AAV capsid variants and uses thereof

Abstract

The disclosure relates to compositions and methods for the preparation, use, and / or formulation of adeno-associated virus capsid protein variants.

Description

Attorney Docket Number: V2071-3046PCT AAV CAPSID VARIANTS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 617,376 filed on January 3, 2024; the entire contents of which are hereby incorporated by reference in their entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on December 30, 2024, is named V2071-3046PCT_SL.xml and is 1,327,104 bytes in size. FIELD OF THE DISCLOSURE

[0003] The disclosure relates to compositions and methods for the preparation, use, and / or formulation of adeno-associated virus capsid proteins and variants thereof. BACKGROUND

[0004] Gene delivery to the central nervous system (CNS) remains a significant challenge in gene therapy. Engineered adeno-associated virus (AAV) capsids with improved brain tropism represent an attractive solution to the limitations of CNS delivery.

[0005] 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 AAV natural variants 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.

[0006] Attempts at providing AAV capsids with improved properties, e.g., improved tropism to a target cell or tissue upon systemic administration, have had limited success. As such, there is a need for improved methods of producing AAV capsids and resulting AAV capsids for delivery of a payload of interest to a target cell or tissue, e.g., a CNS cell or tissue, or a muscle cell or tissue. SUMMARY OF THE DISCLOSURE

[0007] The present disclosure pertains, at least in part, to compositions and methods for the production and use of an AAV particle comprising an AAV capsid polypeptide, e.g., an AAV capsid variant. In some embodiments, the AAV capsid variant has an enhanced tropism for a tissue or a cell, 1 321861031.1Attorney Docket Number: V2071-3046PCT e.g., a CNS tissue or a CNS cell; or a muscle cell or tissue. Said tropism can be useful for delivery of a payload, e.g., a payload described herein, to a cell or tissue, for the treatment of a disorder, e.g., a neurological or a neurodegenerative disorder, a muscular disorder, a muscular dystrophy, a neuromuscular disorder, or a neuro-oncological disorder.

[0008] Accordingly, in one aspect, the present disclosure provides an AAV capsid variant, e.g., an AAV5 capsid variant, which comprises an amino acid other than T at position 578 (e.g., N), P at position 580 (e.g., A), A at position 581 (e.g., Q), T at position 582 (e.g., A), and / or G at position 583 (e.g., Y), numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an N at position 578, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an A at position 580, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a Q at position 581, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an A at position 582, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a Y at position 583, numbered relative to SEQ ID NO: 138.

[0009] In yet another aspect, the present disclosure provides an AAV capsid variant comprising: (a) the amino acid sequence of SEQ ID NO: 943; (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943; (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 NO: 943; 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 NO: 943.

[0010] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (a) the amino acid sequence of any one of SEQ ID NOs: 6-136 or 140-531; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 6-136 or 140-531; (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: 6-136 or 140-531; 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: 6-136 or 140-531.

[0011] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (a) the amino acid sequence of any one of SEQ ID NOs: 7-136 or 140-250; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7-136 or 140-250; (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: 7-136 or 140-250; or (d) an amino sequence comprising one, two, or three but no more than four 2 321861031.1Attorney Docket Number: V2071-3046PCT modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 7-136 or 140-250.

[0012] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (a) the amino acid sequence of any one of SEQ ID NOs: 251-380; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive amino acids from any one of SEQ ID NOs: 251-380; (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: 251-380; 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: 251-380.

[0013] In yet another aspect, the present disclosure provides, an AAV capsid variant comprising (a) the amino acid sequence of any one of SEQ ID NOs: 381-484; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 381-484; (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: 381-484; 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: 381-484.

[0014] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (a) the amino acid sequence of any one of SEQ ID NOs: 485-531; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 485-531; (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: 485-531; 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: 485-531.

[0015] In yet another aspect, the present disclosure provides an AAV capsid variant comprising one, two, three, four, or all of an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138.

[0016] In yet another aspect, the present disclosure provides an AAV capsid variant comprising an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138.

[0017] In another aspect, the present disclosure provides an AAV capsid variant comprising one, two, three, four, five, or all of the amino acid N at position 578, A at position 579, A at position 580, 3 321861031.1Attorney Docket Number: V2071-3046PCT Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138.

[0018] In yet another aspect, present disclosure provides an AAV capsid variant comprising one, two, three, four, or all of the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138.

[0019] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138.

[0020] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138.

[0021] In yet another aspect, the present disclosure provides an AAV capsid variant comprising one, two, three, four, or all of the amino acid substitutions T578N, P580A, A581Q, T582A, and G583Y, numbered according to SEQ ID NO: 138.

[0022] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid substitutions T578N, P580A, A581Q, T582A, and G583Y, numbered according to SEQ ID NO: 138.

[0023] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138.

[0024] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138.

[0025] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138.

[0026] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138.

[0027] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence 4 321861031.1Attorney Docket Number: V2071-3046PCT replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 138.

[0028] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 138.

[0029] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 982.

[0030] In yet another aspect, the present disclosure provides an AAV capsid variant comprising (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 982.

[0031] In yet another aspect, the present disclosure provides an AAV5 capsid variant comprising the amino acid sequence of positions 193-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises an N at position 578 and an A at position 580, numbered according to SEQ ID NO: 982.

[0032] In yet another aspect, the present disclosure provides an AAV5 capsid variant comprising the amino acid sequence of positions 137-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises an N at position 578 and an A at position 580, numbered according to SEQ ID NO: 982.

[0033] In yet another aspect, the present disclosure provides an AAV5 capsid variant comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises an N at position 578 and an A at position 580, numbered according to SEQ ID NO: 982.

[0034] In yet another aspect, the present disclosure provides an AAV5 capsid variant comprising the amino acid sequence of positions 193-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982.

[0035] In yet another aspect, the present disclosure provides an AAV5 capsid variant comprising the amino acid sequence of positions 137-724 of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982. 5 321861031.1Attorney Docket Number: V2071-3046PCT

[0036] In yet another aspect, the present disclosure provides an AAV5 capsid variant comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence at least 95% identical thereto, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982.

[0037] In yet another aspect, the present disclosure provides an AAV capsid variant comprising three or all of the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and / or the amino acid Y at position 583, numbered according to SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 193-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 193-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 985.

[0038] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 193-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 193- 724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% 6 321861031.1Attorney Docket Number: V2071-3046PCT identical to amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 985. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 985.

[0039] In yet another aspect, the present disclosure provides an AAV capsid variant comprising six or all of the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and / or the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 193-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 193-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 986.

[0040] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid 7 321861031.1Attorney Docket Number: V2071-3046PCT sequence at least 98% identical to amino acids 193-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 193- 724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 986.

[0041] In yet another aspect, the present disclosure provides an AAV capsid variant comprising an amino acid other than S at position 575 and / or an amino acid other than S at position 576, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an amino acid other than S at position 575 and an amino acid other than S at position 576, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N or T at position 575, numbered according to SEQ ID NO: 138; and / or the amino acid L, A, T, M, V, or Q at position 576, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 575 and the amino acid L at position 576, numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 575 and the amino acid A at position 576, numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 575 and the amino acid T at position 576, numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid T at position 575 and the amino acid M at position 576, numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 575 and the amino acid V at position 576, numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 575 and the amino acid Q at position 576, numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 575, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant further comprises the amino acid N at position 578, the amino 8 321861031.1Attorney Docket Number: V2071-3046PCT acid A position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138.

[0042] In yet another aspect, the present disclosure provides an AAV capsid variant comprising: (i) the amino acid N or T at position 575, numbered according to SEQ ID NO: 138; (ii) the amino acid L, A, T, M, V, or Q at position 576, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 578, numbered according to SEQ ID NO: 138; (iv) the amino acid A position 580, numbered according to SEQ ID NO: 138; (v) the amino acid Q at position 581, numbered according to SEQ ID NO: 138; (vi) the amino acid A at position 582, numbered according to SEQ ID NO: 138; and (vii) the amino acid Y at position 583, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 193-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 193-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 193-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 193-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 137-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 137-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 137-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 137-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to the amino acid sequence of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to the amino acid sequence of any one of SEQ ID NOs: 138, 982, 985, or 986. In some embodiments, the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 138, 982, 985, or 986.

[0043] In yet another aspect, the present disclosure provides an AAV capsid variant comprising: (i) the amino acid N at position 575, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 138; (iii) the amino acid A position 580, numbered according to SEQ ID NO: 138; (iv) the amino acid Q at position 581, numbered according to SEQ ID NO: 138; (v) the amino acid A at position 582, numbered according to SEQ ID NO: 138; and (vi) the amino acid Y at position 583, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 193-724 9 321861031.1Attorney Docket Number: V2071-3046PCT of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 193-724 of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 193-724 of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to amino acids 137-724 of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to amino acids 137-724 of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 138 or 982.

[0044] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid L at position 581, numbered according to SEQ ID NO: 138, 982, or 985. In some embodiments, the AAV capsid variant further comprises the amino acid N at position 578, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138, 982, or 985. In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138, 982, or 985. In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, the amino acid A at position 580, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0045] In yet another aspect, the present disclosure comprises an AAV capsid variant comprising an amino acid other than A at position 579, numbered according to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises the amino acid G or the amino acid Y at position 579, numbered according to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant further comprises the amino acid N at position 578, the amino acid Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, the amino acid G at position 579, the amino acid Q at position 581, A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises the 10 321861031.1Attorney Docket Number: V2071-3046PCT amino acid N at position 578, the amino acid Y at position 579, the amino acid Q at position 581, A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0046] In another aspect, the present disclosure provides an AAV5 capsid variant comprising an amino acid sequence at least 95% identical to amino acids 193-724 of any one of SEQ ID NO: 138, 982, 985, or 986, wherein the AAV capsid variant comprises: (i) the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 985; (ii) the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 986; (iii) the amino acid N at position 575, the amino acid A at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 575, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 578, the amino acid G at position 579, amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid N at position 578, the amino acid A at position 580, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 575, the amino acid T at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid T at position 575, the amino acid M at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid N at position 575, the amino acid V at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid N at position 575, the amino acid Q at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; or (xi) the amino acid N at position 578, the amino acid Y at position 579, amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138.

[0047] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of positions 193-724 of SEQ ID NO: 982, or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, 11 321861031.1Attorney Docket Number: V2071-3046PCT and Y at position 583, numbered according to SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises positions 193-724 of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises positions 137-724 of SEQ ID NO: 982. In some embodiments the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.

[0048] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of positions 137-724 of SEQ ID NO: 982, or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises positions 137-724 of SEQ ID NO: 982. In some embodiments the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.

[0049] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982. In some embodiments the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.

[0050] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982. In another aspect, the present disclosure provides an AAV capsid variant that consists of the amino acid sequence of SEQ ID NO: 982.

[0051] In yet another aspect, the present disclosure provides an adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 985, wherein the AAV capsid variant comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 985.

[0052] In another aspect, the present disclosure provides an adeno-associated virus (AAV) capsid variant comprising the amino acid sequence of amino acids 193-724 of SEQ ID NO: 985. In another aspect, the present disclosure provides an AAV capsid variant that consists of the amino acid sequence of amino acids 193-724 of SEQ ID NO: 985.

[0053] In yet another aspect, the present disclosure provides an adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 985, wherein the AAV capsid variant comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 985.

[0054] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of amino acids 137-724 of SEQ ID NO: 985. In another aspect, the present 12 321861031.1Attorney Docket Number: V2071-3046PCT disclosure provides an AAV capsid variant that consists of the amino acid sequence of amino acids 137-724 of SEQ ID NO: 985.

[0055] In yet another aspect, the present disclosure provides an AAV5 capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 985, wherein the AAV capsid variant comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 985.

[0056] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 985. In another aspect, the present disclosure provides an AAV capsid variant that consists of the amino acid sequence of SEQ ID NO: 985.

[0057] In yet another aspect, the present disclosure provides an AAV capsid variant comprising an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 986, wherein the AAV capsid variant comprises the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 986.

[0058] In yet another aspect, the present disclosure provides an AAV capsid variant comprising an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 986, wherein the AAV capsid variant comprises the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 986.

[0059] In yet another aspect, the present disclosure provides an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 986, wherein the AAV capsid variant comprises the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 986.

[0060] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of amino acids 193-724 of SEQ ID NO: 986. In another aspect, the present disclosure provides an AAV capsid variant that consists of the amino acid sequence of amino acids 193-724 of SEQ ID NO: 986.

[0061] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of amino acids 137-724 of SEQ ID NO: 986. In another aspect, the presentvariant that consists of the amino acid sequence of amino acids 137-724 of SEQ ID NO: 986. 13 321861031.1Attorney Docket Number: V2071-3046PCT

[0062] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 986. In another aspect, the present disclosure provides an AAV capsid variant that consists of the amino acid sequence of SEQ ID NO: 986.

[0063] In yet another aspect, the present disclosure provides an AAV capsid variant comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 984. In another aspect, the present disclosure provides an AAV capsid variant comprising an amino acid sequence encoded by a nucleotide sequence having at least 95% identity to SEQ ID NO: 984.

[0064] In yet another aspect, the present disclosure provides a polynucleotide encoding an AAV capsid variant, wherein the encoded AAV capsid variant comprises: (a) the amino acid sequence of SEQ ID NO: 943; (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943; (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 NO: 943; 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 NO: 943.

[0065] In another aspect, the present disclosure provides a polynucleotide encoding an AAV capsid variant, wherein the encoded AAV capsid variant comprises: (i) one, two, three, four, or all of an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and / or an amino acid other than G at position 583, numbered according to SEQ ID NO: 138; (ii) an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138; (iii) one, two, three, four, five, or all of the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (v) one, two, three, four, or all of the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vii) one, two, three, four, or all of the amino acid substitutions T578N, P580A, A581Q, T582A, and / or G583Y, numbered according to SEQ ID NO: 138; and / or (viii) the amino acid substitutions T578N, P580A, A581Q, T582A, and G583Y, numbered according to SEQ ID NO: 138.

[0066] In yet another aspect, the present disclosure provides a polynucleotide encoding an AAV capsid variant comprising: (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; 14 321861031.1Attorney Docket Number: V2071-3046PCT and an amino acid other than T at position 578, numbered according to SEQ ID NO: 138; and / or (ii) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and the amino acid N at position 578, numbered according to SEQ ID NO: 138.

[0067] In yet another aspect, the present disclosure provides a polynucleotide encoding an AAV capsid variant comprising: (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence corresponds to positions 580-583 of SEQ ID NO: 982; and an amino acid other than T at position 578, numbered according to SEQ ID NO: 138; and / or (ii) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence corresponds to positions 580-583 of SEQ ID NO: 982; and the amino acid N at position 578, numbered according to SEQ ID NO: 138.

[0068] In yet another aspect, the present disclosure provides a peptide comprising (a) the amino acid sequence of any one of SEQ ID NOs: 6-136 or 140-531; (b) an amino acid sequence comprising at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 6-136 or 140-531; (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: 6-136 or 140-531; 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: 6-136 or 140-531. In some embodiments, the peptide comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, the peptide comprises the amino acid sequence of SEQ ID NO: 8.

[0069] In yet another aspect, the present disclosure provides a peptide comprising (a) the amino acid sequence of SEQ ID NO: 7; (b) an amino acid sequence comprising at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from SEQ ID NO: 7; (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 NO: 7; 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 NO: 7.

[0070] In yet another aspect, the present disclosure provides a peptide comprising (a) the amino acid sequence of SEQ ID NO: 8; (b) an amino acid sequence comprising at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from SEQ ID NO: 8; (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 NO: 8; 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 NO: 8. 15 321861031.1Attorney Docket Number: V2071-3046PCT

[0071] In yet another aspect, the present disclosure provides a peptide comprising: (a) the amino acid sequence of SEQ ID NO: 943; (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943; or (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 NO: 943; 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 NO: 943.

[0072] In yet another aspect, the present disclosure provides a peptide comprising the amino acid sequence of NAAQAY (SEQ ID NO: 943).

[0073] In yet another aspect, the present disclosure provides a peptide comprising the amino acid sequence of ATNNQSSTNAAQAYT (SEQ ID NO: 744).

[0074] In yet another aspect, the present disclosure provides a peptide encoded by the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. In yet another aspect, the present disclosure provides a peptide encoded by (i) a nucleotide sequence comprising 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; or (ii) a nucleotide sequence comprising one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions or deletions, but no more than ten modifications, e.g., substitutions, insertions or deletions, relative to the nucleotide sequence of SEQ ID NO: 944.

[0075] In yet another aspect, the present disclosure provides a peptide, wherein the nucleotide sequence encoding the peptide comprises (i) the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; (ii) a nucleotide sequence comprising 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; or (iii) a nucleotide sequence comprising one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions or deletions, but no more than ten modifications, e.g., substitutions, insertions or deletions, relative to the nucleotide sequence of SEQ ID NO: 944.

[0076] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant described herein. In some embodiments, the AAV particle comprises a nucleic acid sequence encoding a payload. In some embodiments, the AAV particle further comprises a viral genome comprising a promoter operably linked to the nucleic acid sequence encoding the payload.

[0077] In yet another aspect, the present disclosure provides a method of making an AAV particle comprising an AAV capsid polypeptide, e.g., an AAV capsid variant, described herein. In some embodiments, the method comprises providing a host cell comprising a viral genome and incubating 16 321861031.1Attorney Docket Number: V2071-3046PCT the host cell under conditions suitable to enclose the viral genome in the AAV capsid variant, e.g., an AAV capsid variant described herein, thereby making the AAV particle.

[0078] In yet another aspect, the present disclosure provides a method of delivering a payload to a cell or tissue (e.g., a CNS cell or a CNS tissue). The method comprising administering an effective amount of an AAV particle comprising an AAV capsid variant described herein.

[0079] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with having a genetic disorder e.g., a monogenic disorder or a polygenic disorder. The method comprising administering an effective amount of an AAV particle comprising an AAV capsid variant described herein.

[0080] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with having a neurological, e.g., a neurodegenerative, disorder. The method comprising administering an effective amount of an AAV particle comprising an AAV capsid variant described herein.

[0081] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with having a muscular disorder, a muscular dystrophy, or a neuromuscular disorder. The method comprising administering an effective amount of an AAV particle comprising an AAV capsid variant described herein.

[0082] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with having a cardiac disorder, e.g., a cardiac disorder as described herein (e.g., a cardiomyopathy (e.g., arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or hypertrophic cardiomyopathy), congestive heart failure, tachycardia (e.g., catecholaminergic polymorphic ventricular tachycardia), ischemic heart disease, and / or myocardial infarction). The method comprising administering an effective amount of an AAV particle comprising an AAV capsid variant described herein.

[0083] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with having a neuro-oncological disorder. The method comprising administering an effective amount of an AAV particle comprising an AAV capsid variant described herein.

