someembodiments, neurological impairments comprise loss of motor skills, exaggerated startle response, hypotonia, hyperreflexia, neuropathy, neuronopathy, atrophy, fasciculations, balance issues, tremors, dysarthria, dysphagia, and spasticity. In some embodiments, a subject in need of treatment for Sandhoff disease presents with cognitive impairments. In some embodiments, cognitive impairments comprise decreased attentiveness, cognitive decline, deficits in executive function, and deficits in memory. In some embodiments, a subject in need of treatment for Sandhoff disease does not present with hepatosplenomegaly. Sandhoff disease is very similar to Tay-Sachs; treatments for Tay-Sachs therefore 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.

[0173] SCA1: As used herein, “SCA1” refers to spinocerebellar ataxia type 1, which is associated with CAG repeat expansions in ATXN1. See “Spinocerebellar ataxia.”

[0174] SCA2: As used herein, “SCA2” refers to spinocerebellar ataxia type 2, which is associated with CAG repeat expansions in ATXN2. See “Spinocerebellar ataxia.”

[0175] SCA3: As used herein, “SCA3” refers to spinocerebellar ataxia type 3, which is associated with CAG repeat expansions in ATXN3. See “Spinocerebellar ataxia.”

[0176] SCN1A: As used herein, the term “SCN1A” refers to the gene encoding sodium voltage-gated channel alpha subunit 1 (also referred to as DEE6, DEE6A, DEE6B, DRVT, EIEE6, FEB3, FEB3A, FHM3, GEFSP2, HBSCI, NAC1, Nav1.1, SCN1, and SMEI), a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN1A may be a human (Gene ID: 6323), non-human primate (e.g., Gene ID: 704086), or rodent gene (e.g., Gene ID: 20265, Gene ID: 81574). In humans, mutations in an SCN1A gene, such as a loss-of-function mutation in SCN1A, are associated with epilepsy and seizures, and with Dravet syndrome (severe myoclonic epilepsy of infancy (SMEI)). Gain-of- function mutations in SCN1A are associated with other neurological disorders, such as familial hemiplegic migraine, epileptic encephalopathy, and arthrogryposis. See, e.g., 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 often result in reduced function of the encoded protein orno protein expression. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_006920.6 and NM_001165963.4) have been characterized that encode different protein isoforms. In some embodiments, SCN1A, or mutant forms thereof, is associated with pain disorders.

[0177] SCN2A: As used herein, the term “SCN2A” refers to the gene encoding sodium voltage-gated channel alpha subunit 2 (also referred to as BFIC3, BFIS3, BFNIS, DEE11, EA9, EIEE11, HBA, HBSCI, HBSCII, NAC2, Nav1.2, SCN2A1, and SCN2A2), a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN2A may be a human (Gene ID: 6326), non-human primate (e.g., Gene ID: 703298), or rodent gene (e.g., Gene ID: 110876, Gene ID: 24766). In humans, mutations in an SCN2A gene, such as a gain-of-function mutation in SCN2A, are associated with epilepsy and seizures. Loss-of-function mutations in SCN2A are associated with other neurological disorders, including autism spectrum disorder, with or without epilepsy. See, e.g., Zeng, et al. “SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis” Front Mol Neurosci.15: 809951 (2022) doi: 10.3389 / fnmol.2022.809951. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_021007.3 and NM_001040142.2) have been characterized that encode different protein isoforms. In some embodiments, SCN2A, or mutant forms thereof, is associated with pain disorders.

[0178] SCN8A: As used herein, the term “SCN8A” refers to the gene encoding sodium voltage-gated channel alpha subunit 8 (also referred to as BFIS5, CERIII, CIAT, DEE13, EIEE13, MED, MYOCL2, NaCh6, Nav1.6, and PN4), a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN8A may be a human (Gene ID: 6334), non-human primate (e.g., Gene ID: 695972), or rodent gene (e.g., Gene ID: 20273, Gene ID: 29710). In humans, mutations in an SCN8A gene, such as a gain-of-function mutation in SCN8A, are associated with epilepsy and seizures. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_014191.4 and NM_001330260.2) have been characterized that encode different protein isoforms. In some embodiments, SCN8A, or mutant forms thereof, is associated with pain disorders.

[0179] SCN9A: As used herein, the term “SCN9A” refers to a gene encoding sodium voltage- gated channel alpha subunit 9 (also referred to as ETHA, FEB3B, GEFSP7, HSAN2D, NE- NA, NENA, Nav1.7, PN1, and SFNP), a protein involved in the generation and propagation of action potentials in neurons. In some embodiments, SCN9A may be a human (Gene ID: 6335),non-human primate (e.g., Gene ID: 574119), or rodent gene (e.g., Gene ID: 20274, Gene ID: 78956). In humans, mutations in an SCN9A gene are associated with various pain disorders. In some embodiments, mutations in an SCN9A are associated with small fiber neuropathy and nociception-related phenotypes. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_002977.3 and NM_001365536.1) have been characterized that encode different protein isoforms.

[0180] SGCE: As used herein, SGCE refers to the gene encoding sarcoglycan epsilon (also referred to as ESG; DYT11; epsilon-SG), a member of the sarcoglycan family. Sarcoglycans are transmembrane proteins that are components of the dystrophin-glycoprotein complex, which link the actin cytoskeleton to the extracellular matrix. Unlike other family members which are predominantly expressed in striated muscle, the epsilon sarcoglycan is more broadly expressed. In some embodiments, SGCE may be a human (Gene ID: 8910), non-human primate (e.g., Gene ID: 101865326), or rodent gene (e.g., Gene ID: 20392, Gene ID: 432360). In humans, mutations in a gene encoding SGCE are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under 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_001346720.2; NM_001362807.2; NM_001362808.2; and NM_001362809.2) have been characterized that encode different protein isoforms.

[0181] SLC2A1: As used herein, SLC2A1 refers to the gene encoding solute carrier family 2 member 1 (also referred to as CSE; PED; DYT9; GLUT; DYT17; DYT18; EIG12; GLUT1; HTLVR; GLUT-1; SDCHCN; GLUT1DS), a major glucose transporter in the mammalian blood-brain barrier. In some embodiments, SLC2A1 may be a human (Gene ID: 6513), non- human primate (e.g., Gene ID: 102144217), or rodent gene (e.g., Gene ID: 20525, Gene ID: 24778). In humans, mutations in a gene encoding SLC2A1 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Number: NM_006516.4) have been characterized that encode different protein isoforms.

[0182] SMN: As used, herein SMN refers to a gene which encodes the protein survival of motor neuron. Survival of motor neuron protein is involved in transcriptional splicing through its involvement in assembly of ribonucleoproteins that bind with pre-mRNA to form a spliceosome. A lack of survival of motor neuron protein activity results in widespread splicing defects, especially in spinal motor neurons, and degeneration of the spinal cord lower motor neurons. The survival of motor neuron protein is encoded by the genes SMN1 and SMN2,mutations in each of which are associated with spinal muscular atrophy, and both of which may be referred to as “SMN”. Molecular payloads useful in modulating SMN1 may also be useful in modulating SMN2, and vice versa, in the treatment of CNS diseases and disorders.

[0183] SNCA: As used herein, SNCA refers to the gene that encodes alpha-synuclein protein. Alpha-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. Alpha-synuclein is found predominantly in presynaptic termini in both free and membrane-bound forms, with approximately 15% of the protein being membrane-bound at a given time in neurons. Alternative splicing of SNCA transcripts results in the production of at least three isoforms of alpha-synuclein. Alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by the presence of Lewy bodies, including Parkinson’s disease. These pathological conditions are known as synucleinopathies. The aggregation mechanism of alpha- synuclein is uncertain. Several mutations in SNCA have been associated with Parkinson’s disease, including mutations resulting in alpha-synuclein protein with 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 protein has been shown to interact with dopamine transporter, parkin (ligase), phospholipase D1, SNCAIP, tau protein, and beta amyloid.

[0184] SOD1: the term “SOD1” refers to the enzyme superoxide dismutase 1 and the gene which encodes it. SOD1 is an enzyme implicated in apoptosis, amyotrophic lateral sclerosis, and Parkinson’s disease. The SOD1 protein is a 32 kDa homodimer which contains a binuclear Cu / Zn site in each subunit. The Cu / Zn site is responsible for destroying free superoxide radicals in the body by catalyzing disproportionation of superoxide to hydrogen peroxide and dioxygen. Wild-type SOD1 protein has demonstrated antiapoptotic properties in neural cultures, whereas mutant SOD1 protein has been shown to promote apoptosis in neural cells. Mutations in the SOD1 gene have been linked to familial ALS, though wild-type SOD1 has also been implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients. The most frequent SOD1 mutations are A4V, H46R, and G93S. Virtually all known ALS-associated SOD1 mutations act in a dominant fashion, such that a single mutant copy of the SOD1 gene is sufficient to cause the disease. The exact mechanism by which mutations in SOD1 cause ALS is unknown, though 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 DNAoxidation product 8-OHdG, a well-established marker of oxidative DNA damage, accumulates in the mitochondria of motor neurons of ALS patients, suggesting that oxidative damage to DNA (e.g., mitochondrial DNA) of motor neurons resulting from mutated SOD1 may significantly contribute to the etiology of ALS.

[0185] Specifically binds: As used herein, the term “specifically binds” 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 an appropriate control in a binding assay or other binding context. With respect to an antibody, the term, “specifically binds”, refers to the ability of the antibody to bind to a specific antigen with a degree of affinity or avidity, compared with an appropriate reference antigen or antigens, that enables the antibody to be used to distinguish the specific antigen from others, e.g., to an extent that permits preferential targeting to certain cells, e.g., CNS cells, through binding to the antigen, as described herein. In some embodiments, an antibody specifically binds to a target if the antibody has a KD for binding the target of at least about 10-4M, 10-5M, 10-6M, 10-7M, 10-8M, 10-9M, 10-10M, 10-11M, 10-12M, 10-13M, or less. In some embodiments, an antibody specifically binds to the transferrin receptor, e.g., an epitope of the apical domain of transferrin receptor.

[0186] Spinocerebellar ataxia: As used herein, the term “spinocerebellar ataxia” or “SCA” refers to a class of CNS disorders that are generally characterized by problems with coordination due to effects on the cerebellum and spinal cord (also referred to as “autosomal dominant cerebellar ataxias”). SCA is often characterized by slowly progressive incoordination of gait, and is often associated with poor coordination of hands, speech, and eye movements. SCA is a progressive neurodegenerative disorder which is inherited in an autosomal dominant pattern. More than 40 types of SCA, each of which has 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 prominent damage to cerebellar Purkinje neurons with consecutive cerebellar atrophy. In addition, other parts of the CNS, such as the spinal cord, basal ganglia and pontine nuclei in the brainstem, can 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 from: ncbi.nlm.nih.gov / books / NBK557816 / . Of particular relevance to the present disclosure are SCA1, SCA2, SCA3, and SCA associated with MSH3. Many forms of SCA are associated with expansions of trinucleotide repeats within ataxin (ATXN) genes. SCA1 is associated withCAG repeat expansions in ATXN1, SCA2 is associated with CAG repeat expansions in ATXN2, and SCA3 is associated with CAG repeat expansions in ATXN3. There are currently no treatments available for SCA; as such, clinical interventions focus primarily on management of symptoms through physical therapy, occupational therapy, and speech therapy.

[0187] SPR: As used herein, SPR refers to the gene encoding sepiapterin reductase (also referred to as SDR38C1), an aldo-keto reductase that catalyzes the NADPH-dependent reduction of pteridine derivatives. SPR is important in the biosynthesis of tetrahydrobiopterin (BH4). Mutations in this gene result in DOPA-responsive dystonia due to sepiapterin reductase deficiency. In some embodiments, SPR may be a human (Gene ID: 6697), non-human primate (e.g., Gene ID: 102128831), or rodent gene (e.g., Gene ID: 20751, Gene ID: 29270). In humans, mutations in a gene encoding SPR are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Number: NM_003124.5) have been characterized that encode different protein isoforms.

[0188] Subject: As used herein, the term “subject” refers to a mammal. In some embodiments, a subject is non-human primate, or rodent. In some embodiments, a subject is a human. In some embodiments, a subject is a patient, e.g., a human patient that has or is suspected of having a disease. In some embodiments, the subject is a human patient who has or is suspected of having a CNS disease or disorder. In some embodiments, the subject is a human patient who has one or more symptoms associated with a CNS disease or disorder, such as one or more symptoms disclosed herein.

[0189] SYF2: As used herein, SYF2 refers to the gene (also known as P29; CBPIN; NTC31; fSAP29) encoding pre-mRNA-splicing factor SYF2, which is primarily localized in the nucleus. In some embodiments, SYF2 may be a human (Gene ID: 25949), non-human primate (e.g., Gene ID: 102139055), or rodent gene (e.g., Gene ID: 68592, Gene ID: 170933). SYF2 and mutations therein have been implicated in ALS and frontotemporal dementia (FTD). Multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Number: NM_207170.4; NM_015484.5) have been characterized that encode different protein isoforms.

[0190] TAF1: As used herein, TAF1 refers to the gene encoding TATA-box binding protein associated factor 1 (also referred to as OF; XDP; BA2R; CCG1; CCGS; DYT3; KAT4; P250; NSCL2; TAF2A; MRXS33; N-TAF1; TAFII250; DYT3 / TAF1; TAFII-250; TAF(II)250), 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 subunit bindsto core promoter sequences encompassing the transcription start site, and also binds to activators and other transcriptional regulators. In some embodiments, TAF1 may be a human (Gene ID: 6872), non-human primate (e.g., Gene ID: 102118965), or rodent gene (e.g., Gene ID: 270627, Gene ID: 317256). In humans, mutations in a gene encoding TAF1 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under 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_104392.2; NR_104393.2; NR_104394.2; NR_104395.2; NR_104396.2; XM_005262300.3; XM_024452430.2; XM_047442391.1; XM_047442392.1; XM_047442393.1; XM_047442394.1; XM_047442395.1; XM_047442396.1; XM_047442397.1; XM_047442398.1; XM_047442399.1; XM_047442400.1; XM_047442401.1; XM_047442402.1; XM_047442403.1; XM_047442404.1; XM_047442405.1; and XM_047442406.1) have been characterized that encode different protein isoforms.

[0191] Tay-Sachs: As used herein, the term “Tay-Sachs” refers to a genetic disorder that is characterized by destruction of nerve cells in the central nervous system. Tay-Sachs is also known as GM2 gangliosidosis. Tay-Sachs is associated with a mutation in the enzyme hexosaminidase A (HEXA), which leads to a buildup of GM2 ganglioside in lysosomes and nerve cells. Tay-Sachs predominantly affects young children (infantile form) but can come on during adolescence (juvenile form), as well as in adulthood. Tay-Sachs is characterized by neurodegeneration, and its symptoms include: slowing of development, progressive loss of mental ability, dementia, blindness, increase startle reflex to noise, progressive loss of hearing, swallowing issues, seizures, Cherry-red spots in the eyes, muscle weakness, and ataxia. Conventional treatments for Tay-Sachs focus on symptom relief and delay in progression. In some embodiments, a subject in need of treatment for Tay-Sachs has a mutation in a HEXA gene. In some embodiments, a subject in need of treatment for Tay-Sachs has neurodegeneration. In some embodiments, a subject in need of treatment for Tay-Sachs has one or more of the following symptoms: slowing of development, progressive loss of mental ability, dementia, blindness, increase startle reflex to noise, progressive loss of hearing, swallowing issues, seizures, Cherry-red spots in the eyes, muscle weakness, and ataxia. Tay- Sachs is very similar to Sandhoff disease; treatments for Sandhoff disease therefore 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).

