Alpha-synuclein-modulating compositions and methods of use thereof

Abstract

Aspects of the disclosure provide compounds, compositions, and methods for modulating the expression, translation, and / or activity of alpha- synuclein (aSyn). In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of SNCA mRNA in a cell or animal. In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of aSyn in a cell or animal.

Description

ALPHA-SYNUCLEIN-MODULATING COMPOSITIONSAND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U. S. C. § 119(e) of U. S.Provisional Application No. 63 / 730,894, filed December 11, 2024. The disclosure of the prior application is considered part of and is incorporated by reference in its entirety in the disclosure of this application.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (A127870040WO00-SEQ-JIB.xml;Size: 285,821 bytes; and Date of Creation: December 8, 2025) are incorporated herein by reference in their entirety.BACKGROUND

[0003] Alpha- synuclein (aSyn) is primarily found in presynaptic nerve terminals. The function of aSyn remains unclear, but studies suggest that aSyn is involved in the regulation of neurotransmitter release, synaptic function and plasticity, mitochondrial function, gene regulation, and SNARE complex assembly. The role of aSyn in dopaminergic transmission and the presence of aSyn in Lewy bodies implicate aSyn in the cause and progression of Parkinson’s disease (PD). Indeed, aSyn accumulation and aggregation are the common characteristics of neurodegenerative disorders referred to as a-synucleinopathies (synucleinopathies). In addition to PD, aSyn aggregates in neurons or glial cells have been linked to other a-synucleinopathies, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). In PD and DLB, aSyn inclusions, called Lewy bodies (LBs), are located primarily in neurons and neurites. These conditions are believed to be age-related disorders influenced by genetic and environmental factors.

[0004] PD is the most common synucleinopathy, and LBs are associated with the loss of dopaminergic neurons in the substantia nigra, resulting in PD-associated motor symptoms e.g., bradykinesia, resting tremor, muscle rigidity and postural instability. PD is also characterized by lysosomal and proteasomal impairment, mitochondrial dysfunction, increased iron levels, and neuroinflammation. In contrast with PD, DLB features1#14696011vldementia within the first year of parkinsonism. Additionally, the neuronal loss in PD mostly affects the brainstem and the limbic regions, but in DLB, it predominates in the neocortex. The most prevalent symptoms of DLB include fluctuating cognition, recurrent visual hallucinations, and spontaneous extrapyramidal motor features. MSA is distinguishable from PD and DLB based on its pathological and clinical presentation. MSA features aSyn inclusions in the cytoplasm of oligodendrocytes termed glial cytoplasmic inclusions (GCIs) and selective neurodegeneration in multiple brain areas including substantia nigra, striatum, cerebellum, pontine nuclei, and spinal cord, resulting in parkinsonism, cerebellar ataxia and autonomic failure. Other MSA characteristics are neuroinflammation, microglial activation, astrogliosis, and T-cell infiltration. MSA often progresses rapidly leading to death a few years after symptoms start. Additionally, MSA is currently considered a sporadic disease, without clear genetic contribution to its etiology although some multiplex families exist.

[0005] Examples of other synucleinopathies include pure autonomic failure (PAF) and isolated rapid eye movement sleep behavior disorder (iRBD). PAF affects the autonomic nervous system and is characterized by orthostatic hypotension, fixed pulse rate, anhidrosis, erectile dysfunction and constipation without motor features. In PAF, aSyn inclusions are found mostly in autonomic ganglia and nerves of the peripheral nervous system that is associated with the loss of sympathetic ganglia and postganglionic fibers. Some patients with PAF phenotype have progressed into MSA, DLB, and PD, suggesting that PAF could be a prodromal stage of the classical synucleinopathies. In iRBD, neurons in brainstem areas that regulate sleep are lost. iRBD is a common prodromal syndrome in classical synucleinopathies; indeed, more than 80% of iRBD patients eventually develop PD, DLB or MSA.

[0006] As the foregoing examples illustrate, although synucleinopathies all involve misfolded aSyn deposition, they present a wide spectrum of clinical phenotypes with multiple overlapping features. From these observations, one hypothesis posits that the pathological accumulation of aSyn in different cell types and brain areas might arise from distinct aSyn strains that could also result in the different neurodegenerative and disease duration patterns that typify each disorder.

[0007] Protein-based therapies, such as antibodies, have been investigated to target different forms and conformational states of aSyn. Genetic studies have identified single nucleotide 2#14696011vlpolymorphisms, mutations, and multiplications of the SNCA gene (hereinafter “SNCA”), which encodes aSyn, that cause or have been associated with increased risk of PD. For example, variations in the SNCA promoter and untranslated region may increase susceptibility to PD by altering transcription factor binding sites and creating or destroying microRNAs target sites, thereby modifying gene expression. Ideally such genetic correlations would aid in diagnosis and treatment. However, investigations into aSyn’s role in PD have sometimes produced conflicting results. Therefore, there remains a need for effective treatments and prophylactics for synucleinopathies.SUMMARY

[0008] The present disclosure provides compounds, compositions, and methods for modulating the expression, translation, and / or activity of a-synuclein (aSyn). In certain embodiments, the compounds, compositions, and methods can be used to reduce the expression of SNCA mRNA in a cell or animal. In certain embodiments, the compounds, compositions, and methods can be used to reduce the amount of aSyn in a cell or animal. In certain embodiments, the compounds, compositions, and methods can be used to reduce and / or prevent the aggregation of aSyn protein in a cell or animal.

[0009] In certain embodiments, the animal has a central nervous system (CNS) related disease, disorder or condition. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, or Creutzfeldt- Jakob disease.

[0010] In certain embodiments, the compounds and compositions comprise one or more features that are effective for increasing potency. In certain embodiments, the compounds and compositions comprise one or more features that are effective for increasing3#14696011vltolerability. In certain embodiments, compounds and compositions comprise one or more features that are effective for targeting the compound or composition to a cell or tissue. In certain embodiments, the compounds and compositions are more potent, have greater duration of action or have greater therapeutic value than compounds publicly disclosed.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows the structure of a compound of the invention referred to herein as RD7452, which includes strands of Ref ID NO: IA2910 (SEQ ID NO: 82) and Ref ID NO: IS3543 (SEQ ID NO: 111).

[0012] FIG. 2 shows the percent decrease in SNCA mRNA following administration of RD7452 relative to SNCA mRNA concentration following administration of artificial cerebrospinal fluid (aCSF).DETAILED DESCRIPTION

[0013] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0014] All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and GenBank, NCBI and other sequence reference records are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety as of the date of filing this application.

[0015] Herein, the use of the singular includes the plural unless specifically stated otherwise.For example, the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting and is used interchangeably with, the phrase "including but not limited to".Definitions4#14696011vl

[0016] Unless otherwise indicated, the following terms have the following meanings:

[0017] “Alpha-synuclein,” used interchangeably with the terms “a-synuclein” and “aSyn” herein, refers to any nucleic acid or protein of the synuclein alpha (SNCA) gene. SNCA may be referred to in either upper or lower case. SNCA is also known as “PD1”, “NACP”, “PARK1”, and “PARK4”. An exemplary nucleotide sequence of SNCA can be found, for example, at GenBank Accession No. NM_001375287.1 (incorporated herein as SEQ ID NO: 1). Additional examples of SNCA sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM, and may include, for instance: NCBI Accession Nos. NM_000345.4, NM_001146054.2, NM_001146055.2, 001375285.1, NM_001375286.1, NM_001375288.1, NM_001375290.1, and NM_007308.3; UniProt Accession Nos. P37840 (e.g., P37840-1, P37840-2, P37840-3), E7EPV7, D6RA31, H6UYS7, A0A669KBH5, and A0A669KB41; and OMIM Accession No. 163890. Further information on SNCA can be found, for example, on the world wide web at ncbi.nlm.nih.gov / gene / ?term=SNCA. “SNCA,” as used herein, also refers to variations of the SNCA gene including variants provided in the SNP database. Numerous sequence variations within the SNCA gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., ncbi.nlm.nih.gov / snp / ?term=SNCA). “SNCA mRNA” and “aSyn mRNA”, used interchangeably herein, refer to an mRNA encoding an aSyn protein. An exemplary amino acid sequence of aSyn protein can be found, for example, at GenBank Accession No. NP_001362216.1. The entire contents of each of the foregoing GenBank Accession number and the gene database numbers are incorporated herein by reference as of the date of filing of this application.

[0018] “SNCA specific inhibitor” refers to any agent capable of specifically inhibiting SNCA RNA and / or a-synuclein expression or activity at the molecular level. For example, SNCA specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of SNCA RNA and / or a-synuclein.

[0019] “2'-0-methoxyethyl” or “2'-MOE” means a 2'-O(CH2)2-OCH3 modification. A 2'-O- methoxyethyl modified sugar is a modified sugar with 2'-O(CH2)2-OCH3 in the place of the 2'-OH group of a ribosyl ring.

[0020] “5 ' start site” means the nucleotide of the target nucleic acid or region which is complementary to the 3'-most nucleoside of an antisense oligonucleotide.5#14696011vl

[0021] “3' stop site” means the nucleotide of the target nucleic acid or region which is complementary to the 5'-most nucleoside of an antisense oligonucleotide.

[0022] “About” means within ±10% of a value. For example, if it is stated, “a compound achieved about 70% inhibition of aSyn”, it is implied that aSyn levels are inhibited within a range of 60% and 80%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0023] “Administer” or “administering” refers to routes of introducing a compound or composition provided herein to an individual to perform its intended function.Administration may be systemic or local. An example, routes of administration that can be used include, but are not limited to, parenteral administration, such as, subcutaneous, intravenous, or intracranial injection or infusion, e.g. intracerebroventricular (ICV) or intrathecal (IT).

[0024] “Ameliorate” refers to an improvement or lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In certain embodiments, amelioration includes a delay or slowing in the progression or severity of one or more indicators of a condition or disease. The progression or severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art.

[0025] ‘ ‘Animal” refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees.

[0026] “Antisense oligonucleotide” or “antisense strand” means an oligonucleotide which includes a region that is complementary to a target nucleic acid, e.g., a SNCA RNA or a region thereof.

[0027] “Complementarity” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof that is complementary to the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions.Complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G) unless otherwise specified. Complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or 6#14696011vlmore nucleobase mismatches. By contrast, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches.

[0028] “Composition” or “pharmaceutical composition” means a mixture of substances suitable for administering to an individual. For example, a composition may comprise one or more compounds or salt thereof and a sterile aqueous solution.

[0029] “Co-administration” means administration of two or more compounds in any manner in which the pharmacological effects of both are manifest in the patient. Coadministration does not require both compounds to be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of both compounds need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive. Co-administration includes parallel or sequential administration of the one or more compounds.

[0030] “Conjugate group” means a group of atoms that is attached to an oligonucleotide. A conjugate group is optionally attached to an oligonucleotide through a conjugate linker. A conjugate group may, for example, alter the distribution, targeting, or half-life of a compound into which it is incorporated. Conjugate groups include lipids (or lipophilic moieties), ligands, and other targeting moieties.

[0031] “Conjugate linker” means a group of atoms comprising at least one bond that connects a linked moiety to an oligonucleotide.

[0032] “Extracellular Space” means the region immediately adjacent to or surrounding a cell within a tissue compartment or in the extracellular matrix of said tissue.

[0033] In reference to a conjugate group or targeting moiety, a “lipid” or “lipophilic moiety” refers to an aliphatic, cyclic (such as alicyclic), or polycyclic (such as polyalicyclic) compound, such as a steroid (e.g., sterol) or a linear or branched aliphatic hydrocarbon; e.g., includes a saturated or unsaturated Cs-Cso hydrocarbon chain, and in one embodiment a saturated or unsaturated C12-C30 hydrocarbon chain. The term lipid includes cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1 -pyrene butyric acid, dihydrotestosterone, l,3-bis-0(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3- propanediol, heptadecyl group, palmitic acid, myristic acid, 03-(oleoyl)lithocholic acid, 03-(oleoyl)cholenic acid, ibuprofen, naproxen,7#14696011vldimethoxytrityl, or phenoxazine. The term lipid includes a saturated or unsaturated C4- C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C5-C20 hydrocarbon chain (e.g., a linear C5-C20 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C14-C20 hydrocarbon chain (e.g., a linear C14-C20 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated Ce-Cis hydrocarbon chain (e.g., a linear Ce-Cis alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated Ci6 hydrocarbon chain (e.g., a linear Ci6 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C17 hydrocarbon chain (e.g., a linear C17 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated Cis hydrocarbon chain (e.g., a linear Cis alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C22 hydrocarbon chain (e.g., a linear C22 alkyl or alkenyl).

[0034] In reference to a conjugate group or targeting moiety, a ligand of “a.4 1 / 7 integrin receptor” refers to a ligand of heterodimeric integrin receptors formed by association of integrin alpha 4 and integrin beta 1 (i.e., the a401 integrin receptor) and integrin alpha 4 and integrin beta 7 (i.e., the c P? integrin receptor). In certain embodiments, the a.401 / 7 integrin receptor ligand has a higher binding affinity for cuP 1 integrin receptor than c P? integrin receptor. In certain embodiments, the a40i / 7 integrin receptor ligand has a higher binding affinity for c P? integrin receptor than cuP 1 integrin receptor.

[0035] In reference to a conjugate group or targeting moiety, a ligand of “Cannabinoid Receptor Type 1” or “CBi” refers to a ligand of the G protein-coupled receptor for cannabinoids. In humans, CBi is encoded by the CNR1 gene. CBi is also known as cannabinoid receptor 1.

[0036] In reference to a conjugate group or targeting moiety, a ligand of “Tropomyosin Receptor Kinase B” or “TrkB” refers to a ligand of the receptor for brain-derived neurotrophic factor (BDNF) protein encoded by the NTRK2 gene. TrkB is also known as tyrosine receptor kinase B, BDNF / NT-3 growth factors receptor and neurotrophic tyrosine kinase, receptor, type 2.

[0037] “Identity” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof that matches the nucleobase sequence of 8#14696011vlanother oligonucleotide or nucleic acid or one or more regions thereof. Identity of an oligonucleotide to another oligonucleotide or nucleic acid need not require each nucleobase to match and may include one or more different nucleobases. By contrast, “fully identical” or “100% identity” in reference to oligonucleotides means that such oligonucleotides have the same nucleobase at each relative position over its length as the other oligonucleotide or nucleic acid.

[0038] “Individual” means a human or non-human animal selected for treatment or therapy.

[0039] “Inhibiting the expression, translation, and / or activity” with reference to a target nucleic acid or protein means to reduce or block the expression, translation, and / or activity of such target relative to the expression, translation, and / or activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity.

[0040] “Internucleoside linkage” refers to the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, “modified internucleoside linkage” means any intemucleoside linkage other than a phosphodiester intemucleoside linkage.“Phosphorothioate intemucleoside linkage” is a modified intemucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester intemucleoside linkage is replaced with a sulfur atom.

[0041] Representative intemucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising intemucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom intemucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations as further described below. Unless otherwise indicated, chiral intemucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.

[0042] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.9#14696011vl

[0043] “Isotopic variant” refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a therapeutic agent. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium (2H), tritium (3H), carbon-11 (nC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen- 17 (17O), oxygen- 18 (18O), fluorine- 17 (17F), fluorine- 18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine 123 (123I), iodine-125 (125I), iodine- 127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium (2H), tritium (3H), carbon- 11 (nC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen- 18 (18O), fluorine- 17 (17F), fluorine- 18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine 123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I).

[0044] It will be understood that, in a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), any hydrogen can be2H, for example, or any carbon can be13C, for example, or any nitrogen can be15N, for example, or any oxygen can be18O, for example, where feasible according to the judgment of one of skill. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of deuterium (D).

[0045] ‘ ‘Mismatch” or “non-complementary” refers to a first nucleobase of a first nucleobase sequence that does not form a canonical base pair with a second nucleobase at the corresponding position in a second nucleobase sequence when the first and second nucleobase sequences are aligned in an antiparallel orientation. In certain embodiments, the first and second nucleobases of a mismatch do not form a base pair (e.g., through 10#14696011vlhydrogen bonding). In certain embodiments, the first and second nucleobases of a mismatch form a non-canonical base pair. For example, nucleobases including, but not limited to, a universal nucleobase and hypoxanthine (inosine (I)), are capable of forming a non-canonical base pair with one or more other types of nucleobases but may still be referred to as mismatched or non-complementary with respect to the one or more other types of nucleobases. In certain embodiments, a non-canonical base pair comprises a wobble base pair (e.g., I: U, G: U, I: A, I: C). In certain embodiments, an oligonucleotide described herein comprises one or more mismatches. In certain embodiments, an oligonucleotide comprises one or more mismatches relative to a target nucleic acid (e.g., an mRNA encoding aSyn). In certain embodiments, an oligonucleotide sense strand comprises one or more mismatches relative to an oligonucleotide antisense strand. A mismatch can occur at an internal or terminal region of an oligonucleotide duplex; e.g., at an internal or terminal region of a duplex between an oligonucleotide of the present disclosure and a target nucleic acid; at an internal or terminal region of a duplex between sense and antisense strands of the present disclosure.

[0046] “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or intemucleoside linkage is modified. In certain embodiments, the compounds described herein comprise at least one modified oligonucleotide.

[0047] “Modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating SNCA RNA can mean to increase or decrease the level and / or activity of SNCA RNA and / or a-synuclein in a cell, tissue, organ or organism. A “modulator” effects the change in the cell, tissue, organ or organism. For example, a compound can be a modulator that decreases the amount and / or activity of SNCA RNA and / or a-synuclein in a cell, tissue, organ, plasma or organism.

[0048] “Motif’ means the pattern of unmodified and modified sugar moieties, nucleobases, and / or intemucleoside linkages, in an oligonucleotide.

[0049] “Nucleic acid” refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single- stranded nucleic acids, and double- stranded nucleic acids.

[0050] ‘ ‘Nucleobase” means a heterocyclic moiety capable of pairing with a base of another nucleic acid. As used herein a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). A “modified nucleobase” is a naturally 11#14696011vloccurring nucleobase that is chemically modified. A “universal base” or “universal nucleobase” is a nucleobase other than a naturally occurring nucleobase and modified nucleobase and is capable of pairing with any nucleobase.

[0051] ‘ ‘Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or intemucleoside linkage.

[0052] ‘ ‘Nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

[0053] “Oligomeric Compound” means a compound comprising one or more oligonucleotides and optionally one or more additional features, such as a conjugate group or terminal group. Examples of oligomeric compounds include single- stranded and double- stranded compounds, such as, oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA targeting oligonucleotides, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double- stranded compounds (e.g., short-interfering RNA (siRNA) and double- stranded RNA (dsRNA)) and single- stranded compounds (e.g., single- stranded siRNA (ssRNA), single- stranded RNAi (ssRNAi), short hairpin RNA (shRNA) and microRNA mimics) which work at least in part through the RNA-induced silencing complex (RISC) pathway resulting in sequence specific degradation and / or sequestration of a target nucleic acid through a process known as RNA interference (RNAi). The term “RNAi compound” is meant to be equivalent to other terms used to describe nucleic acid compounds that are capable of mediating sequencespecific RNA interference, for example, interfering RNA (iRNA), iRNA agent, RNAi agent, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, and others. Additionally, the term “RNAi” is meant to be equivalent to other terms used to describe sequence-specific RNA interference.