[0084] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following enumerated embodiments. Enumerated Embodiments 1. An adeno-associated virus (AAV) capsid variant comprising: (a) the amino acid sequence of SEQ ID NO: 943; (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943; 17 321861031.1Attorney Docket Number: V2071-3046PCT (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 NO: 943; 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 NO: 943. 2. The AAV capsid variant of embodiment 1, which comprises at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943. 3. The AAV capsid variant of embodiment 1 or 2, wherein the 3 consecutive amino acids comprise NAA. 4. The AAV capsid variant of any one of embodiments 1-3, wherein the 4 consecutive amino acids comprise NAAQ (SEQ ID NO: 2). 5. The AAV capsid variant of any one of embodiments 1-4, wherein the 5 consecutive amino acids comprise NAAQA (SEQ ID NO: 3). 6. The AAV capsid variant of any one of embodiments 1-5, wherein amino acid sequence comprises NAAQAY (SEQ ID NO: 943). 7. The AAV capsid variant of any one of embodiments 1-6, which 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 NAAQAY (SEQ ID NO: 943). 8. The AAV capsid variant of any one of embodiments 1-7, which comprises an amino acid sequence comprising one or two (e.g., no more than two) different amino acids, relative to the amino acid sequence of NAAQAY (SEQ ID NO: 943). 9. The AAV capsid variant of any one of embodiments 1-8, which 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 NAAQAY (SEQ ID NO: 943). 10. The AAV capsid variant of any one of embodiments 1-9, which comprises an amino acid sequence comprising one or two (e.g., no more than two) modifications, e.g., substitutions (e.g., 18 321861031.1Attorney Docket Number: V2071-3046PCT conservative substitutions), insertions, or deletions, relative to the amino acid sequence of NAAQAY (SEQ ID NO: 943). 11. The AAV capsid variant of any one of embodiments 1-10, which comprises an amino acid sequence 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; or (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. 12. The AAV capsid variant of any one of embodiments 1-11, wherein the nucleotide sequence encoding the amino acid sequence comprises: (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; or (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. 13. An adeno-associated virus (AAV) capsid variant comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 7-136 or 140-250; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7-136 or 140-250; (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: 7-136 or 140-250; 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: 7-136 or 140-250. 14. The AAV capsid variant of embodiment 13, which comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 7-131, 213, 216, 235, or 236; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7-131, 213, 216, 235, or 236; (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: 7-131, 213, 216, or 235, 236; or 19 321861031.1Attorney Docket Number: V2071-3046PCT (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: 7-131, 213, 216, 235, or 236. 15. The AAV capsid variant of embodiment 13 or 14, which comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 7, 12, 13, 15-18, 21, 24, 26, 27, 32, 34, 36, 40, 41, 42, 47, 48, 50, 52, 57, 61-63, 66, 67, 72, 74, 77, 78, 80, 82, 87, 93, 95, 96, 100, 102, 103, 105, 109, 110, 114, 119, 122, or 129; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7, 12, 13, 15-18, 21, 24, 26, 27, 32, 34, 36, 40, 41, 42, 47, 48, 50, 52, 57, 61-63, 66, 67, 72, 74, 77, 78, 80, 82, 87, 93, 95, 96, 100, 102, 103, 105, 109, 110, 114, 119, 122, or 129; (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: 7, 12, 13, 15-18, 21, 24, 26, 27, 32, 34, 36, 40, 41, 42, 47, 48, 50, 52, 57, 61-63, 66, 67, 72, 74, 77, 78, 80, 82, 87, 93, 95, 96, 100, 102, 103, 105, 109, 110, 114, 119, 122, or 129; 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: 7, 12, 13, 15-18, 21, 24, 26, 27, 32, 34, 36, 40, 41, 42, 47, 48, 50, 52, 57, 61-63, 66, 67, 72, 74, 77, 78, 80, 82, 87, 93, 95, 96, 100, 102, 103, 105, 109, 110, 114, 119, 122, or 129; optionally wherein the AAV capsid variant which has increased tropism for a heart cell or tissue compared to a reference sequence of SEQ ID NO: 138, in at least two species (e.g., Macaca fascicularis and Callithrix jacchus). 16. The AAV capsid variant of embodiment 13, which comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 7-9, 11-13, 17, 18, 20, 23, 25, 38, 43, 45, 51, 52, 56, 58, 60, 85, 86, 99, 123, 124, 128, 132-136, 140-204, 206, 208, 211, 214, 222, 223, 237, or 238; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7-9, 11-13, 17, 18, 20, 23, 25, 38, 43, 45, 51, 52, 56, 58, 60, 85, 86, 99, 123, 124, 128, 132-136, 140-204, 206, 208, 211, 214, 222, 223, 237, or 238; (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: 7-9, 11-13, 17, 18, 20, 23, 25, 38, 43, 45, 51, 52, 56, 58, 60, 85, 86, 99, 123, 124, 128, 132-136, 140-204, 206, 208, 211, 214, 222, 223, 237, or 238; or 20 321861031.1Attorney Docket Number: V2071-3046PCT (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: 7-9, 11-13, 17, 18, 20, 23, 25, 38, 43, 45, 51, 52, 56, 58, 60, 85, 86, 99, 123, 124, 128, 132-136, 140-204, 206, 208, 211, 214, 222, 223, 237, or 238. 17. The AAV capsid variant of embodiment 13 or 16, which comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 7, 13, 17, 18, 58, 143, 144, 157, 158, 159, 160, 163, 166, 171, 178, 186, or 187; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7, 13, 17, 18, 58, 143, 144, 157, 158, 159, 160, 163, 166, 171, 178, 186, or 187; (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: 7, 13, 17, 18, 58, 143, 144, 157, 158, 159, 160, 163, 166, 171, 178, 186, or 187; 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: 7, 13, 17, 18, 58, 143, 144, 157, 158, 159, 160, 163, 166, 171, 178, 186, or 187; optionally wherein the AAV capsid variant which has increased tropism for a muscle cell or tissue compared to a reference sequence of SEQ ID NO: 138, in at least two species (e.g., Macaca fascicularis and Callithrix jacchus). 18. The AAV capsid variant of embodiment 13, which comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 13, 17, 23, 57, 84, 96, 102, 105, 118, 205, 207, 209, 210-213, 215-221, 224-234, or 239-250; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 13, 17, 23, 57, 84, 96, 102, 105, 118, 205, 207, 209, 210-213, 215-221, 224-234, or 239-250; (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: 13, 17, 23, 57, 84, 96, 102, 105, 118, 205, 207, 209, 210-213, 215-221, 224-234, or 239-250; 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: 13, 17, 23, 57, 84, 96, 102, 105, 118, 205, 207, 209, 210-213, 215-221, 224-234, or 239-250. 19. The AAV capsid variant of embodiment 13 or 18, which comprises: 21 321861031.1Attorney Docket Number: V2071-3046PCT (a) the amino acid sequence of any one of SEQ ID NOs: 219, 221, or 230; (b) an amino acid sequence comprising at least 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 219, 221, or 230; (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: 219, 221, or 230; 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: 219, 221, or 230; optionally wherein the AAV capsid variant has increased tropism in the brain of at least two species, e.g., a non-human primate (e.g., Macaca fascicularis) and rodent (e.g., mouse) species, compared to a reference sequence of SEQ ID NO: 138. 20. An adeno-associated virus (AAV) capsid variant comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 251-380; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive amino acids from any one of SEQ ID NOs: 251-380; (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: 251-380; 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: 251-380. 21. An adeno-associated virus (AAV) capsid variant comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 381-484; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 381-484; (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: 381-484; 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: 381-484. 22. An adeno-associated virus (AAV) capsid variant comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 485-531; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 485-531; 22 321861031.1Attorney Docket Number: V2071-3046PCT (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: 485-531; 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: 485-531. 23. The AAV capsid variant of any one of embodiments 1-22, wherein the amino acid sequence is present in loop VIII, optionally wherein loop VIII comprises positions 571-592, numbered according to SEQ ID NO: 138. 24. The AAV capsid variant of any one of embodiments 1-23, wherein the amino acid sequence replaces one, two, three, four, five, or all of positions 578, 579, 580, 581, 582, and / or 583 (e.g., positions T578, A579, P580, A581, T582, and / or G583), numbered according to the amino acid sequence of SEQ ID NO: 138. 25. The AAV capsid variant of any one of embodiments 1-14, wherein the amino acid sequence replaces positions 578, 579, 580, 581, 582, and 583 (e.g., positions T578, A579, P580, A581, T582, and G583), numbered according to the amino acid sequence of SEQ ID NO: 138. 26. The AAV capsid variant of any one of embodiments 13-25, wherein the amino acid sequence replaces 10, 11, 12, 13, 14, 15, 16, 17, or all of positions 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, and / or 587 (e.g., positions A570, T571, N572, N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, G583, T584, Y585, N586, and / or L587), numbered according to the amino acid sequence of SEQ ID NO: 138. 27. The AAV capsid variant of any one of embodiments 13-22 or 26, wherein the amino acid sequence replaces positions 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, and 587 (e.g., positions A570, T571, N572, N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, G583, T584, Y585, N586, and L587), numbered according to the amino acid sequence of SEQ ID NO: 138. 28. The AAV capsid variant of any one of embodiments 13-20, wherein the amino acid sequence replaces 3, 4, 5, 6, 7, 8, 9, 10 or all of positions 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, and / or 583 (e.g., N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, and / or G583), numbered according to the amino acid sequence of SEQ ID NO: 138. 23 321861031.1Attorney Docket Number: V2071-3046PCT 29. The AAV capsid variant of any one of embodiments 13-20 or 28, wherein the amino acid sequence replaces positions 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, and 583 (e.g., N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, and G583), numbered according to the amino acid sequence of SEQ ID NO: 138. 30. The AAV capsid variant of any one of embodiments 13-19 or 21, wherein the amino acid sequence replaces 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or all of positions 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, and / or 584 (e.g., N572, N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, G583, and / or T584), numbered according to the amino acid sequence of SEQ ID NO: 138. 31. The AAV capsid variant of any one of embodiments 13-19, 21, or 30, wherein the amino acid sequence replaces positions 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, and 584 (e.g., N572, N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, G583, and T584), numbered according to the amino acid sequence of SEQ ID NO: 138. 32. The AAV capsid variant of any one of embodiments 13-19 or 22, wherein the amino acid sequence replaces 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or all of positions 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, and / or 585 (e.g., N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, G583, T584, and / or Y585), numbered according to the amino acid sequence of SEQ ID NO: 138. 33. The AAV capsid variant of any one of embodiments 13-19, 22, or 32, wherein the amino acid sequence replaces positions 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, and 585 (e.g., N573, Q574, S575, S576, T577, T578, A579, P580, A581, T582, G583, T584, and Y585), numbered according to the amino acid sequence of SEQ ID NO: 138. 34. The AAV capsid variant of any one of embodiments 1-33, wherein the amino acid sequence corresponds to positions 578, 579, 580, 581, 582, and 583 (e.g., positions N578, A579, A580, Q581, A582, and Y583) of SEQ ID NO: 982. 35. The AAV capsid variant of any one of embodiments 1-34, which comprises the amino acid sequence of NAAQAY (SEQ ID NO: 943), optionally wherein the amino acid sequence replaces positions 578, 579, 580, 581, 582, 583 (e.g., positions T578, A579, P580, A581, T582, and G583), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 24 321861031.1Attorney Docket Number: V2071-3046PCT 36. The AAV capsid variant of any one of embodiments 1-35, which comprises the amino acid sequence of NAAQAY (SEQ ID NO: 943), optionally wherein the amino acid sequence corresponds to positions 578, 579, 580, 581, 582, 583 (e.g., positions N578, A579, A580, Q581, A582, and Y583) of SEQ ID NO: 982. 37. The AAV capsid variant of any one of embodiments 1-36, which comprises the amino acid sequence of NAAQAY (SEQ ID NO: 943), optionally wherein the amino acid sequence is present at positions 578-583, numbered according to SEQ ID NO: 982. 38. The AAV capsid variant of any one of embodiments 1-36, which comprises the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, and G583), numbered relative to SEQ ID NO: 138. 39. The AAV capsid variant of any one of embodiments 1-36, which comprises the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence is present at positions 580-583, numbered relative to SEQ ID NO: 982. 40. The AAV capsid variant of embodiment 38 or 39, which further comprises an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. 41. The AAV capsid variant of any one of embodiments 38-40, which further comprises the amino acid N at position 578, numbered according to SEQ ID NO: 138. 42. The AAV capsid variant of any one of embodiments 1-41, which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, and G583), numbered relative to SEQ ID NO: 138; and / or (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. 43. The AAV capsid variant of any one of embodiments 1-42, which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and / or (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. 44. The AAV capsid variant of any one of embodiments 1-43, which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, and G583), numbered relative to SEQ ID NO: 138; and / or 25 321861031.1Attorney Docket Number: V2071-3046PCT (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 138. 45. The AAV capsid variant of any one of embodiments 1-44, which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and / or (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 982. 46. The AAV capsid variant of any one of embodiments 1-45, which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence corresponds to positions 580-583 of SEQ ID NO: 982; and / or (ii) the amino acid N at position 578, numbered according to SEQ ID NO: 138. 47. The AAV capsid variant of any one of the preceding embodiments, which comprises one, two, three, four, or all of an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and / or an amino acid other than G at position 583, numbered according to SEQ ID NO: 138. 48. An adeno-associated virus (AAV) capsid variant which comprises one, two, three, four, five, or all of an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and / or an amino acid other than G at position 583, numbered according to SEQ ID NO: 138. 49. The AAV capsid variant of any one of the preceding embodiments, which comprises an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138. 50. An adeno-associated virus (AAV) capsid variant comprising an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138. 51. The AAV capsid variant of any one of the preceding embodiments, which comprises one, two, three, four, five, or all of the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138. 26 321861031.1Attorney Docket Number: V2071-3046PCT 52. The AAV capsid variant of any one of the preceding embodiments, which comprises one, two, three, four, or all of the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138. 53. An adeno-associated virus (AAV) capsid variant comprising one, two, three, four, five, or all of the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138. 54. An adeno-associated virus (AAV) capsid variant comprising one, two, three, four, or all of the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138. 55. The AAV capsid variant of any one of the preceding embodiments, which comprises the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 56. The AAV capsid variant of any one of the preceding embodiments, which comprises the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 57. An adeno-associated virus (AAV) capsid variant comprising the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 58. An adeno-associated virus (AAV) capsid variant comprising the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 59. The AAV capsid variant of any one of embodiments 1-50, which comprises one, two, three, four, or all of the amino acid substitutions T578N, P580A, A581Q, T582A, and / or G583Y, numbered according to SEQ ID NO: 138. 60. An adeno-associated virus (AAV) capsid variant comprising one, two, three, four, or all of the amino acid substitutions T578N, P580A, A581Q, T582A, and / or G583Y, numbered according to SEQ ID NO: 138. 27 321861031.1Attorney Docket Number: V2071-3046PCT 61. The AAV capsid variant of any one of embodiments 1-56, which comprises the amino acid substitutions T578N, P580A, A581Q, T582A, and G583Y, numbered according to SEQ ID NO: 138. 62. An adeno-associated virus (AAV) capsid variant comprising the amino acid substitutions T578N, P580A, A581Q, T582A, and G583Y, numbered according to SEQ ID NO: 138. 63. The AAV capsid variant of any one of the preceding embodiments, which corresponds to positions 578-583 (e.g., N578, A579, A580, Q581, A582, Y583) of SEQ ID NO: 982. 64. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. 65. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. 66. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. 67. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. 68. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) the amino acid other N at position 578, numbered according to SEQ ID NO: 138. 28 321861031.1Attorney Docket Number: V2071-3046PCT 69. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) the amino acid other N at position 578, numbered according to SEQ ID NO: 138. 70. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) the amino acid other N at position 578, numbered according to SEQ ID NO: 982. 71. An adeno-associated virus (AAV) capsid variant which comprises: (i) the amino acid sequence AQAY (SEQ ID NO: 1), wherein the amino acid sequence is present at positions 580-583, numbered according to SEQ ID NO: 982; and (ii) the amino acid other N at position 578, numbered according to SEQ ID NO: 982. 72. The AAV capsid variant of any one of the preceding embodiments, which comprises the amino acid A at position 579, numbered according to SEQ ID NO: 138 or 982. 73. The AAV capsid variant of any one of the preceding embodiments, which corresponds to position 579 of SEQ ID NO: 138 or 982. 74. An adeno-associated virus (AAV) capsid variant which comprises: (i) one, two, three, four or all of amino acid other than N at position 573, an amino acid other than Q at position 574, amino acid other than S at position 575, an amino acid other than S at position 576, and / or amino acid other than T at position 577, numbered according to SEQ ID NO: 138; and (ii) one, two, three, four, five or all of an amino acid other than T at position 578, an amino acid other than A at position 579, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, or amino acid other than G at position 583, numbered according to SEQ ID NO: 138; and wherein the AAV capsid variant comprises: (a) the amino acid N, L, A, V, I, S, Y, F, M, W, or T at position 573, numbered according to SEQ ID NO: 138; (b) the amino acid Q, A, T, G, or S at position 574, numbered according to SEQ ID NO: 138; (c) the amino acid S, N, T, G, H, or A at position 575, numbered according to SEQ ID NO: 138; 29 321861031.1Attorney Docket Number: V2071-3046PCT (d) the amino acid S, L, M, A, T, Y, V, I, P, Q, H, F, N, W, E, D, or K at position 576, numbered according to SEQ ID NO: 138; (e) the amino acid T, V, A, S, Q, I, L, G, H, R, or K at position 577, numbered according to SEQ ID NO: 138; (f) the amino acid N or H at position 578, numbered according to SEQ ID NO: 138; (g) the amino acid A at position 579, numbered according to SEQ ID NO: 138; (h) the amino acid A at position 580, numbered according to SEQ ID NO: 138; (i) the amino acid Q at position 581, numbered according to SEQ ID NO: 138; (j) the amino acid A at position 582, numbered according to SEQ ID NO: 138; and / or (k) the amino acid Y at position 583, numbered according to SEQ ID NO: 138; optionally wherein the AAV capsid variant has increased tropism for a heart cell or a heart tissue, compared to a reference sequence of SEQ ID NO: 138. 75. The AAV capsid variant of embodiment 74, which comprises an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138. 76. The AAV capsid variant of embodiment 74 or 75, which comprises the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 77. The AAV capsid variant of any one of embodiments 74-76, which comprises the amino acid A at position 582, numbered according to SEQ ID NO: 138. 78. The AAV capsid variant of any one of embodiments 1-15, 20, or 23-77, which comprises the amino acid Y at position 583. 79. An adeno-associated virus (AAV) capsid variant comprising the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; and wherein the AAV capsid variant comprises: (a) the amino acid N, L, A, V, I, S, Y, F, M, W, or T at position 573, numbered according to SEQ ID NO: 138; (b) the amino acid Q, A, T, G, or S at position 574, numbered according to SEQ ID NO: 138; (c) the amino acid S, N, T, G, H, or A at position 575, numbered according to SEQ ID NO: 138; 30 321861031.1Attorney Docket Number: V2071-3046PCT (d) the amino acid S, L, M, A, T, Y, V, I, P, Q, H, F, N, W, E, D, or K at position 576, numbered according to SEQ ID NO: 138; and / or (e) the amino acid T, V, A, S, Q, I, L, G, H, R, or K at position 577, numbered according to SEQ ID NO: 138; optionally wherein the AAV capsid variant has increased tropism for a heart cell or a heart tissue, compared to a reference sequence of SEQ ID NO: 138. 80. The AAV capsid variant of any one of embodiments 1-15, 20, or 23-79, which comprises an amino acid other than S at position at position 576, numbered according to SEQ ID NO: 138. 81. The AAV capsid variant of any one of embodiments 1-15, 20, or 23-80, which comprises an amino acid other than S at position at position 575 and S at position at position 576, numbered according to SEQ ID NO: 138. 82. The AAV capsid variant of any one of embodiments 1-15, 20, or 23-81, which comprises: (i) the amino acid N at position 575 and the amino acid L at position 576, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 575 and the amino acid A at position 576, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 575 and the amino acid T at position 576, numbered according to SEQ ID NO: 138; (iv) the amino acid T at position 575 and the amino acid M at position 576, numbered according to SEQ ID NO: 138; (v) the amino acid T at position 575 and the amino acid T at position 576, numbered according to SEQ ID NO: 138; (vi) the amino acid T at position 575 and the amino acid L at position 576, numbered according to SEQ ID NO: 138; (vii) the amino acid T at position 575 and the amino acid Y at position 576, numbered according to SEQ ID NO: 138; (viii) the amino acid T at position 575 and the amino acid V at position 576, numbered according to SEQ ID NO: 138; (ix) the amino acid T at position 575 and the amino acid A at position 576, numbered according to SEQ ID NO: 138; (x) the amino acid G at position 575 and the amino acid L at position 576, numbered according to SEQ ID NO: 138; (xi) the amino acid T at position 575 and the amino acid I at position 576, numbered according to SEQ ID NO: 138; 31 321861031.1Attorney Docket Number: V2071-3046PCT (xii) the amino acid T at position 575 and the amino acid P at position 576, numbered according to SEQ ID NO: 138; (xiii) the amino acid T at position 575 and the amino acid Q at position 576, numbered according to SEQ ID NO: 138; (xiv) the amino acid N at position 575 and the amino acid V at position 576, numbered according to SEQ ID NO: 138; (xv) the amino acid G at position 575 and the amino acid A at position 576, numbered according to SEQ ID NO: 138; (xvi) the amino acid G at position 575 and the amino acid M at position 576, numbered according to SEQ ID NO: 138; (xvii) the amino acid T at position 575 and the amino acid H at position 576, numbered according to SEQ ID NO: 138; (xviii) the amino acid N at position 575 and the amino acid Q at position 576, numbered according to SEQ ID NO: 138; (xix) the amino acid G at position 575 and the amino acid Y at position 576, numbered according to SEQ ID NO: 138; (xx) the amino acid H at position 575 and the amino acid T at position 576, numbered according to SEQ ID NO: 138; (xxi) the amino acid N at position 575 and the amino acid P at position 576, numbered according to SEQ ID NO: 138; (xxii) the amino acid H at position 575 and the amino acid P at position 576, numbered according to SEQ ID NO: 138; (xxiii) the amino acid H at position 575 and the amino acid Q at position 576, numbered according to SEQ ID NO: 138; (xxiv) the amino acid G at position 575 and the amino acid I at position 576, numbered according to SEQ ID NO: 138; (xxv) the amino acid G at position 575 and the amino acid V at position 576, numbered according to SEQ ID NO: 138; (xxvi) the amino acid N at position 575 and the amino acid H at position 576, numbered according to SEQ ID NO: 138; (xxvii) the amino acid N at position 575 and the amino acid N at position 576, numbered according to SEQ ID NO: 138; (xxviii) the amino acid H at position 575 and the amino acid L at position 576, numbered according to SEQ ID NO: 138; (xxix) the amino acid G at position 575 and the amino acid T at position 576, numbered according to SEQ ID NO: 138; 32 321861031.1Attorney Docket Number: V2071-3046PCT (xxx) the amino acid A at position 575 and the amino acid A at position 576, numbered according to SEQ ID NO: 138; (xxxi) the amino acid G at position 575 and the amino acid P at position 576, numbered according to SEQ ID NO: 138; (xxxii) the amino acid N at position 575 and the amino acid K at position 576, numbered according to SEQ ID NO: 138; (xxxiii) the amino acid N at position 575 and the amino acid S at position 576, numbered according to SEQ ID NO: 138; or (xxxiv) the amino acid N at position 575, numbered according to SEQ ID NO: 138. 83. The AAV capsid variant of any one of embodiments 1-15, 20, or 23-80, which comprises an amino acid other than S at position at position 576 and T at position at position 577, numbered according to SEQ ID NO: 138. 84. The AAV capsid variant of any one of embodiments 1-15, 20, 23-80, or 83, which comprises: (i) the amino acid M at position 576 and the amino acid V at position 577, numbered according to SEQ ID NO: 138; (ii) the amino acid L at position 576 and the amino acid A at position 577, numbered according to SEQ ID NO: 138; (iii) the amino acid L at position 576 and the amino acid V at position 577, numbered according to SEQ ID NO: 138; (iv) the amino acid Y at position 576 and the amino acid S at position 577, numbered according to SEQ ID NO: 138; (v) the amino acid Y at position 576 and the amino acid A at position 577, numbered according to SEQ ID NO: 138; (vi) the amino acid Y at position 576 and the amino acid Q at position 577, numbered according to SEQ ID NO: 138; (vii) the amino acid H at position 576 and the amino acid I at position 577, numbered according to SEQ ID NO: 138; (viii) the amino acid L at position 576 and the amino acid S at position 577, numbered according to SEQ ID NO: 138; (ix) the amino acid M at position 576 and the amino acid S at position 577, numbered according to SEQ ID NO: 138; (x) the amino acid H at position 576 and the amino acid L at position 577, numbered according to SEQ ID NO: 138; (xi) the amino acid N at position 576 and the amino acid V at position 577, numbered according to SEQ ID NO: 138; 33 321861031.1Attorney Docket Number: V2071-3046PCT (xii) the amino acid A at position 576 and the amino acid V at position 577, numbered according to SEQ ID NO: 138; (xiii) the amino acid M at position 576 and the amino acid A at position 577, numbered according to SEQ ID NO: 138; (xiv) the amino acid Y at position 576 and the amino acid G at position 577, numbered according to SEQ ID NO: 138; (xv) the amino acid P at position 576 and the amino acid Q at position 577, numbered according to SEQ ID NO: 138; (xvi) the amino acid L at position 576 and the amino acid H at position 577, numbered according to SEQ ID NO: 138; (xvii) the amino acid V at position 576 and the amino acid S at position 577, numbered according to SEQ ID NO: 138; (xviii) the amino acid H at position 576 and the amino acid S at position 577, numbered according to SEQ ID NO: 138; (xix) the amino acid P at position 576 and the amino acid A at position 577, numbered according to SEQ ID NO: 138; (xx) the amino acid T at position 576 and the amino acid H at position 577, numbered according to SEQ ID NO: 138; (xxi) the amino acid I at position 576 and the amino acid S at position 577, numbered according to SEQ ID NO: 138; (xxii) the amino acid H at position 576 and the amino acid Q at position 577, numbered according to SEQ ID NO: 138; (xxiii) the amino acid T at position 576 and the amino acid V at position 577, numbered according to SEQ ID NO: 138; (xxiv) the amino acid M at position 576 and the amino acid H at position 577, numbered according to SEQ ID NO: 138; (xxv) the amino acid A at position 576 and the amino acid Q at position 577, numbered according to SEQ ID NO: 138; (xxvi) the amino acid V at position 576 and the amino acid A at position 577, numbered according to SEQ ID NO: 138; or (xxvii) the amino acid V at position 576 and the amino acid H at position 577, numbered according to SEQ ID NO: 138. 85. The AAV capsid variant of any one of embodiments 1-15, 20, or 23-80, which comprises an amino acid other than N at position at position 573 and Q at position at position 574, numbered according to SEQ ID NO: 138. 34 321861031.1Attorney Docket Number: V2071-3046PCT 86. The AAV capsid variant of any one of embodiments 1-15, 20, 23-80, or 85, which comprises: (i) the amino acid L at position 573 and the amino acid A at position 574, numbered according to SEQ ID NO: 138; (ii) the amino acid L at position 573 and the amino acid T at position 574, numbered according to SEQ ID NO: 138; (iii) the amino acid L at position 573 and the amino acid G at position 574, numbered according to SEQ ID NO: 138; or (iv) the amino acid L at position 573 and the amino acid S at position 574, numbered according to SEQ ID NO: 138. 