[0192] TH: As used herein, TH refers to the gene encoding tyrosine hydroxylase (also referred to as TYH; DYT14; DYT5b), a protein involved in the conversion of tyrosine to dopamine. The tyrosine hydroxylase protein is the rate-limiting enzyme in the synthesis of catecholamines, and hence plays a key role in the physiology of adrenergic neurons. In some embodiments, TH may be a human (Gene ID: 7054), non-human primate (e.g., Gene ID: 102134074), or rodent gene (e.g., Gene ID: 21823, Gene ID: 25085). In humans, mutations in a gene encoding TH are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000360.4; NM_199292.3; NM_199293.3; and XM_011520335.3) have been characterized that encode different protein isoforms.

[0193] THAP1: As used herein, THAP1 refers to the gene encoding THAP domain containing 1 (also referred to as DYT6), a protein that contains a THAP domain, a conserved DNA- binding domain. This protein colocalizes with the apoptosis response protein PAWR / PAR-4 in promyelocytic leukemia (PML) nuclear bodies, and functions as a proapoptotic factor that links PAWR to PML nuclear bodies. In some embodiments, THAP1 may be a human (Gene ID: 55145), non-human primate (e.g., Gene ID: 101926823), or rodent gene (e.g., Gene ID: 73754, Gene ID: 306547). In humans, mutations in a gene encoding THAP1 are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_018105.3 and NM_199003.2) have been characterized that encode different protein isoforms.

[0194] TOR1A: As used herein, TOR1A refers to the gene encoding torsin family 1 member A (also referred to as DQ2; AMC5; DYT1), a is a member of the AAA family of adenosine triphosphatases (ATPases). In some embodiments, TOR1A may be a human (Gene ID: 1861), non-human primate (e.g., Gene ID: 102124758), or rodent gene (e.g., Gene ID: 30931, Gene ID: 266606). In humans, mutations in a gene encoding TOR1A are associated with the development of hereditary dystonia. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Number: NM_000113.3) have been characterized that encode different protein isoforms.

[0195] TPP1: As used herein, “TPP1” refers to the gene encoding tripeptidyl peptidase 1 (also known as GIG1, LPIC, SCAR7, and CLN2). The tripeptidyl peptidase 1 enzyme is implicated in CLN2 Batten disease. Wildtype tripeptidyl peptidase 1 mediates cleavage of N-terminal tripeptides from substrates. In CLN2 Batten disease, mutations in tripeptidyl peptidase 1 enzymes severely decrease its enzymatic activity, leading to the incomplete breakdown, and subsequent accumulation of proteins in lysosomes. The most frequent tripeptidyl peptidase 1mutations are single amino acid changes. Inheritance of CLN2 Batten disease is autosomal recessive. In some embodiments, CLN2 may be a human (Gene ID: 1200), non-human primate (Gene ID: 709838), or rodent (Gene ID: 12751; Gene ID: 83534) gene.

[0196] Transferrin receptor: As used herein, the term, “transferrin receptor” (also known as TFRC, CD71, p90, TFR, or TFR1) refers to an internalizing cell surface receptor that binds transferrin to facilitate iron uptake by endocytosis. In some embodiments, a transferrin receptor may be of human (NCBI Gene ID 7037), non-human primate (e.g., NCBI Gene ID 711568 or NCBI Gene ID 102136007), or rodent (e.g., NCBI Gene ID 22042) origin. In addition, multiple human transcript variants have been characterized that encoded different isoforms of the receptor (e.g., as annotated under GenBank RefSeq Accession Numbers: NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1).

[0197] TREM2: As used herein, TREM2 refers to the gene which encodes triggering receptor expressed on myeloid cells 2 (also referred to as PLOSL2, Trem2a, Trem2b, and Trem2c), a protein involved in inflammation, synaptic pruning, and neuronal cell survival. In the brain, TREM2 is expressed in microglial cells. In some embodiments, TREM2 may be a human (Gene ID: 54209), non-human primate (e.g., Gene ID: 719740), or rodent gene (e.g., Gene ID: 83433, Gene ID: 301227). In humans, mutation in a TREM2 gene is associated with the development of Alzheimer’s disease. In some embodiments, mutations in TREM2 are associated with an increased risk of Alzheimer’s disease. Genetic variants of TREM2 have also been associated with increased risk of multiple neurodegenerative disease, 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 (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_018965.4 and NM_001271821.2) have been characterized that encode different protein isoforms.

[0198] UBE3A: As used herein, the term “UBE3A” refers to a gene encoding ubiquitin protein ligase E3A (also referred to as E6AP, ANCR, AS, EPVE6AP, HPVE6A, and PIX1), a protein implicated in ubiquitination and proteolysis. In some embodiments, UBE3A may be a human (Gene ID: 7337), non-human primate (e.g., Gene ID: 711270), or rodent gene (e.g., Gene ID: 22215, Gene ID: 361585). In humans, mutation in a UBE3A gene is associated with Angelman Syndrome and autism-spectrum disorders. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_130838.4, NM_000462.5, and NM_130839.5) have been characterized that encode different protein isoforms.

[0199] UNC13A: As used herein, the term “UNC13A” refers to a gene encoding Unc-13 homolog A (also referred to as Munc13-1 and unc-13 homolog A (C. elegans)), a member of the UNC13 family of proteins, which are 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 may be a human (Gene ID: 23025), non- human primate (e.g., Gene ID: 720000, Gene ID: 102123626), or rodent gene (e.g., Gene ID: 382018, Gene ID: 64829). In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_001080421.3, NM_001387021.1, NM_001387022.1, NM_001387023.1, XM_011527810.3, XM_011527811.3, XM_017026502.2, XM_054320277.1, XM_054320278.1, and XM_054320279.1) have been characterized that encode different protein isoforms. UNC13A contains a cryptic exon that promotes nonsense-mediated decay. Certain single nucleotide polymorphisms in UNC13A are associated with an increased risk of cryptic exon inclusion in the UNC13A transcript. Such polymorphisms in UNC13A have been 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 UNC13A” Nature 603:124- 130 (2022)).

[0200] VLA-4: As used herein, the term “VLA-4” refers to a gene encoding very late antigen 4 (also referred to as ITGA4, CD49D, and IA4), a protein involved in cell adhesion and signaling. In some embodiments, VLA-4 may be a human (Gene ID: 3676), non-human primate (e.g., Gene ID: 704745), or rodent gene (e.g., Gene ID: 16401, Gene ID: 311144). In humans, mutations in a VLA-4 gene are associated with retinitis pigmentosa 26, isolated macular dystrophy, and multiple sclerosis. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000885.6 and NM_001316312.2) have been characterized that encode different protein isoforms.

[0201] 2’-modified nucleoside: As used herein, the terms “2’-modified nucleoside” and “2’- modified ribonucleoside” are used interchangeably and refer to a nucleoside having a sugar moiety modified at the 2’ position. In some embodiments, the 2’-modified nucleoside is a 2’- 4’ bicyclic nucleoside, where the 2’ and 4’ positions of the sugar are bridged (e.g., via a methylene, an ethylene, or a (S)-constrained ethyl bridge). In some embodiments, the 2’- modified nucleoside is a non-bicyclic 2’-modified nucleoside, e.g., where the 2’ position of the sugar moiety is substituted. 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 the 2’-modified nucleosides have increased affinity to a target sequences, relative to an unmodified oligonucleotide. Examples of structures of 2’-modified nucleosides are provided below:These examples are shown with phosphate groups, but any internucleoside linkages are contemplated between 2’-modified nucleosides. II. Complexes

[0202] Provided herein are complexes that comprise a targeting agent, e.g. an antibody, covalently linked to a molecular payload. In some embodiments, a complex comprises a central nervous system (CNS)-targeting antibody covalently linked to an oligonucleotide. A complex may comprise an antibody that specifically binds a single antigenic site or that binds to at least two antigenic sites that may exist on the same or different antigens.

[0203] A complex may be used to modulate the activity or function of at least one gene, protein, and / or (e.g., and) nucleic acid in cells of the CNS, or to alleviate the symptoms of a CNS disease disorder. In some embodiments, the molecular payload present with a complex is responsible for the modulation of a gene, protein, and / or (e.g., and) nucleic acids. A molecular payload may be a small molecule, protein, nucleic acid, oligonucleotide, or any molecularentity capable of modulating the activity or function of a gene, protein, and / or (e.g., and) nucleic acid in a cell.

[0204] In some embodiments, a CNS targeting agent of the complexes described herein comprises an anti-transferrin receptor 1 (TfR1) antibody, covalently linked to a molecular payload, e.g., an oligonucleotide, polypeptide, small molecule, or gene therapy payload. Antibodies

[0205] In some embodiments, complexes described herein comprise an antibody that binds human transferrin receptor 1 (TfR1). An example human TfR1 amino acid sequence, corresponding to NCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens) is as follows:

[0206] Table 2 provides examples of sequences of an anti-TfR1 antibody useful in the complexes provided herein. Table 2. Examples of anti-TfR1 antibody sequences

[0207] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 1 (according to the IMGT definition system), a heavy chain complementarity determining region 2 (CDR-H2) of SEQ ID NO: 2 (according to the IMGT definition system), a heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 3 (according to the IMGT definition system), a light chain complementarity determining region 1 (CDR-L1) of SEQ ID NO: 4 (according to the IMGT definition system), a light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 5 (according to the IMGT definition system), and a light chain complementarity determining region 3 (CDR-L3) of SEQ ID NO: 6 (according to the IMGT definition system).

[0208] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 7 (according to the Kabat definition system), a heavy chain complementarity determining region 2 (CDR-H2) of SEQ ID NO: 8 (according to the Kabat definition system), a heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 9 (according to the Kabat definition system), a light chain complementarity determining region 1 (CDR-L1) of SEQ ID NO: 10 (according to the Kabat definition system), a light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 11 (according to the Kabat definition system), and a light chaincomplementarity determining region 3 (CDR-L3) of SEQ ID NO: 6 (according to the Kabat definition system).

[0209] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 12 (according to the Chothia definition system), a heavy chain complementarity determining region 2 (CDR- H2) of SEQ ID NO: 13 (according to the Chothia definition system), a heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 14 (according to the Chothia definition system), a light chain complementarity determining region 1 (CDR-L1) of SEQ ID NO: 15 (according to the Chothia definition system), a light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 5 (according to the Chothia definition system), and a light chain complementarity determining region 3 (CDR-L3) of SEQ ID NO: 16 (according to the Chothia definition system).

[0210] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain variable region (VH) containing no more than 25 amino acid variations (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 variation) in the framework regions as compared with the VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises a light chain variable region (VL) containing no more than 25 amino acid variations (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 variation) in the framework regions as compared with the VL comprising the amino acid sequence of SEQ ID NO: 18.

[0211] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or in addition (e.g., in addition), in some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL comprising the amino acid sequence of SEQ ID NO: 18.

[0212] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or in addition (e.g., in addition), in some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 18.

[0213] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising an amino acid sequence 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., in addition), the anti-TfR1 antibody of the present disclosure comprises a light chain comprising an amino acid sequence 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 that comprises a heavy chain comprising an amino acid sequence 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., in addition), the anti-TfR1 antibody of the present disclosure is a Fab that comprises a light chain comprising an amino acid sequence least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the amino acid sequence of SEQ ID NO: 20.

[0214] 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., in addition), 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 that comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure is a Fab that comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0215] In some embodiments, the anti-TfR1 antibody provided herein may have one or more post-translational modifications. In some embodiments, N-terminal cyclization, also called pyroglutamate formation (pyro-Glu), may occur in the antibody at N-terminal Glutamate (Glu) and / or Glutamine (Gln) residues during production. As such, it should be appreciated that an antibody specified as having a sequence comprising an N-terminal glutamate or glutamine residue encompasses antibodies that have undergone pyroglutamate formation resulting from a post-translational modification. In some embodiments, pyroglutamate formation occurs in a heavy chain sequence. In some embodiments, pyroglutamate formation occurs in a light chain sequence. Molecular Payloads

[0216] Some aspects of the disclosure provide molecular payloads, e.g., for modulating a biological outcome, e.g., the transcription of a DNA sequence, the processing of a pre-mRNA transcript, the stability of a pre-mRNA or mRNA transcript, the expression of a protein (e.g.,translation of an mRNA), or the activity of a protein, that can be linked to an anti-TfR1 antibody described herein (e.g., anti-TfR1 antibody in Table 2). In some embodiments, such molecular payloads are targeted to a CNS cell, e.g., via specifically binding to a nucleic acid or protein in or on the CNS cell following delivery to the CNS cell by the linked anti-TfR1 antibody. It should be appreciated that various types of molecular payloads may be used in accordance with the disclosure. For example, the molecular payload may comprise, or consist of, an oligonucleotide (e.g., an antisense oligonucleotide or an RNA interference oligonucleotide), a polypeptide (e.g., a peptide, protein, or antibody that binds 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 that encodes a polypeptide with biological activity in a CNS cell).

[0217] In some embodiments, the molecular payload is an oligonucleotide that comprises a strand having a region of complementarity to a gene (e.g., a gene transcript) provided in Table 3. Table 3. List of central nervous system diseases and corresponding genes.

[0218] In some embodiments, the molecular payload is an oligonucleotide that comprises a strand having a region of complementarity to a gene (e.g., a gene transcript) provided in Table 4. Table 4. List of central nervous system diseases and corresponding genes.Oligonucleotide payloads

[0219] In some embodiments, oligonucleotides are useful in the treatment of various CNS diseases and disorders. For example, oligonucleotides may be useful to modulate the expression or activity of various genes involved in CNS diseases and disorder, such as bymodulating transcription of the genes, modulating stability of mRNA molecules encoded by the genes, modulating translation of the mRNA molecules encoded by the genes, and modulating splicing of pre-mRNA transcripts encoded by the genes. Oligonucleotides may be used to treat various CNS diseases and disorders, for example, by facilitating delivery of the oligonucleotide into cells of the CNS. In some embodiments, oligonucleotides disclosed herein can be delivered into cells of the CNS using complexes disclosed here (e.g., anti-TfR1 antibody complexes comprising the oligonucleotide).

[0220] In some embodiments, oligonucleotides are useful in the treatment of 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; a pain disorder; glycogen synthesis disorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman Syndrome; autism-spectrum disorders; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis.

[0221] In some embodiments, oligonucleotides are useful in the treatment of essential tremor and / or hereditary dystonia.

[0222] In some embodiments, oligonucleotides are useful in the modulation of one or more genes associated with a CNS disease or disorder. In some embodiments, the one or more genes associated with a CNS disease or disorder 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 is 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.

[0223] In some embodiments, the 5’ or 3’ nucleoside (e.g., terminal nucleoside) of any one of the oligonucleotides described herein is conjugated to an amine group, optionally 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, a phosphodiester linkage is present 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 of the oligonucleotides described herein is conjugated to a spacer that is a substituted or unsubstitutedaliphatic, 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-, -each RAis independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, the spacer is a substituted or unsubstituted alkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, -O-, -N(RA)-, or -C(=O)N(RA)2, or a combination thereof.