[0054] “Oligomeric duplex” refers to a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.” The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary 12#14696011vloverhanging nucleosides. In certain embodiments, the terms “duplexed oligomeric compound” and “modified oligonucleotide” are used interchangeably. In other embodiments, the terms “oligomeric duplex” and “compound” are used interchangeably.

[0055] “Oligonucleotide” means a polymer of linked nucleosides, each of which can be modified or unmodified, independent from one another.

[0056] ‘ ‘Parenteral administration” means administration through injection or infusion.Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration.

[0057] “Periphery” or “peripheral” refers to all cells, tissues, organs, organ systems, or other body parts (e.g., limbs) which are not part of the central nervous system (CNS). The CNS refers to parts of the nervous system which are enclosed in the meninges (i.e., dura mater, arachnoid mater, pia mater), including the brain and the spinal cord, as well as the retina, optic nerve, olfactory nerves, and the olfactory epithelium. Notably, blood vessels which supply the CNS, and peripheral nerves are considered part of the periphery.

[0058] “Pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent aids the administration of a compound to and absorption by an individual and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, and the like. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution, such as PBS or water-for-injection. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0059] “Pharmaceutically acceptable salt” refers to physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

[0060] As used herein, a pharmaceutically acceptable salt is any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. The pharmaceutically acceptable salts of the13#14696011vltherapeutic agents disclosed herein include salts that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds or modified oligonucleotides described herein.

[0061] When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.

[0062] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

[0063] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art.

[0064] Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2- naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4- methylbicyclo[2.2.2]-oct-2-ene- 1 -carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium or a potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium salt.

[0065] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The 14#14696011vlparent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0066] “Pharmaceutical agent” means a compound that provides a therapeutic benefit when administered to an individual.

[0067] “Phosphorothioate linkage” means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom.

[0068] “Portion” means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an oligonucleotide.

[0069] “Prevent” refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time.

[0070] ‘ ‘RNA interference compound” or “RNAi compound” means a compound that acts, at least in part, through an RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNase H, to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single- stranded siRNA, and microRNA, including microRNA mimics.

[0071] ‘ ‘Sense oligonucleotide” or “sense strand” means the strand of a double- stranded compound that includes a region that is substantially complementary to a region of the antisense strand of the compound.

[0072] “Specifically inhibit” with reference to a target nucleic acid or protein means to reduce or block expression or activity of the target nucleic acid or protein while minimizing or eliminating effects on non-target nucleic acids or proteins.15#14696011vl

[0073] ‘ ‘Subunit” with reference to an oligonucleotide means a nucleotide, nucleoside, nucleobase or sugar or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.

[0074] “Target nucleic acid,” “target RNA,” and “nucleic acid target” all mean a nucleic acid capable of being targeted by compounds described herein.

[0075] “Target region” means a portion of a target nucleic acid to which one or more compounds is targeted.

[0076] “Targeting moiety” refers to a conjugate group of a compound that provides preferential localization to a selected target, (e.g., a target molecule, cell or cell type, compartment such as a cellular compartment or organ compartment, tissue, organ, or region of the body), as compared to the same compound absent such a moiety. Targeting moieties may include lipids (or lipophilic moieties), ligands, and other compounds or molecular groups that functionally direct the compounds of the present invention to a selected target. In one embodiment, a targeting moiety may target to a selected target molecule, cell or cell type, or compartment. In another embodiment, a targeting moiety is a conjugate group that decreases, prevents, or excludes the conjugate group from binding to, passing through, or associating with a particular molecule, cell or cell type, or tissue compartment.

[0077] In certain embodiments, a targeting moiety provides preferential localization for a selected target by way of an enhanced affinity (e.g., binding affinity) of the compound for the selected target or portion thereof (e.g., a receptor on a target cell); for example, a targeting moiety can be considered to provide preferential localization to the CNS if it has high binding affinity for neurons, neurites, glial cells, and / or oligodendrocytes, for example. In certain embodiments, a targeting moiety provides preferential localization for a selected target by way of an enhanced stability of the compound (e.g., resistance to degradation in a target region of the body); for example, a targeting moiety can be considered to provide preferential localization to the lower intestine if it inhibits or decreases degradation of the compound by the acidic environment of the lower intestine. In certain embodiments, a targeting moiety provides preferential localization for a selected target by way of decreased localization of the compound to a non-target; for example, a targeting moiety can be considered to provide preferential localization to CNS if it is excluded from kidney and / or liver tissue. In certain embodiments, a targeting 16#14696011vlmoiety provides preferential localization for a selected target by way of decreased affinity (e.g., binding affinity) of the compound for a non-target; for example, a targeting moiety can be considered to provide preferential localization to CNS regions if it has decreased affinity for other organs.

[0078] ‘ ‘Terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

[0079] “Therapeutically effective amount” or “effective amount” means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual. A “therapeutically effective amount” or “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat, prevent or ameliorate a disease or reduce one or more symptoms of a disease or condition). An example of a “therapeutically effective amount” or “effective amount” is an amount sufficient to contribute to the treatment, prevention, amelioration, or reduction of a symptom or symptoms of a disease. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to provide a therapeutic benefit to an individual, such as treating, preventing or ameliorating the disease or disorder or symptom thereof, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.

[0080] “Treating” or “treatment” as used herein (and as well-understood in the art) broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not 17#14696011vllimited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms, fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, biochemical endpoints, and patient reported outcomes.

[0081] “Treating” and “treatment” as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. “Treat” refers to administering a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

[0082] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in 18#14696011vlracemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0083] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0084] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0085] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0086] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure (i.e., the R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0087] As used herein, “chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

[0088] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a19#14696011vlhydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or deenriched carbon are within the scope of this disclosure.

[0089] As used herein, “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the results of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate intemucleoside linkage.Certain Embodiments

[0090] In certain aspects, the disclosure relates to methods, compounds and compositions for inhibiting aSyn. In certain embodiments, aSyn is specifically inhibited. In certain embodiments, aSyn is specifically degraded. In certain embodiments, aSyn expression is inhibited. In certain embodiments, aSyn translation is inhibited. In certain embodiments, aSyn activity (e.g., aggregation, accumulation, and / or formation of aSyn inclusions (i.e., Lewy bodies)) is inhibited.

[0091] In certain embodiments, aSyn expression, translation, or activity is reduced by at least 10% relative to the expression, translation, or activity in an untreated or control sample. For example, in certain embodiments, aSyn expression, translation, or activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the expression, translation, or activity in an untreated or control sample.

[0092] In certain embodiments, aggregation and / or accumulation of aSyn protein (e.g., into aSyn inclusions) is reduced by at least 10% relative to aggregation and / or accumulation of aSyn protein in an untreated or control sample. For example, in certain embodiments, aggregation and / or accumulation of aSyn protein is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least20#14696011vl90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the aggregation and / or accumulation of aSyn protein in an untreated or control sample.

[0093] In certain embodiments, aSyn expression, translation, or activity in the CNS is reduced by less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95%, 10-50%, 10- 25%, 25-50%, 25-75%, 50-75%, 50-90%, or 75-95% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aSyn expression, translation, or activity in the CNS is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aggregation and / or accumulation of aSyn protein (e.g., into aSyn inclusions) in the CNS is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10- 50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the aggregation and / or accumulation of aSyn protein in an untreated or control sample.

[0094] In certain embodiments, aSyn expression, translation, or activity in the brainstem (e.g., midbrain) is reduced by less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95%, 10-50%, 10-25%, 25-50%, 25-75%, 50-75%, 50-90%, or 75-95% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aSyn expression, translation, or activity in the brainstem (e.g., midbrain) is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aggregation and / or accumulation of aSyn protein (e.g., into aSyn inclusions) in the brainstem (e.g., midbrain) is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50- 99%, or 75-99% relative to the aggregation and / or accumulation of aSyn protein in an untreated or control sample.21#14696011vl

[0095] In certain embodiments, aSyn expression, translation, or activity in the basal ganglia is reduced by less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95%, 10-50%, 10- 25%, 25-50%, 25-75%, 50-75%, 50-90%, or 75-95% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aSyn expression, translation, or activity in the basal ganglia is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aggregation and / or accumulation of aSyn protein (e.g., into aSyn inclusions) in the basal ganglia is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the aggregation and / or accumulation of aSyn protein in an untreated or control sample.

[0096] In certain embodiments, aSyn expression, translation, or activity in the limbic system (e.g., amygdala, hippocampus) is reduced by less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95%, 10-50%, 10-25%, 25-50%, 25-75%, 50-75%, 50-90%, or 75-95% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aSyn expression, translation, or activity in the limbic system (e.g., amygdala, hippocampus) is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10- 50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aggregation and / or accumulation of aSyn protein (e.g., into aSyn inclusions) in the limbic system (e.g., amygdala, hippocampus) is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the aggregation and / or accumulation of aSyn protein in an untreated or control sample.

[0097] In certain embodiments, aSyn expression, translation, or activity in the neocortex is reduced by less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95%, 10-50%, 10- 22#14696011vl25%, 25-50%, 25-75%, 50-75%, 50-90%, or 75-95% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aSyn expression, translation, or activity in the neocortex is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, aggregation and / or accumulation of aSyn protein (e.g., into aSyn inclusions) in the neocortex is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10- 50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the aggregation and / or accumulation of aSyn protein in an untreated or control sample.

[0098] In certain embodiments, aSyn expression, translation, or activity (e.g., aggregation) is reduced as measured by any suitable assay, including but not limited to, an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq).

[0099] In certain aspects, the disclosure relates to compounds targeted to an aSyn nucleic acid. In certain embodiments, the aSyn nucleic acid has the sequence set forth in SEQ ID NO: 1.

[0100] In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound is single- stranded. In certain embodiments, the compound is double- stranded.

[0101] Certain embodiments provide a compound comprising: a sense strand comprising a modified oligonucleotide; and an antisense strand forming a double-stranded region with the sense strand, where the antisense strand comprises a region of complementarity to an mRNA encoding aSyn or a domain thereof, and where the region of complementarity comprises at least 8 contiguous nucleobases differing by no more than 3 nucleobases from a nucleobase sequence that is fully complementary to the applicable region of SEQ ID NO: 1.

[0102] Certain embodiments provide a compound comprising a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39.23#14696011vl

[0103] Certain embodiments provide a compound comprising a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39.

[0104] Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39.

[0105] In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1. In certain embodiments, the modified oligonucleotide comprises at least one modification selected from a modified intemucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the compound is double- stranded.

[0106] Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide.

[0107] In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence provided in Tables 2 and 3, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide.

[0108] Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide.24#14696011vl

[0109] Certain embodiments provide a compound comprising a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

[0110] Certain embodiments provide a compound comprising a first modified oligonucleotide comprising a 5 '-phosphonate modification, where the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1, and a second modified oligonucleotide comprising one or more ligands described herein (e.g., one or more Tropomyosin receptor B (TrkB) ligands, one or more cannabinoid receptor type 1 (CBi) ligands, or one or more a.4 1 / 7 integrin ligands). In certain embodiments, the first modified oligonucleotide comprises a 5 '-terminal nucleoside comprising the 5'- phosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

[0111] In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68.25#14696011vl

[0112] In certain embodiments, the modified oligonucleotide or first modified oligonucleotide of any preceding compound has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity to SEQ ID NO: 1 over its length. In certain embodiments, the modified oligonucleotide or first modified oligonucleotide has at least 1, at least 2, at least 3 mismatches to a region of SEQ ID NO: 1. In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 14 to 30 linked nucleosides in length. In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 14 to 23 linked nucleosides in length. In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 19 to 23 linked nucleosides in length. In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0113] In certain embodiments, the modified oligonucleotide or first modified oligonucleotide of any preceding compound comprises at least one modification selected from a modified intemucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide of any preceding compound comprises at least one modification selected from the group consisting of a modified intemucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified intemucleoside linkage is a phosphorothioate intemucleoside linkage or a methylphosphonate intemucleoside linkage. In certain embodiments, the phosphorothioate intemucleoside linkage or methylphosphonate intemucleoside linkage is at the 3' terminus of the first or second modified oligonucleotide or at the 5' terminus of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar. In certain embodiments, the modified sugar comprises a 2'-F modification. In certain embodiments, the modified sugar comprises a 2'-OMe modification. In certain embodiments, each nucleoside of the first modified oligonucleotide comprises a modified sugar. In certain embodiments, each nucleoside of the second modified oligonucleotide 26#14696011vlcomprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar or a combination thereof. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2'-M0E, 2'-F, and 2'-0Me or a combination thereof. In certain embodiments, the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.Certain Conjugate Groups

[0114] In certain embodiments, the compound of any preceding embodiment comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more ligands selected from one or more Tropomyosin receptor B (TrkB) ligands, one or more cannabinoid receptor type 1 (CBi) ligands, and one or more a.4 1 / 7 integrin ligands. In certain embodiments, the targeting moiety comprises one or more TrkB ligands. In certain embodiments, the targeting moiety comprises one or more CBi ligands. In certain embodiments, the targeting moiety comprises one or more a.401 / 7 integrin ligands. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide. In certain embodiments, the one or more TrkB ligands is attached at the 5' or 3' end of the oligonucleotide, both the 5' and 3' ends of the oligonucleotide, to a terminal and / or interior base, and / or via intranucleosidic linkage. In certain embodiments, the one or more CBi ligands is attached at the 5' or 3' end of the oligonucleotide or both the 5' and 3' ends of the oligonucleotide. In certain embodiments, the one or more a40i / 7 integrin ligands is attached at the 5' or 3' end of the oligonucleotide or both the 5' and 3' ends of the oligonucleotide.

[0115] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (I) or a salt, solvate, or hydrate thereof:27#14696011vlL1-L2-L3-L4-R1R5R6Formula (I),wherein:R1is the modified oligonucleotide;L1, L2, L3, and L4are as described herein;R2is hydrogen, -OR7, -SR8, or -NR9R10;R3is hydrogen, -OR11, -SR12, or -NR13R14;R4is hydrogen, -OR15, -SR16, or -NR17R18;R5is hydrogen, -OR19, -SR20, or -NR21R22;R6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =0;R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;Y is CH2, NH, S, or O; andZ is optionally substituted aryl or optionally substituted heteroaryl.

[0116] In certain embodiments, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22are each independently optionally substituted unsaturated or partially unsaturated alkyl. In certain embodiments, R7, R8, R9, and R10are each independently alkenyl. In certain embodiments, R7, R8, R9, and R10are each independently alkynyl.

[0117] In certain embodiments, R2is OR7. In certain embodiments, R3is OR11. In certain embodiments, R7and R11are each independently hydrogen, optionally substituted alkyl or

[0118] optionally substituted alkenyl. In certain embodiments, one or both R7and R11are each independently hydrogen. In certain embodiments, one or both R7and R11are each independently optionally substituted alkyl. In certain embodiments, one or both R7and R11are each independently optionally substituted unsaturated or partially unsaturated alkyl. In certain embodiments, one or both R7and R11are each independently alkenyl. In certain embodiments, R7is optionally substituted alkyl and R11is hydrogen. In certain#14696011vlembodiments, R7is hydrogen and R11is optionally substituted alkyl. In certain embodiments, R7is alkenyl and R11is hydrogen. In certain embodiments, R7is hydrogen and R11is optionally substituted alkenyl.

[0119] In certain embodiments, the TrkB ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:Formula (II-A),OFormula (II-B),OFormula (II-C),wherein:R1is the modified oligonucleotide; andL1, L2, L3, L4, and R1are as described herein.

[0120] In certain embodiments, the TrkB ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:OFormula (II-D),29#14696011vlFormula (II-F),wherein:R1is the modified oligonucleotide; andL1, L2, L3, L4, and R1are as described herein.

[0121] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (XXXXXVII) or a salt, solvate, or hydrate thereof:wherein:L1, L2, L3, L4, and R1are as described herein;R11and R13are each independently absent, hydrogen, or optionally substituted alkyl; R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;#14696011vlR16is hydrogen, halogen, -CN, -N3, -SOn16R16A, -SO2NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, -N(0)mi6, -NR16BR16C, -C(O)R16D, -C(O)OR16D, -C(O)NR16BR16C, -OR16A, -NR16BSO2R16A, -NR16BC(O)R16D, -NR16BC(O)OR16D, -NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;3 b s and — are each independently a single bond or a double bond, wherein if = is b b a single bond, then is a double bond and R13is absent; and further wherein if — is a single bond, thenis a double bond and R11is absent;R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, -CF3, -CCl3,-CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;z3 is 0, 1, 2, 3, 4, or 5;nl6 is 0, 1, 2, 3, or 4; andvl6 and ml6 are each independently 1 or 2.

[0122] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (XXXXXIX) or a salt, solvate, or hydrate thereof:R17\N—4F(R18)Z4_L _ _ I 1_i 2_i 3_i 4 _ p1wHO (R19)Z5Formula (XXXXXIX),wherein:L1, L2, L3, L4, and R1are as described herein;31#14696011vlR17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;z4 is 0, 1, or 2; andz5 is 0, 1, 2, or 3.

[0123] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (XXXXXX) or a salt, solvate, or hydrate thereof:(R21)Z7(R20)Z6^ AIAKJR22)Z8C J - L1-L2-L3-L4-R11R23^R24Formula (XXXXXX),wherein:L1, L2, L3, L4, and R1are as described herein;R20is hydrogen, halogen, -CN, -N3, -SOn20R1A, -SOV2oNR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C, -N(O)m20, -NR20BR20C, -C(O)R20D, -C(O)OR20D, -C(O)NR20BR20C, -OR20A, -NR20BSO2R20A, -NR20BC(O)R20D, -NR20BC(O)OR20D, -NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R21is hydrogen, halogen, -CN, -N3, -SOn2iR1A, -SOV2INR21BR21C, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21c, -NHC(O)NR21BR21c, -N(O)m2i, -NR21BR21C, -C(O)R21D, -C(O)OR21D, -C(O)NR21BR21c, -OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, -NR21BC(O)OR21D, -NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;32#14696011vlR24is hydrogen, halogen, -CN, -N3, -SOn24R24A, -SOv24NR24BR24C, -NHNR24BR24C, -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, -N(O)m24, -NR24BR24C, -C(O)R24D, -C(O)OR24D, -C(O)NR24BR24C, -OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, -NR24BC(O)OR24D, -NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R20A,R20B,R20CR20DR21AR21B,R21CR21 DR24AR24B,R24Cand R24Dafe eachindependently hydrogen, halogen, -CF3, -CCI3, -CB13, -CI3 -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2°B, R20C, R21B, R21C, R24B, R24C, R24B, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;n21, n22, n24, z6 and z8 are each independently 0, 1, 2, 3, or 4;v20, v21, v24, m20, m21, and m24 are each independently 1 or 2; andz7 is 0, 1, or 2.