87. The AAV capsid variant of any one of embodiments 1-15, 20, or 23-86, which comprises: (i) the amino acid M at position 576, V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ii) the amino acid L at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iii) the amino acid L at position 576, V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid Y at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid Y at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid Y at position 576, Q at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid H at position 576, I at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid L at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid M at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid H at position 576, L at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xi) the amino acid N at position 576, V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xii) the amino acid A at position 576, V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 35 321861031.1Attorney Docket Number: V2071-3046PCT (xiii) the amino acid M at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiv) the amino acid Y at position 576, G at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xv) the amino acid P at position 576, Q at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvi) the amino acid L at position 576, H at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvii) the amino acid V at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xviii) the amino acid H at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xix) the amino acid P at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xx) the amino acid T at position 576, H at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxi) the amino acid I at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxii) the amino acid H at position 576, Q at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiii) the amino acid T at position 576, V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiv) the amino acid M at position 576, H at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxv) the amino acid A at position 576, Q at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvi) the amino acid V at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; or 36 321861031.1Attorney Docket Number: V2071-3046PCT (xxvii) the amino acid V at position 576, H at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxviii) the amino acid N at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxix) the amino acid N at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxx) the amino acid N at position 575, T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxi) the amino acid T at position 575, M at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxii) the amino acid T at position 575, T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxiii) the amino acid T at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxiv) the amino acid T at position 575, Y at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxv) the amino acid T at position 575, V at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxvi) the amino acid T at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxvii) the amino acid G at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxviii) the amino acid T at position 575, I at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 37 321861031.1Attorney Docket Number: V2071-3046PCT (xxxix) the amino acid T at position 575, P at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xl) the amino acid T at position 575, Q at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xli) the amino acid N at position 575, V at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlii) the amino acid G at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xliii) the amino acid G at position 575, M at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xliv) the amino acid T at position 575, H at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlv) the amino acid N at position 575, Q at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlvi) the amino acid G at position 575, Y at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlvii) the amino acid H at position 575, T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlviii) the amino acid N at position 575, P at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlix) the amino acid H at position 575, P at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (l) the amino acid H at position 575, Q at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (li) the amino acid G at position 575, I at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lii) the amino acid G at position 575, V at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 38 321861031.1Attorney Docket Number: V2071-3046PCT (liii) the amino acid N at position 575, H at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (liv) the amino acid N at position 575, N at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lv) the amino acid H at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lvi) the amino acid G at position 575, T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lvii) the amino acid A at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lviii) the amino acid G at position 575, P at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lix) the amino acid N at position 575, K at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lx) the amino acid L at position 573, A at position 574, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxi) the amino acid L at position 573, T at position 574, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxii) the amino acid L at position 573, G at position 574, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxiii) the amino acid L at position 573, S at position 574, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxiv) the amino acid L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxv) the amino acid M at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxvi) the amino acid L at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxvii) the amino acid A at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxviii) the amino acid I at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxix) the amino acid V at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 39 321861031.1Attorney Docket Number: V2071-3046PCT (lxx) the amino acid I at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxi) the amino acid S at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxii) the amino acid V at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxiii) the amino acid H at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxiv) the amino acid Y at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxv) the amino acid F at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxvi) the amino acid M at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxvii) the amino acid T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxviii) the amino acid F at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxix) the amino acid T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxx) the amino acid F at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxi) the amino acid W at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxii) the amino acid T at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxiii) the amino acid A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxiv) the amino acid N at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxv) the amino acid Q at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxvi) the amino acid Y at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxvii) the amino acid W at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 40 321861031.1Attorney Docket Number: V2071-3046PCT (lxxxviii) the amino acid N at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxxix) the amino acid T at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xci) the amino acid V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xcii) the amino acid G at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; or (xciii) the amino acid H at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 88. The AAV capsid variant of any one of embodiments 74, 75, 77, or 78, which comprises: (i) the amino acid A at position 577, H at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; or (ii) the amino acid V at position 577, H at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 89. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid N at position 578, T at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 578, H at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 578, G at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 578, S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid Q at position 578, H at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid H at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 578, V at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid H at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid N at position 578, I at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 41 321861031.1Attorney Docket Number: V2071-3046PCT (x) the amino acid S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xi) the amino acid N at position 578, G at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xii) the amino acid N at position 578, T at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiii) the amino acid N at position 578, V at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiv) the amino acid N at position 578, H at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xv) the amino acid N at position 578, I at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvi) the amino acid N at position 578, M at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvii) the amino acid N at position 578, L at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xviii) the amino acid N at position 578, P at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xix) the amino acid N at position 578, F at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xx) the amino acid N at position 578, Y at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxi) the amino acid N at position 578, W at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxii) the amino acid N at position 578, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiii) the amino acid N at position 578, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiv) the amino acid N at position 578, A at position 580, Q at position 581, I at position 582, and W at position 583, numbered according to SEQ ID NO: 138; (xxv) the amino acid N at position 578, A at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvi) the amino acid N at position 578, S at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvii) the amino acid N at position 578, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 42 321861031.1Attorney Docket Number: V2071-3046PCT (xviii) the amino acid N at position 578, M at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxix) the amino acid N at position 578, A at position 580, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxx) the amino acid N at position 578, S at position 580, T at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxi) the amino acid N at position 578, A at position 580, M at position 581, R at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxii) the amino acid N at position 578, T at position 579, S at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxiii) the amino acid N at position 578, S at position 579, S at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; or (xxxiv) the amino acid N at position 578, P at position 579, S at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; optionally wherein the AAV capsid variant has increased tropism for a heart cell or a heart tissue, compared to a reference sequence of SEQ ID NO: 138. 90. An adeno-associated virus (AAV) capsid variant comprising one, two, three, four, five, six, or all of: (i) the amino acid N, S, Q, A, V, T, M, E, or G at position 578, numbered according to SEQ ID NO: 138; (ii) the amino acid A, S, T, Y, G, M, H, R, P, or Q at position 579, numbered according to SEQ ID NO: 138; (iii) the amino acid A, P, G, S, R, K, M, V, T, or Q at position 580, numbered according to SEQ ID NO: 138; (iv) the amino acid Q, L, A, M, S, I, G, or T at position 581, numbered according to SEQ ID NO: 138; (v) the amino acid A, Y, I, V, Q, S, C, T, G, or R at position 582, numbered according to SEQ ID NO: 138; (vi) the amino acid Y, F, or T at position 583, numbered according to SEQ ID NO: 138; and / or (vii) the amino acid T, N, G, S, L, or P at position 584, numbered according to SEQ ID NO: 138; optionally wherein the AAV capsid variant has increased tropism for a muscle cell or a muscle tissue, compared to a reference sequence of SEQ ID NO: 138. 91. The AAV capsid variant of embodiment 90, which comprises: 43 321861031.1Attorney Docket Number: V2071-3046PCT (i) the amino acid N, S, Q, A, V, T, M, E, or G at position 578, numbered according to SEQ ID NO: 138; (ii) the amino acid A, S, T, Y, G, M, H, R, P, or Q at position 579, numbered according to SEQ ID NO: 138; (iii) the amino acid A, P, G, S, R, K, M, V, T, or Q at position 580, numbered according to SEQ ID NO: 138; (iv) the amino acid Q, L, A, M, S, I, G, or T at position 581, numbered according to SEQ ID NO: 138; (v) the amino acid A, Y, I, V, Q, S, C, T, G, or R at position 582, numbered according to SEQ ID NO: 138; (vi) the amino acid Y, F, or T at position 583, numbered according to SEQ ID NO: 138; and / or (vii) the amino acid T, N, G, S, L, or P at position 584, numbered according to SEQ ID NO: 138. 92. The AAV capsid variant of embodiment 90 or 91, which comprises: (i) the amino acid N at position 578, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 578, A at position 580, Q at position 581, Y at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 578, A at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 578, A at position 580, I at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 578, G at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, Y at position 583, and N at position 584, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 578, A at position 580, M at position 581, V at position 582, Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid S at position 578, S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid Q at position 578, S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid A at position 578, T at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 44 321861031.1Attorney Docket Number: V2071-3046PCT (xi) the amino acid A at position 578, S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xii) the amino acid N at position 579, Y at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiii) the amino acid Q at position 578, T at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiv) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, F at position 583, and G at position 584, numbered according to SEQ ID NO: 138; (xv) the amino acid S at position 578, T at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvi) the amino acid N at position 578, A at position 580, L at position 581, Q at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvii) the amino acid N at position 578, S at position 580, M at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xviii) the amino acid N at position 578, A at position 580, S at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xix) the amino acid N at position 578, Y at position 579, R at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xx) the amino acid Q at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxi) the amino acid N at position 579, A at position 580, Q at position 581, A at position 582, F at position 583, and S at position 584, numbered according to SEQ ID NO: 138; (xxii) the amino acid N at position 578, A at position 580, Q at position 581, S at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiii) the amino acid S at position 578, G at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiv) the amino acid N at position 578, A at position 580 , V at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxv) the amino acid A at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvi) the amino acid N at position 578, S at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvii) the amino acid N at position 578, G at position 580, M at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxviii) the amino acid N at position 578, A at position 580, M at position 581, S at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 45 321861031.1Attorney Docket Number: V2071-3046PCT (xxix) the amino acid A at position 578, M at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxx) the amino acid N at position 578, K at position 580, A position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxi) the amino acid A at position 578, H at position 579, A position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxii) the amino acid N at position 578, M at position 579, R position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxiii) the amino acid V at position 578, S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxiv) the amino acid T at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxv) the amino acid S at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxvi) the amino acid V at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxvii) the amino acid N at position 578, A at position 580, S at position 581, C at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxviii) the amino acid Q at position 578, G at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxxix) the amino acid N at position 578, A at position 580, Q at position 581, and Y at position 583, numbered according to SEQ ID NO: 138; (xl) the amino acid M at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xli) the amino acid N at position 578, A at position 580, I at position 581, and Y at position 583, numbered according to SEQ ID NO: 138; (xlii) the amino acid N at position 578, A at position 580, L at position 581, and Y at position 583, numbered according to SEQ ID NO: 138; (xliii) the amino acid N at position 578, G at position 579, A at position, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xliv) the amino acid E at position 578, R at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlv) the amino acid N at position 578, A at position 580, L at position 581, S at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlvi) the amino acid A at position 578, P at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 46 321861031.1Attorney Docket Number: V2071-3046PCT (xlvii) the amino acid N at position 578, A at position 580, S at position 581, V at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlviii) the amino acid N at position 578, S at position 580, G at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xlix) the amino acid S at position 578, H at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (l) the amino acid N at position 578, A at position 580, L at position 581, V at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (li) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, Y at position 583, and G at position 584, numbered according to SEQ ID NO: 138; (lii) the amino acid N at position 578, A at position 580, M at position 581, and Y at position 583, numbered according to SEQ ID NO: 138; (liii) the amino acid M at position 578, S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (liv) the amino acid N at position 578, A at position 580, L at position 581, I at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lv) the amino acid N at position 578, M at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lvi) the amino acid N at position 578, A at position 580, Q at position 581, V at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lvii) the amino acid N at position 578, Q at position 579, V at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lviii) the amino acid N at position 578, A at position 580, L at position 581, G at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lix) the amino acid N at position 578, S at position 579, T at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lx) the amino acid G at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxi) the amino acid V at position 578, G at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxii) the amino acid N at position 578, A at position 580, Q at position 581, G at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxiii) the amino acid A at position 578, Q at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxiv) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, T at position 583, and L at position 584, numbered according to SEQ ID NO: 138; 47 321861031.1Attorney Docket Number: V2071-3046PCT (lxv) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, Y at position 583, and P at position 584, numbered according to SEQ ID NO: 138; (lxvi) the amino acid N at position 578, A at position 580, S at position 581, and Y at position 583, numbered according to SEQ ID NO: 138; (lxvii) the amino acid N at position 578, H at position 579, S at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxviii) the amino acid H at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxix) the amino acid N at position 578, Q at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxx) the amino acid S at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxi) the amino acid N at position 578, M at position 579, K at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (lxxii) the amino acid A at position 578, Y at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; or (lxiii) the amino acid N at position 578, A at position 580, T at position 581, R at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 93. An adeno-associated virus (AAV) capsid variant comprising which comprises: (i) one, two, three, four, five, or all of amino acid other than N at position 572, N at position 573, an amino acid other than Q at position 574, amino acid other than S at position 575, an amino acid other than S at position 576, and / or amino acid other than T at position 577, numbered according to SEQ ID NO: 138; and (ii) one, two, three, four, five or all of an amino acid other than T at position 578, an amino acid other than A at position 579, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, or amino acid other than G at position 583, numbered according to SEQ ID NO: 138; and wherein the AAV capsid variant comprises: (a) the amino acid N, G, V, or M at position 572, numbered according to SEQ ID NO: 138; (b) the amino acid N, K, or H at position 573, numbered according to SEQ ID NO: 138; (c) the amino acid Q, M, G, H, or P at position 574, numbered according to SEQ ID NO: 138; (d) the amino acid S, N, T, L, H, G, or K at position 575, numbered according to SEQ ID NO: 138; (e) the amino acid S, V, T, L, Q, A, M, Y, or H at position 576, numbered according to SEQ ID NO: 138; 48 321861031.1Attorney Docket Number: V2071-3046PCT (f) the amino acid T, V, A, S, G, or Q at position 577, numbered according to SEQ ID NO: 138; (g) the amino acid N, S, A, or H, at position 578, numbered according to SEQ ID NO: 138; (h) the amino acid A at position 579, numbered according to SEQ ID NO: 138; (i) the amino acid A at position 580, numbered according to SEQ ID NO: 138; (j) the amino acid Q at position 581, numbered according to SEQ ID NO: 138; (k) the amino acid A at position 582, numbered according to SEQ ID NO: 138; and / or (l) the amino acid Y at position 583, numbered according to SEQ ID NO: 138; optionally wherein the AAV capsid variant has increased tropism for a muscle cell or a muscle tissue, compared to a reference sequence of SEQ ID NO: 138. 94. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 21, 23-73, or 93, which comprises: (i) the amino acid N at position 575 and V at position 576, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 575 and T at position 576, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 575 and L at position 576, numbered according to SEQ ID NO: 138; (iv) the amino acid K at position 573 and M at position 574, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 575 and Q at position 576, numbered according to SEQ ID NO: 138; (vi) the amino acid G at position 572 and H at position 573, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 575, numbered according to SEQ ID NO: 138; (viii) the amino acid N at position 575 and A at position 576, numbered according to SEQ ID NO: 138; (ix) the amino acid T at position 575 and M at position 576, numbered according to SEQ ID NO: 138; (x) the amino acid V at position 572 and K at position 573, numbered according to SEQ ID NO: 138; (xi) the amino acid H at position 573 and G at position 574, numbered according to SEQ ID NO: 138; (xii) the amino acid M at position 572 and K at position 573, numbered according to SEQ ID NO: 138; 49 321861031.1Attorney Docket Number: V2071-3046PCT (xiii) the amino acid L at position 575 and A at position 576, numbered according to SEQ ID NO: 138; (xiv) the amino acid Y at position 576 and A at position 577, numbered according to SEQ ID NO: 138; (xv) the amino acid H at position 575 and L at position 576, numbered according to SEQ ID NO: 138; (xvi) the amino acid H at position 575 and H at position 576, numbered according to SEQ ID NO: 138; (xvii) the amino acid N at position 575 and H at position 576, numbered according to SEQ ID NO: 138; (xviii) the amino acid T at position 575 and Y at position 576, numbered according to SEQ ID NO: 138; (xix) the amino acid G at position 575 and Y at position 576, numbered according to SEQ ID NO: 138; (xx) the amino acid Y at position 576 and S at position 577, numbered according to SEQ ID NO: 138; (xxi) the amino acid H at position 574 and H at position 575, numbered according to SEQ ID NO: 138; (xxii) the amino acid T at position 575 and L at position 576, numbered according to SEQ ID NO: 138; (xxiii) the amino acid Y at position 576 and G at position 577, numbered according to SEQ ID NO: 138; (xxiv) the amino acid Y at position 576 and Q at position 577, numbered according to SEQ ID NO: 138; (xxv) the amino acid H at position 575 and T at position 576, numbered according to SEQ ID NO: 138; (xxvi) the amino acid P at position 574 and K at position 575, numbered according to SEQ ID NO: 138; or (xxvii) the amino acid M at position 576 and V at position 577, numbered according to SEQ ID NO: 138. 95. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 21, 23-73, 93, or 94, which comprises the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; and wherein the AAV capsid variant comprises: (a) the amino acid N, G, V, or M at position 572, numbered according to SEQ ID NO: 138; (b) the amino acid N, K, or H at position 573, numbered according to SEQ ID NO: 138; 50 321861031.1Attorney Docket Number: V2071-3046PCT (c) the amino acid Q, M, G, H, or P at position 574, numbered according to SEQ ID NO: 138; (d) the amino acid S, N, T, L, H, G, or K at position 575, numbered according to SEQ ID NO: 138; (e) the amino acid S, V, T, L, Q, A, M, Y, or H at position 576, numbered according to SEQ ID NO: 138; (f) the amino acid T, V, A, S, G, or Q at position 577, numbered according to SEQ ID NO: 138. 96. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 21, 23-73, or 93-95, which comprises: (i) the amino acid N at position 575, V at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 575, T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid K at position 573, M at position 574, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 575, Q at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid G at position 572, H at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid N at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid T at position 575, M at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid V at position 572, K at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xi) the amino acid V at position 577, S at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xii) the amino acid V at position 577, A at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 51 321861031.1Attorney Docket Number: V2071-3046PCT (xiii) the amino acid H at position 573, G at position 574, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiv) the amino acid M at position 572, K at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xv) the amino acid L at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvi) the amino acid Y at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvii) the amino acid H at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xviii) the amino acid H at position 575, H at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xix) the amino acid N at position 575, H at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xx) the amino acid T at position 575, Y at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xi) the amino acid G at position 575, Y at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xii) the amino acid Y at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiii) the amino acid V at position 577, H at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiv) the amino acid H at position 574, H at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxv) the amino acid T at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvi) the amino acid Y at position 576, G at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvii) the amino acid Y at position 576, Q at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 52 321861031.1Attorney Docket Number: V2071-3046PCT (xxviii) the amino acid H at position 575, T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxix) the amino acid P at position 574, K at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; or (xxx) the amino acid M at position 576, V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 97. An adeno-associated virus (AAV) capsid variant which comprises: (i) one, two, three, four or all of amino acid other than N at position 573, an amino acid other than Q at position 574, amino acid other than S at position 575, an amino acid other than S at position 576, and / or amino acid other than T at position 577, numbered according to SEQ ID NO: 138; and (ii) one, two, three, four, five or all of an amino acid other than T at position 578, an amino acid other than A at position 579, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, or amino acid other than G at position 583, numbered according to SEQ ID NO: 138; and wherein the AAV capsid variant comprises: (a) the amino acid N, H, or K at position 573, numbered according to SEQ ID NO: 138; (b) the amino acid Q or G at position 574, numbered according to SEQ ID NO: 138; (c) the amino acid S, K, G, T, or R at position 575, numbered according to SEQ ID NO: 138; (d) the amino acid S, E, K, R, A, P, Q, V, L, or G at position 576, numbered according to SEQ ID NO: 138; (e) the amino acid T, R, V, Q, G, S, L, A, E, or K at position 577, numbered according to SEQ ID NO: 138; (f) the amino acid N, R, or V at position 578, numbered according to SEQ ID NO: 138; (g) the amino acid A at position 579, numbered according to SEQ ID NO: 138; (h) the amino acid A at position 580, numbered according to SEQ ID NO: 138; (i) the amino acid Q at position 581, numbered according to SEQ ID NO: 138; (j) the amino acid A at position 582, numbered according to SEQ ID NO: 138; and / or (k) the amino acid Y at position 583, numbered according to SEQ ID NO: 138; optionally wherein the AAV capsid variant has increased tropism for a brain cell or a brain tissue, compared to a reference sequence of SEQ ID NO: 138. 98. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 22-73, or 97, which comprises: (i) the amino acid H at position 573, numbered according to SEQ ID NO: 138; 53 321861031.1Attorney Docket Number: V2071-3046PCT (ii) the amino acid K at position 575, numbered according to SEQ ID NO: 138; (iii) the amino acid E at position 576 and R at position 577, numbered according to SEQ ID NO: 138; (iv) the amino acid V at position 577, numbered according to SEQ ID NO: 138; (v) the amino acid G at position 575 and K at position 576, numbered according to SEQ ID NO: 138; (vi) the amino acid R at position 576 and Q at position 577, numbered according to SEQ ID NO: 138; (vii) the amino acid A at position 576 and G at position 577, numbered according to SEQ ID NO: 138; (viii) the amino acid K at position 576, numbered according to SEQ ID NO: 138; (ix) the amino acid P at position 576, numbered according to SEQ ID NO: 138; (x) the amino acid K at position 576 and S at position 577, numbered according to SEQ ID NO: 138; (xi) the amino acid P at position 576 and S at position 577, numbered according to SEQ ID NO: 138; (xii) the amino acid Q at position 576, numbered according to SEQ ID NO: 138; (xiii) the amino acid R at position 576 and L at position 577, numbered according to SEQ ID NO: 138; (xiv) the amino acid S at position 577, numbered according to SEQ ID NO: 138; (xv) the amino acid V at position 576 and S at position 577, numbered according to SEQ ID NO: 138; (xvi) the amino acid K at position 573 and G at position 574, numbered according to SEQ ID NO: 138; (xvii) the amino acid T at position 575 and L at position 576, numbered according to SEQ ID NO: 138; (xviii) the amino acid R at position 576, numbered according to SEQ ID NO: 138; (xix) the amino acid R at position 576 and A at position 577, numbered according to SEQ ID NO: 138; (x) the amino acid G at position 576, numbered according to SEQ ID NO: 138; (xxi) the amino acid T at position 575, numbered according to SEQ ID NO: 138; (xxii) the amino acid K at position 575 and L at position 576, numbered according to SEQ ID NO: 138; (xxiii) the amino acid R at position 575 and A at position 576, numbered according to SEQ ID NO: 138; (xxiv) the amino acid P at position 576 and K at position 577, numbered according to SEQ ID NO: 138; 54 321861031.1Attorney Docket Number: V2071-3046PCT (xxv) the amino acid K at position 577, numbered according to SEQ ID NO: 138; (xxvi) the amino acid L at position 576 and K at position 577, numbered according to SEQ ID NO: 138; (xxvii) the amino acid K at position 576 and A at position 577, numbered according to SEQ ID NO: 138; (xxviii) the amino acid K at position 573, numbered according to SEQ ID NO: 138; or (xxix) the amino acid K at position 575 and A at position 576, numbered according to SEQ ID NO: 138. 99. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 22-73, 97, or 98, which comprises the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138, and wherein the AAV capsid variant comprises: (a) the amino acid N, H, or K at position 573, numbered according to SEQ ID NO: 138; (b) the amino acid Q or G at position 574, numbered according to SEQ ID NO: 138; (c) the amino acid S, K, G, T, or R at position 575, numbered according to SEQ ID NO: 138; (d) the amino acid S, E, K, R, A, P, Q, V, L, or G at position 576, numbered according to SEQ ID NO: 138; (e) the amino acid T, R, V, Q, G, S, L, A, E, or K at position 577, numbered according to SEQ ID NO: 138; (f) the amino acid N, R, or V at position 578, numbered according to SEQ ID NO: 138; (g) the amino acid A at position 579, numbered according to SEQ ID NO: 138; (h) the amino acid A at position 580, numbered according to SEQ ID NO: 138; (i) the amino acid Q at position 581, numbered according to SEQ ID NO: 138; (j) the amino acid A at position 582, numbered according to SEQ ID NO: 138; and / or (k) the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 100. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 22-73, or 97-99, which comprises: (i) the amino acid H at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ii) the amino acid K at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iii) the amino acid E at position 576, R at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid V at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 55 321861031.1Attorney Docket Number: V2071-3046PCT (v) the amino acid G at position 575, K at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid R at position 576, Q at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid A at position 576, G at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid K at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid P at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid K at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xi) the amino acid P at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xii) the amino acid Q at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiii) the amino acid R at position 576, L at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiv) the amino acid S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xv) the amino acid V at position 576, S at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvi) the amino acid K at position 573, G at position 574, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xvii) the amino acid T at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xviii) the amino acid R at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xix) the amino acid R at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid G at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxi) the amino acid T at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxii) the amino acid E at position 577, R at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; 56 321861031.1Attorney Docket Number: V2071-3046PCT (xxiii) the amino acid K at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxiv) the amino acid R at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxv) the amino acid P at position 576, K at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvi) the amino acid K at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxvii) the amino acid K at position 577, V at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xviii) the amino acid L at position 576, K at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxix) the amino acid K at position 576, A at position 577, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xxx) the amino acid K at position 573, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; or (xxxi) the amino acid K at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 101. An adeno-associated virus (AAV) capsid variant comprising one, two, three, four, five, six, seven, or all of: (a) the amino acid N at position 578, numbered according to SEQ ID NO: 138; (b) the amino acid S, or G at position 579, numbered according to SEQ ID NO: 138; (c) the amino acid A at position 580; (d) the amino acid Q, M, T, S, or L at position 581, numbered according to SEQ ID NO: 138; (e) the amino acid A, R, S, or G at position 582, numbered according to SEQ ID NO: 138; (f) the amino acid Y or W at position 583, numbered according to SEQ ID NO: 138; (g) the amino acid S at position 584, numbered according to SEQ ID NO: 138; (h) the amino acid F at position 585, numbered according to SEQ ID NO: 138; optionally wherein the AAV capsid variant has increased tropism for a brain cell or a brain tissue, compared to a reference sequence of SEQ ID NO: 138. 57 321861031.1Attorney Docket Number: V2071-3046PCT 102. The AAV capsid variant of any one of the preceding embodiments, which comprises the amino acid N at position 578 and the amino acid A at position 580, numbered according to SEQ ID NO: 138. 103. The AAV capsid variant of embodiment 101 or 102, which comprises: (i) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, Y at position 583, and S at position 584, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 578, S at position 579, A at position 580, Q at position 581, A at position 582, Y at position 583, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 578, A at position 580, M at position 581, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, Y at position 583, S at position 584, and F at position 585, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 579, A at position 580, T at position 581, R at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid N at position 579, A at position 580, M at position 581, R at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 578, G at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid N at position 578, A at position 580, T at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid N at position 578, A at position 580, S at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid N at position 578, A at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xi) the amino acid N at position 578, A at position 580, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xii) the amino acid N at position 578, T at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138; (xiii) the amino acid N at position 578, A at position 580, Q at position 581, S at position 582, and W at position 583, numbered according to SEQ ID NO: 138; (xiv) the amino acid N at position 578, A at position 580, Q at position 581, and W at position 583, numbered according to SEQ ID NO: 138; or (xv) the amino acid N at position 578, A at position 580, Q at position 581, G at position 582, and W at position 583, numbered according to SEQ ID NO: 138. 58 321861031.1Attorney Docket Number: V2071-3046PCT 104. An adeno-associated virus (AAV) capsid variant comprising the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 985. 105. An adeno-associated virus (AAV) capsid variant comprising the amino acid N at position 575, L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 986. 106. An adeno-associated virus (AAV) capsid variant comprising an amino acid other than A at position 579, numbered according to SEQ ID NO: 138. 107. The AAV capsid variant of embodiment 106, which comprises the amino acid G at position 579, numbered according to SEQ ID NO: 138. 108. The AAV capsid variant of embodiment 103, which comprises the amino acid Y at position 579, numbered according to SEQ ID NO: 138. 109. The AAV capsid variant of any one of embodiments 106-108, which further comprises the amino acid N at position 578, amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 110. The AAV capsid variant of any one of embodiments 106, 107, or 109, which comprises the amino acid N at position 578, the amino acid G at position 579, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 111. The AAV capsid variant of any one of embodiments 106, 108, or 109, which comprises the amino acid N at position 578, the amino acid Y at position 579, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 112. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid N at position 578, the amino acid G at position 579, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; or 59 321861031.1Attorney Docket Number: V2071-3046PCT (ii) the amino acid N at position 578, the amino acid Y at position 579, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 113. An adeno-associated virus (AAV) capsid variant comprising an amino acid other than S at position 575 and an amino acid other than S at position 576, numbered according to SEQ ID NO: 138. 114. The AAV capsid variant of embodiment 113, which comprises: (i) the amino acid N or T at position 575, numbered according to SEQ ID NO: 138; and / or (ii) the amino acid L, A, T, M, V, or Q, at position 576, numbered according to SEQ ID NO: 138. 115. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid N or T at position 575, numbered according to SEQ ID NO: 138; and / or (ii) the amino acid L, A, T, M, V, or Q, at position 576, numbered according to SEQ ID NO: 138. 116. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid N or T at position 575, numbered according to SEQ ID NO: 138; (ii) the amino acid L, A, T, M, V, or Q, at position 576, numbered according to SEQ ID NO: 138; and (iii) one, two, three, four, or all of the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and / or the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 117. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid N or T at position 575, numbered according to SEQ ID NO: 138; (ii) the amino acid L, A, T, M, V, or Q, at position 576, numbered according to SEQ ID NO: 138; and (iii) the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 118. The AAV capsid variant of any one of embodiments 113-117, which comprises: (i) the amino acid N at position 575 and the amino acid L at position 576, numbered according to SEQ ID NO: 138; 60 321861031.1Attorney Docket Number: V2071-3046PCT (ii) the amino acid N at position 575 and the amino acid A at position 576, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 575 and the amino acid T at position 576, numbered according to SEQ ID NO: 138; (iv) the amino acid T at position 575 and the amino acid M at position 576, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 575 and the amino acid V at position 576, numbered according to SEQ ID NO: 138; or (vi) the amino acid N at position 575 and the amino acid Q at position 576, numbered according to SEQ ID NO: 138. 119. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid N at position 575 and the amino acid L at position 576, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 575 and the amino acid A at position 576, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 575 and the amino acid T at position 576, numbered according to SEQ ID NO: 138; (iv) the amino acid T at position 575 and the amino acid M at position 576, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 575 and the amino acid V at position 576, numbered according to SEQ ID NO: 138; or (vi) the amino acid N at position 575 and the amino acid Q at position 576, numbered according to SEQ ID NO: 138. 120. The AAV capsid variant of any one of embodiments 113-119, which comprises the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 121. The AAV capsid variant of any one of embodiments 113-120, which comprises: (i) the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 575, the amino acid A at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; 61 321861031.1Attorney Docket Number: V2071-3046PCT (iii) the amino acid N at position 575, the amino acid T at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid T at position 575, the amino acid M at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 575, the amino acid V at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; or (vi) the amino acid N at position 575, the amino acid Q at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 122. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (ii) the amino acid N at position 575, the amino acid A at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (iii) the amino acid N at position 575, the amino acid T at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid T at position 575, the amino acid M at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 575, the amino acid V at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; or (vi) the amino acid N at position 575, the amino acid Q at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 123. An adeno-associated virus (AAV) capsid variant comprising the amino acid N at position 575, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 62 321861031.1Attorney Docket Number: V2071-3046PCT 124. An adeno-associated virus (AAV) capsid variant comprising: (i) the amino acid L at position 581, numbered according to SEQ ID NO: 138; and (ii) one, two, three, or all of the amino acid N at position 578, the amino acid A at position 580, the amino acid A at position 582, and / or the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 125. The AAV capsid variant of embodiment 124, which comprises the amino acid N at position 578, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 126. The AAV capsid variant of embodiment 124 or 125, which comprises the amino acid N at position 578, the amino acid A at position 580, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 127. The AAV capsid variant of embodiment 124 or 125, which comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 128. The AAV capsid variant of any one of embodiments 124-127, which comprises the amino acid N at position 578, the amino acid A at position 580, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 129. An adeno-associated virus (AAV) capsid variant comprising the amino acid N at position 578, the amino acid A at position 580, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138. 130. The AAV capsid variants of any one of embodiments 104-129, which has an increased tropism for a muscle cell or a muscle tissue (e.g., a diaphragm muscle, a quadriceps muscle, a skeletal muscle, and / or an intercostal muscle), relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138. 131. The AAV capsid variants of any one of embodiments 104-130, which has an increased tropism for a muscle cell or a muscle tissue (e.g., a diaphragm muscle, a quadriceps muscle, a skeletal muscle, and / or an intercostal muscle), relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 982. 63 321861031.1Attorney Docket Number: V2071-3046PCT 132. The AAV capsid variants of any one of embodiments 104-131, which has an increased tropism for a heart cell or a heart tissue, relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138. 133. The AAV capsid variants of any one of embodiments 104-132, which has an increased tropism for a heart cell or a heart tissue, relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 982. 134. The AAV capsid variant of any one of embodiments 10-133, which has an increased tropism for a heart cell or a heart tissue; and / or a muscle cell or a muscle tissue (e.g., a diaphragm muscle, a quadriceps muscle, a skeletal muscle, and / or an intercostal muscle), relative to an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138, in at least two species, e.g., at least two species of non-human primates (NHPs). 135. The AAV capsid variant of embodiment 134, wherein the at least two species are Macaca fascicularis and Callithrix jacchus. 136. The AAV capsid variant, of any one of the preceding embodiments, which further comprises a modification, e.g., an insertion, substitution (e.g., conservative substitution), and / or deletion, in loop I, II, IV, and / or VI. 137. The AAV capsid variant of any one of the preceding embodiments, which 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: 138. 138. The AAV capsid variant, of any one of the preceding embodiments, which 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. 139. The AAV capsid variant, of any one of the preceding embodiments, which comprises the amino acid sequence of SEQ ID NO: 138, 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. 140. The AAV capsid variant, of any one of the preceding embodiments, which comprises the amino acid sequence of SEQ ID NO: 138. 64 321861031.1Attorney Docket Number: V2071-3046PCT 141. The AAV capsid variant, of any one of the preceding embodiments, which comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 137, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 142. The AAV capsid variant, of any one of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 137, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 143. The AAV capsid variant, of any one of the preceding embodiments, which comprises a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof. 144. The AAV capsid variant, of any one of embodiments 1-143, which comprises the amino acid sequence corresponding to positions 137-724, 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. 145. The AAV capsid variant, of any one of embodiments 1-144, which comprises the amino acid sequence corresponding to positions 193-724, 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. 146. The AAV capsid variant, of any one of embodiments 1-145, which comprises the amino acid sequence corresponding to positions 137-724, e.g., a VP2, of SEQ ID NO: 138, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 147. The AAV capsid variant, of any one of embodiments 1-146, which comprises the amino acid sequence corresponding to positions 193-724, e.g., a VP3, of SEQ ID NO: 138, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 148. The AAV capsid variant, of any one of embodiments 1-143, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to amino acids 193-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. 149. The AAV capsid variant, of any one of embodiments 1-143 or 148, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 65 321861031.1Attorney Docket Number: V2071-3046PCT 98%, or at least 99% identical to amino acids 137-724 of any one of SEQ ID NOs: 138, 982, 985, or 986. 150. The AAV capsid variant, of any one of embodiments 1-143, 148, or 149, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of any one of SEQ ID NOs: 138, 982, 985, or 986. 151. The AAV capsid variant of any one of embodiments 1-150, which comprises: (i) the amino acid sequence of amino acids 193-724 of any one of SEQ ID NOs: 138, 982, 985, or 986; (ii) the amino acid sequence of amino acids 137-724 of any one of SEQ ID NOs: 138, 982, 985, or 986; and / or (iii) the amino acid sequence of any one of SEQ ID NOs: 138, 982, 985, or 986. 152. The AAV capsid variant, of any one of embodiments 1-143, comprising an amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of NAAQAY (SEQ ID NO: 943), wherein: (i) the 3 consecutive amino acids comprise NAA; (ii) the 4 consecutive amino acids comprise NAAQ (SEQ ID NO: 2); (iii) the 5 consecutive amino acids comprise NAAQA (SEQ ID NO: 3); (iv) the 6 consecutive amino acids comprise NAAQAY (SEQ ID NO: 943); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137-724 of SEQ ID NO: 138 or positions 137-724 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193-724 of SEQ ID NO: 138 or positions 193-724 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). 153. The AAV capsid variant, of any one of embodiments 1-143, comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of NAAQAY (SEQ ID NO: 943), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137-724 of SEQ ID NO: 138 or positions 137-724 of SEQ ID NO: 982; 66 321861031.1Attorney Docket Number: V2071-3046PCT (c) a VP3 protein comprising the amino acid sequence of positions 193-724 of SEQ ID NO: 138 or positions 193-724 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). 154. The AAV capsid variant, of any one of embodiments 1-153, comprising one or two, but no more than three substitutions relative to the amino acid sequence of NAAQAY (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. 155. The AAV capsid variant, of any one of embodiments 1-153, which 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. 156. The AAV capsid variant, of any one of embodiments 1-155, which comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 95% identity thereto. 157. The AAV capsid variant, of any one of embodiments 1-156, which comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 98% identity thereto. 158. The AAV capsid variant, of any one of embodiments 1-157, which comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 99% identity thereto. 159. The AAV capsid variant of any one of embodiments 1-158, which 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. 160. The AAV capsid variant, of any one of embodiments 1-159, which 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. 161. The AAV capsid variant, of any one of embodiments 1-160, which comprises the amino acid sequence of SEQ ID NO: 982. 67 321861031.1Attorney Docket Number: V2071-3046PCT 162. The AAV capsid variant, of any one of the preceding embodiments 1-161, wherein the nucleotide sequence encoding the 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. 163. The AAV capsid variant, of any one of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant is codon optimized. 164. An AAV capsid variant comprising the amino acid sequence of any one of embodiments 1-73 or 104-135, and further comprising an amino acid sequence at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) identical to SEQ ID NO: 982. 165. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to positions 193-724 of SEQ ID NO: 982, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982. 166. The AAV capsid variant of embodiment 165, which comprises the amino acid sequence of positions 193-724 of SEQ ID NO: 982. 167. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to positions 137-724 of SEQ ID NO: 982, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982. 168. The AAV capsid variant of any one of embodiments 165-167, which comprises the amino acid sequence of positions 137-724 of SEQ ID NO: 982. 169. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 982, wherein the AAV capsid variant comprises an N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 982. 170. The AAV capsid variant of any one of embodiments 165-169, which comprises the amino acid sequence of SEQ ID NO: 982. 68 321861031.1Attorney Docket Number: V2071-3046PCT 171. The AAV capsid variant of any one of the preceding embodiments, which is an AAV5 capsid variant (e.g., a variant of an AAV5 capsid comprising the amino acid sequence of SEQ ID NO: 138, or encoded by the nucleotide sequence of SEQ ID NO: 137). 172. An adeno-associated virus (AAV) capsid variant comprising the amino acid sequence of SEQ ID NO: 982, 985 or 986. 173. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence at least 95% identical thereto. 174. The AAV capsid variant of any one of embodiments 165-173, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence at least 95% identical thereto. 175. The AAV capsid variant of any one embodiments 1-13, 16, 17, 21, 23-73, 90-96, or 104-174, 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: 138 or SEQ ID NO: 139. 176. The AAV capsid variant of any one of embodiments 1-13, 16, 17, 21, 23-73, 90-96, or 104-175, which is enriched at least about 2, 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 1920, 25, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 81, 80, 85, 90, 95, 100, 101, 110, 120, 125, 126, 130, 135, 140, 145, 150, 155, 160, or 163-fold, in the muscle compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 4. 177. The AAV capsid variant of any one of embodiments 1-13, 16, 17, 21, 23-73, 90-96, or 104-176, which is enriched at least about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or 6.5-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. 178. The AAV capsid variant of any one of embodiments 13, 16, 17, 21, 23, 90-96, 104-133 or 174- 177, which is enriched in the muscle of at least two species, e.g., Macaca fascicularis and Callithrix jacchus, e.g., as compared to a reference sequence of SEQ ID NO: 138. 179. The AAV capsid variant of any one of embodiments 13, 16, 17, 21, 23, 90-96, 104-133, or 174- 178, which is enriched at least about 4, 5, 6, 7, 8, or 9-fold, in the muscle of at least two species compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 4. 69 321861031.1Attorney Docket Number: V2071-3046PCT 180. The AAV capsid variant of any one of embodiments 1-13, 16, 17, 21, 23-73, 90-96, or 104-179, which transduces a muscle region, optionally wherein the level of transduction is at least 2, 3, 5, 6, 9, 10, 15, 20, or 25-fold greater as compared to a reference sequence of SEQ ID NO: 138 or 139, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 3. 181. The AAV capsid variant of any one of embodiments 1-13, 16, 17, 21, 23-73, 90-96, or 104-180, which delivers an increased level of a payload to a muscle cell or region, optionally wherein the level of the payload is increased by at least 3, 5, 9, 10, 12, 15, 20, 21, or 25-fold, as compared to a reference sequence of SEQ ID NO: 138 or 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 3. 182. The AAV capsid variant of any one of embodiments 1-13, 16, 17, 21, 23-73, 90-96, or 104-181, which delivers an increased level of viral genomes to a muscle cell or region, optionally wherein the level of viral genomes is increased by at least 2, 2.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 13.8, 14, 16, 18, or 20-fold, as compared to a reference sequence of SEQ ID NO: 138 or 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 3). 183. The AAV capsid variant of any one of embodiments 173-182, wherein the muscle cell or tissue is a gastrocnemius cell or tissue, a vastus lateralis cell or tissue, a diaphragm cell or tissue, a quadriceps cell or tissue, and / or an intercostal cell or tissue. 184. The AAV capsid variant of any one of embodiments 1-15, 20, 23-89, or 104-183, which has increased tropism for a heart cell or tissue, relative to the tropism of a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139. 185. The AAV capsid variant of any one of embodiments 1-15, 20, 23-89, or 104-184, which is enriched at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30-fold, in the heart compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 4. 186. The AAV capsid variant of any one of embodiments 15, 20, 23-89, or 104-185, which is enriched in the heart of at least two species, e.g., Macaca fascicularis and Callithrix jacchus, e.g., as compared to a reference sequence of SEQ ID NO: 138. 70 321861031.1Attorney Docket Number: V2071-3046PCT 187. The AAV capsid variant of any one of embodiments 15, 20, 23-89, or 104-184, which is enriched at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30-fold, in the heart of at least two to three species, e.g., Macaca fascicularis and Callithrix jacchus, compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 4. 188. The AAV capsid variant of any one of embodiments 134 or 178-187, wherein the at least two species are Macaca fascicularis and Callithrix jacchus. 189. The AV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-188, which delivers an increased level of a payload to a heart cell or region, optionally wherein the level of the payload is increased by at least 2, 2.4, 2.5, 2.7, 3, 3.5, 4, 4.5, or 5-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 3). 190. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-189, which delivers an increased level of viral genomes to a heart cell or region, optionally wherein the level of viral genomes is increased by at least 4, 4.5, 5, 6, 7, 8, 9 or 10-fold, as compared to a reference sequence of SEQ ID NO: 138 or 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 3). 191. The AAV capsid variant of any one embodiments 1-13, 18, 19, 23-73, or 97-103 or 136-154, 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 or SEQ ID SEQ ID NO: 139. 192. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-103 or 136-191, which transduces a brain cell or region, (e.g., the caudate, motor cortex, putamen, thalamus, and / or cerebellum (e.g., the molecular and granule layer of the cerebellum)), optionally wherein the level of transduction is at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 24, 25, 29, or 30-fold greater as compared to a reference sequence of SEQ ID NO: 138 or 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 3. 193. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-103 or 136-194, which delivers an increased level of a payload to a brain cell or region, optionally wherein the level of the payload is increased by at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-fold, as compared to a 71 321861031.1Attorney Docket Number: V2071-3046PCT reference sequence of SEQ ID NO: 138 or 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 3). 194. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-103 or 136-193, which delivers an increased level of viral genomes to a brain cell or region, optionally wherein the level of viral genomes is increased by at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 24, 25, 29, or 30-fold, as compared to a reference sequence of SEQ ID NO: 138 or 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 3). 195. The AAV capsid variant of any one of embodiments 189-194, wherein the brain region is a caudate, motor cortex, putamen, thalamus, and / or cerebellum (e.g., the molecular and granule layer of the cerebellum). 196. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-103 or 136-195, which is enriched at least about 4, 4.6, 10, 11, 20, 25, 28, 30, 40, 50, 60, 65, 70, 80, 81, 80, 90, 100, 101, 105, 107, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 225, 230, 240, 250, 260, 265, 270, 280, 290, 295, 300, 320, 325, 350, 375, 400, 500, 550, 600, 650, 675, 677-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, 2, or 4. 197. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-103 or 136-196, which is enriched at least about 2, 3, 4, 5, 6, 7, 8 or 9-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. 198. The AAV capsid variant of any one of embodiments 1-13, 18, 19, 23-73, or 97-161, which is enriched in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., mouse), e.g., as compared to a reference sequence of SEQ ID NO: 138. 199. The AAV capsid variant, of any one of embodiments 1-13, 18, 19, 23-73, or 97-103 or 136-198, which is enriched at least about 4, 4.6, 10, 20, 25, 28, 30, 40, 50, 60, 70, 80, 81, 80, 100, 101, or 110- fold, in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., mouse), compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Examples 1 and 2. 200. The AAV capsid variant of embodiment 199, wherein the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c and / or C57BL6 mice). 72 321861031.1Attorney Docket Number: V2071-3046PCT 201. The AAV capsid variant of any one of embodiments 1-200, which shows preferential transduction in a muscle cell or region relative to the transduction in the liver. 202. The AAV capsid variant of any one of embodiments 1-201, which shows preferential transduction in a heart cell or region relative to the transduction in the liver. 203. The AAV capsid variant of any one embodiments 1-202, which has an decreased tropism for a liver cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID SEQ ID NO: 139. 204. The AAV capsid variant of any one of embodiments 1-203, which shows preferential transduction in a brain cell or region relative to the transduction in the liver. 205. A polynucleotide encoding the AAV capsid variant of any one of embodiments 1-204. 206. The polynucleotide of embodiment 205, which comprises: (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 sequences of SEQ ID NO: 944; (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 sequences of SEQ ID NO: 944; or (iii) the nucleotide sequence of SEQ ID NO: 944, or nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. 207. The polynucleotide of embodiment 205 or 206, which 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. 208. A polynucleotide encoding an adeno-associated virus (AAV) capsid variant, wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 984. 209. A polynucleotide encoding an adeno-associated virus (AAV) capsid variant, wherein the encoded AAV capsid variant comprise the amino acid sequence of SEQ ID NO: 982, 985, or 986. 73 321861031.1Attorney Docket Number: V2071-3046PCT 210. A polynucleotide encoding an adeno-associated virus (AAV) capsid variant, wherein the encoded AAV capsid variant comprises: (a) the amino acid sequence of SEQ ID NO: 943; (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943; (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 NO: 943; 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 NO: 943. 211. A polynucleotide encoding an adeno-associated virus (AAV) capsid variant, wherein the encoded AAV capsid variant comprises: (i) one, two, three, four, or all of an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and / or an amino acid other than G at position 583, numbered according to SEQ ID NO: 138; (ii) an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138; (iii) one, two, three, four, five, or all of the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138; (v) one, two, three, four, or all of the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138; (vii) one, two, three, four, or all of the amino acid substitutions T578N, P580A, A581Q, T582A, and / or G583Y, numbered according to SEQ ID NO: 138; and / or (viii) the amino acid substitutions T578N, P580A, A581Q, T582A, and G583Y, numbered according to SEQ ID NO: 138. 212. A polynucleotide encoding an adeno-associated virus (AAV) capsid variant comprising: 74 321861031.1Attorney Docket Number: V2071-3046PCT (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence corresponds to positions 580-583 of SEQ ID NO: 982; and an amino acid other than T at position 578, numbered according to SEQ ID NO: 138; and / or (ii) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence corresponds to positions 580-583 of SEQ ID NO: 982; and the amino acid N at position 578, numbered according to SEQ ID NO: 138. 213. The polynucleotide of any one of embodiments 210-212, which comprises: (i) the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; (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; or (iii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. 214. The polynucleotide of any one of embodiments 210-213, wherein the AAV capsid variant comprises: (i) 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; (ii) 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 NO: 982; or (iii) an amino acid sequence comprising 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. 215. The polynucleotide of any one of embodiments 210-214, comprising 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. 216. The polynucleotide of any one of embodiments 210-215, which comprises a nucleotide sequence that is codon optimized. 217. A peptide comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 7-136, 140-531, or 943; 75 321861031.1Attorney Docket Number: V2071-3046PCT (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from any one of SEQ ID NOs: 7-136, 140-531, or 943; (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: 7-136, 140-531, or 943; 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: 7-136, 140-531, or 943. 218. A peptide comprising the amino acid sequence of NAAQAY (SEQ ID NO: 943) or any one of SEQ ID NOs: 7-136, or 140-531. 219. A peptide encoded by: (i) the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or (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; (iii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. 220. A peptide wherein the nucleotide sequence encoding the peptide comprises: (i) the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; (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; or (iii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. 221. An AAV capsid variant comprising the peptide of any one of embodiments 217-220. 222. An AAV capsid variant encoded by the polynucleotide of any one of embodiments 205-216. 76 321861031.1Attorney Docket Number: V2071-3046PCT 223. An adeno-associated virus (AAV) particle comprising the AAV capsid variant of any one of embodiments 1-204, 221 or 222, an AAV capsid variant encoded by the polynucleotide of any one of embodiments 205-216, or an AAV capsid variant comprising the peptide of any one of embodiments 217-220. 224. The AAV particle of embodiment 223, which comprises a nucleotide sequence encoding a payload. 225. The AAV particle of embodiment 224, wherein the encoded payload comprises a therapeutic protein or functional variant thereof; an antibody or antibody fragment; an enzyme; a component of a gene editing system; an RNAi agent (e.g., a dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA); or a combination thereof. 226. The AAV particle of embodiment 225, wherein the therapeutic protein or functional variant thereof, e.g., a recombinant protein, is associated with (e.g., aberrantly expressed in) a neurological or neurodegenerative disorder, a muscular, a muscular dystrophy, a neuromuscular disorder, or a neuro- oncological disorder. 227. The AAV particle of embodiment 225 or 226, the therapeutic protein or functional variant thereof is chosen from apolipoprotein E (APOE) (e.g., ApoE2, ApoE3 and / or ApoE4); human survival of motor neuron (SMN) 1 or SMN2; glucocerebrosidase (GBA1); aromatic L-amino acid decarboxylase (AADC); aspartoacylase (ASPA); tripeptidyl peptidase I (CLN2); beta-galactosidase (GLB1); N-sulphoglucosamine sulphohydrolase (SGSH); N-acetyl-alpha-glucosaminidase (NAGLU); iduronate 2-sulfatase (IDS); intracellular cholesterol transporter (NPC1); gigaxonin (GAN); titn; myotubularin; calpain-3 (CAPN-3); dysferlin (DYSF); gamma-sarcoglycan (SGCG); alpha- sarcoglycan (SGCA); microdystrophin; dystrophin; beta-sarcoglycan (SGCB); fukutin-related protein (FKRP); anoctamin-5 (ANO5); or a combination thereof. 228. The AAV particle of embodiment 225, wherein the antibody or antibody binding fragment binds to: (i) a CNS related target, e.g., an antigen associated with a neurological or neurodegenerative disorder, e.g., β-amyloid, APOE, tau, SOD1, TDP-43, huntingtin (HTT), and / or synuclein; (ii) a muscular or neuromuscular related target, e.g., an antigen associated with a muscular or neuromuscular disorder; or (iii) a neuro-oncology related target, e.g., an antigen associated with a neuro-oncological disorder, e.g., HER2, or EGFR (e.g., EGFRvIII). 77 321861031.1Attorney Docket Number: V2071-3046PCT 229. The AAV particle of embodiment 225, wherein the enzyme comprises a meganuclease, a zinc finger nuclease, a TALEN, a recombinase, integrase, a base editor, a Cas9, or a fragment thereof. 230. The AAV particle of embodiment 225, wherein the component of a gene editing system comprises one or more components of a CRISPR-Cas system. 231. The AAV particle of embodiment 230, wherein the one or more components of the CRISPR-Cas system comprises a Cas9, e.g., a Cas9 ortholog or a Cpf1, and a single guide RNA (sgRNA), optionally wherein: (i) the sgRNA is located upstream (5’) of the Cas9 enzyme; or (ii) the sgRNA is located downstream (3’) of the Cas9 enzyme. 232. The AAV particle of embodiment 225, wherein the RNAi agent (e.g., a dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA), modulates, e.g., inhibits, expression of, a CNS related gene, mRNA, and / or protein. 233. The AAV particle of embodiment 232, wherein the CNS related gene is chosen from SOD1, MAPT, APOE, HTT, C9ORF72, TDP-43, APP, BACE, SNCA, ATXN1, ATXN3, ATXN7, SCN1A- SCN5A, SCN8A-SCN11A, or a combination thereof. 234. The AAV particle of any one of embodiments 223-233, which comprises a viral genome comprising a promoter operably linked to the nucleic acid sequence encoding the payload. 235. The AAV particle of embodiment 234, wherein the promoter is chosen from human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a functional fragment, e.g., a truncation, or a functional variant thereof. 78 321861031.1Attorney Docket Number: V2071-3046PCT 236. The AAV particle of embodiment 234 or 235, wherein the promoter is an EF-1a promoter variant, e.g., a truncated EF-1a promoter. 237. The AAV particle of any one of embodiments 234-236, wherein the promoter comprises the nucleotide sequence of any one of SEQ ID NOs: 2100, 2101, 2103, 2104, 2108, 2109, or 2111-2120, or a nucleotide sequence provided in Table 8, a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NOs: 2100, 2101, 2103, 2104, 2108, 2109, or 2111-2120, or a nucleotide sequence provided in Table 8, or a nucleotide sequence with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to any one of SEQ ID NOs: 2100, 2101, 2103, 2104, 2108, 2109, or 2111-2120, or a nucleotide sequence provided in Table 8. 238. The AAV particle of any one of embodiments 234-237 wherein the viral genome further comprises a polyA signal sequence. 239. The AAV particle of any one of embodiments 234-238, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence. 240. The AAV particle of any one of embodiments 234-239, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid sequence encoding the payload. 241. The AAV particle of any one of embodiments 234-240, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the nucleic acid sequence encoding the payload. 242. The AAV particle of any one of embodiments 234-241, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the payload and an ITR sequence positioned 3’ relative to the nucleic acid sequence encoding the payload. 243. The AAV particle of any one of embodiments 234-242, wherein the viral genome further comprises an enhancer, a Kozak sequence, an intron region, and / or an exon region. 244. The AAV particle of any one of embodiments 234-243, wherein the viral genome further comprises a nucleotide sequence encoding a miR binding site, e.g., a miR binding site that modulates, e.g., reduces, expression of payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed. 79 321861031.1Attorney Docket Number: V2071-3046PCT 245. The AAV particle of embodiment 244, wherein the encoded miRNA binding site is complementary, e.g., fully complementary or partially complementary, to a miRNA expressed in a cell or tissue of the DRG, liver, heart, hematopoietic, or a combination thereof. 246. The AAV particle of embodiment 244 or 245, wherein the encoded miR binding site modulates, e.g., reduces, expression of the encoded antibody molecule in a cell or tissue of the DRG, liver, heart, hematopoietic lineage, or a combination thereof. 247. The AAV particle of any one of embodiments 234-246, wherein the viral genome comprises at least 1-5 copies of the encoded miR binding site, e.g., at least 1, 2, 3, 4, or 5 copies. 248. The AAV particle of any one of embodiments 234-247, wherein the viral genome comprises at least 3 copies of an encoded miR binding sites, optionally wherein all three copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise a different miR binding site. 249. The AAV particle of embodiment 248, wherein the 3 copies of the encoded miR binding sites are continuous (e.g., not separated by a spacer). 250. The AAV particle of embodiment 248, wherein the 3 copies of the encoded miR binding sites are separated by a spacer, optionally wherein the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising one, two, or three modifications, e.g., substitutions, insertions, or deletions, but no more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA. 251. The AAV particle of any one of embodiments 234-250, wherein the viral genome comprises at least 4 copies of an encoded miR binding site, optionally wherein all four copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise a different miR binding site. 252. The AAV particle of embodiment 251, wherein the 4 copies of the encoded miR binding sites are continuous (e.g., not separated by a spacer). 253. The AAV particle of embodiment 251, wherein the 4 copies of the encoded miR binding sites are separated by a spacer, optionally wherein the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising at one, two, or three modifications, e.g., substitutions, insertions, or deletions, but no more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA. 80 321861031.1Attorney Docket Number: V2071-3046PCT 254. The AAV particle of any one of embodiments 234-253, wherein the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-1 binding site, a miR-142-3p, or a combination thereof, optionally wherein: (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (ii) the encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; (iii) the encoded miR-1 binding site comprises the nucleotide sequence of SEQ ID NO: 4679, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4679; and / or (iv) the encoded miR-142-3p binding site comprises the nucleotide sequence of SEQ ID NO: 4675, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4675. 255. The AAV particle of any one of embodiments 234-254, wherein the viral genome comprises an encoded miR122 binding site. 256. The AAV particle of any one of embodiments 234-255, wherein the viral genome comprises at least 1-5 copies, e.g., 1, 2, or 3 copies of a miR122 binding site, optionally wherein each copy is continuous (e.g., not separated by a spacer), or each copy is separated by a spacer, optionally wherein the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising one, two, or three modifications, e.g., substitutions, insertions, or deletions, but no more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA. 81 321861031.1Attorney Docket Number: V2071-3046PCT 257. The AAV particle of embodiment 255 or 256, wherein the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673. 258. The AAV particle of any one of embodiments 234-257, wherein the viral genome comprises: (A) (i) a first encoded miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (ii) a first spacer comprising the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising one, two, or three modifications, e.g., substitutions, but no more than four modifications, e.g., substitutions, relative to GATAGTTA; and (iii) a second encoded miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; or (B) (i) a first encoded miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (ii) a first spacer comprising the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising one, two, or three modifications, e.g., substitutions, but no more than four modifications, e.g., substitutions, relative to GATAGTTA; (iii) a second encoded miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or 82 321861031.1Attorney Docket Number: V2071-3046PCT deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (iv) a second spacer comprising the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising one, two, or three modifications, e.g., substitutions, but no more than four modifications, e.g., substitutions, relative to GATAGTTA; and (v) a third encoded miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673. 259. The AAV particle of any one of embodiments 234-258, wherein the viral genome comprises an encoded miR183 binding site. 260. The AAV particle of any one of embodiments 234-259, wherein the viral genome comprises at least 1-5 copies, e.g., 1, 2, or 3 copies of a miR183 binding site, optionally wherein each copy is continuous (e.g., not separated by a spacer), or each copy is separated by a spacer, optionally wherein the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising one, two, or three modifications, e.g., substitutions, insertions, or deletions, but no more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA. 261. The AAV particle of embodiment 259 or 260, wherein the encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673. 262. The AAV particle of any one of embodiments 234-261, wherein the viral genome comprises: (A) (i) a first encoded miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; 83 321861031.1Attorney Docket Number: V2071-3046PCT (ii) a first spacer comprising the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising at least one, two, or three modifications, e.g., substitutions, insertions, or deletions, but no more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA; and (iii) a second encoded miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; or (B) (i) a first encoded miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; (ii) a first spacer comprising the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising at least one, two, or three modifications, e.g., substitutions, insertions, or deletions, but no more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA; (iii) a second encoded miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; (iv) a second spacer comprising the nucleotide sequence of GATAGTTA, or a nucleotide sequence comprising at least one, two, or three modifications, e.g., substitutions, insertions, or deletions, but no more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA; and (v) a third encoded miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676. 84 321861031.1Attorney Docket Number: V2071-3046PCT 263. The AAV particle of any one of embodiments 234-262, wherein the viral genome comprises an encoded miR122 binding site and a miR-1 binding site. 264. The AAV particle of any one of embodiments 234-263, wherein the viral genome is single stranded or self-complementary. 265. The AAV particle of any one of embodiments 234-264, wherein the viral genome further comprises 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). 266. The AAV particle of any one of embodiments 234-265, wherein the AAV particle further comprises 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). 267. The AAV particle of embodiment 2655 or 266, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene. 268. The AAV particle of any one of embodiments 234-267, wherein the viral genome further comprises a nucleotide sequence encoding the AAV capsid variant of any one of embodiments 1-79, 96, or 97. 269. The AAV particle of any one of embodiments 187-232, wherein the AAV particle further comprises a nucleotide sequence encoding the AAV capsid variant of any one of embodiments 1-79, 96, or 97. 270. The AAV capsid variant, polynucleotide, peptide, or AAV particle of any one of the preceding embodiments, which is isolated, e.g., recombinant. 271. A vector comprising a polynucleotide encoding the AAV capsid variant of any one of embodiments 1-204, 221, 222, or 270, the polynucleotide of any one of embodiments 271-516 or 270, or a polynucleotide encoding the peptide of any one of embodiments 217-220 or 270. 272. A cell, e.g., a host cell, comprising the AAV capsid variant of any one of embodiments 1-204, 221, 222, or 270, the polynucleotide of any one of embodiments 271-216 or 270, the peptide of any 85 321861031.1Attorney Docket Number: V2071-3046PCT one of embodiments 217-220 or 270, the AAV particle of any one of embodiments 223-270, or the vector of embodiment 271. 273. The cell of embodiment 272, wherein the cell is a mammalian cell or an insect cell. 274. The cell of embodiment 272 or 273, wherein the cell is a cell of a brain region or a spinal cord region. 275. The cell of any one of embodiments 272-274, wherein the cell is a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, oligodendrocyte, or a muscle cell (e.g., a cell of the heart, diaphragm, or quadriceps). 276. A method of making an AAV particle, comprising (i) providing a host cell comprising a viral genome; and (ii) incubating the host cell under conditions suitable to enclose the viral genome in the AAV capsid variant of any one of embodiments 1-204, 221, 222, or 270, or an AAV capsid variant encoded by the polynucleotide of any one of embodiments 205-216 or 270; thereby making the AAV particle. 277. The method of embodiment 276, further comprising, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the host cell. 278. The method of embodiment 276 or 277, wherein the host cell comprises a second nucleic acid encoding the AAV capsid variant. 279. The method of embodiment 278, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule. 280. A pharmaceutical composition comprising the AAV particle of any one of embodiments 223- 270, an AAV particle comprising the capsid variant of any one of embodiments 1-204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270, and a pharmaceutically acceptable excipient. 281. A method of delivering a payload to a cell or tissue (e.g., a CNS cell or a CNS tissue; a muscle cell or tissue; or a heart cell or tissue), comprising administering an effective amount of the pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223- 86 321861031.1Attorney Docket Number: V2071-3046PCT 270, an AAV particle comprising the capsid variant of any one of embodiments 1-204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270. 282. The method of embodiment 281, wherein the cell is a cell of a brain region or a spinal cord region; the cell is a cell of a heart (e.g., a heart region); or the cell is a cell of a muscle, e.g., a muscle region. 283. The method of embodiment 281 or 282, wherein the cell or tissue is within a subject. 284. The method of embodiment 283, wherein the subject has, has been diagnosed with having, or is at risk of having a genetic disorder, e.g., a monogenic disorder or a polygenic disorder. 285. The method of embodiment 283 or 284, wherein the subject has, has been diagnosed with having, or is at risk of having a neurological, e.g., a neurodegenerative disorder. 286. The method of embodiment 283 or 285, wherein the subject has, has been diagnosed with having, or is at risk of having a muscular disorder, a muscular dystrophy, or a neuromuscular disorder. 287. The method of embodiment 283 or 285, wherein the subject has, has been diagnosed with having, or is at risk of having a neuro-oncological disorder. 288. A method of treating a subject having or diagnosed with having a genetic disorder, e.g., a monogenic disorder or a polygenic disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1- 204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270. 289. A method of treating a subject having or diagnosed with having a neurological disorder, e.g., a neurodegenerative disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223- 270, an AAV particle comprising the capsid variant of any one of embodiments 1-204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270. 290. A method of treating a subject having or diagnosed with having a muscular disorder, a muscular dystrophy, or a neuromuscular disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 87 321861031.1Attorney Docket Number: V2071-3046PCT 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1-204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270. 291. A method of treating a subject having or diagnosed with having a neuro-oncological disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1-204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270. 292. The method of any one of embodiments 284-291, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, muscular disorder, a muscular dystrophy, neuromuscular disorder, or neuro-oncological disorder is Duchenne muscular dystrophy (DMD), Limb-Girdle Muscular Dystrophy (LGMD2A), Becker muscular dystrophy (BMD), congenital muscular dystrophy, Facioscapulohumeral muscular dystrophy, titinopathy, Emery Dreifuss muscular dystrophy, X-linked myotubular myopathy, Huntington’s Disease, Amyotrophic Lateral Sclerosis (ALS), Gaucher Disease, Dementia with Lewy Bodies, Parkinson’s disease, Spinal Muscular Atrophy, Alzheimer’s Disease, a leukodystrophy (e.g., Alexander disease, autosomal dominant leukodystrophy with autonomic diseases (ADLD), Canavan disease, cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, or Refsum disease), or a cancer (e.g., a HER2 / neu positive cancer or a glioblastoma). 293. The method of any one of embodiments 288-292, where treating comprises prevention of progression of the disease or disorder in the subject. 294. The method of any one of embodiments 283-293, wherein the subject is a human. 295. The method of any one of embodiments 288-294, wherein the AAV particle or pharmaceutical composition is administered to the subject intravenously, via intra-cisterna magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly. 296. The method of any one of embodiments 288-295, wherein the AAV particle or pharmaceutical composition 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. 88 321861031.1Attorney Docket Number: V2071-3046PCT 297. The method of any one of embodiments 288-295, wherein the AAV particle or pharmaceutical composition is administered to the subject intravenously. 298. The method of any one of embodiments 288-297, wherein administration of the AAV particle or pharmaceutical composition results in a decreased presence, level, and / or activity of a gene, mRNA, protein, or combination thereof. 299. The method of any one of embodiments 288-298, wherein administration of the AAV particle or pharmaceutical composition results in an increased presence, level, and / or activity of a gene, mRNA, protein, or a combination thereof. 300. The pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1- 204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270, for use in a method of delivering a payload to a cell or tissue. 301. The pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1- 204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270, for use in a method of treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, a muscular dystrophy, a neuromuscular disorder, or a neuro-oncological disorder. 302. The pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1- 204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270, for use in the manufacture of a medicament. 303. Use of the pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1- 204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270, in the manufacture of a medicament. 304. Use of the pharmaceutical composition of embodiment 280, the AAV particle of any one of embodiments 223-270, an AAV particle comprising the capsid variant of any one of embodiments 1- 204, 221, 222, or 270, an AAV particle comprising the peptide of any one of embodiments 217-220 or 270, in the manufacture of a medicament for treating a genetic disorder, a neurological disorder, a 89 321861031.1Attorney Docket Number: V2071-3046PCT neurodegenerative disorder, a muscular disorder, a muscular dystrophy, a neuromuscular disorder, or a neuro-oncological disorder.

