Compositions and methods for the treatment of disorders related to ataxin-2

Abstract

The disclosure relates to compositions and methods for modulating, e.g., reducing or eliminating, the expression of ATXN2 via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful in the treatment of subjects diagnosed with, suspected of having, or having spinocerebellar ataxia type 2 (SCA2) or another ATXN2-related disorder.

Description

Attorney Docket No.14640.0093-00304 COMPOSITIONS AND METHODS FOR THE TREATMENT OF DISORDERS RELATED TO ATAXIN-2 RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to US Provisional Application Serial No. 63 / 519,948, filed August 16, 2023, the contents of which are incorporated herein by reference in their entirety. SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing file, entitled 14640_0093-00304_SL.xml, was created on June 18, 2024, and is 2,602,685 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE

[0003] Described herein are compositions and methods relating to adeno-associated virus (AAV) viral particles for the delivery of polynucleotides, e.g., modulatory polynucleotides for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA, thereby reducing or eliminating ATXN2 protein, and their use in the treatment of spinocerebellar ataxia type 2 (SCA2) and other disorders associated with aberrant ATXN2 protein expression or activity or mutated ATXN2 protein. In some embodiments, compositions described herein may be used to treat a subject in need thereof, such as a human subject having SCA2 or another condition resulting from or associated with mutant ATXN2 protein or aberrant ATXN2 protein expression or activity. BACKGROUND

[0004] The Ataxin-2 protein (also referred to herein as ATXN2 protein) is encoded by the ATXN2 gene (Ensembl Gene ID No. ENSG00000204842), which is also known as ATX2 and TNRC13. It is located on chromosome 12 of the human genome.

[0005] The function of Ataxin-2 is not known, but it is found in the cytoplasm and is thought to interact with the endoplasmic reticulum.

[0006] Mutations in ATXN2 cause disease in human subjects. ATXN2 mutations are known to cause spinocerebellar ataxia type 2 (SCA2). SCA2 is an autosomal dominant cerebellar ataxia. ATXN2 mutations also play a role in other ATXN2-related disorders, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and frontotemporal lobar degeneration (FTLD).

[0007] SCA2 is typically caused by CAG trinucleotide repeat expansions in the ATXN2 gene on 12q24.1. Patients with SCA2 have ATXN2 alleles with 32 or more trinucleotide repeats, resulting in ATXN2 protein with polyQ expansions. PolyQ expansions in ATXN2 (e.g., intermediate length polyQ expansions) have been associated with other diseases, like ALS, as well.Attorney Docket No.14640.0093-00304

[0008] The age of onset of SCA2 is thought to correlate with the number of CAG trinucleotide repeats. Onset is typically later than age 60 in subjects with 32-34 CAG repeats (SEQ ID NO: 6434). Onset is typically between ages 20 and 60 in subjects with 35-40 CAG repeats (SEQ ID NO: 6435). Onset is typically before age 20 for patients with 45 or more CAG repeats (SEQ ID NO: 6436).

[0009] Mutated ATXN2 is thought to produce an Ataxin-2 protein with an abnormally long stretch of glutamine residues. The cellular impact of mutant Ataxin-2 protein is not confirmed. Without wishing to be bound by any particular theory, mutant Ataxin-2 (e.g., Ataxin-2 with a polyQ expansion) may accumulate in cells and cause cell death.

[0010] SCA2 is characterized by progressive cerebellar ataxia, including nystagmus, and slow saccadic eye movements. It may also present with ophthalmoparesis and / or parkinsonism. Later stages of SCA2 mainly involve the brainstem and cerebellum.

[0011] There are no specific treatments for SCA2. Trials have considered riluzole, which inhibits glutamic acid release, for treating SCA2. However, there are no treatments targeting the cause of SCA2. Thus, there remains a long-felt need to develop pharmaceutical compositions and methods for the treatment of SCA2. In particular, a need exists for treatments of SCA2 targeting the brainstem and cerebellum.

[0012] There remains a need for effective methods of treatment using AAV capsids that are capable of delivering a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA (thereby reducing or eliminating ATXN2 protein), to a target cell or tissue, e.g., a CNS cell or tissue. SUMMARY

[0013] The present disclosure addresses these challenges by providing AAV-based compositions, AAV-based compositions for use in methods for treating an ATXN2-related disorder in subjects, and methods for treating an ATXN2-related disorder in subjects, wherein the ATXN2-related disorder is, e.g., SCA2. Disclosed herein are compositions and methods directed to AAV-based gene delivery of modulatory polynucleotides for reducing or eliminating expression of ATXN2 to treat an ATXN2-related disorder, such as SCA2. In some embodiments, the compositions and methods reduce or eliminate expression of ATXN2 mRNA, and thereby reduce or eliminate ATXN2 protein, to treat an ATXN2- related disorder, such as SCA2. The compositions and methods are useful to reduce the effects of mutant ATXN2 or aberrant ATXN2 protein expression or activity, and to slow, halt, or reverse muscular and other symptoms of an ATXN2-related disorder, such as SCA2. In some embodiments, the compositions and methods disclosed herein may reduce or eliminate the expression of aberrant or mutated ATXN2. In some embodiments, aberrant ATXN2 expression refers to expression of ATXN2 mRNA comprising 32 or more CAG trinucleotide repeats (SEQ ID NO: 6437) and thus resulting in ATXN2 protein comprising polyQ expansions. In some embodiments, mutated ATXN2 refers to ATXN2 mRNA comprising 32 or more CAG trinucleotide repeats (SEQ ID NO: 6437) and / or to ATXN2 protein comprising polyQ expansions. As used herein, the terms “ATXN2,” “ATX2,” and “TNRC13” are synonymous terms.Attorney Docket No.14640.0093-00304

[0014] In some embodiments, the present disclosure provides an AAV particle comprising a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2, and an AAV capsid. In some embodiments, the nucleotide sequence encoding the modulatory polynucleotide is comprised in a viral genome. In some embodiments, the modulatory polynucleotide reduces or eliminates ATXN2 mRNA. In some embodiments, the modulatory polynucleotide reduces or eliminates ATXN2 protein by reducing or eliminating ATXN2 mRNA. In some embodiments, the AAV capsid is an AAV capsid variant. In some embodiments, the AAV capsid variant is an AAV5 capsid variant.

[0015] In some embodiments, the AAV capsid variant (e.g., an AAV5 capsid variant) comprises a peptide that has replaced amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant is an AAV5 capsid variant comprising a peptide comprising the amino acid sequence of VQK in loop VIII, wherein, optionally, the amino acid sequence of VQK has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) in loop VIII, or a peptide comprising one, two, or three—but no more than three—substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein, optionally, the amino acid sequence has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) in loop VIII, wherein, optionally, the peptide has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the peptide is present in a VP1 protein, a VP2 protein, and / or a VP3 protein of the AAV capsid variant. In some embodiments, the peptide is present in the VP1, VP2, and VP3 proteins of the AAV capsid variant.

[0016] In some embodiments, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA; and wherein the AAV capsid variant comprises an amino acid sequence having the formula [N2]-[N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1is Y, N, or C; (b) position X2is P, K, T, or Q; (c) position X3is A or P; (d) position X4is E, S, or A; and (e) position X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence VQK, EQK, VKK, VHK, VQQ, or LQK; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% identical thereto.

[0017] In some embodiments, [N2]-[N3] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence SEQ ID NO: 982. In some embodiments, [N2]-[N3] is present immediately subsequent to an amino acid corresponding to position 576 of the amino acid sequence of SEQ ID NO: 982. In some embodiments,Attorney Docket No.14640.0093-00304 the AAV capsid variant is an AAV5 capsid variant comprising [N2]-[N3] in place of an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138. In some embodiments, [N2] comprises the amino acid sequence YP, YPA, YPAE (SEQ ID NO: 21), or YPAEV (SEQ ID NO: 1). In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, [N2]-[N3] comprises the amino acid sequence AEVVQK (SEQ ID NO: 36) or PAEVVQK (SEQ ID NO: 20). In some embodiments, [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0018] In some embodiments, the AAV capsid variant further comprises [N1] comprising positions XD, XE, and XF, wherein: (a) position XDof [N1] is Q, T, S, A, I, L, or H; (b) position XEof [N1] is S, G, A, or R; and (c) position XFof [N1] is S, K, L, R, A, or T; wherein [N1] immediately precedes [N2]- [N3]. In some embodiments, [N1] comprises the amino acid sequence QS, SS, or QSS. In some embodiments, [N1]-[N2] comprises the amino acid sequence QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] comprises the amino acid sequence SSYPAEVVQ (SEQ ID NO: 121) or QSSYPAEVVQK (SEQ ID NO: 150).

[0019] In some embodiments, the AAV capsid variant further comprises [N0] comprising positions XA, XB, and XC, wherein: (a) position XAof [N0] is T, I, or N; (b) position XBof [N0] is N; and (c) position XCof [N0] is N, T, S, or K; wherein [N0] immediately precedes [N1]. In some embodiments, [N0] comprises the amino acid sequence TN, NN, or TNN. In some embodiments, [N0]-[N1] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183). In some embodiments, [N0]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0020] In some embodiments, the AAV capsid variant further comprises [N4] comprising positions XGand XH, wherein: (a) position XGof [N4] is T, P, or N; and (b) position XHof [N4] is A; wherein [N4] is present immediately subsequent to [N3]. In some embodiments, [N4] comprises the amino acid sequence TA. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0021] In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, [N0] is present at amino acids corresponding to positions 571-573 of the amino acid sequence of SEQ ID NO: 982; [N1] is present at amino acids corresponding to positions 574-576 of the amino acid sequence of SEQ ID NO: 982; [N2] is present at amino acids corresponding to positions 577-581 of the amino acid sequence of SEQ ID NO: 982; [N3] is present at amino acids corresponding to positions 582-584 of the amino acid sequence of SEQ ID NO: 982; and [N4] is present at amino acids corresponding to positions 585-586 of the amino acid sequence of SEQ ID NO: 982.

[0022] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA sequence; and (ii) an AAV capsidAttorney Docket No.14640.0093-00304 variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises at least 4, 5, 6, 7, or 8 consecutive amino acids from the amino acid sequence YPAEVVQK (SEQ ID NO: 943). In some embodiments, (i) the at least 4 consecutive amino acids comprise the amino acid sequence YPAE (SEQ ID NO: 21), optionally present at amino acids corresponding to positions 577-580 of the amino acid sequence of SEQ ID NO: 982; (ii) the at least 5 consecutive amino acids comprise the amino acid sequence YPAEV (SEQ ID NO: 1), optionally present at amino acids corresponding to positions 577-581 of the amino acid sequence of SEQ ID NO: 982; (iii) the at least 6 consecutive amino acids comprise the amino acid sequence YPAEVV (SEQ ID NO: 725), optionally present at amino acids corresponding to positions 577-582 of the amino acid sequence of SEQ ID NO: 982; or (iv) the at least 7 consecutive amino acids comprise the amino acid sequence YPAEVVQ (SEQ ID NO: 726), optionally present at amino acids corresponding to positions 577-583 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) present at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982.

[0023] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV capsid variant further comprises (i) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (ii) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0024] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA and the AAV capsid variant comprises (i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943), wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. In some embodiments, the AAV capsid variantAttorney Docket No.14640.0093-00304 comprises (i) the amino acid sequence of SEQ ID NO: 982; (ii) the amino acid sequence of SEQ ID NO: 738; and / or (iii) the amino acid sequence of SEQ ID NO: 739.

[0025] In some embodiments, the modulatory polynucleotide comprises a molecular scaffold, wherein the molecular scaffold comprises: (a) a 5’ flanking region comprising any one of SEQ ID NOs: 6413-6416 or a nucleic acid sequence at least 95% identical thereto; (b) a loop region comprising any one of SEQ ID NOs: 6417-6421 or a nucleic acid sequence at least 95% identical thereto; and (c) a 3’ flanking region comprising any one of SEQ ID NOs: 6422-6427 or a nucleic acid sequence at least 95% identical thereto.

[0026] In some embodiments, (a) the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414 or SEQ ID NO: 6415, or a nucleic acid sequence at least 95% identical thereto; (b) the loop region of the molecular scaffold comprises SEQ ID NO: 6417, SEQ ID NO: 6418, or SEQ ID NO: 6421, or a nucleic acid sequence at least 95% identical thereto; and (c) the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423, SEQ ID NO: 6424, or SEQ ID NO: 6425, or a nucleic acid sequence at least 95% identical thereto.

[0027] In some embodiments, the 5’ flanking region comprises SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6423 or a nucleic acid sequence at least 95% identical thereto.

[0028] In some embodiments, the 5’ flanking region comprises SEQ ID NO: 6415 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6421 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6425 or a nucleic acid sequence at least 95% identical thereto.

[0029] In some embodiments, the 5’ flanking region comprises SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6424 or a nucleic acid sequence at least 95% thereto.

[0030] In some embodiments, the 5’ flanking region comprises SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6418 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6423 or a nucleic acid sequence at least 95% thereto.

[0031] In some embodiments, the modulatory polynucleotide comprises siRNA or shRNA.

[0032] In some embodiments, the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more ATXN2 mRNA transcripts, wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the passenger strand, the loop region, the guide strand, and the 3' flanking region.

[0033] In some embodiments, the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or moreAttorney Docket No.14640.0093-00304 ATXN2 mRNA transcripts, wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the guide strand, the loop region, the passenger strand, and the 3' flanking region.

[0034] In some embodiments, the passenger strand is 15-30 nucleotides in length. In some embodiments, the guide strand is 15-30 nucleotides in length. In some embodiments, the guide strand is 21-25 nucleotides in length and / or the passenger strand is 21-25 nucleotides in length. In some embodiments, the passenger strand is at least 70%, 80%, 90%, or 95%, or is 100%, complementary to the guide strand.

[0035] In some embodiments, the one or more ATXN2 mRNA transcripts comprises SEQ ID NO: 6428, SEQ ID NO: 6429, SEQ ID NO: 6430, SEQ ID NO: 6431, SEQ ID NO: 6434, SEQ ID NO: 6435, SEQ ID NO: 6436, and / or SEQ ID NO: 6437, or a trinucleotide repeat expansion thereof.

[0036] In some embodiments, the viral genome comprises a promoter operably linked to the nucleic acid sequence encoding the modulatory polynucleotide. In some embodiments, the viral genome further comprises an inverted terminal repeat (ITR) sequence. In some embodiments, the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid sequence encoding the modulatory polynucleotide. In some embodiments, the viral genome comprises an ITR sequence positioned 3’ relative to the nucleic acid sequence encoding the modulatory polynucleotide. In some embodiments, the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid sequence encoding the modulatory polynucleotide, and an ITR sequence positioned 3’ relative to the nucleic acid sequence encoding the modulatory polynucleotide.

[0037] In some embodiments, the present disclosure provides a cell disclosed herein, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

[0038] In some embodiments, the present disclosure provides a method of making an AAV particle disclosed herein, wherein the method comprises: (i) providing a cell comprising the viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA and a nucleic acid encoding an AAV capsid variant disclosed herein; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle.

[0039] In some embodiments, the viral genome comprises: (a) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% identical thereto; (b) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6415 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6421 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6425 or a nucleic acid sequence at least 95% identical thereto; (c) a 5’ flanking region comprising theAttorney Docket No.14640.0093-00304 nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6424 or a nucleic acid sequence at least 95% thereto; or (d) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6418 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% thereto; and wherein the AAV capsid variant comprises (i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); or (iii) the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0040] In some embodiments, the viral genome comprises: (a) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% identical thereto; (b) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6415 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6421 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6425 or a nucleic acid sequence at least 95% identical thereto; (c) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6424 or a nucleic acid sequence at least 95% thereto; or (d) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6418 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% thereto; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO: 739. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.Attorney Docket No.14640.0093-00304

[0041] In some embodiments, the method of making the AAV particle further comprises, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell. In some embodiments, the method further comprises, prior to step (i) introducing the nucleic acid encoding the AAV capsid variant into the cell.

[0042] In some embodiments, the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

[0043] In some aspects, the present disclosure provides a pharmaceutical composition comprising an AAV particle disclosed herein and a pharmaceutically acceptable excipient.

[0044] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA to a cell, comprising administering an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the cell is in a subject. In some embodiments, the method reduces or eliminates ATXN2 protein in the subject. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having an ATXN2-related disorder. In some embodiments, the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

[0045] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA to a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the method reduces or eliminates ATXN2 protein in the subject. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having an ATXN2-related disorder. In some embodiments, the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

[0046] In some aspects, the present disclosure provides a method of treating an ATXN2-related disorder in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder. In some embodiments, the subject has one or more mutations in the ATXN2 gene. In some embodiments, the one or more mutations in the ATXN2 gene comprises a trinucleotide repeat expansion. In some embodiments, the trinucleotide repeat expansion in the ATXN2 gene comprises 32 or more CAG repeats (SEQ ID NO: 6437).

[0047] In some embodiments, the treating results in prevention of progression of the ATXN2-related disorder in the subject. In some embodiments, the treating results in amelioration of at least one symptom of the ATXN2-related disorder in the subject. In some embodiments, the at least one symptom comprises progressive cerebellar ataxia, nystagmus, slow saccadic eye movements, ophthalmoparesis, parkinsonism, or a combination thereof. In some embodiments, the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

[0048] In some aspects, the present disclosure provides a method of treating spinocerebellar ataxia type 2 (SCA2) in a subject, comprising administering to the subject an effective amount of aAttorney Docket No.14640.0093-00304 pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having SCA2.

[0049] In some embodiments, the subject is a human.

[0050] In some embodiments, the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the central nervous system (CNS) in the subject. In some embodiments, the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum. In some embodiments, the AAV particle or the pharmaceutical composition is delivered to the subject via intravenous administration.

[0051] In some embodiments, the method of delivering or treating further comprises evaluating, e.g., measuring, the level of modulatory polynucleotide expression, and / or the level of ATXN2 expression, e.g., ATXN2 gene expression, ATXN2 mRNA expression, and / or ATXN2 protein expression, in the subject, e.g., in a cell, tissue, or fluid of the subject. In some embodiments, the level of ATXN2 protein is measured by an ELISA, a Western blot, or an immunohistochemistry assay. In some embodiments, the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the central nervous system (CNS) in the subject. In some embodiments, the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum. In some embodiments, the evaluating of the subject’s level of modulatory polynucleotide expression and / or level of ATXN2 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of modulatory polynucleotide expression and / or the subject’s level of ATXN2 expression prior to administration is compared to the subject’s level of modulatory polynucleotide expression and / or the subject’s level of ATXN2 expression subsequent to administration. In some embodiments, the subject’s level of ATXN2 protein expression subsequent to administration is decreased relative to the subject’s level of ATXN2 protein expression prior to administration.

[0052] In some embodiments, administering the pharmaceutical composition or the AAV particle to the subject results in: (i) a decrease in ATXN2 protein expression in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum), and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or relative to ATXN2 protein expression in a cell, tissue, or fluid of an individual with an ATXN2- related disorder who has not been administered the pharmaceutical composition or AAV particle; (ii) an increase in the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or (iii)Attorney Docket No.14640.0093-00304 a decrease in ATXN2 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or relative to ATXN2 mRNA expression in a cell or tissue of an individual with an ATXN2-related disorder who has not been administered the pharmaceutical composition or AAV particle.

[0053] In some embodiments, the method of delivering or treating further comprises administering to the subject at least one additional therapeutic agent and / or therapy. In some embodiments, the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating the ATXN2-related disorder. In some embodiments, the at least one additional therapeutic agent and / or therapy comprises one or more of: growth and trophic factors, cytokines, hormones, neurotransmitters, enzymes, anti-apoptotic factors, angiogenic factors, modulatory polynucleotides, and any protein known to be mutated in pathological disorders such as ATXN2-related disorders.