[0124] In certain embodiments, the CBi ligand of a modified oligonucleotide is of the Formula (XXXXXXI) or a salt, solvate, or hydrate thereof:wherein:L1, L2, L3, L4, and R1are as described herein;X1is NR10or CRnR12;R10, R11, and R12are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;33#l4696011vlR19is hydrogen, -SOni9R19A, -SOvi9NR19BR19C, -NHNR19BR19C, -ONR19BR19C, -NHC(O)NHNR19BR19C, -NHC(O)NR19BR19C, -NR19BR19C, -C(O)R19D, -C(O)OR19D, -C(O)NR19BR19C, -OR19A, -NR19BSO2R19A, -NR19BC(O)R19D, -NR19BC(O)OR19D, -NR19BOR19D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R19A, R19B, R19C, R19Dare each independently hydrogen, halogen, -CF3, -CCI3, -CBr?, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R19Band R19Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;nl9 is 0, 1, 2, 3, or 4; andvl9 is 1 or 2.

[0125] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXII) or a salt, solvate, or hydrate thereof:NNcrR'oO^OH IINFormula (XXXXXXII),wherein:L1, L2, L3, L4, and R1are as described herein;R2is H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl; andR3, and R4are each independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl.

[0126] In certain embodiments, the a.401 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXIII) or a salt, solvate, or hydrate thereof:#14696011vlH— £ - N L1-L2-L3-L4-R1O R-Formula (XXXXXXIII),wherein:L1, L2, L3, L4, and R1are as described herein;R2, R3, R4, and R5are each independently H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl, or absent;R8is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-Ce)-cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; andR6, and R7are each independently H, halogen, alkyl, or optionally substituted alkyl,optionally substituted heteroalkyl, F

[0127] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXIV) or a salt, solvate, or hydrate thereof:xFormula (XXXXXXIV),wherein:L1, L2, L3, L4, and R1are as described herein;35#14696011vlR2is H, -CONHR4, -CH2OR4, -(CH2)2OR4, -CH2NHCOR4, or -OR4;R3is H, optionally substituted alkyl, or optionally substituted cycloalkyl;R4is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;R5is -OH or absent; andX is H, optionally substituted CH2, optionally substituted NH, or cycloalkyl.

[0128] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXXXIII) or a salt, solvate, or hydrate thereof:N N NH HFormula (XXXXXXXXIII)wherein:L1, L2, L3, L4, and R1are as described herein;R2is H, -CONHR3, -CH2OR3, -(CH2)2OR3, -CH2NHCOR3, or -OR3;each instance of R3is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; andX is H or halogen.

[0129] In certain embodiments, L1, L2, L3, and L4are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker.

[0130] In certain embodiments, L1is an optionally substituted heteroaryl linker.

[0131] In certain embodiments, L1is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.#14696011vl

[0132] In certain embodiments, L1comprises the structure:?.

[0133] In certain embodiments, L1is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or optionally substituted Ci-Cio alkyl chain in which one or more carbon atoms are replaced with O, N, or S.

[0134] In certain embodiments, L1comprises the structure:or1

[0135] In certain embodiments, L comprises the structure:or -N(CH3)-.

[0136] In certain embodiments, L2is an optionally substituted PEG linker.

[0137] In certain embodiments, the PEG linker is five PEG units in length. In certain embodiments, the PEG linker is four PEG units in length. In certain embodiments, the PEG linker is three PEG units in length.

[0138] In certain embodiments, L2is an optionally substituted alkyl linker. In certain embodiments, L2is an optionally substituted C1-20 alkyl linker. In certain embodiments, L2is an optionally substituted Cs alkyl linker. In certain embodiments, L3is an optionally substituted heteroaryl linker.

[0139] In certain embodiments, L3is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

[0140] In certain embodiments, L3comprises the structure:

[0141] In certain embodiments, L3comprises the structure:#14696011vl

[0142] In certain embodiments, L4is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments, L4is an optionally substituted alkyl linker.

[0143] In certain embodiments, the heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring.

[0144] In certain embodiments, L4comprises the structure:

[0145] In certain embodiments, L4comprises the structure:HNwherein X is O or S.

[0146] In certain embodiments, L1- L2-L3-L4comprises the structure:#14696011vlIATT0969VT#6£oTAllO969tzl#OizTAllO969tzl#It7or a salt thereof, wherein X is O or S.42#14696011vl

[0147] In certain embodiments, the TrkB ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:X = O or S Formula (IV), BA-118X = O or S Formula (V),#14696011vlFormula (VI)Formula (VII),Formula (VIII),Formula (IX),44#14696011vlFormula (XI),Formula (XII),45#14696011vlFormula (XV),Formula (XVI),46#14696011vlFormula (XVII),Formula (XVIII),o Formula (XIX),Formula (XX),47#14696011vlBA-169Formula (XXII),BA- 170: mixture of isomers Formula (XXIII),#14696011vlBA-173Formula (XXIV),#14696011vl.0BA-203 Formula (XXVII),BA-196 Formula (XXIX),BA-197 Formula (XXX),Ri O IO-P-OH50#14696011vlo..0.OMe BA-225 Formula (XXXIII), BA-246 Formula (XXXIV),#14696011vlOH Formula (XXXXXXVII),OFormula (XXXXXXIX),Formula (XXXXXXX),#14696011vlFormula (XXXXXXXII),Formula (XXXXXXXIII), and53#14696011vloFormula (XXXXXXXXVII)wherein:R is the modified oligonucleotide; andX is S or O.

[0148] In certain embodiments, the modified oligonucleotide or a salt, solvate, or hydrate thereof comprises Formula (III-A):Formula (III-A).

[0149] In certain embodiments, the CBi ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof#14696011vlFormula (XXXXXXXIV),Formula (XXXXXXXV),Formula (XXXXXXXVII), and55#14696011vlFormula (XXXXXXXVIII),wherein:R is the modified oligonucleotide; andX is S or O.

[0150] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:Formula (XXXXXXXIX),Formula (XXXXXXXX),56#14696011vlFormula (XXXXXXXXI),OHR-O-P=x Formula (XXXXXXXXII), and#14696011vlFormula (XXXXXXXXIV),wherein:R is the modified oligonucleotide; andX is S or O.

[0151] In certain embodiments, the compound of any preceding embodiment comprises a lipid. In certain embodiments, the lipid is attached to an intemucleoside linkage of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more lipids. In certain embodiments, the one or more lipids are attached to one or more intemucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide.

[0152] In certain embodiments, the compound of any preceding embodiment comprises one or more substituted or unsubstituted alkyl or alkenyl. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl is attached to an intemucleoside linkage of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl are attached to one or more intemucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide.

[0153] In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C4-C30 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C5-C20 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C14-C20 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Ci6 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C17 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Cis hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C22 hydrocarbon chain.58#14696011vl

[0154] In certain embodiments, a substituted or unsubstituted alkyl or alkenyl is attached to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the internucleoside linkage is between nucleosides that are within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) from a terminal end (e.g., the 5' and / or 3' end) of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides that are within 5 positions from the 5' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between nucleosides that are within 5 positions from the 3' end of the modified oligonucleotide.

[0155] In certain embodiments, the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 2 and 3 from the 3' end of the modified oligonucleotide.

[0156] In certain embodiments, the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI.59#14696011vl

[0157] In certain embodiments, the modified oligonucleotide comprises Formula (XXXV), or a salt, solvate, or hydrate thereof:Q3Q4— o' R3Formula (XXXV),wherein:Y is -C(=O)N(Rc)-, or -N(Rc)C(=O)-;Q1and Q3are each independently -H, -OR4, a ligand, a linker, or a lipid;Rcis independently -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl;each R9is independently a substituted or unsubstituted heteroaryl;each instance of Z1or Z2is independently a bond, Ci-Ce alkylene, or C2-C6 alkenylene; and#14696011vleach X is independently O or S;or a salt thereof.

[0158] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVI), or a salt, solvate, or hydrate thereof:O'© R3X. P<°AOR5Formula (XXXVI),wherein:Rcis -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.61#14696011vl

[0159] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVII), or a salt, solvate, or hydrate thereof:Formula (XXXVII),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0160] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVIII), or a salt, solvate, or hydrate thereof:62#14696011vlFormula (XXXVIII),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0161] In certain embodiments, the modified oligonucleotide comprises Formula (XXXIX), or a salt, solvate, or hydrate thereof:#14696011vlFormula (XXXIX),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0162] In certain embodiments, the modified oligonucleotide comprises Formula (XXXX), or a salt solvate, or hydrate thereof:64#14696011vlFormula (XXXX),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0163] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXI), or a salt, solvate, or hydrate thereof:65#14696011vl00'0 (DMe. P<°OR5mUemUFormula (XXXXI),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0164] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXII), or a salt, solvate, or hydrate thereof:Cf 0 t)MeAOR5mAemAFormula (XXXXII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.66#14696011vl

[0165] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXIII), or a salt, solvate, or hydrate thereof:O' 0 OMeY-P<0XOR5mAemUFormula (XXXXIII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0166] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXIV), or a salt, solvate, or hydrate thereof:0 \ OMe0NH NH2O' 0 OMeXOR5mAemGFormula (XXXXIV),wherein:#14696011vlR4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0167] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXV), or a salt, solvate, or hydrate thereof:cf © t> MeX^P<°AOR5mAemCFormula (XXXXV),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0168] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVI), or a salt, solvate, or hydrate thereof:cf © t)MeXOR5mUemAFormula (XXXXVI),68#14696011vlwherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0169] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVII), or a salt, solvate, or hydrate thereof:Od G t)MeAOR5mUemGFormula (XXXXVII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0170] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVIII), or a salt, solvate, or hydrate thereof:0mUefC69#14696011vlFormula (XXXXVIII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0171] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXIX), or a salt, solvate, or hydrate thereof:ocf © t)MeY'P<°AOR5fGemUFormula (XXXXIX),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0172] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXX), or a salt, solvate, or hydrate thereof:70#14696011vlOmGefGFormula (XXXXX),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0173] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXXI), or a salt, solvate, or hydrate thereof:ONHzt)MeiP<°OR5mGemCFormula (XXXXXI),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.71#14696011vl

[0174] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXXII), or a salt, solvate, or hydrate thereof:O' © t)MeX"XOR5mCemAFormula (XXXXXII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0175] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXXXXXVI), or a salt, solvate, or hydrate thereof:cf © bMeAOR5mCemUFormula (XXXXXXXXVI),72#14696011vlwherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0176] In certain embodiments, the modified oligonucleotide comprises an internucleoside linkage of one of the following Formulae:Formula (XXXXXIII), Formula (XXXXXIV),Formula (XXXXXV),5' Formula (XXXXXVI).

[0177] In certain embodiments, the compound of any preceding embodiment comprises a 5'- phosphonate modification. For example, in certain embodiments, a modified oligonucleotide comprises one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'- phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5 '-terminal nucleoside (e.g., 5' terminus) comprising the 5 '-phosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'- vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'-ethylenephosphonate modification. In certain embodiments, the modified oligonucleotide is the first modified oligonucleotide or antisense oligonucleotide.73#14696011vl

[0178] Certain embodiments provide a compound comprising: a first modified oligonucleotide comprising a 5 '-phosphonate modification, where the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1; and a second modified oligonucleotide comprising one or more ligands.

[0179] In some embodiments, the first modified oligonucleotide comprises a 5 '-terminal nucleoside comprising the 5 '-phosphonate modification. In some embodiments, the 5'- phosphonate modification is a 5'-vinylphosphonate modification or a 5'- ethylenephosphonate modification. In some embodiments, the 5 '-phosphonate modification is a 5'-vinylphosphonate modification. In some embodiments, the 5'- phosphonate modification is a 5'-ethylenephosphonate modification.

[0180] In some embodiments, the second modified oligonucleotide comprises one or more ligands selected from one or more TrkB ligands, one or more CBi ligands, and one or more a.4 1 / 7 integrin ligands. In some embodiments, the one or more TrkB ligands, the one or more CBi ligands, or the one or more a.401 / 7 integrin ligands are attached to the 5' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands, the one or more CBi ligands, or the one or more ai 1 / ? integrin ligands are attached to the 3' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands, the one or more CBi ligands, or the one or more ai 1 / ? integrin ligands are attached to the 5' end and the 3' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands are selected from any one of Formulae I-XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, xxxxxxxxv, XXXXXXXXVII, and one of the structures of Table 1 (e.g., B18, B27, B28); the one or more CBi ligands are selected from any one of Formulae XXXXXXI and XXXXXXXIV- XXXXXXXVIII; and the one or more ai 1 / ? integrin ligands are selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.

[0181] In some embodiments, the second modified oligonucleotide comprises one or more TrkB ligands. In some embodiments, the one or more TrkB ligands are selected from any one of Formulae I-XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX- XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, xxxxxxxxv, XXXXXXXXVII, and one of the structures of Table 1 (e.g., B18, B27, B28). In some embodiments, the one or more TrkB ligands are selected from any one of Formulae HI- 74#14696011vlVIII, XXIX-XXXI, XXXXXXV, and XXXXXXXXVII. In some embodiments, the one or more TrkB ligands are selected from any one of Formulae III- VIII, XXIX-XXXI, XXXXXXV, XXXXXXXXVII, and one of the structures of Table 1 (e.g., Bl 8, B27, B28). In some embodiments, the one or more TrkB ligands are selected from any one of the structures of Table 1 (e.g., B18, B27, B28). In some embodiments, the second modified oligonucleotide comprises one TrkB ligand. In some embodiments, the second modified oligonucleotide comprises two TrkB ligands. In some embodiments, the second modified oligonucleotide comprises at least two TrkB ligands. In some embodiments, the at least two TrkB ligands are the same. In some embodiments, the at least two TrkB ligands are different.

[0182] In some embodiments, the second modified oligonucleotide comprises one or more CBi ligands. In some embodiments, the one or more CBi ligands are selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII. In some embodiments, the one or more CBi ligands are selected from any one of Formulae XXXXXXXIV-XXXXXXXVI. In some embodiments, the second modified oligonucleotide comprises one CBi ligand. In some embodiments, the second modified oligonucleotide comprises two CBi ligands. In some embodiments, the second modified oligonucleotide comprises at least two CBi ligands. In some embodiments, the at least two CBi ligands are the same. In some embodiments, the at least two CBi ligands are different.

[0183] In some embodiments, the second modified oligonucleotide comprises one or more a.4 1 / 7 integrin ligands. In some embodiments, the one or more c 01 / ? integrin ligands are selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX- XXXXXXXXIV. In some embodiments, the one or more 0401 / 7 integrin ligands are selected from any one of Formulae XXXXXXXXI, XXXXXXXXII, and XXXXXXXXIV. In some embodiments, the second modified oligonucleotide comprises one ct,401 / 7 integrin ligand. In some embodiments, the second modified oligonucleotide comprises two a.401 / 7 integrin ligands. In some embodiments, the second modified oligonucleotide comprises at least two a40i / 7 integrin ligands. In some embodiments, the at least two a40i / 7 integrin ligands are the same. In some embodiments, the at least two c / 4 1 / ? integrin ligands are different.75#14696011vl

[0184] In some embodiments, the second modified oligonucleotide comprises one or more lipids. In some embodiments, the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C4- C30 hydrocarbon chain. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C5-C20 hydrocarbon chain. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C14-C20 hydrocarbon chain. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Ci6 hydrocarbon chain, a saturated or unsaturated C17 hydrocarbon chain, a saturated or unsaturated Cis hydrocarbon chain, or a saturated or unsaturated C22 hydrocarbon chain.

[0185] In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl are attached to an internucleoside linkage of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides that are within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) from a terminal end (e.g., the 5' and / or 3' end) of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides that are within 5 positions from the 5' end of the second modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between nucleosides that are within 5 positions from the 3' end of the second modified oligonucleotide.

[0186] In certain embodiments, the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 from the 5' end of the second modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 5' end of the second modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 2 and 3 from the 5' end of the second modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 376#14696011vland 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 from the 3' end of the second modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 3' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between positions 2 and 3 from the 3' end of the second modified oligonucleotide.

[0187] In some embodiments, the intemucleoside linkage of the second modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI. In some embodiments, the second modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI.

[0188] In some embodiments, the first modified oligonucleotide is 14 to 30 linked nucleosides in length. In some embodiments, the second modified oligonucleotide is 14 to 30 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In some embodiments, the first modified oligonucleotide has a nucleobase sequence comprising at least 14 contiguous nucleobases of any one of SEQ ID NOs: 11-39. In some embodiments, the second modified oligonucleotide has a nucleobase sequence comprising at least 14 contiguous nucleobases of any one of SEQ ID NOs: 40-68. In some embodiments, the first modified oligonucleotide is selected from any one of the IA Ref ID NOs in Table 3. For example, in some embodiments, the first modified oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 71- 99. In some embodiments, the second modified oligonucleotide is selected from any one of the IS Ref ID NOs in Table 3. For example, in some embodiments, the second modified oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 100- 137.

[0189] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of Ref ID NOs listed in Table 3 and a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide.

[0190] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 71-99,77#14696011vland a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide.

[0191] Certain embodiments provide a compound comprising a first modified oligonucleotide and a second modified oligonucleotide, where the second modified oligonucleotide is selected from the group consisting of SEQ ID NOs: 100-137, and the first modified oligonucleotide is 14 to 21 linked nucleosides in length fully complementary to the second modified oligonucleotide.

[0192] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 71-99, and / or a second modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 100-137.

[0193] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 71-99, and a second modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 100-137. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 71, and the second modified oligonucleotide comprises SEQ ID NO: 100. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 72, and the second modified oligonucleotide comprises SEQ ID NO: 101. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 73, and the second modified oligonucleotide comprises SEQ ID NO: 102. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 74, and the second modified oligonucleotide comprises SEQ ID NO: 103. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 75, and the second modified oligonucleotide comprises SEQ ID NO: 104. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 76, and the second modified oligonucleotide comprises SEQ ID NO: 105. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 77, and the second modified oligonucleotide comprises SEQ ID NO: 106. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 78, and the second modified oligonucleotide comprises SEQ ID NO: 107. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 79, and the second modified oligonucleotide comprises SEQ ID NO: 108. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 80, and the second modified oligonucleotide 78#14696011vlcomprises SEQ ID NO: 109. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 81, and the second modified oligonucleotide comprises SEQ ID NO: 110. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 82, and the second modified oligonucleotide comprises SEQ ID NO: 111. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 83, and the second modified oligonucleotide comprises SEQ ID NO: 112. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 84, and the second modified oligonucleotide comprises SEQ ID NO: 113. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 85, and the second modified oligonucleotide comprises SEQ ID NO: 114. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 86, and the second modified oligonucleotide comprises SEQ ID NO: 115. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 87, and the second modified oligonucleotide comprises SEQ ID NO: 116. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 88, and the second modified oligonucleotide comprises SEQ ID NO: 117. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 89, and the second modified oligonucleotide comprises SEQ ID NO: 118. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 90, and the second modified oligonucleotide comprises SEQ ID NO: 119. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 91, and the second modified oligonucleotide comprises SEQ ID NO: 120. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 92, and the second modified oligonucleotide comprises SEQ ID NO: 121. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 93, and the second modified oligonucleotide comprises SEQ ID NO: 122. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 94, and the second modified oligonucleotide comprises SEQ ID NO: 123. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 95, and the second modified oligonucleotide comprises SEQ ID NO: 124. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 96, and the second modified oligonucleotide comprises SEQ ID NO: 125. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 97, and the second modified oligonucleotide comprises SEQ ID NO: 126. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 98, and the 79#14696011vlsecond modified oligonucleotide comprises SEQ ID NO: 127. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 99, and the second modified oligonucleotide comprises SEQ ID NO: 128. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 92, and the second modified oligonucleotide comprises SEQ ID NO: 129. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 94, and the second modified oligonucleotide comprises SEQ ID NO: 130. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 94, and the second modified oligonucleotide comprises SEQ ID NO: 131. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 92, and the second modified oligonucleotide comprises SEQ ID NO: 132. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 76, and the second modified oligonucleotide comprises SEQ ID NO: 133. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 81, and the second modified oligonucleotide comprises SEQ ID NO: 134. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 83, and the second modified oligonucleotide comprises SEQ ID NO: 135. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 84, and the second modified oligonucleotide comprises SEQ ID NO: 136. In some embodiments, the first modified oligonucleotide comprises SEQ ID NO: 82, and the second modified oligonucleotide comprises SEQ ID NO: 137.