[0085] The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Other features, objects and advantages of the disclosure will be apparent from the description. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Certain terms are defined in the Definition section and throughout. DETAILED DESCRIPTION OF THE DISCLOSURE

[0086] Described herein, inter alia, are compositions comprising an AAV capsid variant, e.g., an AAV capsid variant described herein, and methods of making and using the same. Generally, the AAV capsid variant has 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, a CNS cell, a heart cell, a heart tissue, a muscle cell, a muscle tissue, a liver cell, or a liver tissue.

[0087] Without wishing to be bound by theory, certain AAV capsid variants described herein can show multiple advantages over wild-type AAV5, including (i) increased penetrance through the blood brain barrier following intravenous administration, (ii) wider distribution throughout the multiple brain regions, (iii) elevated payload expression in multiple brain regions, (iv) wider distribution in one or more peripheral tissues, e.g., a muscle tissue, and / or (v) elevated payload expression in one or more peripheral tissues, e.g., a muscle tissue. Without wishing to be being bound by theory, it is believed that these advantages may be due, in part, to the dissemination of the AAV capsid variants through the brain vasculature. In some embodiments, the AAV capsids described herein enhance the delivery of a payload to multiple regions of the brain.

[0088] In some embodiments, AAV capsid variants disclosed herein comprise a modification in loop VIII of AAV5, e.g., at positions between 578-583, e.g., at positions 578, 580, 581, 582, and 583, numbered relative to SEQ ID NO: 138. Without wishing to be bound by theory, it is believed in some embodiments that the aforesaid region (e.g., positions between 578-583, e.g., at positions 578, 580, 581, 582, and 583) of the AAV5 capsid 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, loop (e.g., 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 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 4)), numbered according to SEQ ID NO: 138. 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). 90 321861031.1Attorney Docket Number: V2071-3046PCT

[0089] Several approaches have been used to produce AAV capsids with enhanced tropism for a cell or tissue, e.g., a CNS cell or tissue. One approach used co-infection of cultured cells (Grimm et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol.2008 June 82(12):5887–5911) or in situ animal tissue (Lisowski et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 2014506:382-386) with adenovirus, in order to trigger exponential replication of infectious AAV DNA. Another approach involved the use of cell-specific CRE transgenic mice (Deverman et al. Cre- dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol.2016 Feb.34(2)204-209; which is herein incorporated by reference) allowing viral DNA recombination specifically in astrocytes, followed by recovery of CRE-recombined capsid variants. Other approaches apply high throughput DNA synthesis, multiplexing, sequencing technologies, and machine learning to evaluate sequencing reads of viral DNA in different tissues to engineer variant capsids. These approaches are different from the approach disclosed herein.