[0054] In some embodiments, the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), or frontotemporal lobar degeneration (FTLD). In some embodiments, the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

[0055] In some embodiments, the method of delivering or treating further comprises administering an immunosuppressant to the subject. In some embodiments, the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

[0056] In some embodiments, the present disclosure provides a method of treating a subject having or diagnosed with having amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), or frontotemporal lobar degeneration (FTLD), comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the method further comprises administering to the subject at least one additional therapeutic agent and / or therapy. In some embodiments, the at least one additional therapeutic agent and / or therapy comprises one or more of: growth and trophic factors, cytokines, hormones, neurotransmitters, enzymes, anti-apoptotic factors, angiogenic factors, modulatory polynucleotides, and any protein known to be mutated in pathological disorders such as ATXN2-related disorders. In some embodiments, the method further comprises administering an immunosuppressant to the subject. In some embodiments, the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

[0057] In some embodiments, the present disclosure provides a pharmaceutical composition or AAV particle disclosed herein for use in a method of treating a disorder as disclosed herein.

[0058] In some embodiments, the present disclosure provides a pharmaceutical composition or AAV particle disclosed hereinfor use in treating an ATXN2-related disorder, optionally wherein the ATXN2- related disorder is spinocerebellar ataxia type 2 (SCA2). In some embodiments, the subject has, has beenAttorney Docket No.14640.0093-00304 diagnosed with having, or is at risk of having the ATXN2-related disorder, optionally wherein the ATXN2-related disorder is SCA2.