[0194] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs listed in Table 3 (SEQ ID NOs: 71-99) and a second modified oligonucleotide selected from the group consisting of any one of the IS Ref ID NOs listed in Table 3 (SEQ ID NOs: 100- 137). In certain embodiments, the second modified oligonucleotide comprises any one or more TrkB ligands provided herein. In certain embodiments, the TrkB ligand is selected from Formulae I-XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX- XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, xxxxxxxxv, and XXXXXXXXVII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the TrkB ligand is selected from Formulae III- VIII, XXIX-XXXI, XXXXXXV, and XXXXXXXXVII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the TrkB ligand through a phosphodiester group. In certain 80#14696011vlembodiments, the modified oligonucleotide is attached to the TrkB ligand through a phosphorothioate group. In certain embodiments, provided herein is a compound selected from the group consisting of any one of the compounds listed in Table 3.

[0195] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs listed in Table 3 (SEQ ID NOs: 71-99) and a second modified oligonucleotide selected from the group consisting of any one of the IS Ref ID NOs listed in Table 3 (SEQ ID NOs: 100- 137). In certain embodiments, the second modified oligonucleotide comprises any one or more CBi ligands provided herein. In certain embodiments, the CBi ligand is selected from Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the CBi ligand is selected from Formulae XXXXXXXIV-XXXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the CBi ligand through a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the CBi ligand through a phosphorothioate group. In certain embodiments, provided herein is a compound selected from the group consisting of any one of the compounds listed in Table 3.

[0196] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs listed in Table 3 (SEQ ID NOs: 71-99) and a second modified oligonucleotide selected from the group consisting of any one of the IS Ref ID NOs listed in Table 3 (SEQ ID NOs: 100- 137). In certain embodiments, the second modified oligonucleotide comprises any one or more a.4 1 / 7 integrin ligands provided herein. In certain embodiments, the a.401 / 7 integrin ligand is selected from Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX- XXXXXXXXIV, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the a.401 / 7 integrin ligand is selected from Formulae XXXXXXXXI, XXXXXXXXII, and XXXXXXXXIV, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the a40i / 7 integrin ligand through a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the a40i / 7 integrin ligand through a phosphorothioate group. In certain embodiments, provided 81#14696011vlherein is a compound selected from the group consisting of any one of the compounds listed in Table 3.

[0197] In certain embodiments, the pharmaceutically acceptable salt of the modified oligonucleotides provided herein is a sodium salt or a potassium salt. In certain embodiments, the pharmaceutically acceptable salt of the compounds provided herein is a sodium salt or a potassium salt.

[0198] In certain embodiments, provided herein is a population of modified oligonucleotides, wherein all of the phosphorothioate intemucleoside linkages of the modified oligonucleotide are stereorandom. In certain embodiments, provided herein is a population of compounds, wherein all of the phosphorothioate intemucleoside linkages of the modified oligonucleotide are stereorandom.

[0199] In certain embodiments, the compound of any foregoing embodiment is in a pharmaceutically acceptable salt form. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt.

[0200] Certain embodiments provide a composition comprising the compound of any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0201] Certain embodiments provide a composition comprising a compound of any preceding embodiment, for use in therapy.

[0202] Certain embodiments provide a method of treating, preventing, or ameliorating a disease, disorder or condition associated with aSyn in an individual comprising administering to the individual a compound targeted to aSyn, thereby treating, preventing, or ameliorating the disease.

[0203] In certain embodiments, the compound or composition of any foregoing embodiment is administered to an individual. In certain embodiments, the disease, disorder or condition is a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, such as a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy,82#14696011vltuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt- Jakob disease. In certain embodiments, the disease, disorder or condition is Parkinson’s disease. In certain embodiments, the disease, disorder or condition is multiple system atrophy (MSA). In certain embodiments, the disease, disorder or condition is Lewy body dementia (LBD).

[0204] In certain embodiments, administering the compound inhibits or reduces or improves a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt-Jakob disease. In certain embodiments, administering the compound inhibits or reduces or improves Parkinson’s disease. In certain embodiments, administering the compound inhibits or reduces or improves multiple system atrophy (MSA). In certain embodiments, administering the compound inhibits or reduces or improves Lewy body dementia (LBD).

[0205] In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual in a therapeutically effective amount. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg / kg of body weight of the individual. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the compound or composition is administered to the individual one or more times in a day up to the dosage level or fixed dose.83#14696011vl

[0206] In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual daily, weekly, monthly, quarterly or yearly. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per quarter (i.e., once every three months) to about once per year. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per quarter, about once every six months or about once per year.

[0207] Certain embodiments provide a method of inhibiting expression of aSyn in a cell comprising contacting the cell with a compound targeted to aSyn, thereby inhibiting expression of aSyn in the cell. In certain embodiments, the cell is in the CNS of an individual (e.g., neurons, neurites, glial cells, oligodendrocytes). In certain embodiments, the cell is in the peripheral nervous system of an individual (e.g., nerves, autonomic ganglia, sympathetic ganglia, and / or postganglionic nerve fibers). In certain embodiments, the individual has, or is at risk of having, a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico- Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt- Jakob disease.

[0208] Certain embodiments provide a method of reducing or inhibiting a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease in an individual, comprising administering a compound targeted to aSyn to the individual, thereby reducing or inhibiting a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a 84#14696011vlsymptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt-Jakob disease in the individual. In certain embodiments, the individual has, or is at risk of having, a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico- Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt- Jakob disease. In certain embodiments, the compound is a compound targeted to aSyn. In certain embodiments, the compound is any of the foregoing compounds. In certain embodiments, the compound or composition is administered parenterally. In certain embodiments, the compound or composition is administered by intracerebroventricular (ICV) administration.

[0209] Certain embodiments provide use of a compound targeted to aSyn for treating, preventing, or ameliorating a disease, disorder or condition associated with aSyn. In certain embodiments, the disease, disorder or condition is a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico- Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma,85#14696011vlgangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt- Jakob disease. In certain embodiments, the compound is a compound targeted to aSyn. In certain embodiments, the compound is any of the foregoing compounds.

[0210] Certain embodiments provide use of a compound targeted to aSyn in the manufacture of a medicament for treating, preventing, or ameliorating a disease, disorder or condition associated with aSyn. In certain embodiments, the disease, disorder or condition is a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt-Jakob disease. In certain embodiments, the compound is a compound targeted to aSyn. In certain embodiments, the compound is any of the foregoing compounds.

[0211] In certain embodiments, any one of the compounds shown in FIG. 1, Table 2, and Table 3 can be used in any aspect of the disclosure. In some embodiments of a compound, composition, method, or use of the disclosure, the compound is any one of the compounds shown in FIG. 1, Table 2, and Table 3.

[0212] In certain embodiments, any one of the compounds shown in FIG. 1 or Table 3 can be used in any aspect of the disclosure. In some embodiments of a compound, composition, method, or use of the disclosure, the compound is any one of the compounds shown in FIG. 1 or Table 3.86#14696011vl

[0213] In certain embodiments, any one of the compounds in Table 2 can be used in any aspect of the disclosure. In some embodiments of a compound, composition, method, or use of the disclosure, the compound is any one of the compounds in Table 2.

[0214] In certain embodiments, any one of the compounds in Table 3 can be used in any aspect of the disclosure. In some embodiments of a compound, composition, method, or use of the disclosure, the compound is any one of the compounds in Table 3.

[0215] In certain embodiments, any one of the compounds in Table 3 can be used in any aspect of the disclosure. In some embodiments of a compound, composition, method, or use of the disclosure, the compound is any one of the compounds in Table 3. In some embodiments, the 5'-Ligand and / or the 3'-Ligand are attached to the sense strand via a linker. In some embodiments, the linker comprises polyethylene glycol (PEG). In some embodiments, the linker comprises a PEG chain of one, two, three, four, five, six, seven, or eight PEG units in length. In certain embodiments, the linker comprises a PEG chain one PEG unit in length. In certain embodiments, the linker comprises a PEG chain two PEG units in length. In certain embodiments, the linker comprises a PEG chain three PEG units in length. In certain embodiments, the linker comprises a PEG chain four PEG units in length. In certain embodiments, the linker comprises a PEG chain five PEG units in length. In certain embodiments, the linker comprises a PEG chain six PEG units in length. In certain embodiments, the linker comprises a PEG chain seven PEG units in length. In certain embodiments, the linker comprises a PEG chain eight PEG units in length. In some embodiments, the linker comprises an optionally substituted heteroaryl or optionally substituted heterocyclyl group. In certain embodiments, the linker comprises PEG and an optionally substituted heteroaryl or optionally substituted heterocyclyl group.Certain Indications

[0216] In certain aspects, the disclosure relates to methods of inhibiting aSyn expression, which can be useful for treating, preventing, or ameliorating a disease associated with aSyn in an individual, by administration of a compound that targets aSyn. In certain embodiments, the compound can be a SNCA specific inhibitor. In certain embodiments, the compound can be an antisense oligonucleotide, an oligomeric compound, or an oligonucleotide targeted to aSyn (e.g., a compound of any one of the compounds shown in FIG. 1, Table 2, and Table 3).87#14696011vl

[0217] In certain aspects, the disclosure relates to treating, preventing, or ameliorating a disease, disorder or condition associated with aSyn. In certain embodiments, diseases, disorders or conditions associated with aSyn treatable, preventable, and / or ameliorable with the methods provided herein include a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, and / or Creutzfeldt- Jakob disease. Certain compounds provided herein are directed to compounds and compositions that reduce a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease in an animal.

[0218] In certain embodiments, a method of treating, preventing, or ameliorating a disease associated with aSyn in an individual comprises administering to the individual a compound comprising a SNCA specific inhibitor, thereby treating, preventing, or ameliorating the disease. In certain embodiments, the individual is identified as having, or at risk of having, a disease associated with aSyn. In certain embodiments, the disease is a CNS related disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides) in length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain88#14696011vlembodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing embodiments, the compound can be single- stranded or double- stranded. In certain embodiments, a single- stranded compound can be 14 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16, linked nucleosides in length. In certain embodiments, a single- stranded compound can be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, linked nucleosides in length. In certain embodiments, a double- stranded compound can comprise two oligonucleotides of the same or different lengths, as described elsewhere herein. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at 89#14696011vlleast 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intracerebroventricular (ICV) administration. In certain embodiments, administering the compound improves, preserves, or prevents a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease in an animal.

[0219] In certain embodiments, a method of treating, preventing, or ameliorating a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease in an animal comprises administering to the individual a compound comprising a SNCA specific inhibitor, thereby treating, preventing, or ameliorating a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body 90#14696011vldementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing embodiments, the compound can be single- stranded or double- stranded. In any of the 91#14696011vlforegoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, administering the compound improves, preserves, or prevents a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease in an animal. In certain embodiments, the individual is identified as having, or at risk of having, a disease associated with aSyn.

[0220] In certain embodiments, a method of inhibiting expression of aSyn in an individual having, or at risk of having, a disease associated with aSyn comprises administering to the individual a compound comprising a SNCA specific inhibitor, thereby inhibiting expression of aSyn in the individual. In certain embodiments, administering the compound inhibits expression of aSyn in the CNS. In certain embodiments, the disease is a CNS related disease. In certain embodiments, the individual has, or is at risk of having, a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative 92#14696011vldisease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing 93#14696011vlembodiments, the compound can be single- stranded or double- stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intracerebroventricular (ICV) administration. In certain embodiments, administering the compound improves, preserves, or prevents a CNS related disease, disorder or condition or a symptom thereof, a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease.

[0221] In certain embodiments, a method of inhibiting expression of aSyn in a cell comprises contacting the cell with a compound comprising a SNCA specific inhibitor, thereby inhibiting expression of aSyn in the cell. In certain embodiments, the cell is in the CNS of an individual (e.g., neurons, neurites, glial cells, oligodendrocytes). In certain embodiments, the cell is in the peripheral nervous system of an individual (e.g., nerves,94#14696011vlautonomic ganglia, sympathetic ganglia, and / or postganglionic nerve fibers). In certain embodiments, the cell is in the CNS of an individual who has, or is at risk of having, a CNS related disease, disorder or condition or a symptom thereof or a neuro degenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from 95#14696011vlthe group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing embodiments, the compound can be single- stranded or double- stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or sequence of SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or sequence of SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and sequence of SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

[0222] In certain embodiments, a method of reducing or inhibiting a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease in an individual having, or at risk of having, a disease associated with aSyn comprises administering to the individual a compound comprising a SNCA specific inhibitor, thereby reducing or inhibiting a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy 96#14696011vlbody dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease in the individual. In certain embodiments, the individual has, or is at risk of having, a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of sequence of SEQ ID 97#14696011vlNOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing embodiments, the compound can be single- stranded or double- stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intracerebroventricular (ICV) administration. In certain embodiments, the individual is identified as having, or at risk of having, a disease associated with aSyn.

[0223] Certain embodiments are drawn to a compound comprising a SNCA specific inhibitor for use in treating a disease, disorder or condition associated with aSyn. In certain embodiments, the disease, disorder or condition is a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof,98#14696011vlincluding a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing 99#14696011vlembodiments, the compound can be single- stranded or double- stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intracerebroventricular (ICV) administration.

[0224] Certain embodiments are drawn to a compound comprising a SNCA specific inhibitor for use in reducing or inhibiting a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length)100#14696011vlhaving a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

[0225] Certain embodiments are drawn to the use of a compound comprising a SNCA specific inhibitor for the manufacture or preparation of a medicament for treating a disease associated with aSyn. Certain embodiments are drawn to the use of a compound comprising a SNCA specific inhibitor for the preparation of a medicament for treating a disease, disorder or condition associated with aSyn. In certain embodiments, the disease, disorder or condition is a CNS related disease, disorder or condition or a symptom thereof. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple 101#14696011vlsystem atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing embodiments, the compound can be single- stranded or double- stranded. In any of the 102#14696011vlforegoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

[0226] Certain embodiments are drawn to the use of a compound comprising a SNCA specific inhibitor for the manufacture or preparation of a medicament for reducing or inhibiting a CNS related disease, disorder or condition or a symptom thereof in an individual having, or at risk of having, a CNS related disease, disorder or condition or a symptom thereof associated with aSyn. In certain embodiments, the CNS related disease, disorder or condition is a neurodegenerative disease or a symptom thereof, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. Certain embodiments are drawn to use of a compound comprising a SNCA specific inhibitor for the preparation of a medicament for treating a disease, disorder or condition associated with aSyn. In certain embodiments, the disease, disorder or condition is a CNS related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a synucleinopathy,103#14696011vlParkinson’s disease, multiple system atrophy (MSA), Lewy body dementia (LBD), pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to aSyn. In certain embodiments, the compound comprises an oligonucleotide targeted to aSyn. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-39 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 40-68. In any of the foregoing embodiments, the compound can be single- stranded or 104#14696011vldouble- stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68, and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

[0227] In any of the foregoing methods or uses, the compound can be an oligomeric compound. In any of the foregoing methods or uses, the compound can be single- stranded or double- stranded. In any of the foregoing methods or uses, the compound can be targeted to aSyn. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, a modified oligonucleotide is 8 to 80 linked nucleosides in length, 10 to 30 linked nucleosides in length, 14 to 30 linked nucleosides in length, 14 to 23 linked nucleosides in length, or 19 to 23 linked nucleosides in length. In certain embodiments, a modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95% or 100% complementary to any of the nucleobase sequences recited in SEQ ID NO: 1 over its length. In certain embodiments, a modified oligonucleotide comprises at least one modified intemucleoside linkage, at least one modified sugar and / or at least one modified 105#14696011vlnucleobase. In certain embodiments, the modified intemucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, the modified sugar is a bicyclic sugar, 2'-M0E, 2'-F, or 2'-0Me. In certain embodiments, the modified nucleobase is a 5-methylcytosine. In any of the foregoing embodiments, each modified oligonucleotide is independently 12 to 30, 14 to 30, 14 to 25, 14 to 24, 14 to 23, 16 to 23, 17 to 23, 18 to 23, 19 to 23, 19 to 22, or 19 to 20 linked nucleosides in length. In certain embodiments, a modified oligonucleotide has at least 1, at least 2, at least 3 mismatches to a region of SEQ ID NO: 1.

[0228] In any of the foregoing methods or uses, the compound comprises a first and second modified oligonucleotide, wherein there is a region of complementarity between a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the region of complementarity between the first oligonucleotide and the second oligonucleotide is 14 to 23, 19 to 23, or 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide comprises at least one modification selected from a modified intemucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified intemucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified intemucleoside linkage is a phosphorothioate intemucleoside linkage or a methylphosphonate intemucleoside linkage. In certain embodiments, the modified intemucleoside linkage is at the 3' terminus of the first or second modified oligonucleotide or at the 5' terminus of the first or second modified oligonucleotide. In certain embodiments, the first or second modified oligonucleotide comprises one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar. In certain embodiments, the modified sugar comprises a modification selected from group consisting of 2'-MOE, 2'-F, and 2'-OMe or a combination thereof. In certain embodiments, the first or second modified oligonucleotide comprises no more than ten 2'-106#14696011vlF sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0229] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5' end of a modified oligonucleotide. In certain embodiments, the conjugate group is attached to the 3' end of a modified oligonucleotide. In certain embodiments, a conjugate group is attached to the 5' end of a modified oligonucleotide, and a conjugate group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more TrkB ligands. In certain embodiments, the one or more TrkB ligands is attached at the 5' or 3' end of the oligonucleotide, both the 5' and 3' ends of the oligonucleotide, to a terminal and / or interior base, and / or via intranucleosidic linkage. In certain embodiments, the TrkB ligand is selected from Formulae I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, XXXXXXXXV, and XXXXXXXXVII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the TrkB ligand through a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the TrkB ligand through a phosphorothioate group. In certain embodiments, the conjugate group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl). In certain embodiments, the modified oligonucleotide comprises one or more ligands and one or more lipids. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, the one or more lipids are attached to an intemucleoside linkage of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI. In certain embodiments, the modified oligonucleotide comprises one or more TrkB ligands and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl). In certain embodiments, the modified oligonucleotide is the second modified107#14696011vloligonucleotide. In certain embodiments, the one or more TrkB ligands is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands is attached to the 5' end and the 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl) are attached to an intemucleoside linkage of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands is selected from any one of Formulae I-XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX- XXXXXXXIII, XXXXXXXXV, and XXXXXXXXVII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the internucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI, or a salt, solvate, or hydrate thereof. In certain embodiments, the one or more TrkB ligands is selected from any one of Formulae I-XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX- XXXXXXXIII, XXXXXXXXV, and XXXXXXXXVII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the modified oligonucleotide also comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide.