[0224] In some embodiments, the 5’ or 3’ nucleoside of any one of the oligonucleotides described herein is conjugated to a compound of the formula -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, a phosphodiester linkage is present between the compound of the formula NH2- (CH2)n- and the 5’ or 3’ nucleoside of the oligonucleotide. In some embodiments, a compound of the 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.

[0225] In some embodiments, the oligonucleotide is conjugated to a targeting agent, e.g., a CNS targeting agent such as an anti-TfR1 antibody, e.g., via the amine group. a. Oligonucleotide Size / Sequence

[0226] Oligonucleotides may be of a variety of different lengths, e.g., depending on the format. In some embodiments, an 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 length. 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 lengths, 20 to 25 nucleotides in length, etc.

[0227] In some embodiments, a nucleic acid sequence of an oligonucleotide for purposes of the present disclosure is “complementary” to a target nucleic acid when it is specifically hybridizable to the target nucleic acid. In some embodiments, an oligonucleotide hybridizing to a target nucleic acid (e.g., a transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 392-702) results in modulation of 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 hybridizing to a target nucleic acid (e.g., atranscript provided in Table 4, e.g., provided by any one of SEQ ID NOs: 705-803) results in modulation of 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 hybridizing to a target nucleic acid (e.g., a transcript provided in Table 3 or in Table 4, e.g., provided by any one of SEQ ID NOs: 143-148, 167-169, 810-875, and 1059- 1068) results in modulation of 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 hybridizing to a target nucleic acid results in an increase of activity or expression of the target (e.g., increased mRNA translation, such as of a wild-type form of the mRNA; altered pre-mRNA splicing; exon skipping; target mRNA stabilization; etc.). In some embodiments, a nucleic acid sequence of an oligonucleotide has a sufficient degree of complementarity to its target nucleic acid such that it does not hybridize non-target sequences under conditions in which avoidance of non-specific binding is desired, e.g., under physiological conditions. Thus, in some embodiments, an oligonucleotide may be 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% complementary to the consecutive nucleotides of a target nucleic acid. In some embodiments a complementary nucleotide sequence need not be 100% complementary to that of its target to be specifically hybridizable or specific for a target nucleic acid. In certain embodiments, oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid. In certain embodiments, activity relating to the target is reduced by such mismatch, but activity relating to a non-target is reduced by a greater amount (i.e., selectivity for the target nucleic acid is increased and off-target effects are decreased).

[0228] In some embodiments, an oligonucleotide comprises region of complementarity to a target nucleic acid that is in the range of 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, a region of complementarity of an oligonucleotide to a target nucleic acid is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length. In some embodiments, the region of complementarity is complementary with at least 8 consecutive nucleotides of a target nucleic acid. In some embodiments, an oligonucleotide may contain 1, 2 or 3 base mismatches compared to the portion of the consecutive nucleotides of target nucleic acid. In some embodiments the oligonucleotide may have up to 3 mismatches over 15 bases, or up to 2 mismatches over 10 bases.

[0229] In some embodiments, the oligonucleotide is complementary (e.g., at least 85% at least 90%, at least 95%, or 100%) to a target sequence of the any one of the oligonucleotides described herein (e.g., the oligonucleotides listed in Tables 5-19). In some embodiments, the oligonucleotide is complementary (e.g., at least 85% at least 90%, at least 95%, or 100%) to a target sequence provided herein (e.g., a transcript listed in Table 3, e.g., provided by any one of SEQ ID NOs: 392-702). In some embodiments, the oligonucleotide is complementary (e.g., at least 85% at least 90%, at least 95%, or 100%) to a target sequence provided herein (e.g., a transcript listed in Table 4, e.g., provided by any one of SEQ ID NOs: 705-803). In some embodiments, the oligonucleotide is complementary (e.g., at least 85% at least 90%, at least 95%, or 100%) to a target sequence provided herein (e.g., a transcript listed in Table 3 or Table 4, e.g., provided by any one of SEQ ID NOs: 143-148, 167-169, 810-875, and 1059-1068).

[0230] In some embodiments, an oligonucleotide useful for targeting a transcript provided herein comprises 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 5-19). In some embodiments, an oligonucleotide useful for targeting a transcript provided herein comprises a sequence comprising a region of complementarity 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 complementary to a target sequence of an oligonucleotide sequence provided herein (e.g., an oligonucleotide sequence listed in any one of Tables 5-19).

[0231] In some embodiments, it should be appreciated 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) may be equivalently identified as a thymine nucleotide or nucleoside.

[0232] In some embodiments, any one or more of the thymine bases (T’s) in any one of the oligonucleotides provided herein (e.g., the oligonucleotides listed in any one of Tables 5-19) may independently and optionally be uracil bases (U’s), and / or any one or more of the U’s in the oligonucleotides provided herein may independently and optionally be T’s. b. Oligonucleotide Modifications:

[0233] The oligonucleotides described herein may be modified, e.g., comprise a modified sugar moiety, a modified internucleoside linkage, a modified nucleotide or nucleoside and / or (e.g., and) combinations thereof. In addition, in some embodiments, oligonucleotides may exhibit one or more of the following properties: do not mediate alternative splicing; are notimmune stimulatory; are nuclease resistant; have improved cell uptake compared to unmodified oligonucleotides; are not toxic to cells or mammals; have improved endosomal exit internally in a cell; minimizes TLR stimulation; or avoid pattern recognition receptors. Any of the modified chemistries or formats of oligonucleotides described herein can be combined with each other. For example, one, two, three, four, five, or more different types of modifications can be included within the same oligonucleotide.

[0234] In some embodiments, certain nucleotide or nucleoside modifications may be used that make an oligonucleotide into which they are incorporated more resistant to nuclease digestion than the native oligodeoxynucleotide or oligoribonucleotide molecules; these modified oligonucleotides survive intact for a longer time than unmodified oligonucleotides. Specific examples of modified oligonucleotides include those comprising modified backbones, for example, modified internucleoside linkages such as phosphorothioates, phosphotriesters, methyl phosphonates, short chain alkyl or cycloalkyl intersugar linkages or short chain heteroatomic or heterocyclic intersugar linkages. Accordingly, oligonucleotides of the disclosure can be stabilized against nucleolytic degradation such as by the incorporation of a modification, e.g., a nucleotide or nucleoside modification.

[0235] In some embodiments, an oligonucleotide may be of up to 50 or up to 100 nucleotides in length in which 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 oligonucleotide may be of 8 to 30 nucleotides in length in which 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 oligonucleotide may be of 8 to 15 nucleotides in length in which 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 oligonucleotides may have every nucleotide or nucleoside except 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides / nucleosides modified. Oligonucleotide modifications are described further herein. c. Modified Nucleosides

[0236] In some embodiments, the oligonucleotide described herein comprises at least one nucleoside modified at the 2' position of the sugar. In some embodiments, an oligonucleotide comprises at least one 2'-modified nucleoside. In some embodiments, all of the nucleosides in the oligonucleotide are 2’-modified nucleosides.

[0237] In some embodiments, the oligonucleotide described herein comprises one or more non-bicyclic 2’-modified nucleosides, e.g., 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 nucleoside.

[0238] In some embodiments, the oligonucleotide described herein comprises one or more 2’- 4’ bicyclic nucleosides in which the ribose ring comprises a bridge moiety connecting two atoms in the ring, e.g., connecting the 2’-O atom to the 4’-C atom via a methylene (LNA) bridge, an ethylene (ENA) bridge, or a (S)-constrained ethyl (cEt) bridge. Examples of LNAs are described in International Patent Application Publication WO / 2008 / 043753, published on April 17, 2008, and entitled “RNA Antagonist Compounds For The Modulation Of PCSK9”, the contents of which are incorporated herein by reference in its entirety. Examples of ENAs are provided in International Patent Publication No. WO 2005 / 042777, published on 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 entireties. Examples of cEt are provided in US Patents 7,101,993; 7,399,845 and 7,569,686, each of which is herein incorporated by reference in its entirety.

[0239] In some embodiments, the oligonucleotide comprises a modified nucleoside disclosed in one of the following United States Patent or Patent Application Publications: US Patent 7,399,845, issued on July 15, 2008, and entitled “6-Modified Bicyclic Nucleic Acid Analogs”; US Patent 7,741,457, issued on June 22, 2010, and entitled “6-Modified Bicyclic Nucleic Acid Analogs”; US Patent 8,022,193, issued on September 20, 2011, and entitled “6-Modified Bicyclic Nucleic Acid Analogs”; US Patent 7,569,686, issued on August 4, 2009, and entitled “Compounds And Methods For Synthesis Of Bicyclic Nucleic Acid Analogs”; US Patent 7,335,765, issued on February 26, 2008, and entitled “Novel Nucleoside And Oligonucleotide Analogues”; US Patent 7,314,923, issued on January 1, 2008, and entitled “Novel Nucleoside And Oligonucleotide Analogues”; US Patent 7,816,333, issued on October 19, 2010, and entitled “Oligonucleotide Analogues And Methods Utilizing The Same” and US Publication Number 2011 / 0009471 now US 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.

[0240] In some embodiments, the oligonucleotide comprises at least one modified nucleoside that results in an increase in Tm of the oligonucleotide in a range of 1°C, 2 °C, 3°C, 4 °C, or 5°C compared with an oligonucleotide that does not have the at least one modified nucleoside. The oligonucleotide may have a plurality of modified nucleosides that result in a total increase in Tm of the oligonucleotide in a range of 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 with an oligonucleotide that does not have the modified nucleoside.

[0241] The oligonucleotide may comprise a mix of nucleosides of different kinds. For example, an oligonucleotide may comprise a mix of 2’-deoxyribonucleosides or ribonucleosides and 2’-fluoro modified nucleosides. An oligonucleotide may comprise a mix of deoxyribonucleosides or ribonucleosides and 2’-O-Me modified nucleosides. An oligonucleotide may comprise a mix of 2’-fluoro modified nucleosides and 2’-O-Me modified nucleosides. An oligonucleotide may comprise a mix of 2’-4’ bicyclic nucleosides and 2’- MOE, 2’-fluoro, or 2’-O-Me modified nucleosides. An oligonucleotide may comprise a mix 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).

[0242] The oligonucleotide may comprise alternating nucleosides of different kinds. For example, an oligonucleotide may comprise alternating 2’-deoxyribonucleosides or ribonucleosides and 2’-fluoro modified nucleosides. An oligonucleotide may comprise alternating deoxyribonucleosides or ribonucleosides and 2’-O-Me modified nucleosides. An oligonucleotide may comprise alternating 2’-fluoro modified nucleosides and 2’-O-Me modified nucleosides. An oligonucleotide may comprise alternating 2’-4’ bicyclic nucleosides and 2’-MOE, 2’-fluoro, or 2’-O-Me modified nucleosides. An oligonucleotide may comprise alternating 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).

[0243] 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 / Backbones

[0244] In some embodiments, oligonucleotide may contain a phosphorothioate or other modified internucleoside linkage. In some embodiments, the oligonucleotide comprises phosphorothioate internucleoside linkages. In some embodiments, the oligonucleotide comprises phosphorothioate internucleoside linkages between at least two nucleosides. Insome embodiments, the oligonucleotide comprises phosphorothioate internucleoside linkages between all nucleosides. For example, in some embodiments, oligonucleotides comprise modified internucleoside linkages at the first, second, and / or (e.g., and) third internucleoside linkage at the 5' or 3' end of the nucleotide sequence.

[0245] Phosphorus-containing linkages that may be used include, but are not limited to, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates comprising 3'alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates comprising 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'; see US patent nos. 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.

[0246] In some embodiments, oligonucleotides may have heteroatom backbones, such as methylene(methylimino) or MMI backbones; amide backbones (see De Mesmaeker et al. Ace. Chem. Res.1995, 28:366-374); morpholino backbones (see Summerton and Weller, U.S. Pat. No.5,034,506); or peptide nucleic acid (PNA) backbones (wherein the phosphodiester backbone of the oligonucleotide is replaced with a polyamide backbone, the nucleotides being bound directly or indirectly to the aza nitrogen atoms of the polyamide backbone, see Nielsen et al., Science 1991, 254, 1497). e. Stereospecific Oligonucleotides

[0247] In some embodiments, internucleotidic phosphorus atoms of oligonucleotides are chiral, and the properties of the oligonucleotides by adjusted based on the configuration of the chiral phosphorus atoms. In some embodiments, appropriate methods may be used to synthesize P-chiral oligonucleotide analogs in a stereocontrolled manner (e.g., as described in Oka N, Wada T, Stereocontrolled synthesis of oligonucleotide analogs containing chiral internucleotidic phosphorus atoms. Chem Soc Rev.2011 Dec;40(12):5829-43.) In some embodiments, phosphorothioate containing oligonucleotides comprise nucleoside units that are joined together by either substantially all Sp or substantially all Rp phosphorothioate intersugar linkages are provided. In some embodiments, such phosphorothioate oligonucleotides havingsubstantially chirally pure intersugar linkages are prepared by enzymatic or chemical synthesis, as described, for example, in US Patent 5,587,261, issued on December 12, 1996, the contents of which are incorporated herein by reference in their entirety. In some embodiments, chirally controlled oligonucleotides provide selective cleavage patterns of a target nucleic acid. For example, in some embodiments, a chirally controlled oligonucleotide provides single site cleavage within a complementary sequence of a nucleic acid, as described, for example, in US Patent Application Publication 20170037399 A1, published on February 2, 2017, entitled “CHIRAL DESIGN”, the contents of which are incorporated herein by reference in their entirety. f. Morpholinos

[0248] In some embodiments, the oligonucleotide may be a morpholino-based compounds. 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. Pat. No.5,034,506, issued Jul.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 incorporated herein by reference in their entireties). g. Peptide Nucleic Acids (PNAs)

[0249] In some embodiments, both a sugar and an internucleoside linkage (the backbone) of the nucleotide units of an oligonucleotide are replaced with novel groups. In some embodiments, the base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, for example, an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative publications that report the preparation of PNA compounds include, but are not limited to, US patent nos.5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500.h. Mixmers

[0250] In some embodiments, an oligonucleotide described herein may be a mixmer or comprise a mixmer sequence pattern. In general, mixmers are oligonucleotides that comprise both naturally and non-naturally occurring nucleosides or comprise two different types of non- naturally occurring nucleosides typically in an alternating pattern. Mixmers generally have higher binding affinity than unmodified oligonucleotides and may be used to specifically bind a target molecule, e.g., to block a binding site on the target molecule. Generally, mixmers do not recruit an RNase to the target molecule and thus do not promote cleavage of the target molecule. Such oligonucleotides that are incapable of recruiting RNase H have been described, for example, see WO2007 / 112754 or WO2007 / 112753.

[0251] In some embodiments, the mixmer comprises or consists of a repeating pattern of nucleoside analogues and naturally occurring nucleosides, or one type of nucleoside analogue and a second type of nucleoside analogue. However, a mixmer need not comprise a repeating pattern and may instead comprise any arrangement of modified nucleoside s and naturally occurring nucleoside s or any arrangement of one type of modified nucleoside and a second type of modified nucleoside. The repeating pattern, may, for instance be every second or every third nucleoside is a modified nucleoside, such as LNA, and the remaining nucleoside s are naturally occurring nucleosides, such as DNA, or are a 2′ substituted nucleoside analogue such as 2′-MOE or 2′ fluoro analogues, or any other modified nucleoside described herein. It is recognized that the repeating pattern of modified nucleoside, such as LNA units, may be combined with modified nucleoside at fixed positions—e.g. at the 5′ or 3′ termini.