[0059] In some embodiments, the present disclosure provides a use of a pharmaceutical composition or AAV particle disclosed herein in the manufacture of a medicament for the treatment of an ATXN2- related disorder in a subject, optionally wherein the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2). In some embodiments, the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder, optionally wherein the ATXN2-related disorder is SCA2. Enumerated Embodiments 1. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises the formula [N2]-[N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1is Y, N, C, or T; (b) position X2is P, E, K, T, or Q; (c) position X3 is A or P; (d) position X4 is E, S, D, or A; and (e) position X5 is V, L, or E; and (ii) [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 2. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises the formula [N2]-[N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1 is Y, N, or C; (b) position X2 is P, K, T, or Q; (c) position X3 is A or P; (d) position X4 is E, S, or A; and (e) position X5 is V, L, or E; and (ii) [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK;Attorney Docket No.14640.0093-00304 wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 3. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [N0] comprising TNN, TNT, INN, TNS, NNN, or TNK; (ii) an [N1] comprising QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS; (iii) an [N2] comprising YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11); (iv) an [N3] comprising VQK, EQK, VKK, VHK, VQQ, or LQK; and (v) an [N4] comprising TA, PA, or NA; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 4. The AAV particle of embodiment 1 or 2, wherein: (a) position X1is Y or N; (b) position X2is P, T or Q; (c) position X3 is A; (d) position X4 is E or S; and / or (e) position X5 is V or L. 5. The AAV particle of any one of embodiments 1, 2, and 4, wherein [N2] comprises YP, NK, YT, YQ, NP, CP, TH, AE, PS, AA, AS, PA, PP, KA, TA, QA, TP, HA, EV, SL, EE, AV, or SH. 6. The AAV particle any one of embodiments 1, 2, 4, and 5, wherein [N2] comprises YPA, YPP, NKA, YTA, YQA, YTP, NPA, CPA, THA, PAE, PPS, KAE, TAE, QAE, TPS, PAA, HAS, AEV, PSL, AEE, or AAV. 7. The AAV particle of any one of embodiments 1, 2, 4, and 6, wherein [N2] comprises YPAE (SEQ ID NO: 21), YPPS (SEQ ID NO: 22), NKAE (SEQ ID NO: 23), YTAE (SEQ ID NO: 24), YQAE (SEQ ID NO: 25), YTPS (SEQ ID NO: 26), YPAA (SEQ ID NO: 27), NPAE (SEQ ID NO: 28), CPAE (SEQ IDAttorney Docket No.14640.0093-00304 NO: 29), THAS (SEQ ID NO: 30), PAEV (SEQ ID NO: 17), PPSL (SEQ ID NO: 31), KAEV (SEQ ID NO: 32), TAEV (SEQ ID NO: 16), PAEE (SEQ ID NO: 18), QAEV (SEQ ID NO: 15), TPSL (SEQ ID NO: 33), PAAV (SEQ ID NO: 34), or QAEE (SEQ ID NO: 35). 8. The AAV particle of any one of embodiments 1-7, wherein [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11). 9. The AAV particle of any one of embodiments 1, 2, 4, and 8, wherein [N3] comprises the amino acid sequence of VQK, EQK, or VKK. 10. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises VQK. 11. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises EQK. 12. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises VKK. 13. The AAV particle of any one of embodiments 1-12, wherein [N2] is or comprises the amino acid sequence of YPAEV (SEQ ID NO: 1) and [N3] is or comprises the amino acid sequence of VQK. 14. The AAV particle of any one of embodiments 1-12, wherein: (i) [N2] is or comprises the amino acid sequence of YTPSL (SEQ ID NO: 7) and [N3] is or comprises the amino acid sequence of VQK; (ii) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of VQK; (iii) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of EQK; or (iv) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of VKK. 15. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-14, wherein [N2]-[N3] comprises:Attorney Docket No.14640.0093-00304 (i) AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 16. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-15, wherein [N2]-[N3] comprises: (i) PAEVVQK (SEQ ID NO: 20), PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48), TAEVVQK (SEQ ID NO: 49), PAEVEQK (SEQ ID NO: 50), PAEEVQK (SEQ ID NO: 51), QAEVVQK (SEQ ID NO: 52), TPSLVQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61), or QAEEVQK (SEQ ID NO: 62); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 17. The AAV particle of any one of embodiments 1-16, wherein [N2]-[N3] is or comprises: (i) YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948), YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSLVKK (SEQ ID NO: 954), YPAEVVKK (SEQ ID NO: 955), YPAEVVHK (SEQ ID NO: 956), YPAAVVQK (SEQ ID NO: 957), NPAEVVQK (SEQ ID NO: 958), YPAEVVQQ (SEQ ID NO: 959), CPAEVVQK (SEQ ID NO: 960), YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963);Attorney Docket No.14640.0093-00304 (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 18. The AAV particle of any one of embodiments 1-17, which further comprises one, two, three or all of an amino acid other than Q at position 574 (e.g., T, S, A, I, L, or H), an amino acid other than S at position 575 (e.g., G, A, or R), and / or an amino acid other than S at position 576 (e.g., K, L, R, A, or T), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 19. The AAV particle of any one of embodiments 1-17, which further comprises: (i) a Q at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) a T at position 574, an S at position 575, and / or a L at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) an S at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) a Q at position 574, an S at position 575, and / or an R at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (v) a Q at position 574, an S at position 575, and / or a K at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (vi) an A at position 574, a G at position 575, and / or an A at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (vii) an I at position 574, a G at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (viii) a Q at position 574, an A at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ix) an A at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (x) an L at position 574, a G at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xi) a Q at position 574, an S at position 575, and / or a T at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;Attorney Docket No.14640.0093-00304 (xii) an H at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xiii) an L at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or (xiv) a Q at position 574, an R at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 20. The AAV particle of any one of embodiments 1-19, which further comprises [N1], wherein [N1] comprises positions XD, XE, and XF, wherein: (a) position XDis Q, T, S, A, I, L, or H; (b) position XEis S, G, A, or R; and (c) position XFis S, K, L, R, A, or T; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 21. The AAV particle of embodiment 20, wherein [N1] comprises SK, SL, SS, SR, GA, GS, AS, ST, RS, QS, TS, AG, IG, QA, LG, HS, LS, or QR. 22. The AAV particle of any one of embodiments 3, 20, and 21, wherein [N1] is or comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS. 23. The AAV particle of any one of embodiments 20-22, wherein [N1]-[N2] comprises: (i) SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64), SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68), GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70), STNKA (SEQ ID NO: 71), SSYTA (SEQ ID NO: 72), SSYQA (SEQ ID NO: 73), SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77), or SSTHA (SEQ ID NO: 78); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 24. The AAV particle of any one of embodiments 20-23, wherein [N1]-[N2] comprises:Attorney Docket No.14640.0093-00304 (i) SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81), SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84), GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 25. The AAV particle of embodiment 3 or any one of embodiments 20-24, wherein [N1]-[N2] is or comprises: (i) QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), HSSYPAAV (SEQ ID NO: 115), QSSNPAEV (SEQ ID NO: 116), QSSYTAEV (SEQ ID NO: 117), TSLCPAEV (SEQ ID NO: 118), QRSYTAEV (SEQ ID NO: 119), or QSSYQAEE (SEQ ID NO: 120); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 26. The AAV particle of any one of embodiments 20-25, wherein [N1]-[N2]-[N3] comprises: (i) SSYPAEVVQ (SEQ ID NO: 121), SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125), GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127), ASYPAEVVQ (SEQ ID NO: 128), STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO:Attorney Docket No.14640.0093-00304 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVVQ (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134), SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140), SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145), RSYTAEVVQ (SEQ ID NO: 146), SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 27. The AAV particle of embodiment 3 or any one of embodiments 20-26, wherein [N1]-[N2]-[N3] is or comprises: (i) QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).Attorney Docket No.14640.0093-00304 28. The AAV particle of any one of embodiments 1-27, which further comprises [N0], wherein [N0] comprises positions XA, XB, and XC, wherein: (a) position XAis T, I, or N; (b) position XBis N; (c) position XC is N, T, S, or K; and optionally, wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 29. The AAV particle of embodiment 28, wherein [N0] comprises TN, IN, NN, NT, NS, or NK. 30. The AAV particle of embodiment 3, 28, or 29, wherein [N0] is or comprises TNN, TNT, INN, TNS, NNN, or TNK. 31. The AAV particle of embodiment 3 or any one of embodiments 28-30, wherein [N0]-[N1] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 32. The AAV particle of embodiment 3 or any one of embodiments 28-31, wherein [N0]-[N1]-[N2]-[N3] is or comprises: (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514),Attorney Docket No.14640.0093-00304 TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524), TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 551), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557), TNNQSSYTAEVVKK (SEQ ID NO: 558), TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562), or TNKQASYPAEVVQK (SEQ ID NO: 563); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 33. The AAV particle of embodiment 3 or 32, wherein [N0]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 34. The AAV particle of embodiment 3 or 32, wherein [N0]-[N1]-[N2]-[N3] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), or INNQSSYPAEVVQK (SEQ ID NO: 543). 35. The AAV particle of any one of embodiments 1-34, which further comprises [N4], wherein [N4] comprises positions XGand XH, wherein: (a) position XGis T, P, or N; and (b) position XHis A; andAttorney Docket No.14640.0093-00304 optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 36. The AAV particle of embodiment 35, wherein [N4] is or comprises TA, PA, or NA. 37. The AAV particle of any one of embodiments 3, 35, and 36, wherein [N3]-[N4] is or comprises: (i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 38. The AAV particle of embodiment 3 or any one of embodiments 35-37, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises: (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583), TNTASSYQAEVVQKTA (SEQ ID NO: 1584), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEVVQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), TNNQRSYTAEVVQKTA (SEQ ID NO: 1604),Attorney Docket No.14640.0093-00304 TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), , TNKQASYPAEVVQKTA (SEQ ID NO: 1587); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 39. The AAV particle of embodiment 3 or any one of embodiments 35-38, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533). 40. The AAV particle of embodiment 3 or any one of embodiments 35-38, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024). 41. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises the formula [B]-[C] (SEQ ID NO: 6432), wherein (i) [B] comprises positions X1, X2, and X3, wherein: (a) position X1 is Q, T, S, A, I, L, or H; (b) position X2is S, G, or A; and (c) position X3is S, K, L, R, or A; and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 42. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; andAttorney Docket No.14640.0093-00304 wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [A], wherein [A] comprises the amino acid sequence of TNN, TNT, INN, NNN, TNS, or TNK; (ii) a [B], wherein [B] comprises the amino acid sequence of QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS; (iii) a [C], wherein [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); and (iv) a [D], wherein [D] comprises the amino acid sequence of TA or PA; and wherein, optionally, [C] replaces position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; and wherein, further optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 43. The AAV particle of embodiment 41, wherein: (a) position X1 is Q, T, S, A, or H; (b) position X2 is S or G; and (c) position X3is S, K, L, or R. 44. The AAV particle of embodiment 41 or 43, wherein [B] comprises QS, TS, SS, AG, IG, QA, AS, LG, HS, SK, SL, SR, GA, or GS. 45. The AAV particle of any one of embodiments 41-44, wherein [B] is or comprises QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS. 46. The AAV particle of embodiment 41 or any one of embodiments 43-45, wherein [B]-[C] comprises: (i) SSYPAEVVQK (SEQ ID NO: 572), SKYPAEVVQK (SEQ ID NO: 573), SLYPAEVVQK (SEQ ID NO: 574), SRYPAEVVQK (SEQ ID NO: 575), GAYPAEVVQK (SEQ ID NO: 576), GSYPAEVVQK (SEQ ID NO: 580), or ASYPAEVVQK (SEQ ID NO: 582); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 47. The AAV particle of any one of embodiments 41-46, wherein [B]-[C] is or comprises:Attorney Docket No.14640.0093-00304 (i) QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), or HSSYPAEVVQK (SEQ ID NO: 162); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 48. The AAV particle of any one of embodiments 41-47, wherein [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150). 49. The AAV particle of any one of embodiments embodiment 41-47, wherein [B]-[C] is or comprises AGAYPAEVVQK (SEQ ID NO: 156), TSLYPAEVVQK (SEQ ID NO: 152), QSKYPAEVVQK (SEQ ID NO: 151), or QSRYPAEVVQK (SEQ ID NO: 154). 50. The AAV particle of any one of embodiments 1-49, which further comprises one or both of an amino acid other than T at position 571 (e.g., I or N), and / or an amino acid other than N at position 573 (e.g., T, S, or K), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 51. The AAV particle of any one of embodiments 1-49, which further comprises: (i) a T at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) a T at position 571, an N at position 572, and / or a T at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) an I at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) a T at position 571, an N at position 572, and / or an S at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (v) an N at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; orAttorney Docket No.14640.0093-00304 (vi) a T at position 571, an N at position 572, and / or a K at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 52. The AAV particle of any one of embodiments 41-51, which further comprises [A], wherein [A] comprises positions XA, XB, and XC, wherein: (a) position XA is T, I, or N; (b) position XBis N; and (c) position XCis N, T, S, or K; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 53. The AAV particle of embodiment 52, wherein [A] comprises TN, IN, NN, NT, NS, or NK. 54. The AAV particle of any one of embodiments 42, 52, and 53, wherein [A] is or comprises TNN, TNT, INN, NNN, TNS, or TNK. 55. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNHSS (SEQ ID NO: 194), INNQSS (SEQ ID NO: 196), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), or TNKQAS (SEQ ID NO: 201); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 56. The AAV particle of embodiment 42 or any one of embodiments 52-55, wherein [A]-[B]-[C] is or comprises: (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517),Attorney Docket No.14640.0093-00304 TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNHSSYPAEVVQK (SEQ ID NO: 525), INNQSSYPAEVVQK (SEQ ID NO: 543), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNSTSLYPAEVVQK (SEQ ID NO: 556), or TNKQASYPAEVVQK (SEQ ID NO: 563); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 57. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 58. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B]-[C] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNQSRYPAEVVQK (SEQ ID NO: 510), or INNQSSYPAEVVQK (SEQ ID NO: 543). 59. The AAV particle of any one of embodiments 1-58, which further comprises: (i) an amino acid other than T at position 578 (e.g., P or N), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (ii) an amino acid other than T at position 585 (e.g., P or N), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 60. The AAV particle of any one of embodiments 1-58, which further comprises: (i) a T at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or a T at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982; (ii) a P at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or a P at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982; or (iii) an N at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or an N at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 61. The AAV particle of any one of embodiments 41-60, which further comprises [D], wherein [D] comprises positions X4 and X5, wherein: (a) position X4 is T or N; and (b) position X5 is A. 62. The AAV particle of embodiment 42 or 61, wherein [D] is or comprises TA or PA. 63. The AAV particle of any one of embodiments 42, 61, and 62, wherein [C]-[D] is or comprises: (i) YPAEVVQKTA (SEQ ID NO: 584) or YPAEVVQKPA (SEQ ID NO: 586); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 64. The AAV particle of embodiment 42 or any one of embodiments 61-63, wherein [A]-[B]-[C]-[D] is or comprises: (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 65. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).Attorney Docket No.14640.0093-00304 66. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024). 67. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises an amino sequence comprising the formula [N2]- [N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1 is Y or T; (b) position X2 is Q, T, P, or E; (c) position X3 is A; (d) position X4 is E or D; and (e) position X5 is V or E; and (ii) [N3] comprises the amino acid sequence of VQK or VQN; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 68. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [N0] comprising TNN, TNS, TNT, or TNK; (ii) an [N1] comprising QSS, SLS, SLY, SAT, or QTS; (iii) an [N2] comprising YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13); (iv) an [N3] comprising VQK or VQN; and (v) an [N4] comprising TA, PA, TD, NA, or PA; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA.Attorney Docket No.14640.0093-00304 69. The AAV particle of embodiment 1 or 67, wherein [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV, AE, or AD. 70. The AAV particle of any one of embodiments 1, 67, and 69, wherein [N2] comprises^YPA, YQA, YTA, TEA, QAE, TAE, PAE, EAE, PAD, AEV, AEE, or ADV. 71. The AAV particle of any one of embodiments 1, 67, 69, and 70, wherein [N2] comprises YPAE (SEQ ID NO: 21), YQAE (SEQ ID NO: 25), YTAE (SEQ ID NO: 24), TEAE (SEQ ID NO: 587), YPAD (SEQ ID NO: 588), QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), EAEV (SEQ ID NO: 590), or PADV (SEQ ID NO: 19). 72. The AAV particle of embodiment 1 or any one of embodiments 67-71, wherein [N2] is or comprises73. The AAV particle of embodiment 1 or any one of embodiments 67-72, wherein [N3] comprises the amino acid sequence of VQK. 74. The AAV particle of embodiment 1 or 67 or any one of embodiments 69-73, wherein [N2]-[N3] comprises: (i) AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 75. The AAV particle of embodiment 1 or 67 or any one of embodiments 69-74, wherein [N2]-[N3] comprises: (i) PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;Attorney Docket No.14640.0093-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 76. The AAV particle of embodiment 1 or any one of embodiments 57-75, wherein [N2]-[N3] is or comprises: (i) YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 77. The AAV particle of embodiment 1 or any one of embodiments 67-76, wherein [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943). 78. The AAV particle of any one of embodiments 1-77, wherein [N2]-[N3] replaces position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 79. The AAV particle of embodiment 1 or any one of embodiments 67-78, which further comprises one, two, three or all of an amino acid other than Q at position 574 (e.g., S), an amino acid other than S at position 575 (e.g., L, A, or T), and / or an amino acid other than S at position 576 (e.g., Y or T), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 80. The AAV particle of embodiment 1 or any one of embodiments 67-78, which further comprises: (i) a Q at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) an S at position 574, an L at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) an S at position 574, an L at position 575, and / or a Y at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;Attorney Docket No.14640.0093-00304 (iv) an S at position 574, an A at position 575, and / or a T at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or (v) a Q at position 574, a T at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 81. The AAV particle of embodiment 1 or any one of embodiments 67-80, which further comprises [N1], wherein [N1] comprises positions XD, XE, and XF, wherein: (a) position XDis Q or S; (b) position XEis S, L, A, or T; and (c) position XFis S, Y, or T;^and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 82. The AAV particle of embodiment 81, wherein [N1] comprises QS, SL, SA, QT, LS, LY, AT, TS, or SS. 83. The AAV particle of any one of embodiments 68, 81, and 82, wherein [N1] is or comprises QSS, SLS, SLY, SAT, or QTS. 84. The AAV particle of any one of embodiments 81-83, wherein [N1]-[N2] comprises: (i) SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603), or TSTEA (SEQ ID NO: 605); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 85. The AAV particle of any one of embodiments 81-84, wherein [N1]-[N2] comprises: (i) SSYPAE (SEQ ID NO: 79), LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), ATYPAE (SEQ ID NO: 613), LSYPAE (SEQ ID NO: 616), TSTEAE (SEQ ID NO: 619), or LSYPAD (SEQ ID NO: 621); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;Attorney Docket No.14640.0093-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 86. The AAV particle of embodiment 68 or any one of embodiments 81-85, wherein [N1]-[N2] is or comprises: (i)^QSSYPAEV (SEQ ID NO: 96), SLSYQAEV (SEQ ID NO: 622), SLSYTAEV (SEQ ID NO: 623), SLYYPAEV (SEQ ID NO: 624), SATYPAEV (SEQ ID NO: 625), SLSYPAEV (SEQ ID NO: 629), SLSYPAEE (SEQ ID NO: 632), QTSTEAEV (SEQ ID NO: 633), or SLSYPADV (SEQ ID NO: 634); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 87. The AAV particle of embodiment 68 or any one of embodiments 81-86, wherein [N1]-[N2]-[N3] is or comprises: (i) QSSYPAEVVQK (SEQ ID NO: 150), SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), SLSYPAEVVQK (SEQ ID NO: 642), SLSYPAEEVQK (SEQ ID NO: 643), SLSYPAEVVQN (SEQ ID NO: 644), QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 88. The AAV particle of embodiment 68 or any one of embodiments 81-87, wherein [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150).Attorney Docket No.14640.0093-00304 89. The AAV particle of embodiment 1 or any one of embodiments 67-88, which further comprises [N0], wherein [N0] comprises positions XA, XB, and XC, wherein: (a) position XA is T; (b) position XBis N; and (c) position XCis N, T, S, or K; and optionally wherein the AAV capsid comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 90. The AAV particle of embodiment 89, wherein [N0]: (i) comprises TN, NS, NT, NN, or NK; and / or (ii) is or comprises TNS, TNT, TNN, or TNK. 91. The AAV particle of any one of embodiments 68, 89, and 90, wherein [N0]-[N1] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNSSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650), or TNKSAT (SEQ ID NO: 651); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 92. The AAV particle of embodiment 68 or any one of embodiments 89-91, wherein [N0]-[N1]-[N2]- [N3] is or comprises: (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); orAttorney Docket No.14640.0093-00304 (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 93. The AAV particle of embodiment 68 or any one of embodiments 89-92, wherein [N0]-[N1]-[N2]- [N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 94. The AAV particle of embodiment 1 or any one of embodiments 67-93, which further comprises [N4], wherein [N4] comprises positions XGand XH, wherein: (a) position XGis T, P, or N; and (b) position XHis A or D; and optionally wherein the AAV capsid variant comprise an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 95. The AAV particle of embodiment 94, wherein [N4] is or comprises TA, TD, PA, or NA. 96. The AAV particle of embodiment 68, 94, and 95, wherein [N3]-[N4] is or comprises:(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 97. The AAV particle of embodiment 68 or any one of embodiments 94-96, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises: (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), TNNQTSTEAEVVQKTA (SEQ ID NO: 2074), TNKSATYPAEVVQKTA (SEQ ID NO: 2075), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076);Attorney Docket No.14640.0093-00304 (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 98. The AAV particle of embodiment 68 or any one of embodiments 94-97, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533). 99. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises the formula [K1]-[K2], wherein: (i) [K1] comprises LSY or LYY; and (ii) [K2] comprises positions X1, X2, X3, and X4, wherein: (a) position X1 is Q, T, or P; (b) position X2 is A; (c) position X3 is E or D; and (d) position X4is V or E; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 100. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [K0], which comprises TNNS (SEQ ID NO: 14); (ii) an [K1], which comprises LSY or LYY; (iii) an [K2], which comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19); (iv) an [K3], which comprise VQK or VQN; and (v) an [K4], which comprises TA, TD, NA, or PA;Attorney Docket No.14640.0093-00304 wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 101. The AAV particle of embodiment 99 or 100, wherein [K1] comprises LSY. 102. The AAV particle of embodiment 99 or 101, wherein [K2] comprises QA, TA, PA, EV, EE, DV, AE, or AD. 103. The AAV particle of any one of embodiments 99, 101, and 102, wherein [K2] comprises QAE, TAE, PAE, PAD, AEV, AEE, or ADV. 104. The AAV particle of any one of embodiments 99-103, wherein [K2] is or comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19). 105. The AAV particle of embodiment 99 or any one of embodiments 101-104, wherein [K1]-[K2] comprises LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), or LSYPA (SEQ ID NO: 603). 106. The AAV particle of embodiment 99 or any one of embodiments 101-105, wherein [K1]-[K2] comprises: (i) LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), LSYPAE (SEQ ID NO: 616), or LSYPAD (SEQ ID NO: 621); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 107. The AAV particle of any one of embodiments 99-106, wherein [K1]-[K2] is or comprises: (i) LSYQAEV (SEQ ID NO: 667), LSYTAEV (SEQ ID NO: 668), LYYPAEV (SEQ ID NO: 669), LSYPAEV (SEQ ID NO: 671), LSYPAEE (SEQ ID NO: 673), or LSYPADV (SEQ ID NO: 674); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;Attorney Docket No.14640.0093-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 108. The AAV particle of any one of embodiments 99-107, which further comprises an amino acid other than Q at position 574 (e.g., S), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 109. The AAV particle of any one of embodiments 99-108, which further comprises S at position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 110. The AAV particle of any one of embodiments 99-109, which further comprises [K0], wherein [K0] is or comprises TNNS (SEQ ID NO: 14); an amino acid sequence comprising any portion of an amino acid sequence, e.g., any 2 or 3 amino acids, e.g., consecutive amino acids, thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of TNNS (SEQ ID NO: 14); or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of TNNS (SEQ ID NO: 14). 111. The AAV particle of embodiment 110, wherein [K0]-[K1] comprises: (i) TNSSLS (SEQ ID NO: 647) or TNSSLY (SEQ ID NO: 648); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 112. The AAV particle of any one of embodiments 100, 110, and 111, wherein [K0]-[K1] is or comprises: (i) TNSSLSY (SEQ ID NO: 676) or TNSSLYY (SEQ ID NO: 678); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;Attorney Docket No.14640.0093-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 113. The AAV particle of any one of embodiments 110-112, wherein [K0]-[K1]-[K2] comprises: (i) TNSSLSYQA (SEQ ID NO: 679), TNSSLSYTA (SEQ ID NO: 681), TNSSLYYPA (SEQ ID NO: 682), or TNSSLSYPA (SEQ ID NO: 683); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 114. The AAV particle of any one of embodiments 110-113, wherein [K0]-[K1]-[K2] comprises: (i) TNSSLSYQAE (SEQ ID NO: 684), TNSSLSYTAE (SEQ ID NO: 685), TNSSLYYPAE (SEQ ID NO: 686), TNSSLSYPAE (SEQ ID NO: 687), or TNSSLSYPAD (SEQ ID NO: 689); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 115. The AAV particle of embodiment 100 or any one of embodiments 110-114, wherein [K0]-[K1]- [K2] is or comprises: (i) TNSSLSYQAEV (SEQ ID NO: 692), TNSSLSYTAEV (SEQ ID NO: 693), TNSSLYYPAEV (SEQ ID NO: 696), TNSSLSYPAEV (SEQ ID NO: 697), TNSSLSYPAEE (SEQ ID NO: 698), or TNSSLSYPADV (SEQ ID NO: 699); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof;Attorney Docket No.14640.0093-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 116. The AAV particle of any one of embodiments 99-115, which further comprises [K3], wherein [K3] comprises positions XA, XB, and XC, wherein: (a) position XAis V; (b) position XBis Q; and (c) position XCis K or N; and optionally wherein the AAV capsid comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 117. The AAV particle of embodiment 116, wherein [K3]: (i) comprises VQ, QK, or QN; (ii) is or comprises VQK or VQN. 118. The AAV particle of embodiment 100, 116, or 117, wherein [K2]-[K3] is or comprises: (i) QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), PAEVVQN (SEQ ID NO: 594), or PADVVQK (SEQ ID NO: 596); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 119. The AAV particle of embodiment 100 or any one of embodiments 116-118, wherein [K1]-[K2]- [K3] is or comprises: (i) LSYQAEVVQK (SEQ ID NO: 700), LSYTAEVVQK (SEQ ID NO: 701), LYYPAEVVQK (SEQ ID NO: 702), LSYPAEVVQK (SEQ ID NO: 703), LSYPAEEVQK (SEQ ID NO: 704), LSYPAEVVQN (SEQ ID NO: 706), or LSYPADVVQK (SEQ ID NO: 708); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof;Attorney Docket No.14640.0093-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 120. The AAV particle of embodiment 100 or any one of embodiments 116-119, wherein [K0]-[K1]- [K2]-[K3] is or comprises: (i) TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), or TNSSLSYPADVVQK (SEQ ID NO: 665); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 121. The AAV particle of any one of embodiments 99-120, which further comprises [K4], wherein [K4] comprises positions XDand XE, wherein: (a) position XDis T, P, or N; and (b) position XEis A or D; and optionally wherein the AAV capsid variant comprise an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 122. The AAV particle of embodiment 100 or 121, wherein [K4] is or comprises TA, TD, PA, or NA. 123. The AAV particle of embodiment 100, 121, or 122, wherein [K3]-[K4] is or comprises: (i) VQKTA (SEQ ID NO: 564), VQKTD (SEQ ID NO: 714), VQNTA (SEQ ID NO: 715), VQKNA (SEQ ID NO: 570), or VQKPA (SEQ ID NO: 567); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); orAttorney Docket No.14640.0093-00304 (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 124. The AAV particle of embodiments 100 or any one of embodiments 121-123, wherein [K0]-[K1]- [K2]-[K3]-[K4] is or comprises: (i) TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 125. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises [B]-[C] (SEQ ID NO: 6433), wherein: (i) [B] comprises positions X1, X2, and X3, wherein: (a) position X1 is Q or S; (b) position X2 is S, L, or A; and (c) position X3 is S, Y, or T; and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 126. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [A] comprising TNN, TNS, TNT, or TNK;Attorney Docket No.14640.0093-00304 (ii) a [B] comprising QSS, SLY, SAT, or SLS; (iii) a [C] comprising YPAEVVQK (SEQ ID NO: 943); and (iv) a [D] comprising TA, TD, NA, or PA; wherein, optionally, [C] replaces position 577 relative to reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; wherein, further optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 127. The AAV particle of embodiment 125, comprising wherein [B] comprises QS, SL, SA, LY, AT, LS, or SS. 128. The AAV particle of any one of embodiments 125-127, comprising wherein [B] is or comprises QSS, SLY, SAT, or SLS. 129. The AAV particle of any one of embodiments 125, 127, and 128, whereincomprises: (i) SSYPAEVVQK (SEQ ID NO: 572), LYYPAEVVQK (SEQ ID NO: 702), ATYPAEVVQK (SEQ ID NO: 718), or LSYPAEVVQK (SEQ ID NO: 703); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 130. The AAV particle of any one of embodiments 125-129, wherein [B]-[C] is or comprises: (i) QSSYPAEVVQK (SEQ ID NO: 150), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), or SLSYPAEVVQK (SEQ ID NO: 642); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).Attorney Docket No.14640.0093-00304 131. The AAV particle of embodiment 126 or 130, whereinis or comprises QSSYPAEVVQK (SEQ ID NO: 150). 132. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-131, which further comprises an amino acid other than N at position 573 (e.g., T, S, or K), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 133. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-131, which further comprises: (i) a T at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (ii) a T at position 571, an N at position 572, and / or a T at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (iii) a T at position 571, an N at position 572, and / or a S at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (iv) a T at position 571, an N at position 572, and / or a K at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 134. The AAV particle of any one of embodiments 125-133, which further comprises [A], wherein [A] comprises positions XA, XB, and XC, wherein: (a) position XAis T; (b) position XBis N; and (c) position XCis N, T, S, or K; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 135. The AAV particle of embodiment 126 or 134, wherein [A]: (i) comprises TN, NS, NT, NK, or NN; (ii) is or comprises TNN, TNS, TNT, or TNK. 136. The AAV particle of any one of embodiments 126, 134, and 135, wherein [A]-[B] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNSSLS (SEQ ID NO: 647), or TNKSAT (SEQ ID NO: 651); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;Attorney Docket No.14640.0093-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 137. The AAV particle of embodiment 126 or any one of embodiments 134-136, wherein [A]-[B]-[C] is or comprises: (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), or TNKSATYPAEVVQK (SEQ ID NO: 663); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 138. The AAV particle of embodiment 126 or any one of embodiments 134-137, wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 139. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-138, which further comprises one or both of an amino acid other than T at position 578 (e.g., P or N) and / or an amino acid other than A at position 579 (e.g., D), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 140. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-138, which further comprises: (i) a T at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (ii) a T at position 578 and / or a D at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (iii) a P at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (iv) an N at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0093-00304 141. The AAV particle of any one of embodiments 125-140, which further comprises [D], wherein [D] comprises positions X4and X5, wherein: (a) position X4is T, N, or P; and (b) position X5is A or D; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 142. The AAV particle of embodiment 141, wherein [D] is or comprises TA, TD, NA, or PA. 143. The AAV particle of embodiment 126, 141, or 142, wherein [C]-[D] is or comprises: (i) YPAEVVQKTA (SEQ ID NO: 584), YPAEVVQKTD (SEQ ID NO: 719), YPAEVVQKNA (SEQ ID NO: 724), or YPAEVVQKPA (SEQ ID NO: 586); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 144. The AAV particle of embodiment 126 or any one of embodiments 141-143, wherein [A]-[B]-[C]- [D] is or comprises: (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNKSATYPAEVVQKTA (SEQ ID NO: 2075); (ii) (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 145. The AAV particle of embodiment 126 or any one of embodiments 141-144, wherein [A]-[B]-[C]- [D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).Attorney Docket No.14640.0093-00304 146. The AAV particle of any one of the embodiments 1-40, 59, 60, 67-98, 139, and 140, wherein [N2]- [N3] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 147. The AAV particle of any one of embodiments 2, 15-40, 59, 60, 68, 79-98, 139, 137, and 146 wherein [N0], [N1], and / or [N4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 148. The AAV particle of any one of embodiments 2, 15-40, 59, 60, 68, 79-98, 139, 140, 146, and 147, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 149. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-148, wherein [N2] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 150. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-149, wherein [N2] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 151. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-150, wherein [N2] is present immediately subsequent to position 576, and wherein [N2] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 152. The AAV particle of any one of 1-40, 59, 60, 67-98, 139, 140, and 146-151, wherein [N2] corresponds to positions 577-581 (e.g., Y577, P578, A579, E580, V581) of SEQ ID NO: 982. 153. The AAV particle of any one of embodiments 1-152, wherein the capsid variant comprises an amino acid other than T at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0093-00304 154. The AAV particle of any one of embodiments 1-153, wherein the capsid variant comprises a Y at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 155. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-154, wherein X1of [N2] is present at position 577 (e.g., T577), and positions X2-X5of [N2] are present immediately subsequent to position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 156. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-155, wherein X1 of [N2] corresponds to position 577 (e.g., Y577), X2 of [N2] corresponds to position 578 (e.g., P588), X3 of [N2] corresponds to position 579 (e.g., A579), X4 of [N2] corresponds to position 580 (e.g., E580), and X5 of [N2] corresponds to position 581 (e.g., V581) of SEQ ID NO: 982. 157. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-156, wherein [N2]-[N3] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 158. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-157, wherein [N2]-[N3] replaces position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 159. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-158, wherein [N2]-[N3] is present immediately subsequent to position 576, and wherein [N2]-[N3] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 160. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-159, wherein [N2]-[N3] corresponds to positions 577-584 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584) of SEQ ID NO: 982. 161. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-160, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.Attorney Docket No.14640.0093-00304 162. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-161, wherein [N2]-[N3]-[N4] replaces positions 577-579 (e.g., T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 163. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-162, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 576, and wherein [N2]-[N3]-[N4] replaces positions 577-579 (e.g., T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 164. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-163, wherein [N2]-[N3]-[N4] corresponds to positions 577-586 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 165. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-164, wherein [N1] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 166. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-165, wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 167. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-166, wherein [N1] is present immediately subsequent to position 573, and wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 168. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-167, wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 169. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-168, wherein [N1] is present immediately subsequent to position 573, and wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 170. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-169, wherein [N1] corresponds to positions 574-576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 171. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-170, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 172. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-171, wherein [N1]-[N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 173. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-171, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 573, and wherein [N1]- [N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 174. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-173, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 574-586 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 175. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-174 wherein [N0] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 176. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-175, wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 177. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-176, wherein [N0] is present immediately subsequent to position 570, and wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 178. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-177 wherein [N0] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 179. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-178, wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 180. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-179, wherein [N0] is present immediately subsequent to position 570, and wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 181. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-181, wherein [N0] corresponds to positions 571-573 (e.g., T571, N572, and N573) of SEQ ID NO: 982. 182. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-181, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 183. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-182, wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 184. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-183, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 570, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 185. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-184, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 571-586 (e.g., T571, N572, N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586), of SEQ ID NO: 982. 186. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-185, wherein [N4] is present immediately subsequent to position 584, numbered according to SEQ ID NO: 982. 187. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-186, wherein [N4] replaces position 578 and 579, numbered according to SEQ ID NO: 138; or positions 585 and 586 numbered according to SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 188. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-187, wherein [N4] is present immediately subsequent to position 584 and replaces positions 585 and 586 numbered according to SEQ ID NO: 982. 189. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-188, wherein: (i) XAof [N0] is present at position 571, XBof [N0] is present at position 572, and XCof [N0] is present at position 573, numbered according to SEQ ID NO: 982; (ii) XDof [N1] is present at position 574, XEof [N1] is present at position 575, and XFof [N1] is present at position 576, numbered according to SEQ ID NO: 982; (iii) X1of [N2] is present at position 577, X2of [N2] is present at position 578, X3of [N2] is present at position 579, X4of [N2] is present at position 580, and X5of [N2] is present at position 581, numbered according to SEQ ID NO: 982; (iv) [N3] is present at positions 582-584, numbered according to SEQ ID NO: 982; and / or (v) XGof [N4] is present at position 585 and XHof [N4] is present at position 586, numbered according to SEQ ID NO: 982. 190. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-189, wherein: (i) [N0] is present at positions 571-573, numbered according to SEQ ID NO: 982; (ii) [N1] is present at positions 574-576, numbered according to SEQ ID NO: 982; (iii) [N2] is present at positions 577-581, numbered according to SEQ ID NO: 982; (iv) [N3] is present at positions 582-584, numbered according to SEQ ID NO: 982; (v) [N4] is present at positions 585-586, numbered according to SEQ ID NO: 982; (vi) [N2]-[N3] is present at positions 577-584, numbered according to SEQ ID NO: 982; and / or (vii) [N0]-[N1]-[N2]-[N3]-[N4] is present at positions 571-586, numbered according to SEQ ID NO: 982. 191. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-190, wherein [N3] is present immediately subsequent to [N2]. 192. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-191, wherein [N4] is present immediately subsequent to [N3]. 193. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-192, wherein the capsid variant comprises from N-terminus to C-terminus [N2]-[N3].Attorney Docket No.14640.0093-00304 194. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-193, wherein the capsid variant comprises from N-terminus to C-terminus [N1]-[N2]-[N3]. 195. The AAV particle of any one of embodiments 3, 18, 19, 28-40, 59, 60, 68, 89-98, 139, 140, and 146-194, wherein the capsid variant comprises from N-terminus to C-terminus [N0]-[N1]-[N2]-[N3]. 196. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-195, wherein the capsid variant comprises from N-terminus to C-terminus [N1]-[N2]-[N3]-[N4]. 197. The AAV particle of any one of embodiments 3, 18, 19, 28-40, 59, 60, 68, 89-98, 139, 140, and 146-196, wherein the capsid variant comprises from N-terminus to C-terminus [N0]-[N1]-[N2]-[N3]- [N4]. 198. The AAV particle of any one of embodiments 41-66 or any one of embodiments 125-145, wherein [B]-[C] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 199. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198, wherein [A] and / or [D] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 200. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, 198, and 199, wherein [A]- [B]-[C]-[D] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 201. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-200, wherein [B] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 202. The AAV particle of any one of embodiments 41-66, 125-145, and 198-201, wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0093-00304 203. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-202, wherein [B] is present immediately subsequent to position 573, and wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 204. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-203, wherein [B] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 205. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-204, wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 206. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-205, wherein [B] is present immediately subsequent to position 573, and wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 207. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-206, wherein [B] corresponds to positions 574-576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982. 208. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-207, wherein [B]-[C] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 209. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-208, wherein [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 210. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-209, wherein [B]-[C] is present immediately subsequent to position 573, and wherein [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0093-00304 211. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-210, wherein [B]-[C] corresponds to positions 574-584 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584) of SEQ ID NO: 982. 212. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-211, wherein [B]-[C]-[D] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 213. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-212, wherein [B]-[C]-[D] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 214. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-213, wherein [B]-[C]-[D] is present immediately subsequent to position 573, and wherein [B]-[C]-[D] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 215. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-214, wherein [B]-[C]-[D] corresponds to positions 574-586 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 216. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-215, wherein [C] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 217. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-216, wherein [C] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 218. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-217, wherein [C] is present immediately subsequent to position 576, and wherein [C] replaces 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0093-00304 219. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-218, wherein [C] corresponds to positions 577-584 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584) of SEQ ID NO: 982. 220. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-219, wherein [A] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 221. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-220, wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 222. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-221, wherein [A] is present immediately subsequent to position 570, and wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 223. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-222, wherein [A] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 224. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-223, wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 225. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-224, wherein [A] is present immediately subsequent to position 570, and wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 226. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-225, wherein [A] corresponds to positions 571-573 (e.g., T571, N572, and N573) of SEQ ID NO: 982. 227. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-226, wherein [D] is present immediately subsequent to position 584, numbered according to SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 228. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-227, wherein [D] replaces positions 578 and 579 numbered according to SEQ ID NO: 138; or positions 585 and 586, numbered according to SEQ ID NO: 982. 229. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-228, wherein [D] is present immediately subsequent to position 584 and replaces positions 585 and 586, numbered according to SEQ ID NO: 982. 230. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-229, wherein [A]- [B]-[C]-[D] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 231. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-230, wherein [A]- [B]-[C]-[D] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 232. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-231, wherein [A]- [B]-[C]-[D] is present immediately subsequent to position 570, and wherein [A]-[B]-[C]-[D] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 233. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-232, wherein [A]- [B]-[C]-[D] corresponds to positions 571-586 (e.g., T571, N572, N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 234. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-233, wherein: (i) XAof [A] is present at position 571, XBof [A] is present at position 572, and XCof [A] is present at position 573, numbered according to SEQ ID NO: 982; (ii) X1 of [B] is present at position 574, X2 of [B] is present at position 575, and X3 of [B] is present at position 576, numbered according to SEQ ID NO: 982; (iii) [C] is present at positions 577-584, numbered according to SEQ ID NO: 982; and / or (iv) X4 of [D] is present at position 585 and position X5 of [D] is present at position 586, numbered according to SEQ ID NO: 982. 235. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-234, wherein: (i) [A] is present at positions 571-573, numbered according to SEQ ID NO: 982;Attorney Docket No.14640.0093-00304 (ii) [B] is present at positions 574-576, numbered according to SEQ ID NO: 982; (iii) [C] is present at positions 577-584, numbered according to SEQ ID NO: 982; (iv) [D] is present at positions 585-586, numbered according to SEQ ID NO: 982; and / or (v) [A]-[B]-[C]-[D] is present at positions 571-586, numbered according to SEQ ID NO: 982. 236. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-235, wherein [C] is present immediately subsequent to [B]. 237. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-236 wherein [D] is present immediately subsequent to [C]. 238. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-237, wherein the capsid variant comprises from N-terminus to C-terminus [B]-[C]. 239. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-238, wherein the AAV capsid variant comprises from N-terminus to C-terminus [A]-[B]-[C]. 240. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-239, wherein the AAV capsid variant comprises from N-terminus to C-terminus [B]-[C]-[D]. 241. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-240, wherein the AAV capsid variant comprises from N-terminus to C-terminus [A]-[B]-[C]-[D]. 242. The AAV particle of any one of the embodiments 99-124, wherein [K1]-[K2] is present in loop VIII. 243. The AAV particle of any one of embodiments 92-124 or embodiment 242, wherein [K0], [K3], and / or [K4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 244. The AAV particle of any one of embodiments 92-124 embodiment 242, or embodiment 243, wherein [K0]-[K1]-[K2]-[K3]-[K4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 245. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-244, wherein [K1] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 246. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-245, wherein [K1] replaces positions 575-577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 247. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-246, wherein [K1] is present immediately subsequent to position 574, and wherein [K1] replaces positions 575-577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 248. The AAV particle of any one of embodiments 100, 116-124, and 242-247, wherein [K1]-[K2]-[K3] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 249. The AAV particle of any one of embodiments 100, 116-124, and 242-248, wherein [K1]-[K2]-[K3] replaces positions 575-577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 250. The AAV particle of any one of embodiments 100, 116-124, and 242-249, wherein [K1]-[K2]-[K3] is present immediately subsequent to position 574, and wherein [K1]-[K2]-[K3] replaces positions 575- 577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 251. The AAV particle of any one of embodiments 100, 121-124, and 242-250, wherein [K1]-[K2]-[K3]- [K4] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 252. The AAV particle of any one of embodiments 100, 121-124, and 242-251, wherein [K1]-[K2]-[K3]- [K4] replaces positions 575-579 (e.g., S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 253. The AAV particle of any one of embodiments 100, 121-124, and 242-252, wherein [K1]-[K2]-[K3]- [K4] is present immediately subsequent to position 574, and wherein [K1]-[K2]-[K3]-[K4] replacesAttorney Docket No.14640.0093-00304 positions 575-579 (e.g., S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 254. The AAV particle of any one of embodiments 100, 110-124, and 242-253, wherein [K0] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 255. The AAV particle of any one of embodiments 100, 110-124, and 242-254, wherein [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 256. The AAV particle of any one of embodiments 100, 110-124, and 242-255, wherein [K0] is present immediately subsequent to position 570, and wherein [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 257. The AAV particle of any one of embodiments 100, 121-124, and 242-256, wherein [K0]-[K1]-[K2]- [K3]-[K4] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 258. The AAV particle of any one of embodiments 100, 121-124, and 242-257, wherein [K0]-[K1]-[K2]- [K3]-[K4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 259. The AAV particle of any one of embodiments 100, 121-124, and 242-258, wherein [K0]-[K1]-[K2]- [K3]-[K4] is present immediately subsequent to position 570, and wherein [K0]-[K1]-[K2]-[K3]-[K4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 260. The AAV particle of any one of embodiments 100, 116-124, and 242-259, wherein [K3] is present immediately subsequent [K2]. 261. The AAV particle of any one of embodiments 100, 121-124, and 242-260, wherein [K4] is present immediately subsequent [K3].Attorney Docket No.14640.0093-00304 262. The AAV particle of any one of embodiments 100, 121-124, and 242-261, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2]. 263. The AAV particle of any one of embodiments 100, 116-124, and 242-262, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2]-[K3]. 264. The AAV particle of any one of embodiments 100, 116-124, and 242-263, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K0]-[K1]-[K2]-[K3]. 265. The AAV particle of any one of embodiments 100, 121-124, and 242-264, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2]-[K3]-[K4]. 266. The AAV particle of any one of embodiments 100, 121-124, and 242-265, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K0]-[K1]-[K2]-[K3]-[K4]. 267. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 268. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, and 1610-1624;Attorney Docket No.14640.0093-00304 (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591- 1593, 1598-1608, and 1610-1624; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583- 1587, 1590, 1591-1593, 1598-1608, and 1610-1624; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, and 1610-1624; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 269. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 270. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591;Attorney Docket No.14640.0093-00304 (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA. 271. The AAV particle of any one of embodiments 267-270, wherein the AAV capsid variant comprises at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID NO: 943 or any one of SEQ ID NOs: 946- 966. 272. The AAV particle of embodiment 271, wherein the at least 3 consecutive amino acids comprise YPA. 273. The AAV particle of embodiment 271, wherein the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21). 274. The AAV particle of embodiment 271, wherein the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1). 275. The AAV particle of embodiment 271, wherein the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725). 276. The AAV particle of embodiment 271, wherein the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726). 277. The AAV particle of embodiment 271, wherein the amino acid sequence comprises YPAEVVQK (SEQ ID NO: 943). 278. The AAV particle of any one of embodiments 267, 268, and 270, wherein the AAV capsid variant comprises: (i) YTP;Attorney Docket No.14640.0093-00304 (ii) YTPS (SEQ ID NO: 26); (iii) YTPSL (SEQ ID NO: 7); (iv) YTPSLV (SEQ ID NO: 727); (v) YTPSLVQ (SEQ ID NO: 728); and / or (vi) YTPSLVQK (SEQ ID NO: 952). 279. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein: (i) the 3 consecutive amino acids comprise YPP; (ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the 7 consecutive amino acids comprise YPPSLVQ (SEQ ID NO: 732); and / or (vi) the amino acid sequence comprises YPPSLVQK (SEQ ID NO: 946). 280. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein: (i) the 3 consecutive amino acids comprise YPP; (ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 consecutive amino acids comprise YPPSLE (SEQ ID NO: 733); (v) the 7 consecutive amino acids comprise YPPSLEQ (SEQ ID NO: 734); and / or (vi) the amino acid sequence comprises YPPSLEQK (SEQ ID NO: 953). 281. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein: (i) the 3 consecutive amino acids comprise YPP; (ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the 7 consecutive amino acids comprise YPPSLVK (SEQ ID NO: 735); and / or (vi) the amino acid sequence comprises YPPSLVKK (SEQ ID NO: 954). 282. The AAV particle of any one of embodiments 267-277, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 283. The AAV particle of any one of embodiments 267, 268, 270, and 278-281, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four differentAttorney Docket No.14640.0093-00304 amino acids, relative to the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591. 284. The AAV particle of any one of embodiments 267, 268, 270, and 378-281, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any of SEQ ID NOs: 946, 952, 953, and 954. 285. The AAV particle of any one of embodiments 267-277 or embodiment 282, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 286. The AAV particle of any one of embodiments 267, 268, 270, 278-281, and 283, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591. 287. The AAV particle of any one of embodiments 267, 268, 270, 278-281, and 284, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 946, 952, 953, and 954. 288. The AAV particle of any prior embodiment, e.g., any one of embodiments 267-277, 282, and 285, wherein the AAV capsid variant comprises an amino acid sequence encoded by: (i) a nucleotide sequence comprising SEQ ID NO: 944 or a nucleotide sequence that comprises at least one, two, three, four, five, six, seven, eight, nine, or ten modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; or (ii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, eight, nine, or ten, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944. 289. The AAV particle of any one of embodiments 267-277, 282, 285, and 289, wherein the AAV capsid variant is encoded by: (i) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; orAttorney Docket No.14640.0093-00304 (ii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944. 290. The AAV particle of embodiment 267, wherein the capsid variant comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 2024-2063; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 2024-2063; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063. 291. The AAV particle of embodiment 267 or 290, wherein the different amino acids of the amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063, are present at one or more of the following positions: (i) position 1, wherein the different amino acid is T or L; (ii) position 2, wherein the different amino acid is N, L, K, A, T, or P; (iii) position 3, wherein the different amino acid is N, K, L, A, Y, or S; (iv) position 4, wherein the different amino acid is Q, L, T, S, F, Y, K, or A; (v) position 5, wherein the different amino acid is S, H, A, M, Q, T, V, or F; (vi) position 6, wherein the different amino acid is S, P, V, A, Q, L, T, N, or M; (vii) position 7, wherein the different amino acid is Y, H, S, V, A, L, or T; (viii) position 8, wherein the different amino acid is D, P, A, Q, F, L, S, H, or M; (ix) position 9, wherein the different amino acid is F, A, L, D, or Q; (x) position 10, wherein the different amino acid is T, E, I, or S; (xi) position 11, wherein the different amino acid is V, A, N, or S; (xii) position 12, wherein the different amino acid is V, L, or P; (xiii) position 13, wherein the different amino acid is Q, E, or P; (xiv) position 14, wherein the different amino acid is K, N, S, or L; (xv) position 15, wherein the different amino acid is T, V, M, or L; and / or (xvi) position 16, wherein the different amino acid is A, G, or R. 292. The AAV particle of embodiment 267, wherein the capsid variant comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 1632-2023;Attorney Docket No.14640.0093-00304 (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1632-2023; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-2023; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-2023. 293. The AAV particle of embodiment 268 or 292, wherein the different amino acids of the amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-2023, are present at one or more of the following positions: (i) position 1, wherein the different amino acid is T, G, N, S, E, L, Y, V, or I; (ii) position 2, wherein the different amino acid is D, N, K, E, V, G, R, L, H, F, P, T, A, S, I, or Y; (iii) position 3, wherein the different amino acid is Y, N, K, T, W, Q, M, V, C, A, L, F, H, G, R, S, or P; (iv) position 4, wherein the different amino acid is H, Q, P, E, R, K, A, S, V, L, T, D, I, G, M, or N; (v) position 5, wherein the different amino acid is R, S, K, N, H, G, W, A, P, V, Q, Y, L, or F; (vi) position 6, wherein the different amino acid is G, S, F, R, W, H, I, C, M, A, Y, K, N, Q, V, P, E, D, T, or L; (vii) position 7, wherein the different amino acid is D, Y, S, I, H, F, P, K, R, G, L, Q, A, M, T, N, V, W, C, or E; (viii) position 8, wherein the different amino acid is P, L, Q, T, W, V, G, K, I, Y, N, H, R, D, S, M, A, F, or E; (ix) position 9, wherein the different amino acid is A, R, T, Q, S, M, L, E, K, V, G, D, N, H, F, P, or I; (x) position 10, wherein the different amino acid is K, E, Q, H, V, G, R, S, P, I, N, M, A, L, D, or T; (xi) position 11, wherein the different amino acid is V, A, E, N, R, L, M, T, Q, S, K, C, G, D, Y, P, H, F, or I; (xii) position 12, wherein the different amino acid is V, P, L, S, T, N, A, G, K, R, I, H, E, Q, or M; (xiii) position 13, wherein the different amino acid is Q, K, N, A, H, R, T, V, E, I, P, G, S, or L; (xiv) position 14, wherein the different amino acid is K, E, I, Y, Q, R, G, D, L, N, or S; (xv) position 15, wherein the different amino acid is S, T, N, Q, I, P, E, G, K, M, or H; and / orAttorney Docket No.14640.0093-00304 (xvi) position 16, wherein the different amino acid is A, D, L, Y, Q, or T. 294. The AAV particle of any one of embodiments 267-293, wherein the amino acid sequence is present in loop VIII of the AAV capsid variant. 295. The AAV particle of any one of embodiments 267-294, wherein the amino acid sequence is present immediately subsequent to position 570, 571, 572, 573, 574, 575, or 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 296. The AAV particle of any one of embodiments 267-295, wherein the amino acid sequence replaces one, two, three, four, five or all of positions 571, 572, 573, 574, 575, and / or 576 (e.g., positions T571, N572, N573, Q574, S575, S576, T577, T578, and / or A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 297. The AAV particle of any one of embodiments 267-296, wherein the amino acid sequence is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 298. The AAV particle of any one of embodiments 267-297, wherein the AAV capsid variant comprises an amino acid residue other than T at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 299. The AAV particle of any one of embodiments 267-298, wherein the AAV capsid variant comprises the amino acid Y at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 300. The AAV particle of any one of embodiments 267-299, wherein the AAV capsid variant comprises the substitution T577Y, numbered according to SEQ ID NO: 138. 300. The AAV particle of any one of embodiments 267-299, wherein the AAV capsid variant comprises the substitution T577Y, numbered according to SEQ ID NO: 138. 301. The AAV particle of embodiment 298 or 299, wherein the amino acid sequence is or comprises YPAEVVQK (SEQ ID NO: 943), and starts at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.Attorney Docket No.14640.0093-00304 302. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-301, wherein the AAV capsid variant comprises an amino acid other than T at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered relative to SEQ ID NO: 138. 303. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-302, wherein the AAV capsid variant comprises the amino acid Y at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered relative to SEQ ID NO: 138. 304. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-303, wherein the AAV capsid variant comprises the amino acid Y at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577 (e.g., at positions 578-584), numbered relative to SEQ ID NO: 982. 305. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-304, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the amino acid sequence replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 306. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-305, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the amino acid sequence: (i) is present immediately subsequent to position 576; and (ii) replaces position 577 (e.g., T577), wherein in (i) and (ii) are numbered relative to SEQ ID NO: 138. 307. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-306, wherein the AAV capsid variant further comprises an amino acid other than T at position 571 (e.g., I), numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982. 308. The AAV particle of any one of embodiments 267-277, 272, 275, 278, 289, and 294-307, wherein the AAV capsid variant further comprises I at position 571, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982. 309. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-308, wherein the AAV capsid variant further comprises one, two, or all of an amino acid other than Q at position 574Attorney Docket No.14640.0093-00304 (e.g., A or T), S at position 575 (e.g., G), and / or S (e.g., A, L, K, or R) at position 576, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982. 310. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-309, wherein the AAV capsid variant further comprises: (i) A at position 574, G at position 575, and A at position 576, numbered relative to SEQ ID NO: 138 or 982; or (ii) T at position 574 and L at position 576, numbered relative to SEQ ID NO: 138 or 982. 311. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-309, wherein the AAV capsid variant further comprises: (i) K at position 576, numbered relative to SEQ ID NO: 138 or 982; or (ii) R at position 576, numbered relative to SEQ ID NO: 138 or 982. 312. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-310, wherein the capsid variant comprises: (i) A at position 574, G at position 575, A at position 576, and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 313. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-310, wherein the AAV capsid variant comprises: (i) T at position 574, L at position 576, and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 314. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-309, and 311, wherein the AAV capsid variant comprises: (i) K at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 315. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 295-309, and 311, wherein the AAV capsid variant comprises: (i) R at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; andAttorney Docket No.14640.0093-00304 (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 316. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-308, wherein the AAV capsid variant comprises: (i) I at position 571 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 317. The AAV particle of any one of embodiments 267, 268, 270, 278, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence TPSLVQK (SEQ ID NO: 53), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982. 318. The AAV particle of any one of embodiments 267, 268, 270, 279, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLVQK (SEQ ID NO: 47), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982. 319. The AAV particle of any one of embodiments 267, 268, 270, 280, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLEQK (SEQ ID NO: 54), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982. 320. The AAV particle of any one of embodiments 267, 268, 270, 281, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLVKK (SEQ ID NO: 55), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982. 321. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant further comprises a modification, e.g., an insertion, substitution (e.g., conservative substitution), and / or deletion, in loop I, II, IV, and / or VI. 322. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than 30, 20 or 10 modifications,Attorney Docket No.14640.0093-00304 e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NO: 138. 323. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three, but no more than 30, 20 or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 138. 324. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity to SEQ ID NO: 138. [Embodiments 325-327 are intentionally absent.] 328. The AAV particle of any one of the embodiments provided herein, wherein the capsid variant comprises a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof. 329. The AAV particle of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, and 321-328, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 137-731, e.g., a VP2, of SEQ ID NO: 982, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 330. The AAV particle of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, and 321-329, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 193-731, e.g., a VP3, of SEQ ID NO: 982, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 331. The AAV particle of any one of embodiments 1-321, wherein the AAV capsid variant comprises a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity to the amino acid sequence corresponding to positions 137-724, e.g., a VP2, of SEQ ID NO: 138. 332. The AAV particle of any one of embodiments 1-321, wherein the AAV capsid variant comprises a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity to the amino acid sequence corresponding to positions 193-724, e.g., a VP3, of SEQ ID NO: 138. 333. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, and 321-328, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein:Attorney Docket No.14640.0093-00304 (i) the at least 3 consecutive amino acids comprise YPA; (ii) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725); or (v) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726); wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 739. 334. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein: (i) the at least 3 consecutive amino acids comprise YPA; (ii) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725); or (v) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137- 731 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193-731 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). 335. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 334, wherein the AAV capsid variant comprises one, two, or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137-731 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193-731 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). 336. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-335, comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises the aminoAttorney Docket No.14640.0093-00304 acid sequence of SEQ ID NO: 739; or an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 739. 337. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-336, comprising one or two, but no more than three substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 982. 338. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-337, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 339. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-338, wherein the capsid variant comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 95% identity thereto. 340. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-339, wherein the capsid variant comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 98% identity thereto. 341. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-340, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NO: 982. 342. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-341, wherein the capsid variant comprises an amino acid sequence comprising at least one, two or three, but not more than 30, 20 or 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 982. 343. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-342, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.Attorney Docket No.14640.0093-00304 344. The AAV particle of any one of the embodiments provided herein, wherein the nucleotide sequence encoding the AAV capsid variant is codon-optimized. [Embodiments 345-349 are intentionally absent.] 350. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138. 351. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982. 352. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 139. 353. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which transduces a brain region, e.g., a temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum, optionally wherein the level of transduction is at least 1.5, 2.2, 2.4, 2.5, 2.6, 2.7, 3.0, 3.2, 3.5, 3.7, 4.0, 4.2, 4.5, 4.7, 4.9, 5, 10, 15, 20, 25, 30, 35-fold greater as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 2. 354. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 353, which is enriched at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65-fold in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1. 355. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 354, which is enriched at least about 10, 12, 15, 17, 20, 25, 30, 35, 40, 45, 50, 55, 60, 61, 62, 63, 64, orAttorney Docket No.14640.0093-00304 65-fold in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1. 356. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 355, which is enriched in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), e.g., as compared to a reference sequence of SEQ ID NO: 138. 357. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 356, which is enriched at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, 30, 35, 40, 45-fold in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Examples 1, 2, 4, and 5. 358. The AAV particle of embodiment 356 or 357, wherein the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, rat, and / or mouse (e.g., BALB / c mice). 359. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 358, which is enriched at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 125, 150, 175, 200, or 225-fold, in the brain compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 360. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 359, which delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 20, 25, 30, or 35-fold, as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2). 361. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 360, which delivers an increased number and / or level of viral genomes to a brain region, optionally wherein the number and / or level of viral genomes is increased by at least 1.5, 2.2, 2.4, 2.5, 2.6, 2.7, 3.0, 3.2, 3.5, 3.7, 4.0, 4.2, 4.5, 4.7, 4.9, or 5-fold as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2). 362. The AAV particle of any one of embodiments 350-361, wherein the brain region is a temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, cerebellum, or a combination thereof.Attorney Docket No.14640.0093-00304 363. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 362, which is enriched at least about 3, 3.5, 4.0, 4.5, 5, 5.0, 6.0, or 6.5-fold in a spinal cord region compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay as described in Example 2. 364. The AAV particle of any one of embodiments 363, wherein the spinal cord region is a cervical region, a lumbar region, a thoracic region, or a combination thereof. 365. The AAV particle of any one of the embodiments provided herein, which shows preferential transduction in a brain region relative to transduction in the dorsal root ganglia (DRG). 366. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 365, which is capable of transducing neuronal cells. 367. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 366, which is capable of transducing non-neuronal cells, e.g., glial cells (e.g., oligodendrocytes). 368. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 367, which shows preferential transduction in a brain region relative to transduction in the liver. 369. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, and 321-349, which has an increased tropism for a heart cell or heart tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138. 370. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369, which has an increased tropism for a heart cell or tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 139. 371. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, 369, and 370, which delivers an increased level of a payload to a heart region, optionally wherein the level of the payload is increased by at least 1.5, 2, or 2.5-fold, as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., an IHC assay or a RT-ddPCR assay (e.g., as described in Example 2).Attorney Docket No.14640.0093-00304 372. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369-371, which has an increased tropism for a heart cell or tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982. 373. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369-372, which is enriched at least about 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50-fold in the heart compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 374. The AAV particle of any one of embodiments 267, 290, 291, 321-328, 331, 332, and 344, which has an increased tropism for a muscle cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982. 375. The AAV particle of any one of embodiments 267, 290, 291, 321-328, 331, 332, 344, and 374, which is enriched at least about 2, 3, 4, 5, 10, 15, 20, 25, 30, or 35-fold in the muscle compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 376.^The AAV particle of embodiment 374 or 375, wherein the muscle cell or tissue is a heart muscle (e.g., a heart ventricle or a heart atrium, or both), a quadriceps muscle, or both. 377. The AAV particle of any one of embodiments 267, 292, 293, 321-328, 331, 332, and 344, which has an increased tropism for a liver cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982. 378. The AAV particle of any one of embodiments 267, 292, 293, 321-328, 331, 332, 344, and 377, which is enriched at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 130, 140, 150, 160, 170, 180, 185, or 190-fold in the liver compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 379. The AAV particle of any one of embodiments 1-378, wherein the AAV particle comprises a viral genome comprising a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 and a Rep52 protein). 380. The AAV particle of any one of the embodiments provided herein, wherein the AAV particle comprises a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the RepAttorney Docket No.14640.0093-00304 protein comprises a Rep78 protein, a Rep68, Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 and a Rep52 protein). 381. The AAV particle of embodiment 379 or 380, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene. [Embodiments 382-445 are intentionally absent.] 446. A cell, e.g., a host cell, comprising the AAV particle of any one of embodiments 1-381. 447. The cell of embodiment 446, wherein the cell is a mammalian cell or an insect cell. 448. The cell of embodiment 446 or 447, wherein the cell is a cell of the CNS and / or the spinal cord. 449. The cell of any one of embodiments 446-448, wherein the cell is a cell of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum. 450. A method of making an AAV particle of embodiment 381, comprising: (i) providing a host cell comprising a viral genome comprising a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA and a nucleic acid encoding an AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle. 451. The method of embodiment 450, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the host cell. 452. The method of embodiment 450 or 451, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell. 453. The method of embodiment 452, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule. 454. A pharmaceutical composition comprising the AAV particle of any one of embodiments 1-381, and a pharmaceutically acceptable excipient.Attorney Docket No.14640.0093-00304 455. A method of delivering to a subject a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA, comprising administering an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, thereby delivering the modulatory polynucleotide. 456. The method of embodiment 455, wherein the modulatory polynucleotide is delivered to a cell or tissue of the central nervous system (CNS). 457. The method of embodiment 456, wherein the cell or tissue of the CNS is a cell or tissue of a brain or spinal cord region. 458. The method of embodiment 456 or embodiment 457, wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, or cerebellum. 459. The method of any one of embodiments 456-458, wherein the cell or tissue of the CNS comprises a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, or an oligodendrocyte. 460. The method of any one of embodiments 455-459, wherein the subject is a human. 461. The method of embodiment 460, wherein the subject has, has been diagnosed with having, or is at risk of having a genetic disorder. 462. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having a neurological (e.g., a neurodegenerative disorder) or a neuromuscular disorder. 463. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having an ATXN2-related disorder. 464. The method of any one of embodiments 460-463, wherein the subject has, has been diagnosed with having, or is at risk of having spinocerebellar ataxia type 2 (SCA2). 465. A method of treating an ATXN2-related disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particleAttorney Docket No.14640.0093-00304 of any one of embodiments 1-381, optionally wherein the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder. 466. A method of treating a neurological disorder, e.g., a neurodegenerative disorder, in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, optionally wherein the subject has, has been diagnosed with having, or is at risk of having the neurological disorder. 467. A method of treating a muscular disorder or a neuromuscular disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, optionally wherein the subject has, has been diagnosed with having, or is at risk of having the muscular disorder or the neuromuscular disorder. 468. The method of any one of embodiments 465-467, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, muscular disorder, or neuromuscular disorder is SCA2. 469. The method of any one of embodiments 465-468, wherein the treatment comprises prevention of progression of the disease or disorder in the subject. 470. The method of any one of embodiments 460-469, wherein the subject is a human. 471. The method of any one of embodiments 465-470, wherein the AAV particle is administered to the subject intravenously, via intra-cisterna magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly. 472. The method of any one of embodiments 465-471, wherein the AAV particle is administered to the subject via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration. 473. The method of any one of embodiments 465-471, wherein the AAV particle is administered to the subject intravenously. 474. The method of any one of embodiments 455-473, wherein the subject has aberrant expression or activity of ATXN2, e.g., of an ATXN2 gene, ATXN2 mRNA, and / or ATXN2 protein. 475. The method of any one of embodiments 455-474, wherein the subject has a mutated ATXN2 protein.Attorney Docket No.14640.0093-00304 476. The method of any one of embodiments 465-474, wherein administration of the AAV particle results in amelioration of at least one symptom of the ATXN2-related disorder in the subject. 477. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in a method of delivering a payload to a cell or tissue. 478. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in a method of treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, a neuromuscular disorder, or a neuro-oncological disorder. 479. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in the manufacture of a medicament. 480. Use of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381 in the manufacture of a medicament. 481. Use of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381 in the manufacture of a medicament for treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, a neuromuscular disorder, or a neuro- oncological disorder. 482. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the viral genome comprises a modulatory polynucleotide comprising a molecular scaffold, wherein the molecular scaffold comprises: (a) a 5’ flanking region, optionally comprising any one of SEQ ID NOs: 6413-6416; (b) a loop region, optionally comprising any one of SEQ ID NOs: 6417-6421; and (c) a 3’ flanking region, optionally comprising any one of SEQ ID NOs: 6422-6427. 483. The AAV particle of embodiment 482, wherein: (a) the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414 or SEQ ID NO: 6415; (b) the loop region of the molecular scaffold comprises SEQ ID NO: 6417, SEQ ID NO: 6418, or SEQ ID NO: 6421; and (c) the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423, SEQ ID NO: 6424, or SEQ ID NO: 6425.Attorney Docket No.14640.0093-00304 484. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414, the loop region of the molecular scaffold comprises SEQ ID NO: 6417, and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423. 485. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6415, the loop region of the molecular scaffold comprises SEQ ID NO: 6421, and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6425. 486. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414, the loop region of the molecular scaffold comprises SEQ ID NO: 6417, and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6424. 487. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414, the loop region of the molecular scaffold comprises SEQ ID NO: 6418, and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423. 488. The AAV particle of any one of embodiments 482-488, wherein the modulatory polynucleotide comprises an siRNA. 489. The AAV particle of embodiment 488, wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more ATXN2 mRNA transcripts, and wherein the passenger strand and the guide strand are located, respectively, on a 5’ arm and a 3’ arm of a stem loop structure, wherein the passenger strand is located between the 5’ flanking region and the loop region and the guide strand is located between the loop region and the 3’ flanking region. 490. The AAV particle of embodiment 488, wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more ATXN2 mRNA transcripts, and wherein the guide strand and the passenger strand are located, respectively, on a 5’ arm and a 3’ arm of a stem loop structure, wherein the guide strand is located between the 5’ flanking region and the loop region and the passenger strand is located between the loop region and the 3’ flanking region. 491. The AAV particle of embodiment 489 or embodiment 490, wherein the passenger strand is 15-30 nucleotides in length.Attorney Docket No.14640.0093-00304 492. The AAV particle of any one of embodiments 489-491, wherein the guide strand is 15-30 nucleotides in length. 493. The AAV particle of embodiment 492, wherein the guide strand is 21-25 nucleotides in length. 494. The AAV particle of any one of embodiments 489-493, wherein the passenger strand is at least 70% complementary to the guide strand. 495. The AAV particle of any one of embodiments 489-494, wherein the one or more ATXN2 mRNA transcripts comprises SEQ ID NO: 6428, SEQ ID NO: 6429, SEQ ID NO: 6430, and / or SEQ ID NO: 6431, or a trinucleotide repeat expansion thereof. 496. The AAV particle of any one of embodiments 482-495, wherein the viral genome comprises a promoter operably linked to the sequence encoding the modulatory polynucleotide. 497. The AAV particle of any one of embodiments 482-496, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence. 498. The AAV particle of embodiment 497, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the sequence encoding the modulatory polynucleotide. 499. The AAV particle of embodiment 497 or embodiment 498, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the sequence encoding the modulatory polynucleotide. 500. The AAV particle of any of embodiments 497-499, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the sequence encoding the modulatory polynucleotide, and an ITR sequence positioned 3’ relative to the sequence encoding the modulatory polynucleotide. 501. The AAV particle of any one of embodiments 482-500, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) present at positions 577-584 numbered according to SEQ ID NO: 982. 502. The AAV particle of any one of embodiments 482-501, wherein the AAV capsid variant comprises a VP1 protein comprising an amino acid sequence at least 95% identical to SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at positions 577-584 numbered according to SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 503. The AAV particle of embodiment 502, wherein the AAV capsid variant further comprises (i) a VP2 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 738, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (ii) a VP3 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 739, wherein the VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). 504. The AAV particle of any one of embodiments 482-503, wherein the AAV capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 982, wherein the VP1 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) a VP2 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 738, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 739, wherein the VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). 505. The AAV particle of any one of embodiments 482-504, wherein the AAV variant capsid comprises: (i) a VP1 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 982; (ii) a VP2 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 738; and / or (iii) a VP3 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 739. 506. A cell comprising the AAV particle of any one of embodiments 482-505, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell. 507. A method of making the AAV particle of any one of embodiments 482-505, wherein the method comprises: (i) providing a cell comprising a viral genome comprising a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA and a nucleic acid encoding an AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle. 508. The method of embodiment 507, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.Attorney Docket No.14640.0093-00304 509. The method of embodiment 507 or embodiment 508, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the cell. 510. The method of any one of embodiments 507-509, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell. 511. The method of any one of embodiments 507-510, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell. 512. A pharmaceutical composition comprising the AAV particle of any one of embodiments 482-505 and a pharmaceutically acceptable excipient. 513. A method of delivering a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482- 505, thereby delivering the modulatory polynucleotide. 514. The method of embodiment 512, wherein the method reduces or eliminates ATXN2 protein in the subject. 515. The method of embodiment 513 or embodiment 514, wherein the subject has, has been diagnosed with having, or is at risk of having a disease associated with an ATXN2-related disorder. 516. The method of embodiment 515, wherein the disease is spinocerebellar ataxia type 2 (SCA2). 517. A method of treating an ATXN2-related disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505, thereby treating the ATXN2-related disorder. 518. The method of embodiment 517, wherein the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder. 519. The method of embodiment 517 or embodiment 518, wherein the subject has one or more mutations in the ATXN2 gene. 520. The method of embodiment 519, wherein the one or more mutations in the ATXN2 gene comprises a trinucleotide repeat expansion.Attorney Docket No.14640.0093-00304 521. The method of embodiment 520, wherein the trinucleotide repeat expansion in the ATXN2 gene is 32 or more CAG repeats (SEQ ID NO: 6437). 522. The method of any one of embodiments 517-521, wherein the administration results in prevention of progression of the ATXN2-related disorder in the subject. 523. The method of any one of embodiments 517-522, wherein administration results in amelioration of at least one symptom of the ATXN2-related disorder in the subject. 524. The method of embodiment 523, wherein the at least one symptom comprises progressive cerebellar ataxia, nystagmus, slow saccadic eye movements, ophthalmoparesis, parkinsonism, or a combination thereof. 525. The method of any one of embodiments 513-524, further comprising administering at least one additional therapeutic agent and / or therapy comprising an agent and / or therapy for treating the ATXN2- related disorder. 526. The method of any one of embodiments 515-525, wherein the ATXN2-related disorder is SCA2. 527. A method of treating spinocerebellar ataxia type 2 (SCA2) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505, thereby treating SCA2. 528. The method of embodiment 527, wherein the subject has, has been diagnosed with having, or is at risk of having SCA2. 529. The method of any one of embodiments 513-528, wherein the subject is a human subject. 530. The method of any one of embodiments 513-529, wherein the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the CNS. 531. The method of embodiment 530, wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum.Attorney Docket No.14640.0093-00304 532. The method of any one of embodiments 513-531, further comprising evaluating, e.g., measuring, the level of modulatory polynucleotide expression, and / or the level of ATXN2 expression, e.g., ATXN2 gene, ATXN2 mRNA, and / or ATXN2 protein expression, in the subject, e.g., in a cell, tissue, or fluid, of the subject. 533. The method of embodiment 532, wherein the level of ATXN2 protein is measured by an ELISA, a Western blot, or an immunohistochemistry assay. 534. The method of embodiment 532 or embodiment 533, wherein the evaluating of the subject’s level of modulatory polynucleotide expression and / or level of ATXN2 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of modulatory polynucleotide expression and / or the subject’s level of ATXN2 expression prior to administration is compared to the subject’s level of modulatory polynucleotide expression and / or the subject’s level of ATXN2 expression subsequent to administration. 535. The method of any one of embodiments 532-534, wherein subject’s level of ATXN2 protein expression subsequent to administration is decreased relative to the subject’s level of ATXN2 protein expression prior to administration. 536. The method of any one of embodiments 532-535, further comprising evaluating, e.g., measuring, the level of modulatory polynucleotide activity and / or ATXN2 activity in the subject, e.g., in a cell or tissue of the subject. 537. The method of any one of embodiments 513-536, wherein the administration results in: (i) a decrease in ATXN2 protein expression in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum), and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or ATXN2 protein expression in a cell, tissue, or fluid of an individual with an ATXN2-related disorder who has not been administered the pharmaceutical composition or AAV particle; (ii) an increase in the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or (iii) a decrease in ATXN2 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus,Attorney Docket No.14640.0093-00304 hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or ATXN2 mRNA expression in a cell or tissue of an individual with an ATXN2-related disorder who has not been administered the pharmaceutical composition or AAV particle. 538. The method of any one of embodiments 513-537, further comprising administering to the subject at least one additional therapeutic agent and / or therapy. 539. The method of embodiment 538, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy for treating the ATXN2-related disorder, optionally wherein the at least one additional therapeutic agent and / or therapy comprises growth and trophic factors, cytokines, hormones, neurotransmitters, enzymes, anti-apoptotic factors, angiogenic factors, modulatory polynucleotides, and / or any protein known to be mutated in pathological disorders such as ATXN2- related disorders. 540. The method of embodiment 538, wherein the at least one additional therapeutic agent and / or therapy comprises an immunosuppressant, optionally wherein the immunosuppressant is a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine. 541. A method of treating a subject having or diagnosed with having amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), or frontotemporal lobar degeneration (FTLD), comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505. 542. The pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505 for use in a method of treating a disorder according to any one of embodiments 517-538. 543. The pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505 for use in treating an ATXN2-related disorder, optionally wherein the ATXN2- related disorder is SCA2. 544. The pharmaceutical composition or the AAV particle for use of embodiment 542 or embodiment 543, wherein the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder, optionally wherein the ATXN2-related disorder is SCA2.Attorney Docket No.14640.0093-00304 545. Use of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505 in the manufacture of a medicament for treatment of an ATXN2-related disorder in a subject, optionally wherein the ATXN2-related disorder is SCA2. 546. The use of embodiment 545, wherein the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder, optionally wherein the ATXN2-related disorder is SCA2.