[0230] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5' end of a modified oligonucleotide. In certain embodiments, the conjugate group is attached to the 3' end of a modified oligonucleotide. In certain embodiments, a conjugate group is attached to the 5' end of a modified oligonucleotide, and a conjugate group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more CBi ligands. In certain embodiments, the one or more CBi ligands is attached at the 5' or 3' end of the oligonucleotide, both the 5' and 3' ends of the oligonucleotide, to a terminal and / or interior base, and / or via intranucleosidic linkage. In certain embodiments, the CBi ligand is selected from Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII, or a salt, solvate, or hydrate thereof, wherein R is the 108#14696011vlmodified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the CBi ligand through a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the CBi ligand through a phosphorothioate group. In certain embodiments, the conjugate group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl). In certain embodiments, the modified oligonucleotide comprises one or more ligands and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl). In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, the one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl) are attached to an intemucleoside linkage of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI. In certain embodiments, the modified oligonucleotide comprises one or more CBi ligands, and one or more lipids. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, the one or more CBi ligands is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the one or more CBi ligands is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the one or more CBi ligands is attached to the 5' end and the 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipids are attached to an intemucleoside linkage of the modified oligonucleotide. In certain embodiments, the one or more CBi ligands is selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI, or a salt, solvate, or hydrate thereof. In certain embodiments, the one or more CBi ligands is selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the modified oligonucleotide also comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide.109#14696011vl

[0231] In certain embodiments, the targeting moiety comprises one or more NMDA ligands. In certain embodiments, the one or more NMDA ligands is attached at the 5' or 3' end of the oligonucleotide, both the 5' and 3' ends of the oligonucleotide, to a terminal and / or interior base, and / or via intranucleosidic linkage. In reference to a conjugate group or targeting moiety, a ligand of “N-methyl-D-aspartate receptor” or “NMDA receptor” refers to a ligand of the glutamate receptor and ion channel that is found in neurons, e.g., in humans. Many ligands of the NMDA receptor are known in the art including, for example, those disclosed in Neuropharmacology 2007, 53(6), 699-723; J. Med. Chem. 1990, 33(2), 789-808; Neuroscience 2001, 105(3), 663-669; J. Med. Chem. 2022, 65(13), 9063-9075; Drugs Fut. 2004, 29(10), 992; Drugs Fut. 2004, 29(10), 993; and British Journal of Pharmacology 2022, 179(6), 1146-1187, each of which is incorporated by reference herein.

[0232] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5' end of a modified oligonucleotide. In certain embodiments, the conjugate group is attached to the 3' end of a modified oligonucleotide. In certain embodiments, a conjugate group is attached to the 5' end of a modified oligonucleotide, and a conjugate group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more ligands. In certain embodiments, the targeting moiety comprises one or more a.4 1 / 7 integrin ligands. In certain embodiments, the one or more a.401 / 7 integrin ligands is attached at the 5' or 3' end of the oligonucleotide, both the 5' and 3' ends of the oligonucleotide, to a terminal and / or interior base, and / or via intranucleosidic linkage. In certain embodiments, the a.401 / 7 integrin ligand is selected from Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the a40i / 7 integrin ligand through a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the a40i / 7 integrin ligand through a phosphorothioate group. In certain embodiments, the conjugate group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl). In certain embodiments, the modified oligonucleotide comprises one or more ligands and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or 110#14696011vlalkenyl). In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, the one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl) are attached to an intemucleoside linkage of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI. In certain embodiments, the modified oligonucleotide comprises one or more a.4 1 / 7 integrin ligands and one or more lipids. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, the one or more a.401 / 7 integrin ligands is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the one or more a40i / 7 integrin ligands is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the one or more a40i / 7 integrin ligands is attached to the 5' end and the 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipids are attached to an intemucleoside linkage of the modified oligonucleotide. In certain embodiments, the one or more a40i / 7 integrin ligands is selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI, or a salt, solvate, or hydrate thereof. In certain embodiments, the one or more a40i / 7 integrin ligands is selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the modified oligonucleotide also comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide.

[0233] In any of the foregoing methods or uses, in certain embodiments, a compound comprises one or more substituted or unsubstituted alkyl or alkenyl. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl is attached to an intemucleoside linkage of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or 111#14696011vlalkenyl. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl are attached to one or more intemucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C4- C30 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C5-C20 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C14-C20 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Ci6 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C17 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Cis hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C22 hydrocarbon chain.

[0234] In certain embodiments, a substituted or unsubstituted alkyl or alkenyl is attached to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, a substituted or unsubstituted alkyl or alkenyl is attached to an intemucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the intemucleoside linkage is between nucleosides that are within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) from a terminal end (e.g., the 5' and / or 3' end) of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between nucleosides that are within 5 positions from the 5' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between nucleosides that are within 5 positions from the 3' end of the modified oligonucleotide.

[0235] In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 from the 5' end of the modified 112#14696011vloligonucleotide. In certain embodiments, the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the intemucleoside linkage is between positions 2 and 3 from the 3' end of the modified oligonucleotide.

[0236] In certain embodiments, the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI.

[0237] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a 5 '-phosphonate modification. For example, in certain embodiments, a modified oligonucleotide comprises one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5 '-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., 5' terminus) comprising the 5'- phosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'-ethylenephosphonate modification. In certain embodiments, the modified oligonucleotide is the first modified oligonucleotide or antisense oligonucleotide.

[0238] In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs in Table 3 (SEQ ID NOs: 71-99) and a second modified oligonucleotide 14 to 23 linked 113#14696011vlnucleosides in length fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide selected from any one of the IA Ref ID NOs in Table 3 (SEQ ID NOs: 71-99) and a second modified oligonucleotide selected from any one of the IS Ref ID NOs in Table 3 (SEQ ID NOs: 100-137). In certain embodiments, the compound is in a pharmaceutically acceptable salt form. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. In certain embodiments, a composition comprises the compound of any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0239] In any of the foregoing methods or uses, a compound or composition comprising a compound of any preceding embodiment is administered to an individual in a therapeutically effective amount. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg / kg of body weight of the individual. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the composition is administered to the individual one or more times in a day up to the dosage level or fixed dose.

[0240] In any of the foregoing methods or uses, a compound or composition comprising a compound of any preceding embodiment is administered to an individual daily, weekly, monthly, quarterly or yearly. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per month or once per quarter (i.e., once every three months) to about once per year. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per quarter, about once every six months or about once per year.Certain Compounds

[0241] In certain aspects, the disclosure relates to a compound that comprises or consists of an oligomeric compound. In certain embodiments, the oligomeric compound comprises a nucleobase sequence complementary to that of a target nucleic acid.114#14696011vl

[0242] In certain aspects, the disclosure relates to a compound that comprises or consists of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

[0243] In certain aspects, the disclosure relates to a compound that comprises or consists of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

[0244] In certain aspects, the disclosure relates to a compound that is a single- stranded compound. In certain embodiments, the single- stranded compound comprises or consists of an oligomeric compound. In certain embodiments, such an oligomeric compound comprises or consists of an oligonucleotide and optionally a conjugate group. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, the oligonucleotide or modified oligonucleotide of a single- stranded compound comprises a self-complementary nucleobase sequence.

[0245] In certain aspects, the disclosure relates to a compound that is a double- stranded compound. In certain embodiments, the double- stranded compound comprises or consists of an oligomeric compound. In certain embodiments, the double- stranded compound comprises a first oligonucleotide and a second oligonucleotide. In certain embodiments, the first oligonucleotide has a region complementarity to a target nucleic acid and the second oligonucleotide has a region complementarity to the first modified oligonucleotide. In certain embodiments, the double- stranded compound comprises a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a region complementarity to a target nucleic acid. In certain embodiments, the doublestranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide has a region complementarity to a target nucleic acid and the second modified oligonucleotide has a region complementarity to the first modified oligonucleotide. In certain embodiments, an oligonucleotide or modified oligonucleotide of a double- stranded compound is an RNA oligonucleotide. In such embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase.

[0246] In certain embodiments, a compound described herein comprises a conjugate group.In certain embodiments, the first oligonucleotide or first modified oligonucleotide of a 115#14696011vldouble- stranded compound comprises a conjugate group. In certain embodiments, the second oligonucleotide or second modified oligonucleotide of a double-stranded compound comprises a conjugate group. In certain embodiments, a first oligonucleotide or first modified oligonucleotide and a second oligonucleotide or second modified oligonucleotide of a double- stranded compound each comprises a conjugate group.

[0247] In certain embodiments, a compound is 14-30 linked nucleosides in length. In certain embodiments, the first oligonucleotide or first modified oligonucleotide of a doublestranded compound is 14-30 linked nucleosides in length. In certain embodiments, the second oligonucleotide or second modified oligonucleotide is 14-30 linked nucleosides in length. In certain embodiments, the oligonucleotides or modified oligonucleotides of a double- stranded compound are blunt ended at one or both ends of the compound. In certain embodiments, the oligonucleotides or modified oligonucleotides of a doublestranded compound include non-complementary overhanging nucleosides at one or both ends of the compound.

[0248] In certain embodiments, a compound has a nucleobase sequence comprising at least 14 contiguous nucleobases of any of SEQ ID NOs: 11-39. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of a double- stranded compound has a nucleobase sequence comprising at least 14 contiguous nucleobases of any of SEQ ID NOs: 11-39.

[0249] Examples of single-stranded and double- stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, microRNA targeting oligonucleotides, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single- stranded RNAi compounds (e.g. small hairpin RNAs (shRNAs), single stranded siRNAs (ssRNAs) and microRNA mimics).

[0250] In certain embodiments, a compound described herein has a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of the target region of a target nucleic acid to which it is targeted.

[0251] In certain embodiments, a compound described herein comprises an oligonucleotide 12 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 12 to 23 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 14 to 30 linked subunits in 116#14696011vllength. In certain embodiments, compound described herein comprises an oligonucleotide 14 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 15 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 15 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 18 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 18 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 19 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 19 to 23 linked subunits in length. In other words, such oligonucleotides are 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits or 19 to 23 linked subunits, respectively. In certain embodiments, a compound described herein comprises an oligonucleotide 14 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 18 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 19 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 21 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 22 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 23 linked subunits in length. In other 117#14696011vlembodiments, a compound described herein comprises an oligonucleotide 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 23, 18 to 24, 18 to 25, 18 to 50, 19 to 23, 19 to 30, 19 to 50, 20 to 23 or 20 to 30 linked subunits. In certain such embodiments, the compound described herein comprises an oligonucleotide 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked subunits in length, or a range defined by any two of the above values.

[0252] In certain embodiments, the compound may further comprise an additional moiety, such as a conjugate group or delivery moiety. In certain embodiments, such compounds are oligomeric compounds, and the additional moiety is attached to an oligonucleotide. In certain embodiments, a conjugate group is attached to a nucleoside of an oligonucleotide.

[0253] In certain embodiments, compounds may be shortened or truncated. For example, one or more subunits may be deleted from the 5' end (5' truncation), or alternatively from the 3' end (3' truncation) of an oligonucleotide.

[0254] In certain embodiments, compounds may be lengthened. For example, one or more subunits may be attached to the 3' end or 5' end of an oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more subunits) is attached to the 5' end of an oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more subunits) is attached to the 3' end of an oligonucleotide. In certain embodiments, at least one or more subunits may be attached to the 3' end or 5' end of an oligonucleotide of a doublestranded compound creating a 3' and / or 5' end overhang. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more subunits) is attached to the 5' end of both oligonucleotides of a double- stranded compound. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more subunit) is attached to the 3' end of both oligonucleotides of a double- stranded compound.118#14696011vlIn certain embodiments, subunits are attached to both oligonucleotides of a doublestranded compound at the same end (e.g., that subunits are attached to the 3' end of one of the oligonucleotides and subunits are attached to the 5' end of the other oligonucleotide). In certain embodiments, when subunits are attached to both oligonucleotides of a doublestranded compound at the same end, the number of subunits attached to each oligonucleotide may be the same or may be different. In certain embodiments, when subunits are attached to both oligonucleotides of a double- stranded compound at the same end, the number of subunits attached to each oligonucleotide is the same. In certain embodiments, when subunits are attached to both oligonucleotides of a double- stranded compound at the same end, the number of subunits attached to each oligonucleotide is different. This scenario, where subunits are attached to both oligonucleotides of a doublestranded compound at the same end, may occur at one or both ends of a double- stranded compound. In certain embodiments, the subunits attached to the 3' and / or 5' end are modified.

[0255] In certain embodiments, compounds described herein are oligonucleotides. In certain embodiments, compounds described herein are modified oligonucleotides. In certain embodiments, compounds described herein are antisense oligonucleotides. In certain embodiments, compounds described herein are oligomeric compounds. In certain embodiments, compounds described herein are RNAi compounds. In certain embodiments, compounds described herein are siRNA compounds.

[0256] In certain embodiments, a compound described herein can comprise any of the oligonucleotide sequences targeted to aSyn described herein. In certain embodiments, the compound can be double-stranded.

[0257] In certain embodiments, the compound comprises an oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of any one of SEQ ID NOs: 11-39. In certain embodiments, the compound comprises an oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of any one of SEQ ID NOs: 11-39. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of any one of SEQ ID NOs: 40-68.119#14696011vl

[0258] In certain embodiments, the compound comprises ribonucleotides in which the oligonucleotide has uracil (U) in place of thymine (T) for any of the sequences provided here. In certain embodiments, the compound comprises deoxyribonucleotides in which the oligonucleotide has thymine (T) in place of uracil (U) for any of the sequences provided here.Certain Mechanisms

[0259] In certain embodiments, compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, compounds described herein comprise or consist of antisense oligonucleotides. In certain embodiments, compounds comprise or consist of oligomeric compounds. In certain embodiments, compounds described herein are capable of hybridizing to a target nucleic acid. In certain embodiments, compounds described herein selectively affect one or more target nucleic acid. Such compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in a significant undesired activity.

[0260] In certain embodiments, hybridization of a compound described herein to a target nucleic acid results in recruitment of one or more proteins that cause the cleavage of the target nucleic acid. For example, certain compounds described herein or a portion of the compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain compounds described herein result in cleavage of the target nucleic acid by Argonaute. Compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double- stranded (siRNA) or single-stranded (ssRNA).

[0261] In certain embodiments, hybridization of compounds described herein to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain such embodiments, hybridization of the compound to the target nucleic acid results in the alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of the compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain such embodiments, hybridization of the compound to the target nucleic acid results in the alteration of RNA processing. In certain such embodiments, hybridization of the120#14696011vlcompound to a target nucleic acid results in alteration of translation of the target nucleic acid.

[0262] Activities resulting from the hybridization of a compound to a target nucleic acid may be observed directly or indirectly. In certain embodiments, observation or detection of an activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein, and / or a phenotypic change in a cell or animal.Certain Modifications

[0263] In certain aspects, the disclosure relates to compounds that comprise or consist of oligonucleotides. Oligonucleotides consist of linked nucleosides. In certain embodiments, oligonucleotides may be unmodified RNA or DNA or may be modified. In certain embodiments, the oligonucleotides are modified oligonucleotides. In certain embodiments, the modified oligonucleotides comprise at least one modified sugar, modified nucleobase or modified intemucleoside linkage relative to an unmodified RNA or DNA. In certain embodiments, an oligonucleotide has a modified nucleoside. A modified nucleoside may comprise a modified sugar, a modified nucleobase or both a modified sugar and a modified nucleobase. Modified oligonucleotides may also include end modifications, e.g., 5'-end modifications and 3'-end modifications.Sugar Modifications and Motifs

[0264] In certain embodiments, a modified sugar is a substituted furanosyl sugar or non- bicyclic modified sugar. In certain embodiments, a modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, a modified sugar is a sugar surrogate. A sugar surrogate may comprise one or more substitutions described herein.

[0265] In certain embodiments, a modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituent groups, including, but not limited to, substituent groups at the 2', 3', 4', and 5' positions.

[0266] In certain embodiments, substituents at the 2' position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl” or “methoxy”). In certain embodiments, substituent groups at the 2' position suitable for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3,121#14696011vlSO2CH3, ONO2, NO2, N3, and NH2. In certain embodiments, substituent groups at the 2' position include, but are not limited to, O-(Ci-Cio) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O- alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted Ci to C10 alkyl or C2 to C10 alkenyl and alkynyl. In certain embodiments, substituent groups at the 2' position include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O- aralkyl. In certain embodiments, these 2' substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, substituent groups at the 2' position include, but are not limited to, O[(CH2)nO]mCH3, O(CH2)nOCH3, O(CH2)nCH3, O(CH2)nONH2, O(CH2)nNH2, O(CH2)nSCH3, and O(CH2)nON[(CH2)nCH3)]2, where n and m are independently from 1 to about 10. In certain embodiments, substituent groups at the 2' position include, but are not limited to, OCH2CH2OCH3 (“MOE”), O(CH2)2ON(CH3)2 (“DMAOE”), O(CH2)2O(CH2)2N(CH3)2 (“DMAEOE”), and OCH2C(=O)-N(H)CH3(“NMA”).

[0267] In certain embodiments, substituent groups at the 4' position suitable for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, substituent groups at the 5' position suitable for non-bicyclic modified sugars include, but are not limited to, methyl (“Me” or “CH3”) (R or S), vinyl, and methoxy. In certain embodiments, the 5' modification is a 5'-monophosphate ((HO)2(O)P-O-5'); 5'-diphosphate ((HO)2(O)P- O-P(HO)(O)-O-5'); 5'-triphosphate ((HO)2(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'- guanosine cap (7-methylated or non-methylated) (7m-G-O-5'-(HO)(O)P-O-(HO)(O)P-O- P(HO)(O)-O-5'); 5'adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (N-O-5'(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'-monothiophosphate (phosphorothioate; (□□)2(S)P-O-5I); 5'-monodithiophosphate (phosphorodithioate;(HO)(HS)(S)P-O-5'), 5'phosphorothiolate ((HO)2(O)P-S-5'); any additional combination of oxygen / sulfur replaced monophosphate, diphosphate and triphosphates (e.g. 5'-alpha- thiotriphosphate, 5'-gammathiotriphosphate, etc.), 5'-phosphoramidates ((HO)2(O)P-NH- 5', (HO)(NH2)(O)P-O-5'), 5'alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g. RP(OH)(O)-O-5'-, 5'alkenylphosphonates (i.e. vinyl, substituted vinyl),122#14696011vl(OH)2(O)P-5'-CH2-), 5'alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCEh- ), ethoxymethyl, etc., e.g. RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5 '-phosphonate modification. In certain embodiments, the 5 '-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, one or more sugars comprise a 5'- vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-ethylenephosphonate modification. In certain embodiments the 5' modification is at the terminus of an oligonucleotide. In certain embodiments the 5' modification is at the terminus of an antisense oligonucleotide. In certain embodiments, substituents described herein for the 2', 4' and 5' position can be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may comprise more than one non-bridging sugar substituent. In certain such embodiments, non-bicyclic modified sugars substituents include, but are not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, modified sugar substituents include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US2013 / 0203836.