[0252] In some embodiments, a mixmer does not comprise a region of more than 5, more than 4, more than 3, or more than 2 consecutive naturally occurring nucleosides, such as DNA nucleosides. In some embodiments, the mixmer comprises at least a region consisting of at least two consecutive modified nucleosides, such as at least two consecutive LNAs. In some embodiments, the mixmer comprises at least a region consisting of at least three consecutive modified nucleoside units, such as at least three consecutive LNAs.

[0253] In some embodiments, the mixmer does not comprise a region of more than 7, more than 6, more than 5, more than 4, more than 3, or more than 2 consecutive nucleoside analogues, such as LNAs. In some embodiments, LNA units may be replaced with other nucleoside analogues, such as those referred to herein.

[0254] Mixmers may be designed to comprise a mixture of affinity enhancing modified nucleosides, such as in non-limiting example LNA nucleosides and 2’-O-Me nucleosides. In some embodiments, a mixmer 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.

[0255] A mixmer may be produced using any suitable method. Representative U.S. patents, U.S. patent publications, and PCT publications that teach the preparation of mixmers include U.S. patent publication Nos. US20060128646, US20090209748, US20090298916, US20110077288, and US20120322851, and U.S. patent No.7687617.

[0256] In some embodiments, a mixmer comprises one or more morpholino nucleosides. For example, in some embodiments, a mixmer may 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).

[0257] In some embodiments, mixmers are useful for splice correcting or exon skipping, for example, as reported in Touznik A., et al., LNA / DNA mixmer-based antisense oligonucleotides correct alternative splicing of the SMN2 gene and restore SMN protein expression in type 1 SMA fibroblasts 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-Methyl Mixmer Antisense Oligonucleotide, Molecules 2016, 21, 1582, the contents of each which are incorporated herein by reference. i. Multimers

[0258] In some embodiments, molecular payloads may comprise multimers (e.g., concatemers) of 2 or more oligonucleotides connected by a linker. In this way, in some embodiments, the oligonucleotide loading of a complex can be increased beyond the available linking sites on a targeting agent (e.g., available thiol sites on an antibody) or otherwise tuned to achieve a particular payload loading content. Oligonucleotides in a multimer can be the same or different (e.g., targeting different genes or different sites on the same gene or products thereof).

[0259] In some embodiments, multimers comprise 2 or more oligonucleotides linked together by a cleavable linker. However, in some embodiments, multimers comprise 2 or more oligonucleotides linked together by a non-cleavable linker. In some embodiments, a multimer comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 or more oligonucleotides linked together. In some embodiments, a multimer comprises 2 to 5, 2 to 10 or 4 to 20 oligonucleotides linked together.

[0260] In some embodiments, a multimer comprises 2 or more oligonucleotides linked end-to- end (in a linear arrangement). In some embodiments, a multimer comprises 2 or more oligonucleotides linked end-to-end via an oligonucleotide based linker (e.g., poly-dT linker, an abasic linker). In some embodiments, a multimer comprises a 5’ end of one oligonucleotidelinked to a 3’ end of another oligonucleotide. In some embodiments, a multimer comprises a 3’ end of one oligonucleotide linked to a 3’ end of another oligonucleotide. In some embodiments, a multimer comprises a 5’ end of one oligonucleotide linked to a 5’ end of another oligonucleotide. Still, in some embodiments, multimers can comprise a branched structure comprising multiple oligonucleotides linked together by a branching linker.

[0261] Further examples of multimers that may be used in the complexes provided herein are disclosed, for example, in US Patent Application Number 2015 / 0315588 A1, entitled Methods of delivering multiple targeting oligonucleotides to a cell using cleavable linkers, which was published on November 5, 2015; US Patent Application Number 2015 / 0247141 A1, entitled Multimeric Oligonucleotide Compounds, which was published on September 3, 2015, US Patent Application Number US 2011 / 0158937 A1, entitled Immunostimulatory Oligonucleotide Multimers, which was published on June 30, 2011; and US Patent Number 5,693,773, entitled Triplex-Forming Antisense Oligonucleotides Having Abasic Linkers Targeting Nucleic Acids Comprising Mixed Sequences Of Purines And Pyrimidines, which issued on December 2, 1997, the contents of each of which are incorporated herein by reference in their entireties. j. Gapmers

[0262] In some embodiments, the oligonucleotide described herein is a gapmer. A gapmer oligonucleotide generally has the formula 5'-X-Y-Z-3′, with X and Z as flanking regions around a gap region Y. In some embodiments, flanking region X of formula 5'-X-Y-Z-3′ is also referred to as X region, flanking sequence X, 5’ wing region X, or 5’ wing segment. In some embodiments, flanking region Z of formula 5'-X-Y-Z-3′ is also referred to as Z region, flanking sequence Z, 3’ wing region Z, or 3’ wing segment. In some embodiments, gap region Y of formula 5'-X-Y-Z-3′ is also referred to as Y region, Y segment, or gap-segment Y. In some embodiments, each nucleoside in the gap region Y is a 2’-deoxyribonucleoside, and neither the 5’ wing region X or the 3’ wing region Z contains any 2’-deoxyribonucleosides. In some embodiments, a gapmer oligonucleotide comprises a region of complementarity to 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., a transcript listed in Table 3, e.g., provided by any one of SEQ ID NOs: 392-702, or a target sequence of any of the oligonucleotides listed in Tables 5-19) and / or comprises 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 the nucleotide sequence of an oligonucleotide sequence in any oneof Tables 5-19, wherein each thymine base (T) may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T. In some embodiments, a gapmer oligonucleotide comprises a region of complementarity to 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., a transcript listed in Table 4, e.g., provided by any one of SEQ ID NOs: 705-803). In some embodiments, a gapmer oligonucleotide comprises a region of complementarity to 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., a transcript listed in Table 3 or Table 4, e.g., provided by any one of SEQ ID NOs: 143-148, 167-169, 810- 875, and 1059-1068).

[0263] In some embodiments, the Y region is a contiguous stretch of nucleotides, e.g., a region of 6 or more DNA nucleotides, which are capable of recruiting an RNAse, such as RNAse H. In some embodiments, the gapmer binds to the target nucleic acid, at which point an RNAse is recruited and can then cleave the target nucleic acid. In some embodiments, the Y region is flanked both 5' and 3' by regions X and Z comprising high-affinity modified nucleosides, e.g., one to six high-affinity modified nucleosides. 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 flanking sequences X and Z may be of 1-20 nucleotides, 1-8 nucleotides, or 1-5 nucleotides in length. The flanking sequences X and Z may be of similar length or of dissimilar lengths. In some embodiments, the gap-segment Y may be a nucleotide sequence of 5-20 nucleotides, 5-15 nucleotides, 5-12 nucleotides, or 6-10 nucleotides in length.

[0264] In some embodiments, the gap region of the gapmer oligonucleotides may contain modified nucleosides known to be acceptable for efficient RNase H action in addition to DNA nucleosides, such as C4'-substituted nucleosides, acyclic nucleosides, and arabino-configured nucleosides. In some embodiments, the gap region comprises one or more unmodified internucleosides. In some embodiments, one or both flanking regions each independently comprise one or more phosphorothioate 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 nucleotides. In some embodiments, the gap region and two flanking regions each independently comprise 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 nucleotides.

[0265] A gapmer may be produced using appropriate methods. 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. Pat. Nos.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; 9,045,754; 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 herein incorporated by reference in its entirety.

[0266] In some embodiments, the gapmer is 10-40 nucleosides in length. For example, the gapmer may be 10-40, 10-35, 10-30, 10-25, 10-20, 10-15, 15-40, 15-35, 15-30, 15-25, 15-20, 20-40, 20-35, 20-30, 20-25, 25-40, 25-35, 25-30, 30-40, 30-35, or 35-40 nucleosides in length. In some embodiments, 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 length.

[0267] In some embodiments, the gap region Y in the gapmer is 5-20 nucleosides in length. For example, the gap region Y may be 5-20, 5-15, 5-10, 10-20, 10-15, or 15-20 nucleosides in length. In some embodiments, the gap region Y is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleosides in length. In some embodiments, each nucleoside in the gap region Y is a 2’-deoxyribonucleoside. In some embodiments, all nucleosides in the gap region Y are 2’- deoxyribonucleosides. In some embodiments, one or more of the nucleosides in the gap region Y is a modified nucleoside (e.g., a 2’ modified nucleoside such as those described herein). In some embodiments, one or more cytosines in the gap region Y are optionally 5-methyl- cytosines. In some embodiments, each cytosine in the gap region Y is a 5-methyl-cytosine.

[0268] In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) are independently 1-20 nucleosides long. For example, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) may be independently 1-20, 1-15, 1-10, 1-7, 1-5, 1-3, 1-2, 2-5, 2-7, 3-5, 3-7, 5-20, 5-15, 5-10, 10-20, 10-15, or 15-20 nucleosides long. In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-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 long. In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z- 3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) are of thesame length. In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) are of different lengths. In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) is longer than the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula). In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) is shorter than the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula).

[0269] In some embodiments, the gapmer comprises a 5'-X-Y-Z-3′ of 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. The numbers indicate the number of nucleosides in X, Y, and Z regions in the 5'-X-Y-Z-3′ gapmer.

[0270] In some embodiments, one or more nucleosides in the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) or the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) are modified nucleosides (e.g., high-affinity modified nucleosides). In some embodiments, the modified nucleoside (e.g., high-affinity modified nucleosides) is a 2’-modified nucleoside. In some embodiments, the 2’-modified nucleoside is a 2’-4’ bicyclic nucleoside or a non-bicyclic 2’-modified nucleoside. 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’-O-N-methylacetamido (2’-O-NMA)).

[0271] In some embodiments, one or more nucleosides in the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) are high-affinity modified nucleosides. In some embodiments, each nucleoside in the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) is a high- affinity modified nucleoside. In some embodiments, one or more nucleosides in the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) are high-affinity modified nucleosides. In some embodiments, each nucleoside in the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) is a high-affinity modified nucleoside. In some embodiments, one or more nucleosides in the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) are high- affinity modified nucleosides and one or more nucleosides in the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) are high-affinity modified nucleosides. In some embodiments, each nucleoside in the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) is a high- affinity modified nucleoside and each nucleoside in the 3’wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) is high-affinity modified nucleoside.

[0272] In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) comprises the same high affinity nucleosides as the 3’ wing region of the gapmer (Z in the 5'- X-Y-Z-3′ formula). For example, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) may comprise one or more non-bicyclic 2’-modified nucleosides (e.g., 2’-MOE or 2’-O-Me). In another example, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) may comprise one or more 2’-4’ bicyclicnucleosides (e.g., LNA or cEt). In some embodiments, each nucleoside in the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'- X-Y-Z-3′ formula) is a non-bicyclic 2’-modified nucleoside (e.g., 2’-MOE or 2’-O-Me). In some embodiments, each nucleoside in the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) is a 2’-4’ bicyclic nucleoside (e.g., LNA or cEt).

[0273] In some embodiments, the gapmer comprises a 5'-X-Y-Z-3′ configuration, wherein X and Z are independently 1-7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein each nucleoside in X and Z is a non- bicyclic 2’-modified nucleosides (e.g., 2’-MOE or 2’-O-Me) and each nucleoside in Y is a 2’- deoxyribonucleoside. In some embodiments, the gapmer comprises a 5'-X-Y-Z-3′ configuration, wherein X and Z are independently 1-7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein each nucleoside in X and Z is a 2’-4’ bicyclic nucleosides (e.g., LNA or cEt) and each nucleoside in Y is a 2’- deoxyribonucleoside. In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X- Y-Z-3′ formula) comprises different high affinity nucleosides as the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula). For example, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) may comprise one or more non-bicyclic 2’-modified nucleosides (e.g., 2’-MOE or 2’-O-Me) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) may comprise one or more 2’-4’ bicyclic nucleosides (e.g., LNA or cEt). In another example, the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) may comprise one or more non-bicyclic 2’-modified nucleosides (e.g., 2’-MOE or 2’-O-Me) and the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) may comprise one or more 2’-4’ bicyclic nucleosides (e.g., LNA or cEt).

[0274] In some embodiments, the gapmer comprises a 5'-X-Y-Z-3′ configuration, wherein X and Z are independently 1-7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (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'-X-Y-Z-3′ configuration, wherein X and Z are independently 1-7 (e.g., 1, 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (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.

[0275] In some embodiments, the 5’ wing region of the gapmer (X in the 5'-X-Y-Z-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 region of the gapmer (Z in the 5'-X-Y-Z-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 region of the gapmer (X in the 5'- X-Y-Z-3′ formula) and the 3’ wing region of the gapmer (Z in the 5'-X-Y-Z-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).

[0276] In some embodiments, the gapmer comprises a 5'-X-Y-Z-3′ configuration, wherein X and Z are independently 2-7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (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 in X (the 5’-most position is position 1) is a non-bicyclic 2’- modified nucleoside (e.g., 2’-MOE or 2’-O-Me), wherein the rest of the 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'-X-Y-Z-3′ configuration, wherein X and Z are independently 2-7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (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 in Z (the 5’-most position is position 1) is a non-bicyclic 2’-modified nucleoside (e.g., 2’-MOE or 2’-O-Me), wherein the rest of the 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'-X-Y-Z-3′ configuration, wherein X and Z are independently 2-7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (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 in X and at least one of positions but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 in Z (the 5’-most position is position 1) is a non-bicyclic 2’-modified nucleoside (e.g., 2’-MOE or 2’-O-Me), wherein the rest of the 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.

[0277] Non-limiting examples of gapmers configurations with a mix of non-bicyclic 2’- modified nucleoside (e.g., 2’-MOE or 2’-O-Me) and 2’-4’ bicyclic nucleosides (e.g., LNA or cEt) in the 5’wing region of the gapmer (X in the 5'-X-Y-Z-3′ formula) and / or the 3’wing region of the gapmer (Z in the 5'-X-Y-Z-3′ formula) include: 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-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- KKKEEE; LLL-(D)n-LLLEEE; BABA-(D)n-ABAB; KAKA-(D)n-AKAK; LALA-(D)n- ALAL; BEBE-(D)n-EBEB; KEKE-(D)n-EKEK; LELE-(D)n-ELEL; BABA-(D)n-ABAB; KAKA-(D)n-AKAK; LALA-(D)n-ALAL; BEBE-(D)n-EBEB; KEKE-(D)n-EKEK; LELE- (D)n-ELEL; ABAB-(D)n-ABAB; AKAK-(D)n-AKAK; ALAL-(D)n-ALAL; EBEB-(D)n- EBEB; EKEK-(D)n-EKEK; ELEL-(D)n-ELEL; ABAB-(D)n-ABAB; AKAK-(D)n-AKAK; ALAL-(D)n-ALAL; EBEB-(D)n-EBEB; EKEK-(D)n-EKEK; ELEL-(D)n-ELEL; AABB- (D)n-BBAA; 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-BBAA; AAKK-(D)n-KKAA; AALL-(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-BBE; 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; AKKK-(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-BBBAA; AKKK-(D)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-(D)n-LLLAA; EBBB-(D)n-BBBEE; EKKK-(D)n-KKKEE; ELLL-(D)n-LLLEE; AABBB-(D)n-BBB; AAKKK-(D)n-KKK; AALLL-(D)n-LLL; EEBBB-(D)n-BBB; EEKKK- (D)n-KKK; EELLL-(D)n-LLL; AABBB-(D)n-BBB; AAKKK-(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; AALLL-(D)n-LLLA; EEBBB-(D)n-BBBE; EEKKK-(D)n-KKKE; EELLL-(D)n-LLLE; ABBAABB-(D)n-BB; AKKAAKK-(D)n-KK; ALLAALLL-(D)n-LL; EBBEEBB-(D)n-BB; EKKEEKK-(D)n-KK; ELLEELL-(D)n-LL; ABBAABB-(D)n-BB; AKKAAKK-(D)n-KK; ALLAALL-(D)n-LL; EBBEEBB-(D)n-BB; EKKEEKK-(D)n-KK; ELLEELL-(D)n-LL; ABBABB-(D)n-BBB; AKKAKK-(D)n-KKK; 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-KKK; ELLELL-(D)n-LLL; EEEK-(D)n-EEEEEEEE;EEK-(D)n-EEEEEEEEE; EK-(D)n-EEEEEEEEEE; EK-(D)n-EEEKK; K-(D)n-EEEKEKE; K- (D)n-EEEKEKEE; K-(D)n-EEKEK; EK-(D)n-EEEEKEKE; 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; “n” represents the length of the gap segment (Y in the 5'-X-Y-Z-3′ configuration) and is an integer between 1-20.