[0060] The details of various aspects or embodiments of the present disclosure are set forth below. Other features, objects, and advantages of the disclosure will be apparent from the description and the claims. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art in the field of this disclosure. In the case of conflict, the present description will control. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] FIGs.1A-1D show immunohistochemistry images from various CNS and peripheral tissues isolated from NHPs (cynomolgus macaques) at 28 days post intravenous administration of AAV particles comprising the TTN-002 capsid variant (top panels) or AAV9 control capsid (bottom panels) and a self- complementary genome encoding a cynomolgus frataxin protein fused to an HA tag driven by a chicken beta actin (CBA) heterologous promoter. FIG.1A shows, from left to right, the cerebellum (Purkinje cell layer), spinal cord (cervical), cortex (temporal), and the brainstem. FIG.1B shows, from left to right, the globus pallidus, the hippocampus, the thalamus, the putamen, and the dentate. FIG.1C shows, from left to right, the whole brain (level H), the whole brain (level K), and the cerebellum. FIG.1D shows, from left to right, the spinal cord (thoracic), the DRG (thoracic), the liver, and the heart. DETAILED DESCRIPTION Overview

[0062] Described herein, inter alia, are compositions comprising an AAV capsid variant for delivery of modulatory polynucleotides for reducing or eliminating expression of ATXN2 to treat SCA2 or other disorders associated with aberrant ATXN2 protein expression or activity or mutant ATXN2 protein. In some embodiments, the modulatory polynucleotides reduce or eliminate expression of ATXN2 mRNA, thereby reducing or eliminating ATXN2 protein. The AAV capsid variants described herein have enhanced tropism for a cell or tissue, e.g., for the delivery of a payload to said cell or tissue, for example a CNS tissue or a CNS cell.