[0268] In certain embodiments, a modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, a bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form a second ring. In certain embodiments, a bicyclic sugar does not comprise a furanosyl moiety. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4' to 2' bridging substituents include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'- (CH2)3-2', 4'-CH2- 0-2' (“LNA”), 4'-CH2-S-2', 4'-(CH2)2-O-2' (“ENA”), 4'-CH(CH3)-O-2' (“constrained ethyl” or “cEt” when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'- CH(CH2OCH3)-O-2' (“constrained MOE” or “cMOE”) and analogs thereof (e.g., U. S. Patent No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and analogs thereof (e.g., U. S. Patent No.123#14696011vl8,278,283), 4'-CH2-N(OCH3)-2' and analogs thereof (e.g., U. S. Patent No. 8,278,425), 4'- CH2-O-N(CH3)-2' (e.g., U. S. Patent Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2', wherein R is H, C1-C12 alkyl, or a protecting group (e.g., U. S. Patent No. 7,427,672), 4'- CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya el al., J. Org. Chem., 2009, 74, 118- 134), and 4'-CH2-C(=CH2)-2' and analogs thereof (e.g., U. S. Patent No. 8,278,426). The entire contents of each of the foregoing are hereby incorporated herein by reference. Additional representative U. S. Patents and U. S. Patent Publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U. S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207;7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, US 2013 / 0190383; and WO 2013 / 036868, the entire contents of each of which are hereby incorporated herein by reference. Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example a-L-ribofuranose and P-D-ribofuranose (see e.g., WO 99 / 14226). Specified bicyclic nucleosides herein are in the P-D configuration, unless otherwise specified.

[0269] In certain embodiments, a modified sugar is a sugar surrogate. In certain embodiments, a sugar surrogate has the oxygen atom replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar surrogate may also comprise bridging and / or non-bridging substituents as described herein. In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. In certain such embodiments, the sugar surrogate comprises a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a six membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a tetrahydropyran (“THP”) in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a morpholino in place of the pentofuranosyl sugar.Representative US patents that teach the preparation of such modified sugar structures include, but are not limited to, U. S. Patent Nos. 4,981,957; 5,118,800; 5,166,315;5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803; and124#14696011vl9,005,906, the entire contents of each of the foregoing are hereby incorporated herein by reference.

[0270] In some embodiments, sugar surrogates comprise acyclic moieties. In certain embodiments, the sugar surrogate is an unlocked nucleic acid (“UNA”). A UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked "sugar" residue. In one example, UNA also encompasses a monomer where the bonds between Cl’-C4' have been removed (i.e. the covalent carbon-oxygen- carbon bond between the Cl’ and C4' carbons). In another example, the C2'-C3' bond (i.e. the covalent carbon-carbon bond between the C2' and C3' carbons) of the sugar has been removed. Representative U. S. publications that teach the preparation of UNA include, but are not limited to, U. S. Patent No. 8,314,227; and U. S. Patent Publication Nos.2013 / 0096289; 2013 / 0011922; and 2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference. In certain embodiments, sugar surrogates comprise peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378, the entire contents of which is hereby incorporated herein by reference. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

[0271] In certain aspects, the disclosure relates to compounds comprising at least one oligonucleotide wherein the nucleosides of such oligonucleotide comprise one or more types of modified sugars and / or unmodified sugars arranged along the oligonucleotide or region thereof in a defined pattern or “sugar motif’. In certain instances, such sugar motifs include, but are not limited to, any of the patterns of sugar modifications described herein.

[0272] In certain embodiments, an oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two external “wing” regions and a central or internal “gap” region. The gap and wing regions form a contiguous sequence of nucleosides, wherein the majority of nucleoside sugars of each of the wings differ from the majority of nucleoside sugars of the gap. In certain embodiments, the wing regions comprise a majority of modified sugars and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxynucleosides. Compounds with a gapmer sugar motif are described in,125#14696011vlfor example US Patent 8,790,919, the entire contents of which is hereby incorporated herein by reference.

[0273] In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise a triplet sugar motif. An oligonucleotide with a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is at or near the cleavage site of the oligonucleotide. In certain embodiments, an oligonucleotide of a double- stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds with a triplet sugar motif are disclosed, for example, in US Patent 10,668,170, the entire contents of which is incorporated herein by reference.

[0274] In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise a quadruplet sugar motif. An oligonucleotide with a quadruplet sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplet is at or near the cleavage site. In certain embodiments, an oligonucleotide of a double- stranded compound may contain more than one quadruplet sugar motif. In certain embodiments, the identical sugar modification of the quadruplet sugar motif is a 2'-F modification. For a double- stranded compound having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically around the 10, 11, and 12 positions from the 5'-end. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, 11 positions; the 9, 10, 11, 12 positions; the 10, 11, 12, 13 positions; the 11, 12, 13, 14 positions; or the 12, 13, 14, 15 positions of the sense oligonucleotide, counting from the first nucleoside of the 5'-end of the sense oligonucleotide, or, the count starting from the first paired nucleotide within the duplex region from the 5'-end of the sense oligonucleotide. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, 11 positions; the 9, 10, 11, 12 positions; the 10, 11, 12, 13 positions; the 11, 12, 13, 14 positions; or the 12, 13, 14, 15 positions of the antisense oligonucleotide, counting from the first nucleoside of the 5'-end of the antisense oligonucleotide, or, the count starting from the first paired nucleotide within the duplex region from the 5'- end of the antisense oligonucleotide. The cleavage site may change according to the length of the duplex region of the double- stranded compound and may change the position of the quadruplet accordingly.126#14696011vl

[0275] In certain embodiments, an oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both oligonucleotides of a double- stranded compound comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications wherein one or more consecutive nucleosides comprising a first sugar modification alternates with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, B and C each represent one type of modification to the nucleoside, the alternating motif can be “ABABABABABAB...,” “AABBAABBAABB...,” “AABAABAABAAB...,” “AAABAAABAAAB...,” “AAABBBAAABBB...,” or “ABCABCABCABC...” etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleobases along an oligonucleotide. In certain embodiments, the alternating sugar motif is comprised of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.

[0276] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double- stranded compound independently has one or more sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif, is fully modified in that each nucleoside other than the nucleosides comprising the sugar motif comprises a sugar modification.Nucleobase Modifications and Motifs

[0277] In certain embodiments, compounds described herein comprise modified oligonucleotides. In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside.

[0278] In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5- hydroxymethyl cytosine, 5- 127#14696011vlmethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N- methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5- propynyl (OC-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6- azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8- thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3- deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N- benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3- diazaphenoxazine-2-one, l,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-l,3- diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7- deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.

[0279] Further nucleobases include those disclosed in U. S. Patent 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley- VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858- 859; Kroschwitz, J. L., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, dsRNA Research and Applications, pages 289-302; Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which are hereby incorporated herein by reference.

[0280] Publications that teach the preparation of certain of the above noted modified nucleobases, as well as other modified nucleobases include without limitation, US Application Publication Nos. 2003 / 0158403 and 2003 / 0175906; U. S. Patents 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096. 6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 128#14696011vl7,495,088, the entire contents of each of which are hereby incorporated herein by reference.

[0281] In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methylcytosines.

[0282] In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3'-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3'-end of the oligonucleotide. In certain embodiments, the block is at the 5'-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5'-end of the oligonucleotide.Internucleoside Linkage Modifications and Motifs

[0283] A 3' to 5' phosphodiester linkage is the naturally occurring internucleoside linkage of RNA and DNA. In certain embodiments, compounds described herein have one or more modified, i.e. non-naturally occurring, intemucleoside linkages. Certain non-naturally occurring internucleoside linkages may impart desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative phosphorus-containing modified intemucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g. methylphosphonates), phosphoramidates, and phosphorothioates (“P=S”), and phosphorodithioates (“HS-P=S”). Representative non-phosphorus containing intemucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CHs)-O-CH2), thiodiester, thionocarbamate (-0- C(=O)(NH)-S-); siloxane (-O-Sifh-O-); and N, N'- dimethylhydrazine (-CH2-N((CHs)- 129#14696011vlN((CHs)-). Methods of preparation of phosphorous-containing and non-phosphorous- containing internucleoside linkages are well known to those skilled in the art. Neutral intemucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S-CH2-O-5'). Further neutral intemucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See, for example: Carbohydrate Modifications in Antisense Research; YS. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral intemucleoside linkages include nonionic linkages comprising mixed N, O, S and CH2 component parts.

[0284] In certain embodiments, compounds provided herein comprise at least one modified intemucleoside linkage. A modified intemucleoside linkage may be placed at any position of an oligonucleotide. For double- stranded compounds, a modified intemucleoside linkage may be placed within the sense oligonucleotide, antisense oligonucleotide, or both oligonucleotides of the double- stranded compound.

[0285] In certain embodiments, the intemucleoside linkage modification may occur on every nucleoside of an oligonucleotide. In certain embodiments, intemucleoside linkage modifications may occur in an alternating pattern along an oligonucleotide. In certain embodiments, essentially each intemucleoside linking group is a phosphate intemucleoside linkage (P=O). In certain embodiments, each intemucleoside linking group of a modified oligonucleotide is a phosphorothioate (P=S). In certain embodiments, each intemucleoside linking group of a modified oligonucleotide is independently selected from a phosphorothioate and phosphate intemucleoside linkage. In certain embodiments, the pattern of the intemucleoside linkage modification on each oligonucleotide of a double- stranded compound is the same. In certain embodiments, the pattern of the intemucleoside linkage modification on each oligonucleotide of a doublestranded compound is different. In certain embodiments, a double- stranded compound comprises 6-8 modified intemucleoside linkages. In certain embodiments, the 6-8 modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified intemucleoside linkages at either or both 130#14696011vlthe 5'-end and the 3'-end. In certain such embodiments, the modified internucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified intemucleoside linkages at either or both the 5'-end and the 3'-end. In certain such embodiments, the modified intemucleoside linkages are phosphorothioate intemucleoside linkages or alkylphosphonate intemucleoside linkages.

[0286] In certain embodiments, a double- stranded compound comprises an overhang region.In certain embodiments, a double- stranded compound comprises a phosphorothioate or alkylphosphonate intemucleoside linkage modification in the overhang region. In certain embodiments, a double- stranded compound comprises a phosphorothioate or alkylphosphonate intemucleotide linkage linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate intemucleoside linkages between the terminal three nucleosides, in which two of the three nucleosides are overhang nucleosides, and the third is a paired nucleoside next to the overhang nucleoside. These terminal three nucleosides may be at the 3'-end of the antisense oligonucleotide, the 3'-end of the sense oligonucleotide, the 5'- end of the antisense oligonucleotide, or the 5'end of the antisense oligonucleotide.

[0287] In certain embodiments, modified oligonucleotides comprise one or more intemucleoside linkages having chiral centers. Representative chiral intemucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates.Modified oligonucleotides comprising intemucleoside linkages having chiral centers can be prepared as populations of modified oligonucleotides comprising stereorandom intemucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate intemucleoside linkages wherein all of the phosphorothioate intemucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. As is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular131#14696011vlphosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017 / 015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.Conjugate Groups

[0288] In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and, optionally, one or more conjugate groups. Conjugate groups may be attached to either or both ends of an oligonucleotide and / or at any internal position. In certain embodiments, a conjugate group is attached at the 3' end of an oligonucleotide. In certain embodiments, a conjugate group is attached at the 5' end of an oligonucleotide. In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups.

[0289] In certain embodiments, conjugate groups are terminal groups attached to either or both ends of an oligonucleotide. In certain such embodiments, terminal groups are attached at the 3' end of an oligonucleotide. In certain such embodiments, terminal groups are attached at the 5' end of an oligonucleotide. In certain embodiments, terminal groups include, but are not limited to, capping groups, phosphate moieties, protecting groups,132#14696011vlmodified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified, such as an overhang.

[0290] In certain embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including, but not limited to, pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, conjugate groups enhance the affinity of a compound for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a compound absent such a conjugate group. In certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide.

[0291] In certain embodiments, conjugate groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

[0292] In certain embodiments, conjugate groups include an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo- methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial, or an antibiotic.

[0293] In certain embodiments, conjugate groups are targeting moieties. In certain embodiments, a targeting moiety includes, but is not limited to, a lectin, glycoprotein, lipid, protein, peptide, peptide mimetic, receptor ligand, antibody, thyrotropin, melanotropin, surfactant protein A, carbohydrate, carbohydrate derivative, modified carbohydrate, carbohydrate cluster, polysaccharide, modified polysaccharide, or polysaccharide derivative, mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine (GalNAc), N-acetylglucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin,133#14696011vlbisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, vitamin A, biotin, or an RGD peptide or RGD peptide mimetic.

[0294] In certain embodiments, conjugate groups may include, but are not limited to, the conjugate groups described in the following references such as cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060), thioether, e.g., hexyl- S -tritylthiol (e.g., Manoharan et al., Ann. NY. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), aliphatic chains, e.g., do-decan-diol or undecyl residues (e.g., Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), phospholipids, e.g., di-hexadecyl-rac-glycerol or triethyl- ammonium l,2-di-0-hexadecyl-rac-glycero-3-H- phosphonate (e.g, Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), polyamines or a polyethylene glycol chains (e.g., Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), adamantane acetic acid (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), palmityl (e.g., Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), octadecylamine or hexylamino- carbonyloxychole sterol moiety (e.g., Crooke et al. J. Pharmacol. Exp. Then, 1996, 277:923-937), tocopherol (e.g., Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220 and Nishina et al., Molecular Therapy, 2008, 16:734-740), GalNAc and other carbohydrates (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; WD2009 / 073809 and US Patents 8,106,022;8,450,467 and 8,828,957; and WO2014 / 179445; WD2014 / 179620 and US Patents 9,127,276; 9,181,549 and 10,844,379) each of which is incorporated herein by reference in its entirety.

[0295] Conjugate groups may be attached to oligonucleotides through conjugate linkers. In certain embodiments, a conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units or combination of such repeating units. In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, a conjugate linker comprises at least one phosphorus group. In certain embodiments, a conjugate linker comprises at least one 134#14696011vlphosphate group. In certain embodiments, a conjugate linker includes at least one neutral linking group. In certain embodiments, conjugate linkers include, but are not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N- maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include, but are not limited to, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, or substituted or unsubstituted C2-C10 alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, such linker-nucleosides may be modified or unmodified nucleosides. It is typically desirable for linker-nucleosides to be cleaved from the compound after it reaches a target tissue. Accordingly, linker- nucleosides herein can be linked to one another and to the remainder of the compound through cleavable bonds. Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which a compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and / or a specified percent complementarity to a reference nucleic acid and the compound also comprises a conjugate group comprising a conjugate linker comprising linker- nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid.

[0296] In certain embodiments, conjugate groups and conjugate linkers as well as other modifications include, without limitation, those described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006 / 0148740; US 2011 / 0123520;W02013 / 033230; WO2012 / 037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011,19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carhohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem, 1982, 257, 939-945; Pavia et al., Int J Pep Protein Res, 1983, 22, 539-548; Lee et al., Biochem, 1984, 23, 4255-4261; Lee et al., Glycoconjugate J, 1987, 4, 317-328; Toyokuni et al.,135#14696011vlTetrahedron Lett, 1990, 31, 2673-2676; Biessen et al., J Med Chem, 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett, 1997, 38, 3487-3490; Lee et al., Bioconjug Chem, 1997, 8, 762-765; Kato et al., Glycohiol, 2001, 11, 821-829; Rensen et al., J Biol Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362, 38-43; Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee et al., Bioorg Med Chem Lett, 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg Med Chem, 2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494-2500; Kornilova et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618;Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., J Am Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998 / 013381; WO2011 / 038356; WO 1997 / 046098; W02008 / 098788; W02004 / 101619; WO2012 / 037254; W02011 / 120053; W02011 / 100131;WO2011 / 163121; WO2012 / 177947; W02013 / 033230; W02013 / 075035;WO2012 / 083185; WO2012 / 083046; W02009 / 082607; WO2009 / 134487;W02010 / 144740; W02010 / 148013; WO 1997 / 020563; W02010 / 088537;W02002 / 043771; W02010 / 129709; WO2012 / 068187; WO2009 / 126933;W02004 / 024757; WO2010 / 054406; WO2012 / 089352; W02012 / 089602;WO2013 / 166121; WO2013 / 165816; U. S. Patents 4,751,219; 7,582,744; 8,552,163;8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491;8,404,862; 7,851,615; Published U. S. Patent Application Publications US2011 / 0097264; US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799;US2012 / 0035115; US2012 / 0230938; US2005 / 0164235; US2006 / 0183886;136#14696011vlUS2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954;US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132; each of which is incorporated herein by reference in its entirety.Certain Conjugate Groups

[0297] In certain embodiments, a compound provided herein comprises a conjugate group.In certain embodiments, an oligonucleotide provided herein comprises a conjugate group. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more TrkB ligands.

[0298] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (I) or a salt, solvate, or hydrate thereof:R5R6Formula (I),wherein:R1is the modified oligonucleotide;L1, L2, L3, and L4are as described herein;R2is hydrogen, -OR7, -SR8, or -NR9R10;R3is hydrogen, -OR11, -SR12, or -NR13R14;R4is hydrogen, -OR15, -SR16, or -NR17R18;R5is hydrogen, -OR19, -SR20, or -NR21R22;R6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2,optionally substituted -NHAc, -SH, or =0;R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;Y is CH2, NH, S, or O; and137#14696011vlZ is optionally substituted aryl or optionally substituted heteroaryl.

[0299] In certain embodiments, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22are each independently optionally substituted unsaturated or partially unsaturated alkyl. In certain embodiments, R7, R8, R9, and R10are each independently alkenyl. In certain embodiments, R7, R8, R9, and R10are each independently alkynyl.

[0300] In certain embodiments, R2is OR7. In certain embodiments, R3is OR11. In certain embodiments, R7and R11are each independently hydrogen, optionally substituted alkyl or

[0301] optionally substituted alkenyl. In certain embodiments, one or both R7and R11are each independently hydrogen. In certain embodiments, one or both R7and R11are each independently optionally substituted alkyl. In certain embodiments, one or both R7and R11are each independently optionally substituted unsaturated or partially unsaturated alkyl. In certain embodiments, one or both R7and R11are each independently alkenyl. In certain embodiments, R7is optionally substituted alkyl and R11is hydrogen. In certain embodiments, R7is hydrogen and R11is optionally substituted alkyl. In certain embodiments, R7is alkenyl and R11is hydrogen. In certain embodiments, R7is hydrogen and R11is optionally substituted alkenyl.