[0278] In some embodiments, any one of the gapmers described herein comprises one or more modified nucleoside linkages (e.g., a phosphorothioate linkage) in each of the X, Y, and Z regions. In some embodiments, each internucleoside linkage in the any one of the gapmers described herein is a phosphorothioate linkage. In some embodiments, each of the X, Y, and Z regions independently comprises a mix of phosphorothioate linkages and phosphodiester linkages. In some embodiments, each internucleoside linkage in the gap region Y is a phosphorothioate linkage, the 5’ wing region X comprises a mix of phosphorothioate linkages and phosphodiester linkages, and the 3’ wing region Z comprises a mix of phosphorothioate linkages and phosphodiester linkages. Polypeptide payloads

[0279] In some embodiments, polypeptides (e.g., peptides, proteins, including but not limited to enzymes, antibodies, etc.) are useful in the treatment of various CNS diseases and disorders. For example, polypeptides may be useful to modulate the expression or activity of various genes involved in CNS diseases and disorder, such as by modulating expression or activity of a protein involved in the CNS disease or disorder. In one non-limiting example, an enzyme that modifies, degrades, or otherwise affects a particular biological molecule (e.g., a protein or nucleic acid) may be useful in the treatment of a CNS disease or disorder involving that particular biological molecule. Polypeptides may be used to treat various CNS diseases and disorders, for example, by facilitating delivery of the polypeptide into cells of the CNS. In some embodiments, polypeptides disclosed herein can be delivered into cells of the CNS using complexes disclosed here (e.g., anti-TfR1 antibody complexes comprising the polypeptide).

[0280] In some embodiments, polypeptides are useful in the treatment of 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; a pain disorder; glycogen synthesisdisorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman Syndrome; autism-spectrum disorders; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis.

[0281] In some embodiments, polypeptides are useful in the treatment of essential tremor and / or hereditary dystonia.

[0282] In some embodiments, polypeptides are useful in the treatment of 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.

[0283] In some embodiments, polypeptides are useful in the modulation of one or more genes associated with a CNS disease or disorder. In some embodiments, the one or more genes associated with a CNS disease or disorder 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 is 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 payloads

[0284] In some embodiments, small molecules are useful in the treatment of various CNS diseases and disorders. For example, small molecules may be useful to modulate the expression or activity of various genes involved in CNS diseases and disorder, such as by modulating expression or activity of a protein involved in the CNS disease or disorder. In one non-limiting example, small molecule that increases, decreases, or otherwise affects expression of a particular biological molecule (e.g., a protein or nucleic acid) may be useful in the treatment of a CNS disease or disorder involving that particular biological molecule. Small molecules may be used to treat various CNS diseases and disorders, for example, by facilitating delivery of the small molecule into cells of the CNS. In some embodiments, small molecules disclosed herein can be delivered into cells of the CNS using complexes disclosed here (e.g., anti-TfR1 antibody complexes comprising the small molecule).

[0285] In some embodiments, small molecules are useful in the treatment of 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; a pain disorder; glycogen synthesis disorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman Syndrome; autism-spectrum disorders; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis.

[0286] In some embodiments, small molecules are useful in the treatment of essential tremor and / or hereditary dystonia.

[0287] In some embodiments, small molecules are useful in the treatment of 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.

[0288] In some embodiments, small molecules are useful in the modulation of one or more genes associated with a CNS disease or disorder. In some embodiments, the one or more genes associated with a CNS disease or disorder 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 is 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.

[0289] Compounds (e.g., small molecule payloads) described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures 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 syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. Gene therapy payloads

[0290] In some embodiments, gene therapy payloads (e.g., nucleic acids encoding biologically active or otherwise therapeutic molecules) are useful in the treatment of various CNS diseases and disorders. For example, gene therapies may be useful to modulate the expression or activity of various genes involved in CNS diseases and disorder, such as by encoding a protein involved in the CNS disease or disorder. In one non-limiting example, a gene therapy payload that encodes a particular biological molecule (e.g., a protein or nucleic acid) may be useful in the treatment of a CNS disease or disorder involving that particular biological molecule (e.g., a disease or disorder whose etiology involves abnormally low expression of the biological molecule or expression of an inactive form of the biological molecule). Gene therapies may be used to treat various CNS diseases and disorders, for example, by facilitating delivery of the gene therapy payload into cells of the CNS. In some embodiments, gene therapies disclosed herein can be delivered into cells of the CNS using complexes disclosed here (e.g., anti-TfR1 antibody complexes comprising the gene therapy payload).

[0291] In some embodiments, gene therapies are useful in the treatment of 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; a pain disorder; glycogen synthesis disorders; neurodegeneration; small fiber neuropathy; nociception-related phenotypes; Alexander disease; Angelman Syndrome; autism-spectrum disorders; retinitis pigmentosa; isolated macular dystrophy; and / or multiple sclerosis.

[0292] In some embodiments, gene therapies are useful in the treatment of essential tremor and / or hereditary dystonia.

[0293] In some embodiments, gene therapies are useful in the treatment of 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.

[0294] In some embodiments, gene therapies are useful in the modulation of one or more genes associated with a CNS disease or disorder. In some embodiments, the one or more genesassociated with a CNS disease or disorder 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 is 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. Molecular payloads for the treatment of ALS

[0295] Various molecular payloads may be useful in the treatment of ALS, including oligonucleotides, polypeptides (e.g., peptides, proteins, enzymes, antibodies, etc.), small molecules (e.g., small molecule inhibitors, etc.), and gene therapies (e.g., nucleic acids and / or nucleic acid vectors encoding therapeutic molecules, such as therapeutic proteins). Molecular payloads useful in the treatment of ALS may include, in some embodiments, molecular payloads which modulate (e.g., increase or decrease) expression or activity of SOD1, ATXN2, C9orf72, and / or FUS.

[0296] Examples of oligonucleotides useful for the treatment of ALS, e.g., oligonucleotides targeting (e.g., directly or indirectly modulating the expression or activity of) genes associated with ALS (e.g., SOD1, ATXN2, C9orf72, FUS, etc.), include those listed in Table 5 below. Each oligonucleotide provided in Table 5 may have any modification pattern disclosed herein. Table 5. Oligonucleotides for the treatment of ALSmodified sugar. In each sequence listed in Table 5, each T may be optionally and independently replaced with a U.

[0297] Examples of oligonucleotides useful for the treatment of ALS, e.g., oligonucleotides targeting (e.g., directly or indirectly modulating the expression or activity of) genes associated with ALS (e.g., PIKFYVE, SYF2, UNC13A, etc.), include those listed in Table 6 below. Each oligonucleotide provided in Table 6 may have any modification pattern disclosed herein. Table 6. Oligonucleotides for the treatment of ALS

[0298] Examples of small molecules useful for the treatment of ALS include:,, and, and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof. Additional examples of small molecules useful for the treatment of ALS include:, apilimod, APY0201, YM-201636, and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof.

[0299] Examples of polypeptides useful for the treatment of 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 payloads targeting SOD1

[0300] The superoxide dismutase 1 (SOD1) gene, and mutations therein, are implicated in ALS, which predominantly affects upper and lower motor neurons. Modulation of SOD1 expression and activity (e.g., by suppressing the expression and / or activity of mutant SOD1 protein) therefore in some embodiments can have a therapeutic effect in subjects with ALS.Oligonucleotides

[0301] SOD1 expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting SOD1 sequences.

[0302] In some embodiments, an oligonucleotide useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) SOD1, comprises a region of complementarity to a SOD1 transcript provided in Table 3, e.g., provided by SEQ ID NO: 392.

[0303] In some embodiments, examples of oligonucleotides useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating 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; US Patent Application Publication No.20040091919A1, published on May 13, 2004, entitled “Antisense Modulation of Superoxide Dismutase 1, Soluble Expression”; US Patent Application Publication No.20090306005A1, published December 10, 2009, entitled “Compounds and methods for modulating expression of PCSK9”; US Patent Application Publication No.20140378533A1, published December 25, 2014, entitled “Modulation of RNA by repeat targeting”; US Patent Application Publication No. 20150184154A1, published July 2, 2015, entitled “New Treatment for Neurodegenerative Diseases”; US Patent Application Publication No.20160272976A1, published September 22, 2016, entitled “Products and Methods for Treatment of Familial Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20160222391A1, published August 4, 2016, entitled “Compositions and Methods for Treating Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20170037399A1, published February 9, 2017, entitled “Chiral Design”; US Patent Application Publication No.20170037410A1, published February 9, 2017, entitled “Compositions for Modulating SOD-1 Expression”; US Patent Application Publication No.20170152517A1, published June 1, 2017, entitled “Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20160089453A1, published March 31, 2016, entitled “RNA-Modulating Agents”; US Patent Application Publication No. 20180282732A1, published October 4, 2018, entitled “Compositions and Methods of Treating Amyotrophic Lateral Sclerosis (ALS)”; International Patent Application Publication No. WO2016180784A1, published November 17, 2016, entitled “Improved Treatments Using Oligonucleotides”; US Patent Application Publication No.20180161357A1, published June 14, 2018, entitled “MIR-155 Inhibitors for Treating Amyotrophic Lateral Sclerosis (ALS)”; USPatent Application Publication No.20180195072A1, published July 12, 2018, entitled “Nucleic acid molecules targeting superoxide dismutase 1 (sod1)”; US Patent Application Publication No.20180216107A1, published August 2, 2018, entitled “Oligonucleotide compositions and methods thereof”; US Patent Application Publication No.20210228615A1, published July 29, 2021, entitled “Oligonucleotide compositions and methods thereof”; US Patent Application Publication No.20190167815A1, published June 6, 2019, entitled “Methods and compositions for the treatment of rare diseases”; US Patent Application Publication No.20210054383A1, published February 25, 2021, entitled “Oligonucleotides for modulating tmem106b expression”; US Patent Application Publication No.20210269881A1, published September 2, 2021, entitled “Long non-coding RNAs (lncRNAs) for the diagnosis and therapeutics of brain disorders, in particular cognitive disorders”; US Patent Publication No.10808247B2, published October 20, 2020, entitled “Methods for treating neurological disorders using a synergistic small molecule and nucleic acids therapeutic approach”; US Patent Publication No.11118179B2, published September 14, 2021, entitled “Mixed tricyclo- DNA, 2′-modified RNA oligonucleotide compositions and uses thereof”; International Patent Application Publication No. WO2020198270A1, published October 1, 2020, entitled “Compositions and methods for treating neurodegenerative disorders”; US Patent Application Publication No.20220170025A1, published June 2, 2022, entitled “Compositions and methods for inhibiting gene expression in the central nervous system”; US Patent Publication No. 10174328B2, published January 8, 2019, entitled “Compositions and methods for treating amyotrophic lateral sclerosis”; International Patent Application Publication No. WO2020222182A1, published November 5, 2020, entitled “Treatment for SOD1 associated disease”; International Patent Application Publication No. WO2020247419A2, published December 10, 2020, entitled “Oligonucleotides and methods of use for treating neurological diseases”; International Patent Application Publication No. WO2021029896A1, published February 18, 2021, entitled “Splice modulating oligonucleotides targeting receptor for advanced glycation end products and methods of use”; US Patent Application Publication No. 20220090036A1, published March 24, 2022, entitled “Compositions and methods for the targeting of SOD1”; International Patent Application Publication No. WO2021108602A1, published November 25, 2020, entitled “Methods and compositions for neuroprotection”; International Patent Application Publication No. WO2021156832A1, published February 6, 2021, entitled “Use of miRNA-485 inhibitors for treating amyotrophic lateral sclerosis (ALS)”; US Patent Application Publication No.20220073930A1, published March 10, 2022, entitled“Compositions and methods for treating and preventing amyotrophic lateral sclerosis”; the entire contents of each of which are herein incorporated by reference.

[0304] Certain oligonucleotides provided in this section may be useful in treating ALS by modulating the activity of genes and / or gene products other than SOD1 genes / gene products, such as C9orf72, ATXN2, and / or FUS genes / gene products. Polypeptides

[0305] SOD1 expression and / or activity in some embodiments can be modulated by the use of SOD1 polypeptides or polypeptides that can interact with SOD1 (e.g., to modulate its enzymatic activity).

[0306] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of 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; US Patent Application Publication No. 20090124993A1, published May 14, 2009, entitled “Treating neurological disorders”; US Patent Application Publication No.20140044722A1, published February 13, 2014, entitled “Anti-SOD1 Antibodies and Uses Thereof”; US Patent Application Publication No. 20140301945, published October 9, 2014, entitled “Human Anti-SOD1 Antibodies”; International Patent Application Publication No. WO2013106672A1, published July 18, 2013, entitled “Methods and Compositions for the Treatment of Neurodegenerative Disease”; US Patent Application Publication No.20150184154A1, published July 2, 2015, entitled “New Treatment for Neurodegenerative Diseases”; US Patent Application Publication No. 20150259391A1, published September 17, 2015, entitled “Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20160115245A1, published April 28, 2016, entitled “Single Domain Antibodies Against SOD1 and Their Use in Medicine”; US Patent Application Publication No.20190022179A1, published January 24, 2019, entitled “Composition and method for treating amyotrophic lateral sclerosis”; US Patent Application Publication No.20200247854A1, published August 6, 2020, entitled “Pharmaceutical composition for preventing or treating neurodegenerative disease comprising nckap1 protein or gene encoding same”; US Patent Application Publication No.20210206876A1, published July 8, 2021, 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”; International Patent Application Publication No. WO2019104311A1, published May31, 2019, entitled “Compositions and methods for suppressing neurological disease”; US Patent Application Publication No.20210100869A1, published April 8, 2021, entitled “Compositions and methods of using same for treating amyotrophic lateral sclerosis (ALS)”; US Patent Application Publication No.20200172590A1, published June 4, 2020, entitled “Methods of treating neurological diseases”; US Patent Application Publication No. 20210162002A1, published June 3, 2021, entitled “Regenerating functional neurons for treatment of spinal cord injury and ALS”; US Patent Publication No.10808247B2, published October 20, 2020, entitled “Methods for treating neurological disorders using a synergistic small molecule and nucleic acids therapeutic approach”; US Patent Application Publication No.20210284702A1, published September 16, 2021, entitled “Fusion proteins comprising progranulin”; US Patent Application Publication No.20220017634A1, published January 20, 2022, entitled “Engineered bispecific proteins”; US Patent Application Publication No. 20220034907A1, published February 3, 2022, entitled “Neurofilament protein for guiding therapeutic intervention in amyotrophic lateral sclerosis”; the entire contents of each of which are herein incorporated by reference.