[0063] AAVs have proven to be useful as a biological tool due to their relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. Engineered adeno-associated virus (AAV) capsids with improved brain tropism represent an attractiveAttorney Docket No.14640.0093-00304 solution to the limitations of CNS delivery. AAV-derived vectors are promising tools for clinical gene transfer because of their non-pathogenic nature, their low immunogenic profile, low rate of integration into the host genome, and long-term transgene expression in non-dividing cells. However, the transduction efficiency of naturally occurring AAVs in certain organs is too low for clinical applications, and capsid neutralization by pre-existing neutralizing antibodies may prevent treatment of a large proportion of patients. For these reasons, considerable efforts have been devoted to obtaining capsid variants with enhanced properties. Of many approaches tested so far, significant advances have resulted from directed evolution of AAV capsids using in vitro or in vivo selection of capsid variants created by capsid sequence randomization using either error-prone PCR, shuffling of various parent serotypes, or insertion of fully randomized short peptides at defined positions.

[0064] The genome of the virus may be modified to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload. The genome of the virus may encode a modulatory polynucleotide, e.g., a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA, thereby reducing or eliminating ATXN2 protein, and the viral particle comprising said genome may be delivered to a target cell, tissue, or organism. In some embodiments, the genome encodes a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA, thereby reducing or eliminating ATXN2 protein. In some embodiments, the target cell is a CNS cell. In some embodiments, the target tissue is a CNS tissue. In some embodiments, the target CNS tissue is brain tissue. In some embodiments, the target CNS tissue comprises spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and cerebellum, or a combination thereof. In some embodiments, the target CNS tissue is in the forebrain. In some embodiments, the target CNS tissue is brainstem. In some embodiments, the target CNS tissue is cerebellum. In some embodiments, the target CNS tissues are brainstem and cerebellum.

[0065] Gene therapy presents an alternative approach for SCA2 and related diseases sharing single- gene etiology. AAVs are commonly used in gene therapy approaches as a result of a number of advantageous features. Without wishing to be bound by theory, it is believed in some embodiments, that an AAV particle described herein can be used to administer and / or deliver a modulatory polynucleotide, in order to achieve sustained, high concentrations, allowing for longer lasting efficacy, fewer dose treatments, broad biodistribution, and / or more consistent levels of the modulatory polynucleotide, relative to a non-AAV therapy.

[0066] Provided herein are compositions and methods which may provide for improved features compared to prior AAV-mediated enzyme replacement approaches, including (i) increased biodistribution throughout the CNS (e.g., the cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord), (ii) elevated modulatory polynucleotide expression in multiple brain regions (e.g., cortex,Attorney Docket No.14640.0093-00304 thalamus, and brainstem); and (iii) preferential biodistribution in the CNS over the liver and / or DRG, of the subject.

[0067] Also provided herein are AAV capsid variants (e.g., AAV5 capsid variants) with improved properties compared to wildtype AAV5 and / or wildtype AAV9, such as (i) increased penetrance through the blood brain barrier following intravenous administration, (ii) wider distribution throughout the multiple brain regions, e.g., temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum, and / or (iii) and / or elevated modulatory polynucleotide expression in multiple brain regions. In some embodiments, the AAV capsids described herein enhance the delivery of a modulatory polynucleotide to multiple regions of the brain including, for example, the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum. In some embodiments, the AAV capsids described herein enhance the delivery of a modulatory polynucleotide to the spinal cord. In some embodiments, the AAV capsid variants with enhanced brain tropism described herein are capable of significantly increasing modulatory polynucleotide expression in the brain. In some embodiments, the AAV capsid variants with enhanced brain tropism described herein are capable of significantly reducing or eliminating expression of ATXN2 mRNA in the brain.

[0068] Thus, the compositions and methods described herein can be used in the treatment of ATXN2-related disorders (e.g., SCA2). In some embodiments, the disclosure provides an AAV particle comprising a AAV capsid variants disclosed herein and an AAV viral genome comprising a nucleotide sequence comprising a promoter and a sequence encoding a modulatory polynucleotide for use in treating an ATXN2-related disorder. In some embodiments, the modulatory polynucleotide reduces or eliminates expression of Ataxin-2 (ATXN2) mRNA, e.g., a modulatory polynucleotide comprising an RNAi agent targeting ATXN2 mRNA. In some embodiments, the ATXN2-related disorder is SCA2. I. Compositions Adeno-associated viral (AAV) vectors

[0069] AAVs have a genome of about 5,000 nucleotides in length and contains two open reading frames encoding the proteins responsible for replication (Rep) and the structural protein of the capsid (Cap). The open reading frames are flanked by two Inverted Terminal Repeat (ITR) sequences, which serve as the origin of replication of the viral genome. The wild-type AAV viral genome comprises nucleotide sequences for two open reading frames, one for the four non-structural Rep proteins (Rep78, Rep68, Rep52, Rep40, encoded by Rep genes) and one for the three capsid, or structural, proteins (VP1, VP2, VP3, encoded by capsid genes or Cap genes). The Rep proteins are important for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid. Alternative splicing and alternate initiation codons and promoters result in the generation of four different Rep proteins from a single open reading frame and the generation of three capsid proteins from a single open reading frame. Though it varies by AAV serotype, as a non-limiting example, for AAV5Attorney Docket No.14640.0093-00304 (SEQ ID NO: 138 and 137) VP1 refers to amino acids 1-724, VP2 refers to amino acids 137-724, and VP3 refers to amino acids 193-724. In some embodiments, e.g., for the amino acid sequence of SEQ ID NO: 982, VP1 comprises amino acids 1-731, VP2 comprises amino acids 137-731, and VP3 comprises amino acids 193-731. In other words, VP1 is the full-length capsid protein sequence, while VP2 and VP3 are shorter components of the whole. As a result, changes in the sequence in the VP3 region, are also changes to VP1 and VP2, however, the percent difference as compared to the parent sequence will be greatest for VP3 since it is the shortest sequence of the three. Though described here in relation to the amino acid sequence, the nucleic acid sequence encoding these proteins can be similarly described. Together, the three capsid proteins assemble to create the AAV capsid. While not wishing to be bound by theory, the AAV capsid typically comprises a molar ratio of 1:1:10 of VP1:VP2:VP3.

[0070] The AAV particle typically requires a co-helper (e.g., adenovirus) to undergo productive infection in cells. In the absence of such helper functions, the AAV virions essentially enter host cells but do not integrate into the cells’ genome.

[0071] AAV particles have been investigated for delivery of gene therapeutics because of several unique features. Non-limiting examples of the features include (i) the ability to infect both dividing and non-dividing cells; (ii) a broad host range for infectivity, including human cells; (iii) wild-type AAV has not been associated with any disease and has not been shown to replicate in infected cells; (iv) the lack of cell-mediated immune response against the vector, and (v) the non-integrative nature in a host chromosome thereby reducing potential for long-term genetic alterations. Moreover, infection with AAV particles has minimal influence on changing the pattern of cellular gene expression (Stilwell and Samulski et al., Biotechniques, 2003, 34, 148, the contents of which are herein incorporated by reference in their entirety).

[0072] Typically, AAV particles for delivery of a modulatory polynucleotide may be recombinant viral vectors which are replication defective as they lack sequences encoding functional Rep and Cap proteins within the viral genome. In some cases, the replication defective AAV particles may lack most or all coding sequences and essentially only contain one or two AAV ITR sequences and a nucleic acid sequence encoding a modulatory polynucleotide (e.g., a modulatory polynucleotide for reducing or eliminating ATXN2).

[0073] In some embodiments, the AAV particles of the present disclosure may be introduced into mammalian cells.

[0074] AAV particles may be modified to enhance the efficiency of delivery. Such modified AAV particles of the present disclosure can be packaged efficiently and can be used to successfully infect the target cells at high frequency and with minimal toxicity.

[0075] In other embodiments, AAV particles of the present disclosure may be used to deliver a modulatory polynucleotide to the central nervous system (see, e.g., U.S. Pat. No.6,180,613; the contents of which are herein incorporated by reference in their entirety) or to specific tissues of the CNS.Attorney Docket No.14640.0093-00304

[0076] It is understood that the compositions described herein may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0077] In some embodiments, AAV capsid variants disclosed herein comprise one or more modifications (e.g., one or more substitutions) in the loop VIII region of AAV5. In some embodiments, the AAV5 loop VIII region comprises amino acid positions 571-579, e.g., position 577, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV5 loop VIII region (e.g., positions 571-579, e.g., position 577) protrudes above the 3-fold axis of symmetry, e.g., is a surface-exposed location in the AAV5 capsid, e.g., as described in Govindasamy et al. “Structural Insights into Adeno-Associated Virus Serotype 5,” Journal of Virology, 2013, 87(20):11187-11199 (the contents of which are hereby incorporated by reference in their entirety). In some embodiments, the term “loop” (e.g., as used in loop VIII) is used interchangeably herein with the term "variable region" (e.g., variable region VIII), or “VR” (e.g., VR-VIII). In some embodiments, loop VIII (e.g., VR-VIII) comprises positions 571-599 (e.g., amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)), numbered according to SEQ ID NO: 982. In some embodiments, loop VIII or variable region VIII (VR-VIII) is as described in Govindasamy et al. (supra) (the contents of which are hereby incorporated by reference in their entirety).

[0078] The AAV particles and payloads of the disclosure may be delivered to one or more target cells, tissues, organs, or organisms. In some embodiments, the AAV particles of the disclosure demonstrate enhanced tropism for a target cell type, tissue, or organ. As a non-limiting example, the AAV particle may have enhanced tropism for cells and tissues of the central or peripheral nervous systems (CNS and PNS, respectively). In some embodiments, an AAV particle of the disclosure may, in addition, or alternatively, have decreased tropism for a cell-type, tissue or organ.

[0079] In some embodiments, AAV are used as a biological tool due to a relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. The genome of the virus may be manipulated to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload.

[0080] In some embodiments, the AAV is a recombinant AAV. In some embodiments, the wild-type AAV viral genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length. In some embodiments, inverted terminal repeats (ITRs) cap the viral genome at both the 5’ and the 3’ end, providing origins of replication for the viral genome. In some embodiments, an AAV viral genome comprises two ITR sequences. In some embodiments, the ITRs have a characteristic T- shaped hairpin structure defined by a self-complementary region (145nt in wild-type AAV) at the 5’ and 3’ ends of the ssDNA which form an energetically stable double stranded region. In some embodiments, the double stranded hairpin structures comprise multiple functions including, but not limited to, acting as an origin for DNA replication by functioning as primers for the endogenous DNA polymerase complex of the host viral replication cell.Attorney Docket No.14640.0093-00304

[0081] AAV particles of the present disclosure may be produced recombinantly and may be based on adeno-associated virus (AAV) reference sequences. In addition to single-stranded AAV viral genomes (e.g., ssAAVs), the present disclosure also provides for self-complementary AAV (scAAVs) viral genomes. scAAV viral genomes contain DNA strands which anneal together to form double-stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the transduced cell. In some embodiments, the AAV particle of the present disclosure is an scAAV. In some embodiments, the AAV particle of the present disclosure is an ssAAV.

[0082] Methods for producing and / or modifying AAV particles are disclosed in the art such as pseudotyped AAV vectors (PCT Patent Publication Nos. WO200028004; WO200123001; WO2004112727; WO2005005610; and WO2005072364, the content of each of which is incorporated herein by reference in its entirety).

[0083] As described herein, the AAV particles of the disclosure comprising an AAV capsid variant and a viral genome have enhanced tropism for a cell-type or a tissue, e.g., a CNS cell-type, region, or tissue. Capsid Peptides

[0084] Disclosed herein are AAV particles comprising an AAV capsid variant comprising a peptide (e.g., inserted into a wildtype AAV capsid and / or in substitution of an amino acid or peptide in a wildtype AAV capsid) for enhanced or improved transduction of a target tissue (e.g., cells of the CNS or PNS). In some embodiments, the nucleic acid encoding the peptide is an isolated nucleic acid. In some embodiments, the nucleic acid encoding the peptide is a recombinant nucleic acid.

[0085] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of the CNS. The cell of the CNS may be, but is not limited to, neurons (e.g., excitatory, inhibitory, motor, sensory, autonomic, sympathetic, parasympathetic, Purkinje, Betz, etc.), glial cells (e.g., microglia, astrocytes, oligodendrocytes) and / or supporting cells of the brain such as immune cells (e.g., T cells). The tissue of the CNS may be, but is not limited to, the cortex (e.g., frontal, parietal, occipital, temporal), thalamus, hypothalamus, striatum, putamen, caudate nucleus, hippocampus, entorhinal cortex, basal ganglia, or deep cerebellar nuclei. In some embodiments, the tissue of the CNS is spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum.

[0086] In some embodiments, the peptide may modulate distribution of an AAV particle to a cell, region, or tissue of the CNS. In some embodiments, the peptide may decrease distribution of an AAV particle to the DRG.

[0087] In some embodiments, the peptide may increase distribution of an AAV particle to the CNS (e.g., the cortex) after intravenous administration. In some embodiments, the peptide may increase distribution of an AAV particle to the CNS (e.g., the cortex) following focused ultrasound (FUS), e.g.,Attorney Docket No.14640.0093-00304 coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0088] In some embodiments, the peptide may modulate distribution of an AAV particle to the PNS (e.g., DRG) after intravenous administration. In some embodiments, the peptide may increase distribution of an AAV particle to non-DRG cells of the PNS following focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration. In some embodiments, the peptide may decrease distribution of an AAV particle to the DRG following focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0089] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of a heart, e.g., a heart atrium or a heart ventricle. In some embodiments, the peptide may increase distribution of an AAV particle to a heart cell, region, or tissue after intravenous administration.

[0090] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of a muscle. In some embodiments, the muscle is a heart muscle (e.g., a heart atrium or a heart ventricle) or a quadriceps. In some embodiments, the peptide may increase distribution of an AAV particle to a muscle cell, region, or tissue after intravenous administration.

[0091] In some embodiments, a peptide may comprise a sequence as set forth in Table 1 (e.g., comprising the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590-1593, 1598-1624, or 2064-2079). In some embodiments, a peptide may comprise a sequence as set forth in Table 2A or 2B. In some embodiments, the peptide may comprise a sequence set forth in Table 11 or 20-25. Table 1. Exemplary Peptide SequencesAttorney Docket No.14640.0093-00304Table 2A. Exemplary Peptide SequencesTable 2B. Exemplary Peptide Sequences

[0092] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5and [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, position X1of [N2] is Y, N, C, or T. In some embodiments, position X2of [N2] is P, E, K, T, or Q. In some embodiments, position X3of [N2] is A or P. In some embodiments, position X4of [N2] is E, S, D, or A. In some embodiments, position X5of [N2] is V, L, or E. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X5. In some embodiments, the amino acid sequence of [N3] comprises VQK. In some embodiments, the amino acid sequence of [N3] consists of VQK.