[0302] In certain embodiments, the TrkB ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:Formula (II- A),OFormula (II-B),138#14696011vlL1-L2-L3-L4-R1OH HCk X X)Formula (II-C),wherein:R1is the modified oligonucleotide;L1, L2, L3, L4, and R1are as described herein.

[0303] In certain embodiments, the TrkB ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:OCH3CO X.Formula (II-D),OCH3X. / OFormula (II-E),Formula (II-F),wherein:R1is the modified oligonucleotide; and139#14696011vlL1, L2, L3, L4, and R1are as described herein.

[0304] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (XXXXXVII) or a salt, solvate, or hydrate thereof:wherein:L1, L2, L3, L4, and R1are as described herein;R11and R13are each independently absent, hydrogen, or optionally substituted alkyl; R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R16is hydrogen, halogen, -CN, -N3, -SOn16R16A, -SO2NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, -N(0)mi6, -NR16BR16C, -C(O)R16D, -C(O)OR16D, -C(O)NR16BR16C, -OR16A, -NR16BSO2R16A, -NR16BC(O)R16D, -NR16BC(O)OR16D, -NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;a b Q = and — are each independently a single bond or a double bond, wherein if = is b b a single bond, then is a double bond and R13is absent; and further wherein if — is a single bond, thenis a double bond and R11is absent;R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, -CF3, -CCh,-CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to140#14696011vlform a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;z3 is 0, 1, 2, 3, 4, or 5;nl6 is 0, 1, 2, 3, or 4; andvl6 and ml6 are each independently 1 or 2.

[0305] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (XXXXXIX) or a salt, solvate, or hydrate thereof:R17L1— L2-L3-L4— R1HO (R19)Z5Formula (XXXXXIX),wherein:L1, L2, L3, L4, and R1are as described herein;R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;z4 is 0, 1, or 2; andz5 is 0, 1, 2, or 3.

[0306] In certain embodiments, the TrkB ligand of a modified oligonucleotide is of the Formula (XXXXXX) or a salt, solvate, or hydrate thereof:(R21)Z7(R20)Z6)Z8C-jKX X - L1— L2-L3-L4— R1XR23^R24Formula (XXXXXX),wherein:L1, L2, L3, L4, and R1are as described herein;#14696011vlR20is hydrogen, halogen, -CN, -N3, -SOn20R1A, -SOV2oNR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C, -N(O)m20, -NR20BR20C, -C(O)R20D, -C(O)OR20D, -C(O)NR20BR20C, -OR20A, -NR20BSO2R20A, -NR20BC(O)R20D, -NR20BC(O)OR20D, -NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R21is hydrogen, halogen, -CN, -N3, -SOn2iR1A, -SOV2INR21BR21C, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21c, -NHC(O)NR21BR21c, -N(O)m2i, -NR21BR21C, -C(O)R21D, -C(O)OR21D, -C(O)NR21BR21c, -OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, -NR21BC(O)OR21D, -NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R24is hydrogen, halogen, -CN, -N3, -SOn24R24A, -SOv24NR24BR24C, -NHNR24BR24C, -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, -N(O)m24, -NR24BR24C, -C(O)R24D, -C(O)OR24D, -C(O)NR24BR24C, -OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, -NR24BC(O)OR24D, -NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R20A,R20B,R20CR20DR21AR2WR21CR21 DR24AR24B,R24CAND R24DAFE EACHindependently hydrogen, halogen, -CF3, -CC13, -CBr3, -CI3,-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R20B, R20C, R21B, R21C, R24B, R24C, R24B, and R24Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;n21, n22, n24, z6 and z8 are each independently 0, 1, 2, 3, or 4;v20, v21, v24, m20, m21, and m24 are each independently 1 or 2; andz7 is 0, 1, or 2.142#14696011vl

[0307] In certain embodiments, the CBi ligand of a modified oligonucleotide is of the Formula (XXXXXXI) or a salt, solvate, or hydrate thereof:Ix19. N.. N. JL1-L2-L3-L4-R1Formula (XXXXXXI),wherein:L1, L2, L3, L4, and R1are as described herein;X1is NR10or CRnR12;R10, R11, and R12are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R19is hydrogen, -SOni9R19A, -SOvi9NR19BR19C, -NHNR19BR19C, -ONR19BR19C, -NHC(O)NHNR19BR19C, -NHC(O)NR19BR19C, -NR19BR19C, -C(O)R19D, -C(O)OR19D, -C(O)NR19BR19C, -OR19A, -NR19BSO2R19A, -NR19BC(O)R19D, -NR19BC(O)OR19D, -NR19BOR19D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R19A, R19B, R19C, R19Dare each independently hydrogen, halogen, -CF3, -CCh,-CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R19Band R19Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;nl9 is 0, 1, 2, 3, or 4; andvl9 is 1 or 2.

[0308] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXII) or a salt, solvate, or hydrate thereof:#14696011vlFormula (XXXXXXII),wherein:L1, L2, L3, L4, and R1are as described herein;R2is H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl; andR3, and R4are each independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl.

[0309] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXIII) or a salt, solvate, or hydrate thereof:Formula (XXXXXXIII),wherein:E1, E2, L3, L4, and R1are as described herein;R2, R3, R4, and R5are each independently H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl, or absent;R8is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl, or optionally substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; and#14696011vlR6, and R7are each independently H, halogen, alkyl, or optionally substituted alkyl,optionally substituted heteroalkyl, F— N

[0310] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXIV) or a salt, solvate, or hydrate thereof:xR2i IlI0ii'N' *NFormula (XXXXXXIV),wherein:L1, L2, L3, L4, and R1are as described herein;R2is H, -CONHR4, -CH2OR4, -(CH2)2OR4, -CH2NHCOR4, or -OR4;R3is H, optionally substituted alkyl, or optionally substituted cycloalkyl;R4is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;R5is -OH or absent; andX is H, optionally substituted CH2, optionally substituted NH, or cycloalkyl.

[0311] In certain embodiments, the a.401 / 7 integrin ligand of a modified oligonucleotide is of the Formula (XXXXXXXXIII) or a salt, solvate, or hydrate thereof:110flH HFormula (XXXXXXXXIII),145#14696011vlwherein:L1, L2, L3, L4, and R1are as described herein;R2is H, -CONHR3, -CH2OR3, -(CH2)2OR3, -CH2NHCOR3, or -OR3;each instance of R3is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; andX is H or halogen.

[0312] In certain embodiments, L1, L2, L3, and L4are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker.

[0313] In certain embodiments, L1is an optionally substituted heteroaryl linker.

[0314] In certain embodiments, L1is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

[0315] In certain embodiments, L1comprises the structure:

[0316] In certain embodiments, L1is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or optionally substituted C1-C10 alkyl chain in which one or more carbon atoms are replaced with O, N, or S.HN^

[0317] In certain embodiments, L1comprises the structure:0or0.

[0318] In certain embodiments, L1comprises the structure:or -N(CHs)-.

[0319] In certain embodiments, L2is an optionally substituted PEG linker.

[0320] In certain embodiments, the PEG linker is five PEG units in length. In certain embodiments, the PEG linker is four PEG units in length. In certain embodiments, the PEG linker is three PEG units in length.146#14696011vl

[0321] In certain embodiments, L2is an optionally substituted alkyl linker. In certain embodiments, L2is an optionally substituted C1-20 alkyl linker. In certain embodiments, L2is an optionally substituted Cs alkyl linker. In certain embodiments, L3is an optionally substituted heteroaryl linker.

[0322] In certain embodiments, L3is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

[0323] In certain embodiments, L3comprises the structure:)•. N

[0324] In certain embodiments, L3comprises the structure

[0325] In certain embodiments, L4is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments, L4is an optionally substituted alkyl linker.

[0326] In certain embodiments, the heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring.

[0327] In certain embodiments, L4comprises the structure:OHboor a salt thereof, wherein X is O or S.

[0328] In certain embodiments, L4comprises the structure:OH,o4-o-|X HNor a salt thereof, wherein X is O or S.147#14696011vl

[0329] In certain embodiments, L1- L2-L3-L4comprises the structure:#14696011vlTAllO969tzl#61zTTAllO969tzl#OST\ > N, or a salt thereof, wherein X is O or S.

[0330] In certain embodiments, the TrkB ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:151#14696011vlX = O orS Formula (III),X = O orS Formula (IV),Formula (V),X = O or S Formula (VI),152#14696011vlFormula (VII),Formula (VIII),Formula (IX),153#14696011vlFormula (X),Formula (XI),Formula (XII),154#14696011vlR i 0Formula (XIII),Formula (XV),#14696011vlFormula (XVI),o Formula (XVII),Formula (XVIII),Formula (XIX),156#14696011vlFormula (XX),BA-169Formula (XXII),157#14696011vlFormula (XXIII),BA-173 Formula (XXIV),BA-183Formula (XXV),158#14696011vlBA-201Formula (XXVI),BA-196 Formula (XXIX),BA-197Formula (XXX),159#14696011vlFormula (XXXI),Formula (XXXIII),Formula (XXXIV),Formula (XXXXXXV),160#14696011vlFormula (XXXXXXIX),Formula (XXXXXXX),161#14696011vlFormula (XXXXXXXIII),Formula (XXXXXXXXV), and162#14696011vloFormula (XXXXXXXXVII)wherein:R is the modified oligonucleotide; andX is S or O.

[0331] In certain embodiments, the CBi ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereofFormula (XXXXXXXV),163#14696011vlCl Formula (XXXXXXXVI),o Formula (XXXXXXXVII), andFormula (XXXXXXXVIII),wherein:R is the modified oligonucleotide; andX is S or O.

[0332] In certain embodiments, the a.4 1 / 7 integrin ligand of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof:164#14696011vlFormula (XXXXXXXX),o'Formula (XXXXXXXXI),165#14696011vlOH R-O-P=XFormula (XXXXXXXXIV),wherein:R is the modified oligonucleotide; andX is S or O.

[0333] In certain embodiments, a compound provided herein comprises a conjugate group.In certain embodiments, an oligonucleotide provided herein comprises a conjugate group.In certain embodiments, the conjugate group is a lipid. In certain embodiments, an intemucleoside linkage of a modified oligonucleotide provided herein comprises one or more lipids.166#14696011vl

[0334] In certain embodiments, the modified oligonucleotide comprises Formula (XXXV), or a salt solvate, or hydrate thereof:k "R2Q3Q4— o' R3Formula (XXXV),wherein:Y is -C(=O)N(Rc)-, or -N(Rc)C(=O)-;Q1and Q3are each independently -H, -OR4, a ligand, a linker, or a lipid;o Ie— p—Q2and Q4are each independently a bond, X, a ligand, a linker, or a lipid;Rcis independently -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl;each R9is independently a substituted or unsubstituted heteroaryl;each instance of Z1or Z2is independently a bond, Ci-Ce alkylene, or C2-C6 alkenylene; and167#14696011vleach X is independently O or S;or a salt thereof.

[0335] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVI), or a salt solvate, or hydrate thereof:O'© R3X. P<°AOR5Formula (XXXVI),wherein:Rcis -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.168#14696011vl

[0336] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVII), or a salt solvate, or hydrate thereof:Formula (XXXVII),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0337] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVIII), or a salt, solvate, or hydrate thereof:169#14696011vl<5 © 'R3X. P<°XOR5Formula (XXXVIII),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0338] In certain embodiments, the modified oligonucleotide comprises Formula (XXXIX), or a salt, solvate, or hydrate thereof:170#14696011vlFormula (XXXIX),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0339] In certain embodiments, the modified oligonucleotide comprises Formula (XXXX), or a salt solvate, or hydrate thereof:171#14696011vld-' e 'R3X-P<°XOR5Formula (XXXX),wherein:each R2is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6), or -SR6;each R3is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7), or -SR7;R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide;each R6is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R7is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;each R8is independently a substituted or unsubstituted heteroaryl ring;each R9is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S;or a salt or prodrug thereof.

[0340] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXI), or a salt solvate, or hydrate thereof:172#14696011vloO'© t)Me. P<°OR5mUemUFormula (XXXXI),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0341] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXII), or a salt, solvate, or hydrate thereof:<5 © t)MeXOR5mAemAFormula (XXXXII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.173#14696011vl

[0342] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXIII), or a salt, solvate, or hydrate thereof:© t)MeY-P<°xOR5mAemUFormula (XXXXIII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0343] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXIV), or a salt, solvate, or hydrate thereof:mAemGFormula (XXXXIV),wherein:174#14696011vlR4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0344] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXV), or a salt, solvate, or hydrate thereof:cf © t> MeX^P<°AOR5mAemCFormula (XXXXV),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0345] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVI), or a salt, solvate, or hydrate thereof:Cf © t)MeAOR5mUemA#14696011vlFormula (XXXXVI),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0346] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVII), or a salt, solvate, or hydrate thereof:OO>' © t)MeAOR5mUemGFormula (XXXXVII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0347] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVIII), or a salt, solvate, or hydrate thereof:#14696011vlmUefCFormula (XXXXVIII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0348] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXIX), or a salt, solvate, or hydrate thereof:ocf © t> MexOR5fGemUFormula (XXXXIX),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.177#14696011vl

[0349] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXX), or a salt, solvate, or hydrate thereof:mGefGFormula (XXXXX),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0350] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXXI), or a salt, solvate, or hydrate thereof:mGemCFormula (XXXXXI),wherein:#14696011vlR4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0351] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXXII), or a salt, solvate, or hydrate thereof:mCemAFormula (XXXXXII),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0352] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXXXXXVI), or a salt, solvate, or hydrate thereof:#14696011vlcf © t)MeX^P<°XOR5mCemUFormula (XXXXXXXXVI),wherein:R4and R5are independently an oligonucleotide, or R4and R5are joined together to form a single oligonucleotide; andeach X is independently O or S.

[0353] In certain embodiments, the modified oligonucleotide comprises an internucleoside linkage of one of the following Formulae:Formula (XXXXXIV),Formula (XXXXXV),5' Formula (XXXXXVI).180#14696011vl

[0354] In certain embodiments, the compound of any preceding embodiment comprises one or more lipid conjugate groups. In certain embodiments, the one or more lipid conjugate groups are attached to one or more intemucleoside linkages of the modified oligonucleotide. In certain embodiments, the one or more lipid conjugate groups are attached to the 5' or 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipid conjugate groups are attached to an internucleoside linkage and the 5' or 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipid conjugate groups are attached to an internucleoside linkage and both the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, the one or more ligands (e.g., one or more TrkB ligands, one or more CBi ligands, one or more a.4 1 / 7 integrin ligands) are attached to the 5' or 3' end of the modified oligonucleotide or both the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, the one or more conjugate groups comprise at least one ligand (e.g., at least one TrkB ligand, at least one CBi ligand, at least one a.401 / 7 integrin ligand) attached to the 5' or 3' end of the modified oligonucleotide or both the 5' and 3' ends of the modified oligonucleotide and at least one lipid. In certain embodiments, the one or more conjugate groups comprise at least one ligand (e.g., at least one TrkB ligand, at least one CBi ligand, at least one a40i / 7 integrin ligand) attached to the 5' or 3' end of the modified oligonucleotide or both the 5' and 3' ends of the modified oligonucleotide and one or more lipid conjugate groups attached to one or more intemucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises a ligand (e.g., a TrkB ligand, a CBi ligand, an a40i / 7 integrin ligand) and a lipid. In certain embodiments, the modified oligonucleotide comprises one or more ligands (e.g., one or more TrkB ligands, one or more CBi ligands, one or more a40i / 7 integrin ligands) and one or more lipids. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide.

[0355] In certain embodiments, the compound of any preceding embodiment comprises one or more substituted or unsubstituted alkyl or alkenyl. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl is attached to an intemucleoside linkage of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl are attached to one or more intemucleoside linkages of the modified oligonucleotide. In certain181#14696011vlembodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C4-C30 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C5-C20 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C14-C20 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Ci6 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C17 hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Cis hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C22 hydrocarbon chain.

[0356] In certain embodiments, a substituted or unsubstituted alkyl or alkenyl is attached to an internucleoside linkage of...

Claims

1. CLAIMS2.What is claimed is:

1. A compound comprising a modified oligonucleotide 14 to 30 linked nucleosides in length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39.

2. A compound comprising a modified oligonucleotide 14 to 23 linked nucleosides in length having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39.

3. A compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39.

4. The compound of any one of claims 1-3, wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO:

1.

5. The compound of any one of claims 1-4, wherein the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

6. The compound of any one of claims 1-5, wherein the compound is double- stranded.

7. A compound comprising a first modified oligonucleotide 14 to 23 linked nucleosides in length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide 14 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

8. A compound comprising a first modified oligonucleotide 14 to 23 linked nucleosides in length having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-39 or SEQ ID NOs: 40-68, and a second modified oligonucleotide 14 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.10.21511.#14696011vl 9. A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-39 and SEQ ID NOs: 40-68 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

10. The compound of any one of claims 7-9, wherein the first modified oligonucleotide has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity to SEQ ID NO: 1 over its length.

11. The compound of any one of claims 7-10, wherein the first modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches to a region of SEQ ID NO: 1 that is the same length as the first modified oligonucleotide.

12. The compound of any one of claims 7-11, wherein the region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide is 14 to 23 linked nucleosides in length.

13. The compound of any one of claims 7-11, wherein the region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide is 19 to 23 linked nucleosides in length.

14. The compound of any one of claims 7-11, wherein the region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide is 21 to 23 linked nucleosides in length.

15. The compound of any one of claims 7-11, wherein the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

16. The compound of any one of claims 7-15, wherein the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

17. The compound of any one of claims 7-16, wherein the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified intemucleoside linkage, a modified sugar, and a modified nucleobase.20.21621.#14696011vl 18. The compound of any one of claims 5, 16 and 17, wherein the modified intemucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate intemucleoside linkage.

19. The compound of claim 18, wherein the phosphorothioate intemucleoside linkage or methylphosphonate intemucleoside linkage is at the 3' terminus of the first or second modified oligonucleotide or at the 5' terminus of the first modified oligonucleotide.

20. The compound of any one of claims 5, 16 and 17, wherein the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar.

21. The compound of claim 20, wherein the modified sugar comprises a 2'-F modification.

22. The compound of claim 20, wherein the modified sugar comprises a 2'-OMe modification.

23. The compound of any one of claims 7-22, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.

24. The compound of any one of claims 7-23, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar.

25. The compound of claim 23 or 24, wherein the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar, or a combination thereof.

26. The compound of claim 25, wherein the modified sugar comprises a modification selected from group consisting of LNA, cEt, 2'-MOE, 2'-F, 2'-OMe, and 2'-deoxy, or a combination thereof.