[0307] Certain polypeptides provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than SOD1 genes / gene products, such as C9orf72, ATXN2, and / or FUS genes / gene products. Small molecules

[0308] SOD1 expression and / or activity in some embodiments can be modulated by the use of small molecules that can modulate SOD1 (e.g., to modulate its enzymatic activity, or its expression).

[0309] In some embodiments, examples of small molecules useful in the treatment of ALS are provided in US Patent Application Publication No.20040219552A1, published November 4, 2004, entitled “Novel Molecular Target for Neurotoxicity”; US Patent Application Publication No.20030130357A1, published July 10, 2003, entitled “Use of Polyamine Analogs for Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20100152125A1, published June 17, 2010, entitled “Compositions and Methods for the Diagnosis, Treatment, and Prevention of Amyotrophic Lateral Sclerosis and Related Neurological Diseases”; US Patent Application Publication No.20100331417A1, published December 30, 2010, entitled “Treatment of Neural Diseases or Conditions”; US Patent Application Publication No. 20110076236A1, published March 31, 2011, entitled “Compositions and Methods of Treatment Using Modulators of Motoneuron Diseases”; US Patent Application Publication No.20110166115A1, published July 7, 2011, entitled “Use of Mifepristone for the Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20150164901A1, published June 18, 2015, entitled “Compounds, Compositions and Methods for Treating or Preventing Neurodegenerative Disorders”; US Patent Application Publication No. 20160082015A1, published March 24, 2016, entitled “Methods, Compositions and Kits for Promoting Motor Neuron Survival and Treating and Diagnosing Neurodegenerative Disorders”; US Patent Application Publication No.20160287549A1, published October 6, 2016, entitled “Novel Methods for Treating Neurodegenerative Diseases”; US Patent Application Publication No.20150210679A1, published July 30, 2015, entitled “Small Molecule Inhibitors of Superoxide Dismutase Expression”; International PCT Application Publication No. WO2021174167A1, published September 2, 2021, entitled “Compounds and methods for modulating splicing”; US Patent Application Publication No.20180028520A1, published February 1, 2018, entitled “Methods and Pharmaceutical Compositions for Treatment of Amyotrophic Lateral Sclerosis”; International Patent Application Publication No. WO2016114655A1, published July 21, 2016, entitled “Treating neuromuscular or neurologic disease through reducing gabaergic and / or glycinergic inhibitory neurotransmitter overstimulation”; US Patent Application Publication No.20170157197A1, published June 8, 2017, entitled “Methods of Using GM604 in Modulating ALS Disease Biomarkers Leading to Prognosis and Therapeutic Treatment for ALS Disease”; US Patent Application Publication No.20170354639A1, published December 14, 2017, entitled “Diterpenoid derivatives and methods of use thereof”; US Patent Application Publication No.20180289655A1, published October 11, 2018, entitled “Methods and Compositions for the Intravenous Administration of Fumarates for the Treatment of Neurological Diseases”; US Patent Application Publication No. 20170226127A1, published August 10, 2017, entitled “Compound, compositions, and methods”; US Patent Application Publication No.20170362206A1, published June 15, 2017, entitled “Compound, compositions, and methods”; US Patent Application Publication No. 20180327391A1, published November 15, 2018, entitled “Compound, compositions, and methods”; US Patent Application Publication No.20190300537A1, published October 3, 2019, entitled “Compound, compositions, and methods”; US Patent Application Publication No.20190194170A1, published June 27, 2019, entitled “Polymorphs and solid forms of a pyrimidinylamino-pyrazole compound, and methods of production”; US Patent Publication No.9669014B2, published June 6, 2017, entitled “Small molecule inhibitors of superoxide dismutase expression”; US Patent Application Publication No.20210130308A1, published May 6, 2021, entitled “Modulators of eukaryotic initiation factor 2”; US Patent ApplicationPublication No.20180353480A1, published December 13, 2018, entitled “Isoxazolidine derived inhibitors of receptor interacting protein kinase 1 (RIPK1)”; US Patent Application Publication No.20200079784A1, published March 12, 2020, entitled “Compound, compositions, and methods”; US Patent Application Publication No.20200331900A1, published October 22, 2020, entitled “Compounds, compositions, and methods”; US Patent Application Publication No.20210147435A1, published May 20, 2021, entitled “Compounds, compositions, and methods”; US Patent Application Publication No.20210292311A1, published September 23, 2021, entitled “Compounds, compositions, and methods”; US Patent Application Publication No.20220177456A1, published June 9, 2022, entitled “Compounds, compositions, and methods”; US Patent Application Publication No.20200087319A1, published March 19, 2020, entitled “Kinase Inhibitors and Uses Thereof”; US Patent Application Publication No.20190359634A1, published November 28, 2019, entitled “ASK1 inhibiting agents”; US Patent Application Publication No.20200368267A1, published November 26, 2020, entitled “Prophylactic and / or therapeutic agent for amyotrophic lateral sclerosis”; US Patent Application Publication No.20210115020A1, published April 22, 2021, entitled “ASK1 inhibiting agents”; US Patent Application Publication No.20210317103A1, published October 14, 2021, entitled “ASK1 inhibiting agents”; US Patent Application Publication No.20210300946A1, published September 30, 2021, entitled “Pyridine macrocycle compounds as ASK1 inhibiting agents”; US Patent Application Publication No. 20210353611A1, published November 18, 2021, entitled “Methods of treating amyotrophic lateral sclerosis”; US Patent Application Publication No. US20210023062A1, published January 28, 2021, 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”; International Patent Application Publication No. WO2021040627A1, published March 4, 2021, entitled “A method of promoting survival and / or function of a motor neuron and related agents, uses and methods”; the entire contents of each of which are herein incorporated by reference.

[0310] In some embodiments, the small molecule is a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein.

[0311] Certain small molecules provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than SOD1 genes / gene products, such as C9orf72, ATXN2, and / or FUS genes / gene products.Gene therapies

[0312] SOD1 expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate SOD1 (e.g., by delivery of nucleic acids encoding SOD1 or other molecules that interact with SOD1).

[0313] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of ALS are provided in US Patent Application Publication No.20030161814A1, published August 28, 2003, entitled “Adeno-Associated Virus-Mediated Delivery of GDNF to Skeletal Muscles”; US Patent Application Publication No.20130287736A1, published October 31, 2013, entitled “Gene Therapy for Neurodegenerative Disorders”; US Patent Application Publication No. 20150182637A1, published July 2, 2015, entitled “Widespread Gene Delivery of Gene Therapy Vectors”; US Patent Application Publication No.20150259391A1, published September 17, 2015, entitled “Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20160272976A1, published September 22, 2016, entitled “Products and Methods for Treatment of Familial Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20160130567A1, published May 12, 2016, entitled “Messenger UNA Molecules and Uses Thereof”; US Patent Application Publication No.20180021364A1, published January 25, 2018, entitled “Central Nervous System Targeting Polynucleotides”; US Patent Application Publication No.20200297868A1, published September 24, 2020, entitled “Methods and compositions for the treatment of ALS”; US Patent Application Publication No. 20180327471A1, published November 15, 2018, entitled “Translatable molecules and synthesis thereof”; US Patent Application Publication No.20200247854A1, published August 6, 2020, entitled “Pharmaceutical composition for preventing or treating neurodegenerative disease comprising nckap1 protein or gene encoding same”; US Patent Application Publication No.20210024907A1, published January 28, 2021, entitled “Nucleic acid-based therapeutics”; US Patent Application Publication No.20210254103A1, published August 19, 2021, entitled “Treatment of amyotrophic lateral sclerosis and disorders associated with the spinal cord”; US Patent Application Publication No.20200172590A1, published June 4, 2020, entitled “Methods of treating neurological diseases”; US Patent Application Publication No. 20220090036A1, published March 24, 2022, entitled “Compositions and methods for the targeting of SOD1”; International Patent Application Publication No. WO2021205010A1, published October 14, 2021, entitled “Nucleic acids encoding human FUS protein and use in the treatment of amyotrophic lateral sclerosis (ALS)”; International Patent Application Publication No. WO2022060857A1, published March 24, 2022, entitled “Compositions andmethods for treating amyotrophic lateral sclerosis (ALS) with aav-miR-SOD1”; the entire contents of each of which are herein incorporated by reference.

[0314] Certain gene therapies provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than SOD1 genes / gene products, such as C9orf72, ATXN2, and / or FUS genes / gene products. Molecular payloads targeting ATXN2

[0315] The ATXN2 gene, which encodes the ataxin-2 protein, and mutations therein, are implicated in ALS, which predominantly affects upper and lower motor neurons. Modulation of ATXN2 expression and activity (e.g., by suppressing the expression and / or activity of mutant ATXN2 protein and / or its interactions with other proteins) therefore in some embodiments can have a therapeutic effect in subjects with ALS. Oligonucleotides

[0316] ATXN2 (and / or ataxin-2 protein encoded by ATXN2) expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting ATXN2 sequences.

[0317] In some embodiments, an oligonucleotide useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) ATXN2, comprises a region of complementarity to an ATXN2 transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 396-400.

[0318] In some embodiments, examples of oligonucleotides useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating 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; US Patent Application Publication No.20110142789A1, published June 16, 2011, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20130225659A1, published August 29, 2013, entitled “Modulation of nuclear-retained RNA”; US Patent Publication No.1107486B2, published August 3, 2021, entitled “Compounds and methods for reducing ATXN2 expression”; US Patent Application Publication No.20220064639A1, published March 3, 2022, entitled “Compounds and methods for reducing ATXN2 expression”; US Patent Publication No. 10533178B2, published January 14, 2020, entitled “Methods for modulating Ataxin 2 expression”; US Patent Publication No.10006027B2, published June 26, 2018, entitled“Methods for modulating Ataxin 2 expression”; US Patent Publication No.10308934B2, published June 4, 2019, entitled “Compositions for modulating Ataxin 2 expression”; US Patent Publication No.11111494B2, published September 7, 2021, entitled “Compositions for modulating Ataxin 2 expression”; US Patent Publication No.11345915B2, published May 31, 2022, entitled “RNA modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders”; US Patent Application Publication No. 20140378533A1, published December 25, 2014, entitled “Modulation of RNA by repeat targeting”; US Patent Application Publication No.20150148404A1, published May 28, 2015, entitled “RNA Modulating Oligonucleotides with Improved Characteristics for the Treatment of Neuromuscular Disorders”; US Patent Application Publication No.20210169914A1, published June 10, 2021, entitled “Nucleic acids and nucleic acid analogs for treating, preventing, and disrupting pathological polynucleotide-binding protein inclusions”; US Patent Application Publication No.20160040163A1, published February 11, 2016, entitled “DNAi for the modulation of genes”; US Patent Publication No.10174328B2, published January 8, 2019, entitled “Compositions and methods for treating amyotrophic lateral sclerosis”; US Patent Application Publication No.20220162615A1, published May 26, 2022, entitled “Methods for reducing ataxin-2 expression”; the entire contents of each of which are herein incorporated by reference.

[0319] Certain oligonucleotides provided in this section may be useful in treating ALS by modulating the activity of genes and / or gene products other than ATXN2 genes / gene products, such as C9orf72, SOD1, and / or FUS genes / gene products. Polypeptides

[0320] ATXN2 expression and / or activity in some embodiments can be modulated by the use of ataxin-2 polypeptides or polypeptides that can interact with ataxin-2 (e.g., to modulate its biological activity and / or its interaction with other biomolecules).

[0321] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of ALS are provided in US Patent Application Publication No.20110142789A1, published June 16, 2011, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis”; US Patent Publication No.10066007B2, published September 4, 2019, entitled “Dipeptide-repeat proteins as therapeutic target in neurodegenerative diseases with hexanucleotide repeat expansion”; US Patent Publication No.11273149B2, published March 15, 2022, entitled “Compositions and methods for the treatment of amyotrophic lateral sclerosis, Parkinson'sdisease, Parkinson's disease with dementia, dementia with Lewy bodies, and multiple system atrophy”; US Patent Publication No.8673852B2, entitled “Methods of treating neuronal disorders using MNTF peptides and analogs thereof”; International PCT Application Publication No. WO2021222168A2, published November 4, 2021, entitled “Compositions and methods for the treatment of tdp-43 proteinopathies”; the entire contents of each of which are herein incorporated by reference.

[0322] Certain polypeptides provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than ATXN2 genes / gene products, such as C9orf72, SOD1, and / or FUS genes / gene products. Small molecules

[0323] ATXN2 expression and / or activity in some embodiments can be modulated by the use of small molecules that can modulate ATXN2 (e.g., to modulate its biological activity, its expression, and / or its interaction with other biomolecules).

[0324] In some embodiments, examples of small molecules useful in the treatment of ALS are provided in US Patent Application Publication No.20110142789A1, published June 16, 2011, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20130303562A1, published November 14, 2013, entitled “Chemical and RNAi suppressors of neurotoxicity in Huntington’s disease”; US Patent Application Publication No.20140228333A1, published March 29, 2016, entitled “Methods for inhibiting muscle atrophy”; International PCT Application Publication No. WO2021174167A1, published September 2, 2021, entitled “Compounds and methods for modulating splicing”; International PCT Patent Application Publication No. WO2013043669A1, published March 28, 2013, entitled “Peptoid compositions for the treatment of Alzheimer's disease and polyglutamine expansion disorder”; US Patent Publication No.10159670B2, published December 25, 2018, entitled “Methods of diagnosing and treating motor neuron diseases and other cellular stress-related diseases”; US Patent Publication No.9790188B2, published October 17, 2017, entitled “Benzimidazole derivatives and uses thereof”; the entire contents of each of which are herein incorporated by reference.

[0325] In some embodiments, the small molecule is a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein.

[0326] Certain small molecules provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than ATXN2 genes / gene products, such as C9orf72, SOD1, and / or FUS genes / gene products. Gene therapies

[0327] ATXN2 expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate ATXN2 (e.g., by delivery of nucleic acids encoding ATXN2 or other molecules that interact with ATXN2).

[0328] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of ALS are provided in US Patent Application Publication No.20110142789A1, published June 16, 2011, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20100047261A1, published February 25, 2010, entitled “Base-modified RNA for increasing the expression of a protein”; US Patent Application Publication No.20100203076A1, published August 12, 2010, entitled “Complexes of RNA and cationic peptides for transfection and for immunostimulation”; US Patent Publication No.10815463B2, published October 27, 2020, entitled “Messenger UNA molecules and uses thereof”; US Patent Publication No.11155817B2, published October 26, 2021, entitled “Therapeutic for treatment of diseases including the central nervous system”; US Patent Application Publication No.20180327471A1, published November 15, 2018, entitled “Translatable molecules and synthesis thereof”; the entire contents of each of which are herein incorporated by reference.

[0329] Certain gene therapies provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than ATXN2 genes / gene products, such as C9orf72, SOD1, and / or FUS genes / gene products. Molecular payloads targeting C9orf72

[0330] The C9orf72 gene, which encodes the chromosome 9 open reading frame 72 protein, and mutations therein, are implicated in ALS, which predominantly affects upper and lower motor neurons. Modulation of C9orf72 expression and activity (e.g., by suppressing the expression of mutant C9orf72 and / or activity of the protein encoded thereby) therefore in some embodiments can have a therapeutic effect in subjects with ALS.Oligonucleotides

[0331] C9orf72 expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting C9orf72 sequences.