[0093] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5 and [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, [N3] comprises the amino acid sequence of VQK, EQK, or VKK. In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, [N3] consists of the amino acid sequence VQK. In some embodiments, position X1of [N2] is Y, N, or C. In some embodiments, position X1of [N2] is Y or N. In some embodiments, position X2of [N2] is P, K, T, or Q. In some embodiments, position X2of [N2] is P, T, or Q. In some embodiments, position X3of [N2] is A or P. In some embodiments, position X3of [N2]Attorney Docket No.14640.0093-00304 is A. In some embodiments, position X4of [N2] is E, S, or A. In some embodiments, position X5of [N2] is V, L, or E. In some embodiments, position X5of [N2] is V or L. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X5. In some embodiments, [N2] comprises YPA, YPP, NKA, YTA, YQA, YTP, NPA, CPA, THA, PAE, PPS, KAE, TAE, QAE, TPS, PAA, HAS, AEV, PSL, AEE, or AAV. In some embodiments, [N2] comprises YPAE (SEQ ID NO: 21), YPPS (SEQ ID NO: 22), NKAE (SEQ ID NO: 23), YTAE (SEQ ID NO: 24), YQAE (SEQ ID NO: 25), YTPS (SEQ ID NO: 26), YPAA (SEQ ID NO: 27), NPAE (SEQ ID NO: 28), CPAE (SEQ ID NO: 29), THAS (SEQ ID NO: 30), PAEV (SEQ ID NO: 17), PPSL (SEQ ID NO: 31), KAEV (SEQ ID NO: 32), TAEV (SEQ ID NO: 16), PAEE (SEQ ID NO: 18), QAEV (SEQ ID NO: 15), TPSL (SEQ ID NO: 33), PAAV (SEQ ID NO: 34), or QAEE (SEQ ID NO: 35). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11). In some embodiments, [N2] comprises the amino acid sequence of YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises the amino acid sequence of AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46). In some embodiments, [N2]-[N3] comprises the amino acid sequence PAEVVQK (SEQ ID NO: 20), PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48), TAEVVQK (SEQ ID NO: 49), PAEVEQK (SEQ ID NO: 50), PAEEVQK (SEQ ID NO: 51), QAEVVQK (SEQ ID NO: 52), TPSLVQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61), or QAEEVQK (SEQ ID NO: 62). In some embodiments, [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948), YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSLVKK (SEQ ID NO: 954), YPAEVVKK (SEQ ID NO: 955), YPAEVVHK (SEQ ID NO: 956), YPAAVVQK (SEQ ID NO: 957), NPAEVVQK (SEQ ID NO: 958), YPAEVVQQ (SEQ ID NO: 959), CPAEVVQK (SEQ ID NO: 960), YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an aminoAttorney Docket No.14640.0093-00304 acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943). In some embodiments, [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0094] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [N2]-[N3], further comprises [N1], which comprises positions XD, XE, and XF. In some embodiments, position XDof [N1] is Q, T, S, A, I, L, or H. In some embodiments, position XEof [N1] is S, G, A, or R. In some embodiments, position XFof [N1] is S, K, L, R, A, or T. In some embodiments, [N1] comprises SK, SL, SS, SR, GA, GS, AS, ST, RS, QS, TS, AG, IG, QA, LG, HS, LS, or QR. In some embodiments, [N1] is or comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS. In some embodiments, the amino acid sequence of [N1] is QSS. In some embodiments, [N1]-[N2] comprises SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64), SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68), GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70), STNKA (SEQ ID NO: 71), SSYTA (SEQ ID NO: 72), SSYQA (SEQ ID NO: 73), SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77), or SSTHA (SEQ ID NO: 78). In some embodiments, [N1]-[N2] comprises SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81), SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84), GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95). In some embodiments, [N1]-[N2] is or comprises QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), HSSYPAAV (SEQ ID NO: 115), QSSNPAEV (SEQ ID NO: 116), QSSYTAEV (SEQ ID NO: 117), TSLCPAEV (SEQ ID NO: 118), QRSYTAEV (SEQ ID NO: 119), or QSSYQAEE (SEQ ID NO: 120); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [N1]-[N2] is QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] comprises SSYPAEVVQ (SEQ ID NO: 121),Attorney Docket No.14640.0093-00304 SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125), GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127), ASYPAEVVQ (SEQ ID NO: 128), STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO: 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVVQ (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134), SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140), SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145), RSYTAEVVQ (SEQ ID NO: 146), SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149). In some embodiments, [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [N1]-[N2]-[N3] is QSSYPAEVVQK (SEQ ID NO: 150).

[0095] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N0], wherein [N0] comprises positions XA, XB, and XC. In some embodiments, position XAof [N0] is T, I, or N. In some embodiments, positions XBof [N0] is N. In some embodiments, position XCof [N0] is N, T, S, or K. In some embodiments, [N0] comprises TN, IN, NN, NT, NS, or NK. In some embodiments, [N0] is or comprises TNN, TNT, INN, TNS, NNN, or TNK. In some embodiments, the amino acid sequence of [N0] is TNN. In some embodiments, [N0]-[N1] is or comprises TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGSAttorney Docket No.14640.0093-00304 (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1] is TNNQSS (SEQ ID NO: 183). In some embodiments, [N0]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524), TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 551), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557), TNNQSSYTAEVVKK (SEQ ID NO: 558), TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562) or TNKQASYPAEVVQK (SEQ ID NO: 563); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3] is TNNQSSYPAEVVQK (SEQ ID NO: 500).Attorney Docket No.14640.0093-00304

[0096] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N4], which comprises positions XGand XH. In some embodiments, position XG of [N4] is T, P, or N. In some embodiments, position XG of [N4] is T. In some embodiments, position XHof [N4] is A. In some embodiments, [N4] is or comprises TA, PA, or NA. In some embodiments, [N4] is TA. In some embodiments, [N3]-[N4] is or comprises VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N3]-[N4] is VQKTA (SEQ ID NO: 564). In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583), TNTASSYQAEVVQKTA (SEQ ID NO: 1584), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEVVQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), TNNQRSYTAEVVQKTA (SEQ ID NO: 1604), TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g.,Attorney Docket No.14640.0093-00304 conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3]- [N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0097] In some embodiments, a peptide described herein comprises the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5 and [N3] comprises the amino acid sequence of VQK or VQN. In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, position X1of [N2] is Y or T. In some embodiments, position X2of [N2] is Q, T, P, or E. In some embodiments, position X3of [N2] is A. In some embodiments, position X4of [N2] is E or D. In some embodiments, position X4of [N2] is E or D. In some embodiments, position X5of [N2] is V or E. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X5. In some embodiments, [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV, AE, or AD. In some embodiments, [N2] comprises YPA, YQA, YTA, TEA, QAE, TAE, PAE, EAE, PAD, AEV, AEE, or ADV. In some embodiments, [N2] comprises YPAE (SEQ ID NO: 21), YQAE (SEQ ID NO: 25), YTAE (SEQ ID NO: 24), TEAE (SEQ ID NO: 587), YPAD (SEQ ID NO: 588), QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), EAEV (SEQ ID NO: 590), or PADV (SEQ ID NO: 19). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13). In some embodiments, [N2] is YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593). In some embodiments, [N2]-[N3] comprises PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596). In some embodiments, [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943).

[0098] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [N2]-[N3], further comprises [N1], which comprises positions XD, XE, and XF. In someAttorney Docket No.14640.0093-00304 embodiments, position XDof [N1] is Q or S. In some embodiments, position XEof [N1] is S, L, A, or T. In some embodiments, position XFof [N1] is S, Y, or T. In some embodiments, [N1] comprises QS, SL, SA, QT, LS, LY, AT, TS, or SS. In some embodiments, [N1] is or comprises QSS, SLS, SLY, SAT, or QTS. In some embodiments, [N1] is QSS. In some embodiments, [N1]-[N2] comprises SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603), or TSTEA (SEQ ID NO: 605). In some embodiments, [N1]-[N2] comprises SSYPAE (SEQ ID NO: 79), LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), ATYPAE (SEQ ID NO: 613), LSYPAE (SEQ ID NO: 616), TSTEAE (SEQ ID NO: 619), or LSYPAD (SEQ ID NO: 621). In some embodiments, [N1]-[N2] is or comprises QSSYPAEV (SEQ ID NO: 96), SLSYQAEV (SEQ ID NO: 622), SLSYTAEV (SEQ ID NO: 623), SLYYPAEV (SEQ ID NO: 624), SATYPAEV (SEQ ID NO: 625), SLSYPAEV (SEQ ID NO: 629), SLSYPAEE (SEQ ID NO: 632), QTSTEAEV (SEQ ID NO: 633), or SLSYPADV (SEQ ID NO: 634); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N1]-[N2] is QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), SLSYPAEVVQK (SEQ ID NO: 642), SLSYPAEEVQK (SEQ ID NO: 643), SLSYPAEVVQN (SEQ ID NO: 644), QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N1]-[N2]-[N3] is QSSYPAEVVQK (SEQ ID NO: 150).

[0099] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N0], wherein [N0] comprises positions XA, XB, and XC. In some embodiments, position XAof [N0] is T. In some embodiments, positions XBof [N0] is N. In some embodiments, position XCof [N0] is N, T, S, or K. In some embodiments, [N0] comprises TN, NS, NT, NN, or NK. In some embodiments, [N0] is or comprises TNS, TNT, TNN, or TNK. In some embodiment, [N0] is TNN. In some embodiments, [N0]-[N1] is or comprises TNNQSS (SEQ ID NO: 183), TNSSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650), or TNKSAT (SEQ ID NO: 651); an amino acid sequence comprising anyAttorney Docket No.14640.0093-00304 portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1] is TNNQSS (SEQ ID NO: 183). In some embodiments, [N0]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0100] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N4], which comprises positions XG and XH. In some embodiments, position XGof [N4] is T, P, or N. In some embodiments, position XHof [N4] is A or D. In some embodiments, [N4] is or comprises TA, TD, PA, or NA. In some embodiments, [N4] is TA. In some embodiments, [N3]-[N4] is or comprises VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N3]-[N4] is VQKTA (SEQ ID NO: 564). In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073),Attorney Docket No.14640.0093-00304 TNNQTSTEAEVVQKTA (SEQ ID NO: 2074), TNKSATYPAEVVQKTA (SEQ ID NO: 2075), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0101] In some embodiments, [N1] is present immediately subsequent to [N0]. In some embodiments, [N2] is present immediately subsequent to [N1]. In some embodiments, [N3] is present immediately subsequent to [N2]. In some embodiments, [N4] is present immediately subsequent to [N3]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [N2]-[N3]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [N1]-[N2]-[N3]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [N1]-[N2]-[N3]-[N4]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [N0]-[N1]-[N2]-[N3]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [N0]-[N1]-[N2]-[N3]-[N4].

[0102] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [B]-[C], wherein [B] comprises positions X1, X2, and X3, and [C] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). In some embodiments, position X1 of [B] X1 is Q, T, S, A, I, L, or H. In some embodiments, position X1of [B] X1is Q, T, S, A, or H. In some embodiments, position X2of [B] is S, G, or A. In some embodiments, position X2of [B] is S or G. In some embodiments, position X3of [B] is S, K, L, R, or A. In some embodiments, position X3of [B] is S, K, L, or R. In some embodiments, [B] comprises Q at position X1. In some embodiments, [B] comprises S at position X2. In some embodiments, [B] comprises S at position X3. In some embodiments, [B] comprises QS, TS, SS, AG, IG, QA, AS, LG, HS, SK, SL, SR, GA, or GS. In some embodiments, [B] is or comprises QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS. In some embodiments, the amino acid sequence of [B] is QSS. In some embodiments, [B]-[C] comprises SSYPAEVVQK (SEQ ID NO: 572), SKYPAEVVQK (SEQ ID NO: 573), SLYPAEVVQK (SEQ ID NO: 574), SRYPAEVVQK (SEQ ID NO: 575), GAYPAEVVQK (SEQ ID NO: 576), GSYPAEVVQK (SEQ ID NO: 580), or ASYPAEVVQK (SEQ ID NO: 582). In some embodiments, [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), or HSSYPAEVVQK (SEQ ID NO: 162); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; anAttorney Docket No.14640.0093-00304 amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [B]-[C] is QSSYPAEVVQK (SEQ ID NO: 150).

[0103] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [A], which comprises positions XA, XB, and XC. In some embodiments, position XAof [A] is T, I, or N. In some embodiments, position XBof [A] is N. In some embodiments, position XCof [A] is N, T, S, or K. In some embodiments, [A] comprises TN, IN, NN, NT, NS, or NK. In some embodiments, [A] is or comprises TNN, TNT, INN, NNN, TNS, or TNK. In some embodiments, [A] is TNN. In some embodiments, [A]-[B] is or comprises TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNHSS (SEQ ID NO: 194), INNQSS (SEQ ID NO: 196), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), or TNKQAS (SEQ ID NO: 201); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNHSSYPAEVVQK (SEQ ID NO: 525), INNQSSYPAEVVQK (SEQ ID NO: 543), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNSTSLYPAEVVQK (SEQ ID NO: 556), or TNKQASYPAEVVQK (SEQ ID NO: 563); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is TNNQSSYPAEVVQK (SEQ ID NO: 500).Attorney Docket No.14640.0093-00304

[0104] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [D], wherein [D] comprises position X4and X5. In some embodiments, position X4of [D] is T or N. In some embodiments, position X5 of [D] is A. In some embodiments, [D] is or comprises TA or PA. In some embodiments, the amino acid sequence of [D] is TA. In some embodiments, [C]-[D] is or comprises YPAEVVQKTA (SEQ ID NO: 584) or YPAEVVQKPA (SEQ ID NO: 586); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence ofis YPAEVVQKTA (SEQ ID NO: 584). In some embodiments, [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [C]-[D] is YPAEVVQKTA (SEQ ID NO: 584). In some embodiments, [A]-[B]-[C]-[D] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0105] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [B]-[C], wherein [B] comprises positions X1, X2, and X3, and [C] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). In some embodiments, position X1of [B] is Q or S. In some embodiments, position X2of [B] is S, L, or A. In some embodiments, position X3of [B] is S, Y, or T. In some embodiments, [B] comprises Q at position X1. In some embodiments, [B] comprises S at position X2. In some embodiments, [B] comprises S at position X3. In some embodiments, [B] comprises QS, SL, SA, LY, AT, LS, or SS. In some embodiments, [B] is or comprises QSS, SLY, SAT, or SLS. In some embodiments, [B] is QSS. In some embodiments, [B]-[C] comprises SSYPAEVVQK (SEQ ID NO: 572), LYYPAEVVQK (SEQ ID NO: 702), ATYPAEVVQK (SEQ ID NO: 718), or LSYPAEVVQK (SEQ ID NO: 703). In some embodiments, [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150),Attorney Docket No.14640.0093-00304 SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), or SLSYPAEVVQK (SEQ ID NO: 642); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [B]-[C] is QSSYPAEVVQK (SEQ ID NO: 150).

[0106] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [A], which comprises positions XA, XB, and XC. In some embodiments, position XAof [A] is T. In some embodiments, position XBof [A] is N. In some embodiments, position XCof [A] is N, T, S, or K. In some embodiments, [A] comprises TN, NS, NT, NK, or NN. In some embodiments, [A] is or comprises TNN, TNS, TNT, or TNK. In some embodiments, the amino acid sequence of [A] is TNN. In some embodiments, [A]-[B] is or comprises TNNQSS (SEQ ID NO: 183), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNSSLS (SEQ ID NO: 647), or TNKSAT (SEQ ID NO: 651); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), or TNKSATYPAEVVQK (SEQ ID NO: 663); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0107] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [D], wherein [D] comprises position X4and X5. In some embodiments, position X4of [D] is T, N, or P. In some embodiments, position X5 of [D] is A or D. In some embodiments, [D] is or comprises TA, TD, NA, or PA. In some embodiments, the amino acid sequence of [D] is TA. In some embodiments, [C]-[D] is or comprises YPAEVVQKTA (SEQ ID NO: 584), YPAEVVQKTD (SEQ ID NO: 719), YPAEVVQKNA (SEQ ID NO: 724), or YPAEVVQKPA (SEQ ID NO: 586); an amino acid sequenceAttorney Docket No.14640.0093-00304 comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [C]-[D] is YPAEVVQKTA (SEQ ID NO: 584). In some embodiments, [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNKSATYPAEVVQKTA (SEQ ID NO: 2075); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B]-[C]-[D] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0108] In some embodiments, [B] is present immediately subsequent to [A]. In some embodiments, [C] is present immediately subsequent to [B]. In some embodiments, [D] is present immediately subsequent to [C]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [B]-[C]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [B]-[C]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [A]-[B]-[C]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [B]-[C]-[D]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [A]-[B]-[C]-[D].

[0109] In some embodiments, a peptide described herein comprises the formula [K1]-[K2], wherein, [K1] comprises LSY or LYY, and [K2] comprises positions X1, X2, X3, and X4. In some embodiments, [K1] comprises LSY. In some embodiments, position X1of [K2] is Q, T or P. In some embodiments, position X2of [K2] is A, in some embodiments, position X3of [K2] is E or D. In some embodiments, position X4of [K2] is V or E. In some embodiments, [K2] comprises QA, TA, PA, EV, EE, DV, AE, or AD. In some embodiments, [K2] comprises QAE, TAE, PAE, PAD, AEV, AEE, or ADV. In some embodiments, [K2] is or comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19). In some embodiments, [K1]-[K2] comprises LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), or LSYPA (SEQ ID NO: 603). In some embodiments, [K1]-[K2] comprises LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), LSYPAE (SEQ ID NO: 616), or LSYPAD (SEQ ID NO: 621). In some embodiments, [K1]-[K2] is or comprises LSYQAEV (SEQ ID NO: 667), LSYTAEV (SEQ ID NO: 668), LYYPAEV (SEQ ID NO: 669), LSYPAEV (SEQ ID NO: 671),Attorney Docket No.14640.0093-00304 LSYPAEE (SEQ ID NO: 673), or LSYPADV (SEQ ID NO: 674); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0110] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [K1]-[K2], further comprises [K0], which comprises TNNS (SEQ ID NO: 14). In some embodiments, [K0]-[K1] comprises TNSSLS (SEQ ID NO: 647) or TNSSLY (SEQ ID NO: 648). In some embodiments, [K0]-[K1] is or comprises TNSSLSY (SEQ ID NO: 676) or TNSSLYY (SEQ ID NO: 678); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [K0]-[K1]-[K2] comprises TNSSLSYQA (SEQ ID NO: 679), TNSSLSYTA (SEQ ID NO: 681), TNSSLYYPA (SEQ ID NO: 682), or TNSSLSYPA (SEQ ID NO: 683). In some embodiments, [K0]-[K1]-[K2] comprises TNSSLSYQAE (SEQ ID NO: 684), TNSSLSYTAE (SEQ ID NO: 685), TNSSLYYPAE (SEQ ID NO: 686), TNSSLSYPAE (SEQ ID NO: 687), or TNSSLSYPAD (SEQ ID NO: 689). In some embodiments, [K0]- [K1]-[K2] is or comprises TNSSLSYQAEV (SEQ ID NO: 692), TNSSLSYTAEV (SEQ ID NO: 693), TNSSLYYPAEV (SEQ ID NO: 696), TNSSLSYPAEV (SEQ ID NO: 697), TNSSLSYPAEE (SEQ ID NO: 698), or TNSSLSYPADV (SEQ ID NO: 699); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0111] In some embodiments, peptide comprising the amino acid sequence comprising the formula of [K1]-[K2], further comprises [K3], wherein [K3] comprises positions XA, XB, and XC. In some embodiments, position XAof [K3] is V. In some embodiments, position XBof [K3] is Q. In some embodiments, position XCof [K3] is K or N. In some embodiments, [K3] comprises VQ, QK, or QN. In some embodiments, [K3] is or comprises VQK or VQN. In some embodiments, K2]-[K3] is or comprises QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51) ,PAEVVQN (SEQ ID NO: 594), or PADVVQK (SEQ ID NO: 596); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one,Attorney Docket No.14640.0093-00304 two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [K1]-[K2]-[K3] is or comprises LSYQAEVVQK (SEQ ID NO: 700), LSYTAEVVQK (SEQ ID NO: 701), LYYPAEVVQK (SEQ ID NO: 702), LSYPAEVVQK (SEQ ID NO: 703), LSYPAEEVQK (SEQ ID NO: 704), LSYPAEVVQN (SEQ ID NO: 706), or LSYPADVVQK (SEQ ID NO: 708); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [K0]-[K1]-[K2]-[K3] is or comprises TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), or TNSSLSYPADVVQK (SEQ ID NO: 665); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0112] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [K1]-[K2], further comprises [K4], wherein [K4] comprises positions XDand XE. In some embodiments, position XDof [K4] is T, P, or N. In some embodiments, position XEof [K4] is A or D. In some embodiments, [K4] is or comprises TA, TD, PA, or NA. In some embodiments, [K3]-[K4] is or comprises VQKTA (SEQ ID NO: 564), VQKTD (SEQ ID NO: 714), VQNTA (SEQ ID NO: 715), VQKNA (SEQ ID NO: 570), or VQKPA (SEQ ID NO: 567); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071),Attorney Docket No.14640.0093-00304 TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0113] In some embodiments, [K2] is present immediately subsequent to [K1]. In some embodiments, [K1] is present immediately subsequent to [K0]. In some embodiments, [K3] is present immediately subsequent to [K2]. In some embodiments, [K4] is present immediately subsequent to [K3]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [K1]-[K2]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [K0]-[K1]-[K2]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [K1]-[K2]-[K3]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [K0]-[K1]-[K2]-[K3]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [K1]-[K2]-[K3]-[K4]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [K0]-[K1]-[K2]-[K3]-[K4].