27. The compound of claim 26, wherein the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications.

28. The compound of claim 26 or 27, wherein the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

29. The compound of any preceding claim, comprising a conjugate group.33.21734.#14696011vl 30. The compound of claim 29, wherein the conjugate group is attached to the 5' end of the modified oligonucleotide.

31. The compound of claim 29 or 30, wherein the conjugate group comprises a targeting moiety.

32. The compound of claim 31, wherein the targeting moiety comprises one or more ligands selected from one or more Tropomyosin receptor B (TrkB) ligands, one or more cannabinoid receptor type 1 (CBi) ligands, and one or more a.4 1 / 7 integrin ligands.

33. The compound of any one of claims 30-32, wherein the modified oligonucleotide is the second modified oligonucleotide.

34. The compound of claim 33, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more a.401 / 7 integrin ligands are attached to the 5' end of the second modified oligonucleotide.

35. The compound of claim 33, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more ai 1 / ? integrin ligands are attached to the 3' end of the second modified oligonucleotide.

36. The compound of claim 33, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more ai 1 / ? integrin ligands are attached to the 5' end and the 3' end of the second modified oligonucleotide.

37. The compound of claim 33, wherein:42.the one or more TrkB ligands are selected from any one of Formulae I- XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, XXXXXXXXV, XXXXXXXXVII, and one of the structures of Table 1;43.the one or more CBi ligands are selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII; and44.the one or more a40i / 7 integrin ligands are selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.

38. The compound of any one of claims 29-37, wherein the conjugate group comprises one or more lipids.46.21847.#14696011vl 39. The compound of claim 38, wherein the modified oligonucleotide is the second modified oligonucleotide.

40. The compound of claim 38 or 39, wherein the one or more lipids are attached to an intemucleoside linkage of the modified oligonucleotide.

41. The compound of claim 40, wherein the internucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI.

42. The compound of any one of claims 38-40, wherein the modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI.

43. The compound of any one of claims 32-42, wherein the modified oligonucleotide comprises one or more TrkB ligands, one or more CBi ligands, or one or more a.4 1 / 7 integrin ligands.

44. The compound of claim 43, wherein the modified oligonucleotide comprises one or more TrkB ligands.

45. The compound of claim 44, wherein the one or more TrkB ligands are selected from any one of Formulae I-XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, xxxxxxxxv, XXXXXXXXVII, and one of the structures of Table 1.

46. The compound of claim 45, wherein the one or more TrkB ligands are selected from any one of Formulae III- VIII, XXIX-XXXI, XXXXXXV, and XXXXXXXXVII.

47. The compound of any one of claims 44-46, wherein the modified oligonucleotide comprises one or two TrkB ligands.

48. The compound of any one of claims 44-46, wherein the modified oligonucleotide comprises at least two TrkB ligands.

49. The compound of claim 48, wherein the at least two TrkB ligands are the same.

50. The compound of claim 48, wherein the at least two TrkB ligands are different.

51. The compound of claim 43, wherein the modified oligonucleotide comprises one or more CBi ligands.58.21959.#14696011vl 52. The compound of claim 51, wherein the one or more CBi ligands are selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII.

53. The compound of claim 52, wherein the one or more CBi ligands are selected from any one of Formulae XXXXXXXIV-XXXXXXXVI.

54. The compound of any one of claims 51-53, wherein the modified oligonucleotide comprises one or two CBi ligands.

55. The compound of any one of claims 51-53, wherein the modified oligonucleotide comprises at least two CBi ligands.

56. The compound of claim 55, wherein the at least two CBi ligands are the same.

57. The compound of claim 55, wherein the at least two CBi ligands are different.

58. The compound of claim 43, wherein the modified oligonucleotide comprises one or more a.4 1 / 7 integrin ligands.

59. The compound of claim 58, wherein the one or more a.401 / 7 integrin ligands are selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.

60. The compound of claim 59, wherein the one or more a40i / 7 integrin ligands are selected from any one of Formulae XXXXXXXXI, XXXXXXXXII, and XXXXXXXXIV.

61. The compound of any one of claims 58-60, wherein the modified oligonucleotide comprises one or two a40i / 7 integrin ligands.

62. The compound of any one of claims 58-60, wherein the modified oligonucleotide comprises at least two a40i / 7 integrin ligands.

63. The compound of claim 62, wherein the at least two a40i / 7 integrin ligands are the same.

64. The compound of claim 62, wherein the at least two a40i / 7 integrin ligands are different.

65. The compound of any one of claims 44-64, wherein the modified oligonucleotide comprises one or more lipids.71.22072.#14696011vl 66. The compound of claim 65, wherein the modified oligonucleotide is the second modified oligonucleotide.

67. The compound of any one of claims 44-66, wherein the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl.

68. The compound of claim 67, wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C4-C30 hydrocarbon chain.

69. The compound of claim 68, wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C5-C20 hydrocarbon chain, optionally wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C14-C20 hydrocarbon chain.

70. The compound of claim 69, wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Ci6 hydrocarbon chain, a saturated or unsaturated C17 hydrocarbon chain, a saturated or unsaturated Cis hydrocarbon chain, or a saturated or unsaturated C22 hydrocarbon chain.

71. The compound of any one of claims 67-70, wherein the one or more substituted or unsubstituted alkyl or alkenyl are attached to an intemucleoside linkage of the modified oligonucleotide.

72. The compound of claim 71, wherein the internucleoside linkage is between positions I and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions I I and 12, positions 12 and 13, or positions 13 and 14 from the 5' end of the modified oligonucleotide.

73. The compound of claim 72, wherein the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 5' end of the modified oligonucleotide.

74. The compound of claim 71, wherein the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions81.22182.#14696011vl 11 and 12, positions 12 and 13, or positions 13 and 14 from the 3' end of the modified oligonucleotide.

75. The compound of claim 74, wherein the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 3' end of the modified oligonucleotide.

76. The compound of any one of claims 71-75, wherein the intemucleoside linkage of the modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI.

77. The compound of any one of claims 65-76, wherein the modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI.

78. The compound of any one of claims 1-6, wherein the modified oligonucleotide comprises a 5'-phosphonate modification.

79. The compound of any one of claims 7-77, wherein the first modified oligonucleotide comprises a 5'-phosphonate modification.

80. The compound of claim 78 or 79, wherein the 5 '-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

81. A compound comprising:89.a first modified oligonucleotide comprising a 5 '-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1; and90.a second modified oligonucleotide comprising one or more ligands.

82. The compound of claim 81, wherein the first modified oligonucleotide comprises a 5'-terminal nucleoside comprising the 5 '-phosphonate modification.

83. The compound of claim 81 or 82, wherein the 5 '-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

84. The compound of any one of claims 81-83, wherein the 5 '-phosphonate modification is a 5'-vinylphosphonate modification.

85. The compound of any one of claims 81-83, wherein the 5 '-phosphonate modification is a 5'-ethylenephosphonate modification.95.22296.#14696011vl 86. The compound of any one of claims 81-85, wherein the second modified oligonucleotide comprises one or more ligands selected from one or more Tropomyosin receptor B (TrkB) ligands, one or more cannabinoid receptor type 1 (CBi) ligands, and one or more a.4 1 / 7 integrin ligands.

87. The compound of claim 86, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more a.401 / 7 integrin ligands are attached to the 5' end of the second modified oligonucleotide.

88. The compound of claim 86, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more ai 1 / ? integrin ligands are attached to the 3' end of the second modified oligonucleotide.

89. The compound of claim 86, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more ai 1 / ? integrin ligands are attached to the 5' end and the 3' end of the second modified oligonucleotide.

90. The compound of claim 86, wherein:101.the one or more TrkB ligands are selected from any one of Formulae I- XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, XXXXXXXXV, XXXXXXXXVII, and one of the structures of Table 1;102.the one or more CBi ligands are selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII; and103.the one or more a40i / 7 integrin ligands are selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.

91. The compound of any one of claims 81-90, wherein the second modified oligonucleotide comprises one or more TrkB ligands.

92. The compound of claim 91, wherein the one or more TrkB ligands are selected from any one of Formulae I-XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, XXXXXXXXV, and XXXXXXXXVII.106.223107.#14696011vl 93. The compound of claim 92, wherein the one or more TrkB ligands are selected from any one of Formulae III- VIII, XXIX-XXXI, XXXXXXV, XXXXXXXXVII, and one of the structures of Table 1.

94. The compound of any one of claims 91-93, wherein the second modified oligonucleotide comprises one or two TrkB ligands.

95. The compound of any one of claims 91-93, wherein the second modified oligonucleotide comprises at least two TrkB ligands.

96. The compound of claim 95, wherein the at least two TrkB ligands are the same.

97. The compound of claim 95, wherein the at least two TrkB ligands are different.

98. The compound of any one of claims 81-90, wherein the second modified oligonucleotide comprises one or more CBi ligands.

99. The compound of claim 98, wherein the one or more CBi ligands are selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII.

100. The compound of claim 99, wherein the one or more CBi ligands are selected from any one of Formulae XXXXXXXIV-XXXXXXXVI.

101. The compound of any one of claims 98-100, wherein the second modified oligonucleotide comprises one or two CBi ligands.

102. The compound of any one of claims 98-100, wherein the second modified oligonucleotide comprises at least two CBi ligands.

103. The compound of claim 102, wherein the at least two CBi ligands are the same.

104. The compound of claim 102, wherein the at least two CBi ligands are different.

105. The compound of any one of claims 81-90, wherein the second modified oligonucleotide comprises one or more a.4 1 / 7 integrin ligands.

106. The compound of claim 105, wherein the one or more a.401 / 7 integrin ligands are selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.117.224118.#14696011vl 107. The compound of claim 106, wherein the one or more a.4 1 / 7 integrin ligands are selected from any one of Formulae XXXXXXXXI, XXXXXXXXII, and XXXXXXXXIV.

108. The compound of any one of claims 105-107, wherein the second modified oligonucleotide comprises one or two a.401 / 7 integrin ligands.

109. The compound of any one of claims 105-107, wherein the second modified oligonucleotide comprises at least two a40i / 7 integrin ligands.

110. The compound of claim 109, wherein the at least two a40i / 7 integrin ligands are the same.

111. The compound of claim 109, wherein the at least two a40i / 7 integrin ligands are different.

112. The compound of any one of claims 81-111, wherein the second modified oligonucleotide comprises one or more lipids.

113. The compound of any one of claims 81-111, wherein the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl.

114. The compound of claim 113, wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C4-C30 hydrocarbon chain.

115. The compound of claim 114, wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C5-C20 hydrocarbon chain, optionally wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated C14-C20 hydrocarbon chain.

116. The compound of claim 115, wherein the one or more substituted or unsubstituted alkyl or alkenyl comprise a saturated or unsaturated Ci6 hydrocarbon chain, a saturated or unsaturated C17 hydrocarbon chain, a saturated or unsaturated Cis hydrocarbon chain, or a saturated or unsaturated C22 hydrocarbon chain.

117. The compound of any one of claims 113-116, wherein the one or more substituted or unsubstituted alkyl or alkenyl are attached to an intemucleoside linkage of the second modified oligonucleotide.129.225130.#14696011vl 118. The compound of claim 117, wherein the internucleoside linkage is between positions I and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions I I and 12, positions 12 and 13, or positions 13 and 14 from the 5' end of the second modified oligonucleotide.

119. The compound of claim 118, wherein the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 5' end of the second modified oligonucleotide.

120. The compound of claim 117, wherein the internucleoside linkage is between positions I and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions I I and 12, positions 12 and 13, or positions 13 and 14 from the 3' end of the second modified oligonucleotide.

121. The compound of claim 120, wherein the internucleoside linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 from the 3' end of the second modified oligonucleotide.

122. The compound of any one of claims 117-121, wherein the intemucleoside linkage of the second modified oligonucleotide is selected from any one of Formulae XXXXXIII-XXXXXVI.

123. The compound of any one of claims 112-122, wherein the second modified oligonucleotide comprises any one of Formulae III-A, XXXV-XXXXXVI, and XXXXXXXXVI.

124. The compound of any one of claims 81-123, wherein the first modified oligonucleotide is 14 to 30 linked nucleosides in length.

125. The compound of any one of claims 81-124, wherein the second modified oligonucleotide is 14 to 30 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.138.226139.#14696011vl 126. The compound of any one of claims 81-125, wherein the first modified oligonucleotide has a nucleobase sequence comprising at least 14 contiguous nucleobases of any one of SEQ ID NOs: 11-39.

127. The compound of any one of claims 81-126, wherein the second modified oligonucleotide has a nucleobase sequence comprising at least 14 contiguous nucleobases of any one of SEQ ID NOs: 40-68.

128. The compound of any one of claims 81-127, wherein the first modified oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 71-99.

129. The compound of any one of claims 81-128, wherein the second modified oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 100-137.

130. A compound comprising a first modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 71-99, and a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide.

131. A compound comprising a first modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 71-99, and a second modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 100-137.

132. A compound comprising a first modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 71-99, and / or a second modified oligonucleotide selected from the group consisting of any one of SEQ ID NOs: 100-137.

133. The compound of claim 130, 131, or 132, comprising a conjugate group.

134. The compound of claim 133, wherein the conjugate group is attached to the 5' end of the first or second modified oligonucleotide.

135. The compound of claim 133 or 134, wherein the conjugate group comprises a targeting moiety.

136. The compound of claim 135, wherein the targeting moiety comprises one or more ligands selected from one or more Tropomyosin receptor B (TrkB) ligands, one or more cannabinoid receptor type 1 (CBi) ligands, and one or more a.4 1 / 7 integrin ligands.150.227151.#14696011vl 137. The compound of claim 136, wherein the modified oligonucleotide is the second modified oligonucleotide.

138. The compound of claim 137, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more a.4 1 / 7 integrin ligands are attached to the 5' end of the modified oligonucleotide.

139. The compound of claim 137, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more a.401 / 7 integrin ligands are attached to the 3' end of the modified oligonucleotide.

140. The compound of claim 137, wherein the one or more TrkB ligands, the one or more CBi ligands, or the one or more ai 1 / ? integrin ligands are attached to the 5' end and the 3' end of the modified oligonucleotide.

141. The compound of claim 137, wherein:156.the one or more TrkB ligands are selected from any one of Formulae I- XXVII, XXIX-XXXI, XXXIII-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, XXXXXXIX-XXXXXXXIII, XXXXXXXXV, XXXXXXXXVII, and one of the structures of Table 1;157.the one or more CBi ligands are selected from any one of Formulae XXXXXXI and XXXXXXXIV-XXXXXXXVIII; and158.the one or more a40i / 7 integrin ligands are selected from any one of Formulae XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.

142. A compound of any one of the preceding claims, wherein the compound is in a pharmaceutically acceptable salt form.

143. The compound of claim 142, wherein the pharmaceutically acceptable salt is a sodium salt.

144. The compound of claim 142, wherein the pharmaceutically acceptable salt is a potassium salt.

145. A composition comprising the compound of any preceding claim and a pharmaceutically acceptable carrier.

146. A composition comprising a compound of any preceding claim, for use in therapy.164.228165.#14696011vl 147. A method of treating, preventing or ameliorating a disease, disorder or condition associated with aSyn in an individual comprising administering to the individual a compound targeted to aSyn, thereby treating, preventing, or ameliorating the disease, disorder or condition.

148. A method of administering the compound of any one of claims 1-144 or composition of claim 146 to an individual.

149. The method of claim 147 or 148, wherein the disease, disorder or condition is a neurodegenerative disease.

150. The method of claim 149, wherein the disease, disorder or condition is Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD).

151. The method of claim 149, wherein the disease, disorder or condition is a synucleinopathy, pure autonomic failure (PAF), Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic gram disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden- Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer’s disease, Huntington’s disease, Down’s syndrome, psychosis, schizophrenia, or Creutzfeldt- Jakob disease.

152. The method of any one of claims 147-151, wherein administering the compound inhibits or reduces or improves a neurodegenerative disease, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD).

153. A method of inhibiting expression of a-synuclein in a cell comprising contacting the cell with a compound targeted to aSyn, thereby inhibiting expression of a-synuclein in the cell.

154. The method of claim 153, wherein the cell is in the brain of an individual.

155. The method of claim 154, wherein the individual has, or is at risk of having, a neurodegenerative disease, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD).174.229175.#14696011vl 156. A method of reducing or inhibiting a neurodegenerative disease, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD) in an individual, comprising administering a compound targeted to aSyn to the individual, thereby reducing or inhibiting a neurodegenerative disease, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD) in the individual.

157. The method of claim 156, wherein the individual has, or is at risk of having, a neurodegenerative disease, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD).

158. The method of any one of claims 147-157, wherein the compound is a compound targeted to aSyn.

159. The method of any one of claims 147-158, wherein the compound is the compound of any one of claims 1-144 or composition of claim 146.

160. The method of claim 159, wherein the compound or composition is administered parenterally.

161. The method of claim 159, wherein the compound or composition is administered by intrathecal administration.

162. Use of a compound targeted to aSyn for treating, preventing, or ameliorating a disease, disorder or condition associated with a-synuclein.

163. The use of claim 162, wherein the disease, disorder or condition is a neurodegenerative disease, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD).

164. The use of claim 162 or 163, wherein the compound is a compound targeted to aSyn.

165. The use of any one of claims 162-164, wherein the compound is the compound of any one of claims 1-144 or composition of claim 146.

166. Use of a compound targeted to aSyn in the manufacture of a medicament for treating, preventing, or ameliorating a disease, disorder or condition associated with a-synuclein.186.230187.#14696011vl 167. The use of claim 166, wherein the disease is a neurodegenerative disease, including a synucleinopathy, Parkinson’s disease, multiple system atrophy (MSA), or Lewy body dementia (LBD).

168. The use of claim 166 or 167, wherein the compound is a compound targeted to aSyn.

169. The use of any one of claims 166-168, wherein the compound is the compound of any one of claims 1-144 or composition of claim 146.

170. The method or use of any preceding claim, wherein the compound or composition is administered to an individual about once every three months to about once every year.

171. The method or use of any preceding claim, wherein the compound or composition is administered to an individual about once every three months, about once every six months, or about once every year.

172. A method for delivering a therapeutic oligonucleotide to the brain of a subject, comprising administration of a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, of any one of claims 1-144 or composition of claim 146 to the subject.

173. The method of claim 172, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, the cerebellum, the brain stem, the hippocampus, the frontal cortex, and the spinal cord.

174. A method for treating or ameliorating a disease, disorder, or symptom thereof in a subject, comprising administration of a compound, or a stereoisomer, tautomer, prodrug, or salt thereof, of any one of claims 1-144 or composition of claim 146 to the subject.

175. The method of claim 174, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.

176. The method of claim 174 or 175, wherein the disease, disorder, or symptom thereof is Parkinson’s disease, or a symptom thereof.

177. The method of any one of claims 172-176, wherein the administration is intrathecal administration or intracerebroventricular (ICV) administration.198.231199.#14696011vl 178. A method of delivering one or more cargo molecules to a cell or tissue of a subject in vivo, comprising administering to the subject a compound of any one of claims 1-144 or composition of claim 146.

179. The method of claim 178, wherein the cell or tissue is CNS cell or tissue.201.232202.#14696011vl

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