[0332] In some embodiments, an oligonucleotide useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) C9orf72, comprises a region of complementarity to a C9orf72 transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 393-395.

[0333] In some embodiments, examples of oligonucleotides useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) C9orf72, are provided in US Patent Publication No.10577604B2, published March 3, 2020, entitled “Methods for monitoring C9ORF72 expression”; US Patent Publication No.10443052B2, published October 15, 2019, entitled “Compositions for modulating C9ORF72 expression”; US Patent Publication No.10793855B2, published October 6, 2020, entitled “Compositions for modulating expression of C9ORF72 antisense transcript”; US Patent Publication No. 10815483B2, published October 27, 2020, entitled “Compositions for modulating C9ORF72 expression”; US Patent Publication No.11260073B2, published March 1, 2022, entitled “Compositions and methods for modulating C9ORF72”; US Patent Publication No. 10407678B2, published October 9, 2019, entitled “Compositions for modulating expression of C9ORF72 antisense transcript”; US Patent Publication No.11162096B2, published November 2, 2021, entitled “Compositions for modulating expression of C9ORF72 antisense transcript”; US Patent Publication No. US10066228B2, published September 4, 2018, entitled “Oligonucleotides for treating expanded repeat diseases”; US Patent Publication No. 11345915B2, published May 31, 2022, entitled “RNA modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders”; US Patent Publication No.9963699B2, published May 8, 2018, entitled “Methods for modulating C9ORF72 expression”; US Patent Publication No.10221414B2, published March 5, 2019, entitled “Compositions for modulating C9ORF72 expression”; US Patent Application Publication No. 20160108396A1, published April 21, 2016, entitled “Oligomers targeting hexanucleotide repeat expansion in human C9ORF72 gene”; US Patent Publication No.10538762, published January 21, 2020, entitled “Allele selective inhibition of mutant C9orf72 foci expression by duplex RNAS targeting the expanded hexanucleotide repeat”; US Patent Publication No. 10597660B2, published March 24, 2020, entitled “Compositions and methods of treating amyotrophic lateral sclerosis (ALS)”; US Patent Publication No.11118179B2, published September 14, 2021, entitled “Mixed tricyclo-DNA, 2′-modified RNA oligonucleotidecompositions and uses thereof”; US Patent Application Publication No.20210284629A1, published September 16, 2021, entitled “Methods and compounds for the treatment of genetic disease”; US Patent Application Publication No.20210269825A1, published September 2, 2021, entitled “Compositions and methods for reducing spliceopathy and treating rna dominance disorders”; US Patent Application Publication No.20200385737A1, published December 10, 2020, entitled “OLIGONUCLEOTIDE-BASED MODULATION OF C9orf72”; US Patent Application Publication No.20200385723A1, published December 10, 2020, entitled “Anti-c9orf72 oligonucleotides and related methods”; US Patent Application Publication No.20220145300A1, published May 12, 2022, entitled “Oligonucleotide compositions and methods of use thereof”; US Patent Application Publication No. 20210032620A1, published February 4, 2021, entitled “Oligonucleotide compositions and methods thereof”; International PCT Application Publication No. WO2021119226A1, published December 10, 2020, entitled “Human chromosome 9 open reading frame 72 (c9orf72) irna agent compositions and methods of use thereof”; US Patent Application Publication No.20210340535A1, published November 4, 2021, entitled “DUAL-ACTING siRNA BASED MODULATION OF C9orf72”; International PCT Application Publication No. WO2021205005A2, published October 14, 2021, entitled “Antisense sequences for treating amyotrophic lateral sclerosis”; the entire contents of each of which are herein incorporated by reference.

[0334] Certain oligonucleotides provided in this section may be useful in treating ALS by modulating the activity of genes and / or gene products other than C9orf72 genes / gene products, such as ATXN2, SOD1, and / or FUS genes / gene products. Polypeptides

[0335] C9orf72 expression and / or activity of the protein encoded thereby in some embodiments can be modulated by the use of polypeptides, such as polypeptides that can interact with C9orf72 and / or its encoded protein (e.g., to modulate its biological activity and / or its interaction with other biomolecules).

[0336] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of ALS are provided in US Patent Publication No.10295547B2, published May 21, 2019, entitled “Use and treatment of di- amino acid repeat-containing proteins associated with ALS”; US Patent Publication No. 11197911B2, published December 14, 2021, entitled “Peptidylic inhibitors targeting C9ORF72 hexanucleotide repeat-mediated neurodegeneration”; US Patent Application Publication No.20220153874A1, published May 19, 2022, entitled “Human-derived anti-(poly-ga) dipeptide repeat (dpr) antibody”; US Patent Publication No.9329182B2, published May 3, 2016, entitled “Method of treating motor neuron disease with an antibody that agonizes MuSK”; the entire contents of each of which are herein incorporated by reference.

[0337] Certain polypeptides provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than C9orf72 genes / gene products, such as ATXN2, SOD1, and / or FUS genes / gene products. Small molecules

[0338] C9orf72 expression and / or the activity of the protein it encodes in some embodiments can be modulated by the use of small molecules that can modulate C9orf72 (e.g., to modulate its biological activity, its expression, and / or its interaction with other biomolecules).

[0339] In some embodiments, examples of small molecules useful in the treatment of ALS are provided in US Patent Publication No.10675293B2, published June 9, 2020, entitled “Nucleoside agents for the reduction of the deleterious activity of extended nucleotide repeat containing genes”; International PCT Application Publication No. WO2021174167A1, published September 2, 2021, entitled “Compounds and methods for modulating splicing”; US Patent Publication No.11241417B2, published February 8, 2022, entitled “Compositions and methods for the treatment and prevention of neurological disorders”; the entire contents of each of which are herein incorporated by reference.

[0340] In some embodiments, the small molecule is a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein.

[0341] Certain small molecules provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than C9orf72 genes / gene products, such as ATXN2, SOD1, and / or FUS genes / gene products. Gene therapies

[0342] C9orf72 expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate C9orf72 (e.g., by delivery of nucleic acids encoding C9orf72 or other molecules that interact with the protein it encodes).

[0343] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of ALS are provided in US Patent Publication No.10597660B2, published March 24, 2020, entitled “Compositions and methods of treating amyotrophic lateral sclerosis (ALS)”; US Patent ApplicationPublication No.20210269825A1, published September 2, 2021, entitled “Compositions and methods for reducing spliceopathy and treating rna dominance disorders”; US Patent Publication No.10801027B2, published October 13, 2020, entitled “Inhibitors of SRSF1 to treat neurodegenerative disorders”; International PCT Application Publication No. WO2021160464A1, published August 19, 2021, entitled “Gene therapy”; the entire contents of each of which are herein incorporated by reference.

[0344] Certain gene therapies provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than C9orf72 genes / gene products, such as ATXN2, SOD1, and / or FUS genes / gene products. Molecular payloads targeting FUS

[0345] The FUS gene, which encodes RNA-binding protein FUS / TLS, and mutations therein, are implicated in ALS, which predominantly affects upper and lower motor neurons. Modulation of FUS expression and activity (e.g., by suppressing the expression of mutant FUS and / or activity of the protein encoded thereby) therefore in some embodiments can have a therapeutic effect in subjects with ALS. Oligonucleotides

[0346] FUS expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting FUS sequences.

[0347] In some embodiments, an oligonucleotide useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) FUS, comprises a region of complementarity to a FUS transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 401-404.

[0348] In some embodiments, examples of oligonucleotides useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) FUS, are provided in International PCT Application Publication No. WO2020243292A1, published December 3, 2020, entitled “Compounds and methods for reducing fus expression”; US Patent Publication No.11332733B2, published May 17, 2022, entitled “Modified compounds and uses thereof”; US Patent Application Publication No.20100256223A1, published October 7, 2010, entitled “Oligonucleotides for modulating target rna activity”; US Patent Publication No. 9150860B2, published October 6, 2015, entitled “FUS / TLS-based compounds and methods for diagnosis, treatment and prevention of amyotrophic lateral sclerosis and related motor neuron diseases”; US Patent Application Publication No.20120252875A1, published October 4, 2012, entitled “Methods and compositions for treating diseases, disorders or injury of theCNS”; US Patent Publication No.10781445B2, published September 22, 2020, entitled “Decoy oligonucleotides for the treatment of diseases”; US Patent Application Publication No. 20190127733A1, published May 2, 2019, entitled “Oligonucleotide compositions and methods thereof”; US Patent Publication No.11197883B2, published December 14, 2021, entitled “Inhibition of stress granule formation through manipulation of UBAP2L”; US Patent Application Publication No.20210169914A1, published June 10, 2021, entitled “Nucleic acids and nucleic acid analogs for treating, preventing, and disrupting pathological polynucleotide- binding protein inclusions”; International PCT Application Publication No. WO2021203043A2, published October 7, 2021, entitled “Targeted inhibition using engineered oligonucleotides”; International PCT Application Publication No. WO2021207854A1, published October 21, 2021, entitled “Compositions and methods for inhibiting tdp-43 and fus aggregation”; the entire contents of each of which are herein incorporated by reference.

[0349] Certain oligonucleotides provided in this section may be useful in treating ALS by modulating the activity of genes and / or gene products other than FUS genes / gene products, such as ATXN2, SOD1, and / or C9orf72 genes / gene products. Polypeptides

[0350] FUS expression and / or activity of the protein encoded thereby in some embodiments can be modulated by the use of polypeptides, such as polypeptides that can interact with FUS nucleic acids and / or its encoded protein (e.g., to modulate its biological activity, its localization within the cell, and / or its interaction with other biomolecules).

[0351] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of ALS are provided in US Patent Publication No.1132504B2, published May 17, 2022, entitled “Methods of reducing FUS / TLS- or TDP-43-mediated neuronal cytotoxicity by UPF1”; US Patent Application Publication No.20180360925A1, published December 20, 2018, entitled “Extracellular dna as a therapeutic target in neurodegeneration”; the entire contents of each of which are herein incorporated by reference.

[0352] Certain polypeptides provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than FUS genes / gene products, such as ATXN2, SOD1, and / or C9orf72 genes / gene products. Small molecules

[0353] FUS expression and / or the activity of the protein it encodes in some embodiments can be modulated by the use of small molecules that can modulate FUS (e.g., to modulate itsbiological activity, its expression, its localization, and / or its interaction with other biomolecules).

[0354] In some embodiments, examples of small molecules useful in the treatment of ALS are provided in US Patent Application Publication No.20120272345A1, published October 25, 2012, entitled “Diagnosis marker, diagnosis method and therapeutic agent for amyotrophic lateral sclerosis, and animal model and cell model developing amyotrophic lateral sclerosis”; US Patent Publication No.10159670B2, published December 25, 2018, entitled “Methods of diagnosing and treating motor neuron diseases and other cellular stress-related diseases”; US Patent Application Publication No.20200216563A1, published July 9, 2020, entitled “Hdac6 and protein aggregation”; International PCT Application Publication No. WO2021174167A1, published September 2, 2021, entitled “Compounds and methods for modulating splicing”; US Patent Application Publication No.20200368267A1, published November 26, 2020, entitled “Prophylactic and / or therapeutic agent for amyotrophic lateral sclerosis”; US Patent Application Publication No.20220071955A1, published March 10, 2022, entitled “Methods of Treatment, Prevention and Diagnosis”; the entire contents of each of which are herein incorporated by reference.

[0355] In some embodiments, the small molecule is a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein.

[0356] Certain small molecules provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than FUS genes / gene products, such as ATXN2, SOD1, and / or C9orf72 genes / gene products. Gene therapies

[0357] FUS expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate FUS (e.g., by delivery of nucleic acids encoding FUS or other molecules that interact with FUS transcripts or the protein encoded by FUS).

[0358] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of ALS are provided in International PCT Application Publication No. WO2021205010A1, published 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 herein incorporated by reference.

[0359] Certain gene therapies provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than FUS genes / gene products, such as ATXN2, SOD1, and / or C9orf72 genes / gene products. Molecular payloads targeting PIKFYVE

[0360] The PIKFYVE gene, which encodes the phosphatidylinositol-3-phosphate 5-kinase type III (PIPKIII) protein, and mutations therein, are implicated in ALS. Modulation of PIKFYVE expression and activity (e.g., by suppressing the expression and / or activity of mutant PIPKIII protein and / or its interactions with other proteins) therefore in some embodiments can have a therapeutic effect in subjects with ALS. Oligonucleotides

[0361] PIKFYVE (and / or PIPKIII protein encoded by PIKFYVE) expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting PIKFYVE sequences.

[0362] In some embodiments, an oligonucleotide useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) PIKFYVE, comprises a region of complementarity to a PIKFYVE transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 143-148.

[0363] In some embodiments, examples of oligonucleotides useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) PIKFYVE, are provided in US20220411804A1, published December 29, 2022, entitled “Pikfyve antisense oligonucleotides”; the entire contents of which are herein incorporated by reference.

[0364] Certain oligonucleotides provided in this section may be useful in treating ALS by modulating the activity of genes and / or gene products other than PIKFYVE genes / gene products, such as other genes / gene products associated with ALS. Polypeptides

[0365] PIKFYVE expression and / or activity in some embodiments can be modulated by the use of PIPKIII polypeptides or polypeptides that can interact with PIPKIII (e.g., to modulate its biological activity and / or its interaction with other biomolecules).

[0366] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of ALS include PIPKIII protein and functional fragments thereof.

[0367] Certain polypeptides provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than PIKFYVE genes / gene products, such as other genes / gene products associated with ALS. Small molecules

[0368] PIKFYVE expression and / or activity in some embodiments can be modulated by the use of small molecules that can modulate PIPKIII (e.g., to modulate its biological activity, its expression, and / or its interaction with other biomolecules).

[0369] In some embodiments, examples of small molecules useful in the treatment of ALS are provided in US20190192527A1, published June 27, 2019, entitled “Compositions comprising pikfyve inhibitors and methods related to inhibition of rank signaling”; WO2017040971A1, published March 9, 2017, entitled “Methods of using inhibitors of pikfyve for the treatment of lysosomal storage disorders and neurodegenerative diseases”; WO2022086993A1, published April 28, 2022, entitled “Novel inhibitors of pikfyve and methods using same”; US20210139505A1, published May 13, 2021, entitled “PIKfyve Inhibitors”; US10758545B2, published September 1, 2020, entitled “Methods to treat neurological diseases”; US11066410B2, published July 20, 2021, entitled “Fused triazolo-pyrimidine compounds having useful pharmaceutical application”; the entire contents of each of which are herein incorporated by reference.

[0370] In some embodiments, the small molecule is a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein.

[0371] Certain small molecules provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than PIKFYVE genes / gene products, such as other genes / gene products associated with ALS. Gene therapies

[0372] PIKFYVE expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate PIKFYVE (e.g., by delivery of nucleic acids encoding PIKFYVE or other molecules that interact with PIKFYVE).

[0373] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of ALS include payloads which encode PIPKIII or functional fragments thereof.