[0114] In some embodiments, a peptide described herein comprises an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 11, and 20-25. In some embodiments, the peptide comprises an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID Nos: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583- 1587, 1590, 1591-1593, 1598-1608, and 1610-1624. In some embodiments, the peptide comprises an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID Nos: 943 or 2064-2080. In some embodiments, the peptide comprises at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID Nos: 943 or any one of SEQ ID Nos: 946-966.

[0115] In some embodiments, the 3 consecutive amino acids comprise YPA. In some embodiments, the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21). In some embodiments, the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1). In some embodiments, the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725). In some embodiments, the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726). In some embodiments, the amino acid sequence comprises YPAEVVQK (SEQ ID NO: 943). In some embodiments, the amino acid sequence consists of YPAEVVQK (SEQ ID NO: 943).

[0116] In some embodiments, a peptide described herein comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of the sequencesAttorney Docket No.14640.0093-00304 provided in Tables 1, 2A, 2B, 11, and 20-25. In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of the sequences provided in Tables 1, 2A, 2B, 11, and 20-25. In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583- 1587, 1590, 1591-1593, 1598-1608, and 1610-1624. In some...

Claims

Attorney Docket No.14640.0093-00304 CLAIMS 1. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA; and wherein the AAV capsid variant comprises an amino acid sequence having the formula [N2]- [N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1is Y, N, or C; (b) position X2is P, K, T, or Q; (c) position X3is A or P; (d) position X4is E, S, or A; and (e) position X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence VQK, EQK, VKK, VHK, VQQ, or LQK; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% identical thereto.

2. The AAV particle of claim 1, wherein [N2]-[N3] is present in loop VIII, wherein loop VIII is present at amino acids comprises those corresponding to positions 571-599 of the amino acid sequence SEQ ID NO:

982.

3. The AAV particle of claim 1 or claim 2, wherein [N2]-[N3] is present immediately subsequent to an amino acid corresponding to position 576 of the amino acid sequence of SEQ ID NO:

982.

4. The AAV particle of any one of claims 1-3, wherein the AAV capsid variant is an AAV5 capsid variant comprising [N2]-[N3] in place of an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO:

138.

5. The AAV particle of any one of claims 1-4, wherein [N2] comprises the amino acid sequence YP, YPA, YPAE (SEQ ID NO: 21), or YPAEV (SEQ ID NO: 1).

6. The AAV particle of any one of claims 1-5, wherein [N3] comprises the amino acid sequence VQK.

7. The AAV particle of any one of claims 1-6, wherein [N2]-[N3] comprises the amino acid sequence AEVVQK (SEQ ID NO: 36) or PAEVVQK (SEQ ID NO: 20).Attorney Docket No.14640.0093-00304 8. The AAV particle of any one of claims 1-7, wherein [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

9. The AAV particle of any one of claims 1-8, wherein the AAV capsid variant further comprises [N1] comprising positions XD, XE, and XF, wherein: (a) position XD of [N1] is Q, T, S, A, I, L, or H; (b) position XEof [N1] is S, G, A, or R; and (c) position XFof [N1] is S, K, L, R, A, or T; wherein [N1] immediately precedes [N2]-[N3].

10. The AAV particle of claim 9, wherein [N1] comprises the amino acid sequence QS, SS, or QSS.

11. The AAV particle of claim 9 or claim 10, wherein [N1]-[N2] comprises the amino acid sequence QSSYPAEV (SEQ ID NO: 96).

12. The AAV particle of any one of claims 9-11, wherein [N1]-[N2]-[N3] comprises the amino acid sequence SSYPAEVVQ (SEQ ID NO: 121) or QSSYPAEVVQK (SEQ ID NO: 150).

13. The AAV particle of any one of claims 9-12, wherein the AAV capsid variant further comprises [N0] comprising positions XA, XB, and XC, wherein: (a) position XAof [N0] is T, I, or N; (b) position XBof [N0] is N; and (c) position XCof [N0] is N, T, S, or K; wherein [N0] immediately precedes [N1].

14. The AAV particle of claim 13, wherein [N0] comprises the amino acid sequence TN, NN, or TNN.

15. The AAV particle of claim 13 or claim 14, wherein [N0]-[N1] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183).

16. The AAV particle of any one of claims 13-15, wherein [N0]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYPAEVVQK (SEQ ID NO: 500).

17. The AAV particle of any one of claims 13-16, wherein the AAV capsid variant further comprises [N4] comprising positions XGand XH, wherein: (a) position XGof [N4] is T, P, or N; and (b) position XHof [N4] is A;Attorney Docket No.14640.0093-00304 wherein [N4] is present immediately subsequent to [N3].

18. The AAV particle of claim 17, wherein [N4] comprises the amino acid sequence TA.

19. The AAV particle of claim 17 or claim 18, wherein [N0]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

20. The AAV particle of any one of claims 16-18, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO:

982.

21. The AAV particle of claim 20, wherein: (i) [N0] is present at amino acids corresponding to positions 571-573 of the amino acid sequence of SEQ ID NO: 982; (ii) [N1] is present at amino acids corresponding to positions 574-576 of the amino acid sequence of SEQ ID NO: 982; (iii) [N2] is present at amino acids corresponding to positions 577- 581 of the amino acid sequence of SEQ ID NO: 982; (iv) [N3] is present at amino acids corresponding to positions 582-584 of the amino acid sequence of SEQ ID NO: 982; and (v) [N4] is present at amino acids corresponding to positions 585-586 of the amino acid sequence of SEQ ID NO:

982.

22. An adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA sequence; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises at least 4, 5, 6, 7, or 8 consecutive amino acids from the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

23. The AAV particle of claim 22, wherein: (i) the at least 4 consecutive amino acids comprise the amino acid sequence YPAE (SEQ ID NO: 21), optionally present at amino acids corresponding to positions 577-580 of the amino acid sequence of SEQ ID NO: 982;Attorney Docket No.14640.0093-00304 (ii) the at least 5 consecutive amino acids comprise the amino acid sequence YPAEV (SEQ ID NO: 1), optionally present at amino acids corresponding to positions 577-581 of the amino acid sequence of SEQ ID NO: 982; (iii) the at least 6 consecutive amino acids comprise the amino acid sequence YPAEVV (SEQ ID NO: 725), optionally present at amino acids corresponding to positions 577-582 of the amino acid sequence of SEQ ID NO: 982; or (iv) the at least 7 consecutive amino acids comprise the amino acid sequence YPAEVVQ (SEQ ID NO: 726), optionally present at amino acids corresponding to positions 577-583 of the amino acid sequence of SEQ ID NO:

982.

24. The AAV particle of claim 22 or claim 23, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) present at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO:

982.

25. An adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO:

982.

26. The AAV particle of claim 25, wherein the AAV capsid variant further comprises (i) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (ii) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

27. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a modulatory polynucleotide for reducing or eliminating expression of Ataxin-2 (ATXN2) mRNA and the AAV capsid variant comprises (i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943);Attorney Docket No.14640.0093-00304 (ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943), wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting ATXN2 mRNA.

28. The AAV particle of any one of claims 1-27, wherein the AAV capsid variant comprises (i) the amino acid sequence of SEQ ID NO: 982; (ii) the amino acid sequence of SEQ ID NO: 738; and / or (iii) the amino acid sequence of SEQ ID NO:

739.

29. The AAV particle of any one of claims 1-28, wherein the modulatory polynucleotide comprises a molecular scaffold, wherein the molecular scaffold comprises: (a) a 5’ flanking region comprising any one of SEQ ID NOs: 6413-6416 or a nucleic acid sequence at least 95% identical thereto; (b) a loop region comprising any one of SEQ ID NOs: 6417-6421 or a nucleic acid sequence at least 95% identical thereto; and (c) a 3’ flanking region comprising any one of SEQ ID NOs: 6422-6427 or a nucleic acid sequence at least 95% identical thereto.

30. The AAV particle of claim 29, wherein: (a) the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414 or SEQ ID NO: 6415, or a nucleic acid sequence at least 95% identical thereto; (b) the loop region of the molecular scaffold comprises SEQ ID NO: 6417, SEQ ID NO: 6418, or SEQ ID NO: 6421, or a nucleic acid sequence at least 95% identical thereto and (c) the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423, SEQ ID NO: 6424, or SEQ ID NO: 6425, or a nucleic acid sequence at least 95% identical thereto.

31. The AAV particle of claim 30, wherein the 5’ flanking region comprises SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6423 or a nucleic acid sequence at least 95% identical thereto.Attorney Docket No.14640.0093-00304 32. The AAV particle of claim 30, wherein the 5’ flanking region comprises SEQ ID NO: 6415 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6421 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6425 or a nucleic acid sequence at least 95% identical thereto.

33. The AAV particle of claim 30, wherein the 5’ flanking region comprises SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6424 or a nucleic acid sequence at least 95% thereto.

34. The AAV particle of claim 30, wherein the 5’ flanking region comprises SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, the loop region comprises SEQ ID NO: 6418 or a nucleic acid sequence at least 95% identical thereto, and the 3’ flanking region comprises SEQ ID NO: 6423 or a nucleic acid sequence at least 95% thereto.

35. The AAV particle of any one of claims 1-34, wherein the modulatory polynucleotide comprises siRNA or shRNA.

36. The AAV particle of claim 35, wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more ATXN2 mRNA transcripts, wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the passenger strand, the loop region, the guide strand, and the 3' flanking region.

37. The AAV particle of claim 35, wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more ATXN2 mRNA transcripts, wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the guide strand, the loop region, the passenger strand, and the 3' flanking region.

38. The AAV particle of claim 36 or claim 37, wherein the passenger strand is 15-30 nucleotides in length.

39. The AAV particle of any one of claims 36-38, wherein the guide strand is 15-30 nucleotides in length.

40. The AAV particle of claim 39, wherein the guide strand is 21-25 nucleotides in length and / or the passenger strand is 21-25 nucleotides in length.Attorney Docket No.14640.0093-00304 41. The AAV particle of any one of claims 36-40, wherein the passenger strand is at least 70%, 80%, 90%, or 95%, or is 100%, complementary to the guide strand.

42. The AAV particle of any one of claims 36-41, wherein the one or more ATXN2 mRNA transcripts comprises SEQ ID NO: 6428, SEQ ID NO: 6429, SEQ ID NO: 6430, SEQ ID NO: 6431, SEQ ID NO: 6434, SEQ ID NO: 6435, SEQ ID NO: 6436, and / or SEQ ID NO: 6437, or a trinucleotide repeat expansion thereof.

43. The AAV particle of any one of claims 1-42, wherein the viral genome comprises a promoter operably linked to the nucleic acid sequence encoding the modulatory polynucleotide.

44. The AAV particle of any one of claims 1-43, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.

45. The AAV particle of claim 44, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid sequence encoding the modulatory polynucleotide.

46. The AAV particle of claim 44 or claim 45, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the nucleic acid sequence encoding the modulatory polynucleotide.

47. The AAV particle of any of claims 44-46, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid sequence encoding the modulatory polynucleotide, and an ITR sequence positioned 3’ relative to the nucleic acid sequence encoding the modulatory polynucleotide.

48. A cell comprising the AAV particle of any one of claims 1-47, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

49. A method of making the AAV particle of any one of claims 1-47, wherein the method comprises: (i) providing a cell comprising the viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA and a nucleic acid encoding the AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle.

50. The method of claim 49, wherein the viral genome comprises: (a) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQAttorney Docket No.14640.0093-00304 ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% identical thereto; (b) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6415 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6421 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6425 or a nucleic acid sequence at least 95% identical thereto; (c) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6424 or a nucleic acid sequence at least 95% thereto; or (d) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6418 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% thereto; and wherein the AAV capsid variant comprises (i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); or (iii) the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

51. The method of claim 49, wherein the viral genome comprises: (a) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% identical thereto; (b) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6415 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQAttorney Docket No.14640.0093-00304 ID NO: 6421 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6425 or a nucleic acid sequence at least 95% identical thereto; (c) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6417 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6424 or a nucleic acid sequence at least 95% thereto; or (d) a 5’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence at least 95% identical thereto, a loop region comprising the nucleic acid sequence of SEQ ID NO: 6418 or a nucleic acid sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleic acid sequence of SEQ ID NO: 6423 or a nucleic acid sequence at least 95% thereto; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO:

739.

52. The method of claim 49, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO:

982.

53. The method of any one of claims 49-52, further comprising, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell.

54. The method of any one of claims 49-53, further comprising, prior to step (i) introducing the nucleic acid encoding the AAV capsid variant into the cell.

55. The method of any one of claims 49-54, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

56. A pharmaceutical composition comprising the AAV particle of any one of claims 1-47 and a pharmaceutically acceptable excipient.

57. A method of delivering an AAV particle encoding a modulatory polynucleotide for reducing or eliminating expression of ATXN2 mRNA to a cell, comprising administering an effective amount of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-47.

58. The method of claim 57, wherein the cell is in a subject, optionally wherein the method reduces or eliminates ATXN2 protein in the subject.Attorney Docket No.14640.0093-00304 59. The method of claim 58, wherein the subject has, has been diagnosed with having, or is at risk of having an ATXN2-related disorder.

60. The method of claim 59, wherein the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

61. A method of treating an ATXN2-related disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-47.

62. The method of claim 61, wherein the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder.

63. The method of claim 61 or claim 62, wherein the subject has one or more mutations in the ATXN2 gene.

64. The method of claim 63, wherein the one or more mutations in the ATXN2 gene comprises a trinucleotide repeat expansion.

65. The method of claim 64, wherein the trinucleotide repeat expansion in the ATXN2 gene comprises 32 or more CAG repeats (SEQ ID NO: 6437).

66. The method of any one of claims 61-65, wherein the treating results in prevention of progression of the ATXN2-related disorder in the subject.

67. The method of any one of claims 61-66, wherein the treating results in amelioration of at least one symptom of the ATXN2-related disorder in the subject.

68. The method of claim 69, wherein the at least one symptom comprises progressive cerebellar ataxia, nystagmus, slow saccadic eye movements, ophthalmoparesis, parkinsonism, or a combination thereof.

69. The method of any one of claims 61-68, wherein the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).Attorney Docket No.14640.0093-00304 70. A method of treating spinocerebellar ataxia type 2 (SCA2) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-47.

71. The method of claim 70, wherein the subject has, has been diagnosed with having, or is at risk of having SCA2.

72. The method of any one of claims 58-69, wherein the subject is a human.

73. The method of any one of claims 58-72, wherein the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the central nervous system (CNS) in the subject.

74. The method of claim 73, wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum.

75. The method of any one of claims 58-74, wherein the AAV particle or the pharmaceutical composition is delivered to the subject via intravenous administration.

76. The method of any one of claims 58-75, further comprising evaluating, e.g., measuring, the level of modulatory polynucleotide expression, and / or the level of ATXN2 expression, e.g., ATXN2 gene expression, ATXN2 mRNA expression, and / or ATXN2 protein expression, in the subject, e.g., in a cell, tissue, or fluid of the subject.

77. The method of claim 76, wherein the level of ATXN2 protein is measured by an ELISA, a Western blot, or an immunohistochemistry assay.

78. The method of claim 76 or claim 77, wherein the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the central nervous system (CNS) in the subject.

79. The method of claim 78, wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum.

80. The method of any one of claims 76-79, wherein the evaluating of the subject’s level of modulatory polynucleotide expression and / or level of ATXN2 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s levelAttorney Docket No.14640.0093-00304 of modulatory polynucleotide expression and / or the subject’s level of ATXN2 expression prior to administration is compared to the subject’s level of modulatory polynucleotide expression and / or the subject’s level of ATXN2 expression subsequent to administration.

81. The method of any one of claims 58-80, wherein the subject’s level of ATXN2 protein expression subsequent to administration is decreased relative to the subject’s level of ATXN2 protein expression prior to administration.

82. The method of any one of claims 58-81, further comprising evaluating, e.g., measuring, the level of modulatory polynucleotide activity and / or ATXN2 activity in the subject, e.g., in a cell or tissue of the subject.

83. The method of any one of claims 57-82, wherein administering the pharmaceutical composition or the AAV particle to the subject results in in: (i) a decrease in ATXN2 protein expression in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum), and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or relative to ATXN2 protein expression in a cell, tissue, or fluid of an individual with an ATXN2-related disorder who has not been administered the pharmaceutical composition or AAV particle; (ii) an increase in the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or (iii) a decrease in ATXN2 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or relative to ATXN2 mRNA expression in a cell or tissue of an individual with an ATXN2-related disorder who has not been administered the pharmaceutical composition or AAV particle.

84. The method of any one of claims 58-83, further comprising administering to the subject at least one additional therapeutic agent and / or therapy.

85. The method of claim 84, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating the ATXN2-related disorder.Attorney Docket No.14640.0093-00304 86. The method of claim 84 or claim 85, wherein the at least one additional therapeutic agent and / or therapy comprises one or more of: growth and trophic factors, cytokines, hormones, neurotransmitters, enzymes, anti-apoptotic factors, angiogenic factors, modulatory polynucleotides, and any protein known to be mutated in pathological disorders such as ATXN2-related disorders.

87. The method of claim 85 or claim 86, wherein the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), or frontotemporal lobar degeneration (FTLD).

88. The method of any one of claims 85-87, wherein the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

89. The method of any one of claims 58-88, further comprising administering an immunosuppressant to the subject.

90. The method of claim 89, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

91. A method of treating a subject having or diagnosed with having amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), or frontotemporal lobar degeneration (FTLD), comprising administering to the subject an effective amount of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-47.

92. The method of claim 91, further comprising administering to the subject at least one additional therapeutic agent and / or therapy.

93. The method of claim 92, wherein the at least one additional therapeutic agent and / or therapy comprises one or more of: growth and trophic factors, cytokines, hormones, neurotransmitters, enzymes, anti-apoptotic factors, angiogenic factors, modulatory polynucleotides, and any protein known to be mutated in pathological disorders such as ATXN2-related disorders.

94. The method of any one of claims 91-93, further comprising administering an immunosuppressant to the subject.Attorney Docket No.14640.0093-00304 95. The method of claim 94, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

96. The pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-47 for use in a method of treating a disorder according to any one of claims 70-95.

97. The pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-47 for use in treating an ATXN2-related disorder, optionally wherein the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

98. The pharmaceutical composition or the AAV particle for use of claim 97, wherein the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder, optionally wherein the ATXN2-related disorder is SCA2.

99. Use of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-47 in the manufacture of a medicament for the treatment of an ATXN2-related disorder in a subject, optionally wherein the ATXN2-related disorder is spinocerebellar ataxia type 2 (SCA2).

100. The use of claim 99, wherein the subject has, has been diagnosed with having, or is at risk of having the ATXN2-related disorder, optionally wherein the ATXN2-related disorder is SCA2.

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