[0090] There are some limitations to the art-known capsid generation methods. For example, the transgenic CRE system used by Deverman et al. (2016) has limited capabilities in other animal species and AAV variants selected by directed evolution in mouse tissue do not show similar properties in large animals. Previously described transduction-specific approaches are not amenable to large animal studies because: 1) many tissues of interest (e.g., CNS) are not readily accessible to adenovirus co-infection, 2) the specific adenovirus tropism itself would bias the library distribution, and 3) large animals are typically not amenable to transgenesis or genetic engineering to express CRE recombinase in defined cell types.

[0091] To address these limitations, a broadly applicable functional AAV capsid library screening platform for cell type-specific biopanning in non-transgenic animals has been developed and is described in the appended Examples. In the TRACER (Tropism Redirection of AAV by Cell type- specific Expression of RNA) platform system, the capsid gene is placed under the control of a cell type-specific promoter to drive capsid mRNA expression in the absence of helper virus co-infection. Without wishing to be bound by theory, it is believed that this RNA-driven screen increases the selective pressure in favor of capsid variants which transduce a specific cell type. The TRACER platform allows for generation of AAV capsid libraries whereby specific recovery and subcloning of capsid mRNA expressed in transduced cells is achieved with no need for transgenic animals or helper virus co-infection. Without wishing to be bound by theory, it is believed that since mRNA transcription is a hallmark of full transduction, the methods disclosed herein allow identification of fully infectious AAV capsid mutants, and in addition to its higher stringency, this method allows identification of capsids with high tropism for particular cell types using libraries designed to express CAP mRNA under the control of any cell-specific promoter such as, but not limited to, synapsin-1 promoter (neurons), GFAP promoter (astrocytes), TBG promoter (liver), CAMK promoter (skeletal 91 321861031.1Attorney Docket Number: V2071-3046PCT muscle), MYH6 promoter (cardiomyocytes). Described herein are AAV capsid variants generated using the TRACER method which demonstrate enhance tropism in for example a CNS cell, a CNS tissue, a muscle cell, or a muscle tissue.

[0092] 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.

[0093] In some embodiments, an AAV particle is 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.

[0094] In some embodiments, the AAV particle is a naturally occurring (e.g., wild-type) AAV or 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 typically comprises two ITR sequences. These 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. 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.

[0095] In some embodiments, the wild-type AAV viral genome further 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 used for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid polypeptide, e.g., an AAV capsid variant. 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 AAV5 (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, for the amino acid sequence of SEQ ID NO: 982, VP1 comprises amino acids 1-724, 92 321861031.1Attorney Docket Number: V2071-3046PCT VP2 comprises amino acids 137-724, and VP3 comprises amino acids 193-724. In other words, VP1 is the full-length capsid 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 protein. While not wishing to be bound by theory, the AAV capsid protein typically comprises a molar ratio of 1:1:10 of VP1:VP2:VP3.

[0096] 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.

[0097] Methods for producing and / or modifying AAV particles are disclosed in the art such as pseudotyped AAV particles (PCT Patent Publication Nos. WO200028004; WO200123001; WO2004112727; WO2005005610; and WO2005072364, the content of each of which is incorporated herein by reference in its entirety).

[0098] 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. Peptides

[0099] Disclosed herein are peptides, and associated AAV particles comprising an AAV capsid variant and a peptide for enhanced or improved transduction of a target tissue (e.g., cells of the CNS or PNS). In some, embodiments, the peptide is an isolated, e.g., recombinant, peptide. In some embodiments, the nucleic acid encoding the peptide is an isolated, e.g., recombinant, nucleic acid.

[0100] 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, and / or 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 a temporal cortex, perirhinal cortex, globus pallidus, putamen, 93 321861031.1Attorney Docket Number: V2071-3046PCT caudate, thalamus, hippocampus, geniculate nucleus, Purkinje Layer, deep cerebellar nuclei, cerebellum, cervical spinal cord, thoracic spinal cord, or lumbar spinal cord.

[0101] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of the PNS. The cell or tissue of the PNS may be, but is not limited to, a dorsal root ganglion (DRG).

[0102] 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., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0103] In some embodiments, the peptide may increase 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 the PNS (e.g., DRG) following focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0104] A peptide may vary in length. In some embodiments, the peptide is about 3 to about 20 amino acids in length. As non-limiting examples, the peptide may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 3-5, 3-8, 3-10, 3-12, 3-15, 3-18, 3-20, 5-10, 5-15, 5-20, 10-12, 10-15, 10- 20, 12-20, or 15-20 amino acids in length. In some embodiments, a peptide comprises about 6 to 12 amino acids in length, e.g., about 9 amino acids in length. In some embodiments, a peptide comprises about 7 to 11 amino acids in length, e.g., about 8 amino acids in length. In some embodiments, a peptide comprises about 5 to 10 amino acids in length, e.g., about 7 amino acids in length. In some embodiments, a peptide comprises about 4 to 9 amino acids in length, e.g., about 6 amino acids in length.

[0105] In some embodiments a peptide may comprise a sequence as set forth in Tables 1A (e.g., comprising the amino acid sequence of SEQ ID NO: 943 or 744), 1B, or 28-36. In some embodiments, the peptide is isolated, e.g., recombinant. Table 1A Exemplary Peptide Sequences S I N 9744 ATNNQSSTNAAQAYT 745 GCGACGAATAATCAGTCTTCTACGAATGCGGCGCAGGCGTATACG Ta : N N NQ Q Q Q Q Q Q NQSMVNAAQAY 254 NQSHSNAAQAY 348 NHGSSTNAAQAYT 442 94 321861031.1Attorney Docket Number: V2071-3046PCT NQSLTNAAQAY 255 NQSSTHAAQAY 349 MKQSSTNAAQAYT 443 N N N N N N N N N N N L N N N A N N N N N N N N N V N N N N N N N I N S N N N N N N N N N N N N N N N N N L Y NQ Q Q Q Q NQSSTNSAQAY 312 NNQSSTNAAASYT 406 NQSSTNGPQAYTY 500 95 321861031.1Attorney Docket Number: V2071-3046PCT NQHPTNAAQAY 313 NNQNATNAAQAYT 407 NQSPTNAAQAYTY 501 N N N F M N L N N N N N N N N N N N N N N N L N W T N N N N N

[0106] In some embodiments, a peptide described herein comprises an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943. In some embodiments, the 3 consecutive amino acids comprise NAA. In some embodiments, the 4 consecutive amino acids comprise NAAQ (SEQ ID NO: 2). In some embodiments, the 5 consecutive amino acids comprise NAAQA (SEQ ID NO: 3). In some embodiments, the 6 consecutive amino acids comprise NAAQAY (SEQ ID NO: 943).

[0107] In some embodiments, a peptide described herein 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 NAAQAY (SEQ ID NO: 943). In some embodiments, the peptide comprises one or two (e.g., no more than two) different amino acids, relative to the amino acid sequence of NAAQAY (SEQ ID NO: 943).

[0108] 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 NAAQAY (SEQ ID NO: 943). In some embodiments, the peptide comprises an amino acid sequence comprising 96 321861031.1Attorney Docket Number: V2071-3046PCT one or two (e.g., no more than two) modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of NAAQAY (SEQ ID NO: 943).

[0109] In some embodiments, the peptide comprises the amino acid sequence of any of the sequences provided in Tables 1A, 1B, or 28-36. In some embodiments, the peptide comprises the amino acid sequence of SEQ ID NOs: 943 or 744. In some embodiments, the peptide comprises the amino acid sequence of SEQ ID NO: 943. In some embodiments, the peptide comprises the amino acid sequence of SEQ ID NO: 744.

[0110] In some embodiments, the peptide comprises an amino acid sequence encoded by a nucleotide sequence described herein, e.g., a nucleotide sequence of Tables 1A, 1B, or 28-36. In some embodiments, the peptide comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. In some embodiments, the peptide comprises an amino acid sequence encoded by 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. In some embodiments, the peptide comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. In some embodiments, the peptide comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 745. In some embodiments, the peptide comprises an amino acid sequence encoded by 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: 745. In some embodiments, the peptide comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 745, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.

[0111] In some embodiments, the nucleotide sequence encoding a peptide described herein comprises a nucleotide sequence described herein, e.g., as described in Table 1A. In some embodiments, the nucleotide sequence encoding a peptide described herein is codon optimized. In some embodiments, the nucleotide sequence encoding a peptide described herein is isolated, e.g., recombinant.

[0112] In some embodiments, the nucleotide sequence encoding a peptide described herein comprises the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide 97 321861031.1Attorney Docket Number: V2071-3046PCT sequence of SEQ ID NO: 944. In some embodiments, the nucleotide sequence encoding a peptide described herein comprises 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. In some embodiments the nucleic acid encoding a peptide described herein comprises a nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.

[0113] In some embodiments, the nucleotide sequence encoding a peptide described herein comprises the nucleotide sequence of SEQ ID NO: 745, or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 745. In some embodiments, the nucleotide sequence encoding a peptide described herein comprises 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: 745. In some embodiments the nucleic acid encoding a peptide described herein comprises a nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 745, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.

[0114] The present disclosure also provides a nucleic acid or polynucleotide encoding any of the peptides described herein and AAV capsid variants, AAV particles, vectors, and cells comprising the same. AAV Capsid Variant

[0115] In some embodiments, an AAV particle described herein comprises an AAV capsid variant, e.g., an AAV capsid variant described herein (e.g., an AAV capsid variant comprising a peptide or an amino acid sequence described herein). In some embodiments, an AAV capsid variant comprises a peptide as set forth in Tables 1 or 9.

[0116] In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from SEQ ID NO: 943. In some embodiments, the amino acid sequence is present in loop VIII. In some embodiments, the amino acid sequence replaces one, two, three, four, five, or all of positions 578, 579, 580, 581, 582, and / or 583 (e.g., positions T578, A579, P580, A581, T582, and / or G583), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises one or more amino acid substitutions at positions 578, 579, 580, 581, 582, 583 (e.g., positions T578, A579, P580, A581, T582, and / or G583), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 98 321861031.1Attorney Docket Number: V2071-3046PCT

[0117] In some embodiments, the 3 consecutive amino acids comprise NAA. In some embodiments, the 4 consecutive amino acids comprise NAAQ (SEQ ID NO: 2). In some embodiments, the 5 consecutive amino acids comprise NAAQA (SEQ ID NO: 3). In some embodiments, the 6 consecutive amino acids comprise NAAQAY (SEQ ID NO: 943).

[0118] In some embodiments, an AAV capsid variant 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 sequences provided in Tables 1A, 1B, or 28-36. In some embodiments, the AAV capsid variant comprises amino acid sequence comprising one or two (e.g., no more than two) modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of the sequences provided in Tables 1A, 1B, or 28-36. In some embodiments, 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 one of the sequences provided in Tables 1A, 1B, or 28-36. In some embodiments, the AAV capsid variant comprises an amino acid sequence comprising one or two (e.g., no more than two) different amino acids, relative to the amino acid sequence of any one of the sequences provided in Tables 1A, 1B, or 28-36.

[0119] In some embodiments, 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 NAAQAY (SEQ ID NO: 943). In some embodiments, the peptide comprises an amino acid sequence comprising one or two (e.g., no more than two) modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of NAAQAY (SEQ ID NO: 943). In some embodiments, 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 NAAQAY (SEQ ID NO: 943). In some embodiments, the peptide comprises one or two (e.g., no more than two) different amino acids, relative to the amino acid sequence of NAAQAY (SEQ ID NO: 943). In some embodiments, the amino acid sequence is present in loop VIII. In some embodiments, the amino acid sequence replaces one, two, three, four, five, or all of positions 578, 579, 580, 581, 582, and / or 583 (e.g., positions T578, A579, P580, A581, T582, and / or G583), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the amino acid sequence replaces positions 578, 579, 580, 581, 582, and 583 (e.g., positions T578, A579, P580, A581, T582, and / or G583), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0120] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of NAAQAY (SEQ ID NO: 943), wherein the amino acid sequence replaces positions 578, 99 321861031.1Attorney Docket Number: V2071-3046PCT 579, 580, 581, 582, and 583 (e.g., positions T578, A579, P580, A581, T582, and / or G583), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0121] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of NAAQAY (SEQ ID NO: 943), wherein the amino acid sequence corresponds to positions 578, 579, 580, 581, 582, and 583 of SEQ ID NO: 982.

[0122] In some embodiments, an AAV capsid variant described herein comprises an amino acid other than T at position 578 (e.g., N), P at position 580 (e.g., A), A at position 581 (e.g., Q), T at position 582 (e.g., A), and / or G at position 583 (e.g., Y), numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an N at position 578, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an A at position 580, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a Q at position 581, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an A at position 582, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a Y at position 583, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant corresponds to positions 578-583 of SEQ ID NO: 982.

[0123] In some embodiments, an AAV capsid variant described herein comprises one, two, three, four, or all of an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and / or an amino acid other than G at position 583, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an amino acid other than T at position 578, an amino acid other than P at position 580, an amino acid other than A at position 581, an amino acid other than T at position 582, and an amino acid other than G at position 583, numbered according to SEQ ID NO: 138.

[0124] In some embodiments, an AAV capsid variant described herein comprises one, two, three, four, five, or all of the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, A at position 579, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138.

[0125] In some embodiments, an AAV capsid variant described herein comprises one, two, three, four, or all of the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and / or Y at position 583, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138. 100 321861031.1Attorney Docket Number: V2071-3046PCT

[0126] In some embodiments, an AAV capsid variant described herein comprises one, two, three, four, or all of the amino acid substitutions T578N, P580A, A581Q, T582A, and / or G583Y, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid substitutions T578N, P580A, A581Q, T582A, and G583Y, numbered according to SEQ ID NO: 138.

[0127] In some embodiments, an AAV capsid variant described herein comprises (i) the amino acid sequence AQAY (SEQ ID NO: 1), optionally wherein the amino acid sequence replaces positions 580-583 (e.g., P580, A581, T582, G583), numbered according to SEQ ID NO: 138; and (ii) an amino acid other than T at position 578, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, numbered according to SEQ ID NO: 138.

[0128] In some embodiments, the AAV capsid variant (e.g., an AAV capsid variant described herein), comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. In some embodiments, the AAV capsid variant described herein, comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. In some embodiments, the AAV capsid variant comprises an amino acid sequence encoded by 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.

[0129] In some embodiments, the nucleotide sequence encoding the AAV capsid variant (e.g., an AAV capsid variant described herein), comprises the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. In some embodiments, the nucleic acid sequence encoding the AAV capsid variant comprises a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequences of SEQ ID NO: 944. In some embodiments, the nucleotide sequence encoding an AAV capsid variant described herein comprises 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.

[0130] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of NQSSTNAPLAY (SEQ ID NO: 252), which is present at positions 573-583, numbered according to SEQ ID NO: 138 or 985. 101 321861031.1Attorney Docket Number: V2071-3046PCT

[0131] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of NNQSSTNAPLAYT (SEQ ID NO: 383), which is present at positions 572-584, numbered according to SEQ ID NO: 138 or 985.

[0132] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of ATNNQSSTNAPLAYTYNL (SEQ ID NO: 7), which is present at positions 570-587, numbered according to SEQ ID NO: 138 or 985.

[0133] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of NQNLTNAAQAY (SEQ ID NO: 253), which is present at positions 573-583, numbered according to SEQ ID NO: 138 or 986.

[0134] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of NNQNLTNAAQAYT (SEQ ID NO: 389), which is present at positions 572-584, numbered according to SEQ ID NO: 138 or 986.

[0135] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of ATNNQNLTNAAQAYTYNL (SEQ ID NO: 8), which is present at positions 570-587, numbered according to SEQ ID NO: 138 or 986.

[0136] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of any one of SEQ ID NOs: 252, 253, 256-258, 262, 263, 265, 290, 297, or 303, which is present at positions 573-583, numbered according to any one of SEQ ID NOs: 138, 982, 985, or 986.

[0137] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of any one of SEQ ID NOs: 382, 383, 385, 386, 389, 392, 397, 400, 407, 413, or 435, which is present at positions 572-584, numbered according to any one of SEQ ID NOs: 138, 982, 985, or 986.

[0138] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of any one of SEQ ID NOs: 7, 8, 11-13, 17, 18, 20, 45, 52, or 58, which is present at positions 570-587, numbered according to SEQ ID NO: 138 or 982.

[0139] In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to amino acids 193-274 of SEQ ID NO: 138 or 982, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 252, 253, 256-258, 262, 263, 265, 290, 297, or 303, which is present at positions 573-583, numbered according to SEQ ID NO: 138 or 982.

[0140] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 193-274 of SEQ ID NO: 138 or 982, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 252, 253, 256-258, 262, 263, 265, 290, 297, or 303, which is present at positions 573-583, numbered according to SEQ ID NO: 138 or 982. 102 321861031.1Attorney Docket Number: V2071-3046PCT

[0141] In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to amino acids 137-274 of SEQ ID NO: 138 or 982, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 252, 253, 256-258, 262, 263, 265, 290, 297, or 303, which is present at positions 573-583, numbered according to SEQ ID NO: 138 or 982.

[0142] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 137-274 of SEQ ID NO: 138 or 982, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 252, 253, 256-258, 262, 263, 265, 290, 297, or 303, which is present at positions 573-583, numbered according to SEQ ID NO: 138 or 982.

[0143] In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 138 or 982, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 252, 253, 256-258, 262, 263, 265, 290, 297, or 303, at positions 573-583, numbered according to SEQ ID NO: 138 or 982.

[0144] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 138 or 982, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 252, 253, 256-258, 262, 263, 265, 290, 297, or 303, which is present at positions 573-583, numbered according to SEQ ID NO: 138 or 982.

[0145] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 985 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 985, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 252 at positions 573-583, numbered according to SEQ ID NO: 138 or 982.

[0146] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 986 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 986, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 253 at positions 573-583, numbered according to SEQ ID NO: 986.

[0147] In some embodiments, an AAV capsid variant described herein comprises the amino acid N at position 578, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 985.

[0148] In some embodiments, an AAV capsid variant described herein comprises the amino acid N at position 575, L at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 986. 103 321861031.1Attorney Docket Number: V2071-3046PCT

[0149] In some embodiments, an AAV capsid variant described herein comprises the amino acid N at position 575, A at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0150] In some embodiments, an AAV capsid variant described herein comprises the amino acid N at position 575, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0151] In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, G at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0152] In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, A at position 580, L at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0153] In some embodiments, an AAV capsid variant described herein comprises the amino acid N at position 575, T at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0154] In some embodiments, an AAV capsid variant described herein comprises the amino acid T at position 575, M at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0155] In some embodiments, an AAV capsid variant described herein comprises the amino acid N at position 575, V at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0156] In some embodiments, an AAV capsid variant described herein comprises the amino acid N at position 575, Q at position 576, N at position 578, A at position 580, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0157] In some embodiments, the AAV capsid variant comprises the amino acid N at position 578, Y at position 579, Q at position 581, A at position 582, and Y at position 583, numbered according to SEQ ID NO: 138 or 982.