[0374] Certain gene therapies provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than PIKFYVE genes / gene products, such as other genes / gene products associated with ALS. Molecular payloads targeting SYF2

[0375] The SYF2 gene, which encodes the pre-mRNA-splicing factor SYF2 protein, and mutations therein, are implicated in ALS. Modulation of SYF2 expression and activity (e.g., by suppressing the expression and / or activity of mutant pre-mRNA-splicing factor SYF2 protein and / or its interactions with other proteins) therefore in some embodiments can have a therapeutic effect in subjects with ALS. Oligonucleotides

[0376] SYF2 (and / or pre-mRNA-splicing factor SYF2 protein encoded by SYF2) expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting SYF2 sequences.

[0377] In some embodiments, an oligonucleotide useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) SYF2, comprises a region of complementarity to a SYF2 transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 167-168.

[0378] In some embodiments, examples of oligonucleotides useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) SYF2, are provided in US20230066380A1, published March 2, 2023, entitled “Antagonism as a therapy for tdp-43 proteinopathies”; the entire contents of which are herein incorporated by reference.

[0379] Certain oligonucleotides provided in this section may be useful in treating ALS by modulating the activity of genes and / or gene products other than SYF2 genes / gene products, such as other genes / gene products associated with ALS. Polypeptides

[0380] SYF2 expression and / or activity in some embodiments can be modulated by the use of pre-mRNA-splicing factor SYF2 polypeptides or polypeptides that can interact with pre- mRNA-splicing factor SYF2 (e.g., to modulate its biological activity and / or its interaction with other biomolecules).

[0381] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of ALS include pre-mRNA-splicing factor SYF2 protein and functional fragments thereof.

[0382] Certain polypeptides provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than SYF2 genes / gene products, such as other genes / gene products associated with ALS. Small molecules

[0383] SYF2 expression and / or activity in some embodiments can be modulated by the use of small molecules that can modulate pre-mRNA-splicing factor SYF2 protein (e.g., to modulate its biological activity, its expression, and / or its interaction with other biomolecules).

[0384] In some embodiments, examples of small molecules useful in the treatment of ALS are small molecules that increase or decrease expression of SYF2, and / or that increase or decrease pre-mRNA-splicing factor SYF2 protein levels or activity.

[0385] Certain small molecules provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than SYF2 genes / gene products, such as other genes / gene products associated with ALS. Gene therapies

[0386] SYF2 expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate SYF2 (e.g., by delivery of nucleic acids encoding SYF2 or other molecules that interact with SYF2).

[0387] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of ALS include payloads which encode pre-mRNA-splicing factor SYF2 protein or functional fragments thereof.

[0388] Certain gene therapies provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than SYF2 genes / gene products, such as other genes / gene products associated with ALS. Molecular payloads targeting UNC13A

[0389] The UNC13A gene, which encodes the unc-13 homolog A protein, and mutations therein, are implicated in ALS. Modulation of UCN13A expression and activity (e.g., by suppressing the expression and / or activity of mutant unc-13 homolog A protein and / or its interactions with other proteins) therefore in some embodiments can have a therapeutic effect in subjects with ALS.Oligonucleotides

[0390] UNC13A (and / or unc-13 homolog A protein encoded by UNC13A) expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting UNC13A sequences.

[0391] In some embodiments, an oligonucleotide useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) UNC13A, comprises a region of complementarity to a UNC13A transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 169 and 810-818.

[0392] In some embodiments, examples of oligonucleotides useful for the treatment of ALS, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) UNC13A, are provided in WO2022246251A2, published November 24, 2022, entitled “Compounds for modulating unc13a expression”; WO2023102225, published December 2, 2022, entitled “Treatment of neurological diseases using modulators of unc13a gene transcripts”; US20230125137, published April 27, 2023, entitled “Unc13a antisense oligonucleotides”; WO2022122872, published June 16, 2022, entitled “Therapeutics for the treatment of neurodegenerative disorders”; WO2023102242, published June 8, 2023, entitled “Splice switcher antisense oligonucleotides with modified backbone chemistries”; WO2023104964, published June 15, 2023, entitled “Therapeutics for the treatment of neurodegenerative disorders”; and US20220033818A1, published February 3, 2023, entitled “Oligonucleotides targeting rna binding protein sites”; the entire contents of which are herein incorporated by reference.

[0393] Certain oligonucleotides provided in this section may be useful in treating ALS by modulating the activity of genes and / or gene products other than UNC13A genes / gene products, such as other genes / gene products associated with ALS. Polypeptides

[0394] UNC13A expression and / or activity in some embodiments can be modulated by the use of unc-13 homolog A polypeptides or polypeptides that can interact with unc-13 homolog A (e.g., to modulate its biological activity and / or its interaction with other biomolecules).

[0395] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of ALS include unc-13 homolog A protein and functional fragments thereof.

[0396] Certain polypeptides provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than UNC13A genes / gene products, such as other genes / gene products associated with ALS. Small molecules

[0397] UNC13A expression and / or activity in some embodiments can be modulated by the use of small molecules that can modulate unc-13 homolog A protein (e.g., to modulate its biological activity, its expression, and / or its interaction with other biomolecules).

[0398] In some embodiments, examples of small molecules useful in the treatment of ALS are small molecules that increase or decrease expression of UNC13A, and / or that increase or decrease unc-13 homolog A protein levels or activity.

[0399] Certain small molecules provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than UNC13A genes / gene products, such as other genes / gene products associated with ALS. Gene therapies

[0400] UNC13A expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate UNC13A (e.g., by delivery of nucleic acids encoding UNC13A or other molecules that interact with UNC13A).

[0401] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of ALS include payloads which encode unc-13 homolog A protein or functional fragments thereof.

[0402] Certain gene therapies provided in this section may be useful in treating ALS by modulating the activity of genes and gene products other than UNC13A genes / gene products, such as other genes / gene products associated with ALS. Molecular payloads for the treatment of Spinocerebellar ataxia

[0403] Various molecular payloads may be useful in the treatment of spinocerebellar ataxia (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 therapies (e.g., nucleic acids and / or nucleic acid vectors encoding therapeutic molecules, such as therapeutic proteins). Molecular payloads useful in the treatment of spinocerebellar ataxia may include, in some embodiments, molecular payloads which modulate (e.g., increase or decrease) expression or activity of ATXN1, ATXN2, ATXN3, and / or MSH3.

[0404] Examples of oligonucleotides useful for the treatment of spinocerebellar ataxia, e.g., oligonucleotides targeting (e.g., directly or indirectly modulating the expression or activity of) genes associated with cerebellar ataxia (e.g., ATXN1, ATXN2, ATXN3, MSH3, etc.), include those listed in Table 7 below. Each oligonucleotide provided in Table 7 may have any modification pattern disclosed herein. Table 7. Oligonucleotides for the treatment of spinocerebellar ataxia

[0405] Examples of small molecules useful for the treatment of spinocerebellar ataxia (e.g., SCA1, SCA2, SCA3, and / or other types of SCA) include: baclofen, chlorzoxazone, A71623, and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof.

[0406] Examples of polypeptides useful for the treatment of spinocerebellar ataxia (e.g., SCA1, SCA2, SCA3, and / or other types of SCA) include antibodies, proteins, peptides, and enzymes. In some embodiments, polypeptides useful for the treatment of SCA include: A71623 (Boc-Trp-Lys(Tac)-Asp-N-methyl-Phe-NH2) (SEQ ID NO: 807). Molecular payloads targeting ATXN1

[0407] The ATXN1 gene, which encodes the ataxin-1 protein, and mutations therein, are implicated in SCA type 1 (SCA1). Modulation of ATXN1 expression and activity (e.g., by suppressing the expression and / or activity of mutant ATXN1 protein and / or its interactions with other proteins) therefore in some embodiments can have a therapeutic effect in subjects with SCA1. Oligonucleotides

[0408] ATXN1 (and / or ataxin-1 protein encoded by ATXN1) expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting ATXN1 sequences.

[0409] In some embodiments, an oligonucleotide useful for the treatment of SCA, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) ATXN1, comprises a region of complementarity to a ATXN1 transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 819-820.

[0410] In some embodiments, examples of oligonucleotides useful for the treatment of SCA1, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) ATXN1, are provided in US11542504B2, published January 3, 2023, entitled “Compounds and methods formodulating ATXN1”; US11345915B2, published May 31, 2022, entitled “RNA modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders”; the entire contents of each of which are herein incorporated by reference.

[0411] Certain oligonucleotides provided in this section may be useful in treating SCA1 by modulating the activity of genes and / or gene products other than ATXN1 genes / gene products, such as other genes / gene products associated with SCA and / or SCA1. Polypeptides

[0412] ATXN1 expression and / or activity in some embodiments can be modulated by the use of ataxin-1 polypeptides or polypeptides that can interact with ataxin-1 (e.g., to modulate its biological activity and / or its interaction with other biomolecules).

[0413] In some embodiments, examples of polypeptides (e.g., peptides; proteins, such as enzymes; antibodies; etc.) useful in the treatment of SCA1 are provided in US10989719B2, published April 27, 2021, entitled “Methods for treating spinocerebellar ataxia type I using RPA1”; US10973812B2, published April 13, 2021, entitled “Ataxia therapeutic compositions and methods”; the entire contents of each of which are herein incorporated by reference.

[0414] Certain polypeptides provided in this section may be useful in treating SCA1 by modulating the activity of genes and gene products other than ATXN1 genes / gene products, such as other genes / gene products associated with SCA and / or SCA1. Small molecules

[0415] ATXN1 expression and / or activity in some embodiments can be modulated by the use of small molecules that can modulate ATXN1 (e.g., to modulate its biological activity, its expression, and / or its interaction with other biomolecules).

[0416] In some embodiments, examples of small molecules useful in the treatment of SCA1 are provided in US11382897B2, published July 12, 2022, entitled “Therapeutic combination for treatment of cerebellar ataxia”; the entire contents of each of which are herein incorporated by reference.

[0417] In some embodiments, the small molecule is a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug of a small molecule provided herein.

[0418] Certain small molecules provided in this section may be useful in treating SCA1 by modulating the activity of genes and gene products other than ATXN1 genes / gene products, such as other genes / gene products associated with SCA and / or SCA1.Gene therapies

[0419] ATXN1 expression and / or activity in some embodiments can be modulated by the use of gene therapies that can modulate ATXN1 (e.g., by delivery of nucleic acids encoding ATXN1 or other molecules that interact with ATXN1).

[0420] In some embodiments, gene therapies, such as those involving administration of a compounds encoding useful therapeutic agents, useful in the treatment of SCA1 are provided in US20110016540A1, published January 20, 2011, entitled “Genome editing of genes associated with trinucleotide repeat expansion disorders in animals”; US10989719B2, published April 27, 2021, entitled “Methods for treating spinocerebellar ataxia type I using RPA1”; US11027024B2, published June 8, 2021, entitled “Methods of delivery of transgenes for treating brain diseases”; US20210238226A1, published August 5, 2021, entitled “Methods and compounds for the treatment of genetic disease”; the entire contents of each of which are herein incorporated by reference.

[0421] Certain gene therapies provided in this section may be useful in treating SCA1 by modulating the activity of genes and gene products other than ATXN1 genes / gene products, such as other genes / gene products associated with SCA and / or SCA1. Molecular payloads targeting ATXN2

[0422] The ATXN2 gene, which encodes the ataxin-2 protein, and mutations therein, are implicated in SCA type 2 (SCA2). Modulation of ATXN2 expression and activity (e.g., by suppressing the expression and / or activity of mutant ATXN2 protein and / or its interactions with other proteins) therefore in some embodiments can have a therapeutic effect in subjects with SCA2. Oligonucleotides

[0423] ATXN2 (and / or ataxin-2 protein encoded by ATXN2) expression and / or activity in some embodiments can be modulated by the use of oligonucleotides targeting ATXN2 sequences.

[0424] In some embodiments, an oligonucleotide useful for the treatment of SCA, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) ATXN2, comprises a region of complementarity to a ATXN2 transcript provided in Table 3, e.g., provided by any one of SEQ ID NOs: 396-400.

[0425] In some embodiments, examples of oligonucleotides useful for the treatment of SCA2, e.g., targeting (e.g., directly or indirectly modulating the expression or activity of) ATXN2, are provided in Becker et al. (2017) “Therapeutic reduction of ataxin-2 extends lifespan andreduces 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; US Patent Application Publication No.20110142789A1, published June 16, 2011, entitled “Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis”; US Patent Application Publication No.20130225659A1, published August 29, 2013, entitled “Modulation of nuclear-retained RNA”; US Patent Publication No.1107486B2, published August 3, 2021, entitled “Compounds and methods for reducing ATXN2 expression”; US Patent Application Publication No.20220064639A1, published March 3, 2022, entitled “Compounds and methods for reducing ATXN2 expression”; US Patent Publication No. 10533178B2, published January 14, 2020, entitled “Methods for modulating Ataxin 2 expression”; US Patent Publication No.10006027B2, published June 26, 2018, entitled “Methods for modulating Ataxin 2 expression”; US Patent Publication No.10308934B2, published June 4, 2019, entitled “Compositions for modulating Ataxin 2 expression”; US Patent Publication No.11111494B2, published September 7, 2021, entitled “Compositions for modulating Ataxin 2 expression”; US Patent Publication No.11345915B2, published May 31, 2022, entitled “RNA modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders”; US Patent Application Publication No. 20140378533A1, published December 25, 2014, entitled “Modulation of RNA by repeat targeting”; US Patent Application Publication No.20150148404A1, published May 28, 2015, entitled “RNA Modulating Oligonucleotides with Improved Characteristics for the Treatment of Neuromuscular Disorders”; US Patent Application Publication No.20210169914A1, pu...

Claims

CLAIMS What is claimed is:

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

2. The complex of claim 1, wherein the anti-TfR1 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 17 and a light chain variable region (VL) comprising an 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 an amino acid sequence of SEQ ID NO: 19 and a light chain comprising an 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 payload 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 payload comprises an oligonucleotide, a polypeptide, a small molecule, or a gene therapy payload, optionally wherein the gene therapy payload 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 a structure of formula (I):wherein n is any number from 0-10, and wherein m is any number from 0-10, optionally wherein n is 3 and / or m is 4; and wherein L1 is a spacer that is 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)2NRA-, -NRAS(O)2-, or a combination thereof, wherein each RAis 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 formula (J):wherein n is any number from 0-10, and wherein m is any number from 0-10, 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 payload to the cell of the CNS across the blood-brain barrier.

10. The complex of any one of claims 1 to 8, wherein the complex delivers the molecular payload to the cell 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 region of complementarity to a transcript as set forth in any one of SEQ ID NOs: 392-702, or to a target sequence of an oligonucleotide listed in any one of Tables 5-19, optionally wherein the oligonucleotide comprises an oligonucleotide structure listed in any one of Tables 5-19.

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

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

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) a glycogen synthesis disorder; neurodegeneration; small fiber neuropathy; a nociception-related phenotype; Alexander disease; Angelman Syndrome; an 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 neuron disease; (iv) Dravet syndrome; (v) Batten disease; (vi) GM1 gangliosidosis; (vii) Niemann-Pick Type A; (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]-[1208], optionally wherein the molecular payload is a molecular payload disclosed in any one of 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 of any one of claims 1 to 20.

22. A method of delivering a molecular payload to the CNS of a subject, the method comprising administering to the subject a 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 administration.

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

26. The method of any one of claims 22 to 25, wherein the complex is detectable in 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 administration.

28. The method of any one of claims 22 to 27, wherein the molecular payload 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, lewy body dementia, 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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