[0158] In some embodiments, the AAV capsid variant further comprises a modification, e.g., an insertion, substitution, and / or deletion in loop I, II, IV, and / or VI. In some embodiments, loop I, II, IV, VI, and VIII can be identified as described in Govindasamy et al. Structurally Mapping the Diverse Phenotype of Adeno-Associated Virus Serotype 4. Journal of Virology.2006 Dec. 80(23):11556-11570; and Govindasamy et al. Structural Insights into Adeno-Associated Virus Serotype 5. Journal of Virology.2013 Oct.87(20):11187-11199; the contents of which are each hereby incorporated by reference in their entirety.

[0159] In some embodiments, additional modifications, e.g., substitutions (e.g., conservative substitutions), insertions, and / or deletions can be introduced into an AAV capsid variant described 104 321861031.1Attorney Docket Number: V2071-3046PCT herein at positions determined using a structural map of wild-type AAV5, e.g., a structural map described and generated by Govindasamy et al. et al. Structural Insights into Adeno-Associated Virus Serotype 5. Journal of Virology.2013 Oct.87(20):11187-11199 (the contents of which are hereby incorporated herein by reference in their entirety) or Walters et al. “Structure of Adeno-Associated Virus Serotype 5,” Journal of Virology, 2004, 78(7):3361-3371 (the contents of which are hereby incorporated by reference in their entirety).

[0160] In some embodiments, an AAV capsid variant described herein comprises a modification as described in Jose et al. “High-Resolution Structural Characterization of a New Adenoassociated Virus Serotype 5 Antibody Epitope toward Engineering Antibody-Resistant Recombinant Gene Delivery Vectors,” Journal of Virology, 2020, 93(1): e01394-18; Qian et al. “Directed Evolution of AAV Serotype 5 for Increased Hepatocyte Transduction and Retained Low Humoral Seroreactivity,” Molecular Therapy: Methods and Clinical Development, 2021, 20:122-132; Afione et al. “Identification and Mutagenesis of the Adeno-Associated Virus 5 Sialic Acid Binding Region,” Journal of Virology, 2015, 89(3):1660-1672; and / or Wang et al. “Directed evolution of adeno- associated virus 5 capsid enables specific liver tropism,” Mol Ther Nucleic Acids, 2022, 28:293-306; the contents of each of which are hereby incorporated by reference in their entirety.

[0161] In some embodiments, the AAV capsid variant, further 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, of the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant, further 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: 138. In some embodiments, the AAV capsid variant further comprises the amino acid sequence of SEQ ID NO: 138, or an amino acid sequence with at least 70% (e.g., at least about 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0162] In some embodiments, the AAV capsid variant further comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 137, or a sequence with at least 70% (e.g., at least about 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, the AAV capsid variant further comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two or three modifications, e.g., substitutions, insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 137. In some embodiments, the AAV capsid variant further comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two or three, but not more than 30, 20 or 10 different nucleotides, relative to the amino acid sequence of SEQ ID NO: 137. 105 321861031.1Attorney Docket Number: V2071-3046PCT

[0163] In some embodiments, the nucleotide sequence encoding the AAV capsid variant further comprises the nucleotide sequence of SEQ ID NO: 137, or a sequence with at least 70% (e.g., at least about 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, the nucleotide sequence encoding the AAV capsid variant further comprises a nucleotide sequence comprising at least one, two or three modifications, e.g., substitutions, insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 137. In some embodiments, the nucleotide sequence encoding the AAV capsid variant further comprises a nucleotide sequence comprising at least one, two or three, but not more than 30, 20 or 10 different nucleotides, relative to the amino acid sequence of SEQ ID NO: 137.

[0164] In some embodiments, an AAV capsid variant of the present disclosure comprises an amino acid sequence as described herein, e.g., an amino acid sequence of an AAV capsid variant of TTK-001, e.g., as described in Tables 3 and 4.

[0165] In some embodiments, an AAV capsid variant described herein comprises a VP1, VP2, and / or VP3 protein comprising an amino acid sequence described herein, e.g., an amino acid sequence of an AAV capsid variant of TTK-001, e.g., as described in Tables 3 and 4.

[0166] In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence encoded by a nucleotide sequence as described herein, e.g., a nucleotide sequence of an AAV capsid variant of TTK-001, e.g., as described in Tables 3 and 5.

[0167] In some embodiments, a polynucleotide or nucleic acid encoding an AAV capsid variant, of the present disclosure comprises a nucleotide sequence described herein, e.g., a nucleotide sequence of an AAV capsid variant of TTK-001, e.g., as described in Tables 3 and 5. Table 3. Exemplary full length capsid sequencesTable 4. Exemplary full length capsid amino acid sequences N A T N ( N a A 5 W 5 S n D re P I Q u VQ G QGS SQ G G S S Q R VAYNVGGQMATNNQSSTNAAQAYTYNLQEIVPGSVWMERDVYLQGPIWAKIPETGA 106 321861031.1Attorney Docket Number: V2071-3046PCT HFHPSPAMGGFGLKHPPPMMLIKNTPVPGNITSFSDVPVSSFITQYSTGQVTVEME T N ( N a A 5 W a S n D re P I Q u V R A E T N ( N a A 5 W 5 S a D n P re Q I V u R A ETable 5. Exemplary full length capsid nucleic acid sequences N A T ( s e a s S 7 uGCCC GGGCCG CCC GGGC GG CC GGGC CCGGGG C CCGCGCC G G TCAGCGCCTTCGCCACGACCAATAGGATGGAGCTCGAGGGCGCGAGTTACCAGGTG 107 321861031.1Attorney Docket Number: V2071-3046PCT CCCCCGCAGCCGAACGGCATGACCAACAACCTCCAGGGCAGCAACACCTATGCCCT

[0168] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence with at least 70% (e.g., at least about 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 90% sequence identity thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 95% sequence identity thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 96% sequence identity thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 97% sequence identity thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 98% sequence identity thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 99% sequence identity thereto. In some embodiments, an AAV capsid variant described herein 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. In some embodiments, the AAV 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.

[0169] In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 70% (e.g., at least about 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two or three, but not more than 30, 20 or 10 different nucleotides, relative to the amino acid sequence of SEQ ID NO: 984. In some embodiments, an AAV capsid variant described herein comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two or three modifications, e.g., substitutions, 108 321861031.1Attorney Docket Number: V2071-3046PCT insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 984.

[0170] In some embodiments, the nucleotide sequence encoding an AAV capsid variant, described herein comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 70% (e.g., at least about 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, the nucleotide sequence encoding an AAV capsid variant described herein comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 70% (e.g., at least about 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, the nucleotide sequence encoding an AAV capsid variant described herein, comprises a nucleotide sequence comprising at least one, two or three modifications, e.g., substitutions, insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 984. In some embodiments, the nucleotide sequence encoding an AAV capsid variant described herein, comprises a nucleotide sequence comprising at least one, two or three, but not more than 30, 20 or 10 different nucleotides, relative to the amino acid sequence of SEQ ID NO: 984. In some embodiments, the nucleic acid sequence encoding an AAV capsid variant described herein is codon optimized.

[0171] In some embodiments, an AAV capsid variant described herein comprises a VP1, VP2, VP3 protein, or a combination thereof. In some embodiments, an AAV capsid variant comprises the amino acid sequence corresponding to positions 137-724, e.g., a VP2, of SEQ ID NO: 982, or a sequence with at least 70% (e.g., at least about 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, the AAV capsid protein comprises the amino acid sequence corresponding to positions 193-724, e.g., a VP3, of SEQ ID NO: 982, or a sequence with at least 70% (e.g., at least about 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. In some embodiments, the AAV capsid variant comprises the amino acid sequence corresponding to positions 1-724, e.g., a VP1, of SEQ ID NO: 982, or an amino acid sequence with at least 70% (e.g., at least about 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0172] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 982, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 982, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. 109 321861031.1Attorney Docket Number: V2071-3046PCT

[0173] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 985, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 985, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 985, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto.

[0174] In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 986, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 986, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In some embodiments, an AAV capsid variant described herein comprises the amino acid sequence of SEQ ID NO: 986, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto.

[0175] In some embodiments, an AAV capsid variant described herein 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: 138, SEQ ID NO: 139, and / or SEQ ID NO: 982. In some embodiments, the AAV capsid variant delivers an increased level of a payload to a muscle cell or region, optionally wherein the level of the payload is increased by at least 5, 10, 12, 15, 20, 21, or 25-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139. In some embodiments, the AAV capsid variant delivers an increased level of viral genomes to a muscle cell or region, optionally wherein the level of viral genomes is increased by at least 2, 2.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 13.8, or 14-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139. In some embodiments, the muscle cell or region, is a heart cell or region or a quadriceps cell or region.

[0176] In some embodiments, an AAV capsid variant described herein has an increased tropism for a heart cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138, SEQ ID NO: 139, and / or SEQ ID NO: 982. In some embodiments, the AAV capsid variant delivers an increased level of a payload to a heart cell or region, optionally wherein the level of the payload is increased by at least 2, 2.5, 3, 3.5, 4, 4.5 or 5-fold, as compared to a reference sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant delivers an increased level of viral genomes to a heart cell or region, optionally wherein the level of viral 110 321861031.1Attorney Docket Number: V2071-3046PCT genomes is increased by at least 5, 6, 7, 8, 9 or 10-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139.

[0177] In some embodiments, an AAV capsid variant described herein 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. In some embodiments, the AAV capsid variant transduces a brain cell or region, optionally wherein the level of transduction is at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 24, 25, 29, or 30-fold greater as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139. In some embodiments, the AAV capsid variant delivers an increased level of a payload to a brain cell or region, optionally wherein the level of the payload is increased by at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139. In some embodiments, the AAV capsid variant delivers an increased level of viral genomes to a brain cell or region, optionally wherein the level of viral genomes is increased by at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 24, 25, 29, or 30-fold, as compared to a reference sequence of SEQ ID NO: 138 or SEQ ID NO: 139. In some embodiments, the brain region is a caudate, motor cortex, putamen, thalamus, and / or cerebellum (e.g., the molecular and granule layer of the cerebellum).

[0178] In some embodiments, an AAV capsid variant described herein is enriched at least about 4, 4.6, 10, 20, 25, 28, 30, 40, 50, 60, 70, 80, 81, 80, 100, 101, or 110-fold in the brain compared to a reference sequence of SEQ ID NO: 138.

[0179] In some embodiments, an AAV capsid variant described herein is enriched in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., mouse) species, compared to a reference sequence of SEQ ID NO: 138. In some embodiments, an AAV capsid variant described herein is enriched at least about 4, 4.6, 10, 20, 25, 28, 30, 40, 50, 60, 70, 80, 81, 80, 100, 101, or 110- fold in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., mouse) species, compared to a reference sequence of SEQ ID NO: 138 or 982. In some embodiments, the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, rat and / or mouse (e.g., BALB / c mice and / or C57BL6 mice).

[0180] In some embodiments an AAV capsid variant described herein shows preferential transduction in a muscle region relative to the transduction in the liver.

[0181] In some embodiments an AAV capsid variant described herein shows preferential transduction in a heart region relative to the transduction in the liver.

[0182] In some embodiments an AAV capsid variant described herein shows preferential transduction in a brain region relative to the transduction in the liver.

[0183] In some embodiments, an AAV capsid variant described herein has decreased tropism for a liver cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID SEQ ID NO: 139. 111 321861031.1Attorney Docket Number: V2071-3046PCT

[0184] In some embodiments, an AAV capsid variant described herein is capable of transducing neuronal cells.

[0185] In some embodiments, an AAV capsid variant o...

Claims

Attorney Docket Number: V2071-3046PCT We claim:

1. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to amino acids 193-724 of any one of SEQ ID NO: 138, 982, 985, or 986, wherein the AAV capsid variant comprises: (i) the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 985; (ii) the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 986; (iii) the amino acid N at position 575, the amino acid A at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 575, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 578, the amino acid G at position 579, amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid N at position 578, the amino acid A at position 580, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 575, the amino acid T at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid T at position 575, the amino acid M at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (ix) the amino acid N at position 575, the amino acid V at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid N at position 575, the amino acid Q at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; or (xi) the amino acid N at position 578, the amino acid Y at position 579, amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

138. 196 321861031.1Attorney Docket Number: V2071-3046PCT 2. The AAV capsid variant of claim 1, which comprises: (i) an amino acid sequence at least 98% or at least 99% identical to amino acids 193-724 of any one of SEQ ID NO: 138, 982, 985, or 986; (ii) an amino acid sequence at least 95%, at least 98% or at least 99% identical to amino acids 137-724 of any one of SEQ ID NO: 138, 982, 985, or 986; and / or (iii) an amino acid sequence at least 95%, at least 98%, or at least 99% identical to the amino sequence of any one of SEQ ID NO: 138, 982, 985, or 986.

3. The AAV capsid variant of claim 1 or 2, which comprises the sequence of amino acids 193-724 of any one of SEQ ID NO: 138, 982, 985, or 986; the sequence of amino acids 137-724 of any one of SEQ ID NO: 138, 982, 985, or 986; and / or the amino acid sequence of any one of SEQ ID NO: 138, 982, 985, or 986, wherein: (i) the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 985; (ii) the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138 or 986; (iii) the amino acid N at position 575, the amino acid A at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (iv) the amino acid N at position 575, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (v) the amino acid N at position 578, the amino acid G at position 579, amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (vi) the amino acid N at position 578, the amino acid A at position 580, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (vii) the amino acid N at position 575, the amino acid T at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (viii) the amino acid T at position 575, the amino acid M at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; 197 321861031.1Attorney Docket Number: V2071-3046PCT (ix) the amino acid N at position 575, the amino acid V at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; (x) the amino acid N at position 575, the amino acid Q at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO: 138; or (xi) the amino acid N at position 578, the amino acid Y at position 579, amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

138.

4. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 985, wherein the AAV capsid variant comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

985.

5. The AAV capsid variant of claim 4, which comprises the sequence of amino acids 193-724 of SEQ ID NO: 985, or an amino acid sequence at least 98% or at least 99% identical thereto.

6. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 985, wherein the AAV capsid variant comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

985.

7. The AAV capsid variant of any one of claims 4-6, which comprises the sequence of amino acids 137-724 of SEQ ID NO: 985, or an amino acid sequence at least 98% or at least 99% identical thereto.

8. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to SEQ ID NO: 985, wherein the AAV capsid variant comprises the amino acid N at position 578, the amino acid L at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

985.

9. The AAV capsid variant of any one of claims 4-8, which comprises the amino acid sequence of SEQ ID NO: 985, or an amino acid sequence at least 98% or at least 99% identical thereto.

10. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to amino acids 193-724 of SEQ ID NO: 986, wherein the AAV capsid variant comprises the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the 198 321861031.1Attorney Docket Number: V2071-3046PCT amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

986.

11. The AAV capsid variant of claim 10, which comprises the amino acid sequence of amino acids 193-724 of SEQ ID NO: 986, or an amino acid sequence at least 98% or at least 99% identical thereto.

12. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to amino acids 137-724 of SEQ ID NO: 986, wherein the AAV capsid variant comprises the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

986.

13. The AAV capsid variant of any one of claims 10-12, which comprises the amino acid sequence of amino acids 137-724 of SEQ ID NO: 986, or an amino acid sequence at least 98% or at least 99% identical thereto.

14. An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to SEQ ID NO: 986, wherein the AAV capsid variant comprises the amino acid N at position 575, the amino acid L at position 576, the amino acid N at position 578, the amino acid A at position 580, the amino acid Q at position 581, the amino acid A at position 582, and the amino acid Y at position 583, numbered according to SEQ ID NO:

986.

15. The AAV capsid variant of any one of claims 10-14, which comprises the amino acid sequence of SEQ ID NO: 986, or an amino acid sequence at least 98% or at least 99% identical thereto.

16. An adeno-associated virus (AAV) capsid variant comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 7-136 or 140-531; (b) an amino acid sequence comprising at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7-136 or 140-531; (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: 7-136 or 140-531; 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: 7-136 or 140-531.

17. The AAV capsid variant of any one of claims 1-16, wherein the AAV capsid variant: 199 321861031.1Attorney Docket Number: V2071-3046PCT (i) has an increased tropism for a muscle cell or a muscle tissue, relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (ii) has an increased tropism for a heart cell or a heart tissue, relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; and / or (iii) has an increased tropism for a brain cell or a brain tissue, relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO:

982.

18. A polynucleotide encoding the AAV capsid variant of any one of claims 1-17.

19. The polynucleotide of claim 18, which comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence at least 95% identical thereto.

20. A peptide comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 7-136 or 140-531; (b) an amino acid sequence comprising at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 consecutive amino acids from any one of SEQ ID NOs: 7-136 or 140-531; (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: 7-136 or 140-531; 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: 7-136 or 140-531.

21. An adeno-associated virus (AAV) capsid variant comprising the peptide of claim 21.

22. An adeno-associated virus (AAV) particle comprising the AAV capsid variant of any one of claims 1-17 or 21, an AAV capsid variant encoded by the polynucleotide of claim 18 or 19, or an AAV capsid variant comprising the peptide of claim 20.

23. The AAV particle of claim 22, which comprises a nucleotide sequence encoding a payload, optionally wherein the encoded payload comprises a protein or functional variant thereof; an antibody or antibody fragment; an enzyme; a component of a gene editing system; an iRNA agent (e.g., a dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA); or a combination thereof.

24. The AAV particle of claim 23, wherein: (i) the protein or functional variant thereof, e.g., a recombinant protein, is associated with (e.g., aberrantly expressed in) a neurological or neurodegenerative disorder, a muscular, a muscular 200 321861031.1Attorney Docket Number: V2071-3046PCT dystrophy, neuromuscular disorder, or a neuro-oncological disorder, optionally wherein the protein or functional variant thereof is chosen from apolipoprotein E (APOE) (e.g., ApoE2, ApoE3 and / or ApoE4); human survival of motor neuron (SMN) 1 or SMN2; glucocerebrosidase (GBA1); aromatic L-amino acid decarboxylase (AADC); aspartoacylase (ASPA); tripeptidyl peptidase I (CLN2); beta- galactosidase (GLB1); N-sulphoglucosamine sulphohydrolase (SGSH); N-acetyl-alpha- glucosaminidase (NAGLU); iduronate 2-sulfatase (IDS); intracellular cholesterol transporter (NPC1); gigaxonin (GAN); titn; myotubularin; calpain-3 (CAPN-3); dysferlin (DYSF); gamma-sarcoglycan (SGCG); alpha-sarcoglycan (SGCA); microdystrophin; dystrophin; beta-sarcoglycan (SGCB); fukutin-related protein (FKRP); anoctamin-5 (ANO5); or a combination thereof; (ii) the antibody or antibody binding fragment binds to (a) a CNS related target, e.g. an antigen associated with a neurological or neurodegenerative disorder, e.g., β-amyloid, APOE, tau, superoxide dismutase 1 (SOD1), transactive response DNA binding protein 43 (TDP-43), huntingtin (HTT), and / or synuclein; (b) a muscular or neuromuscular related target, e.g., an antigen associated with a muscular or neuromuscular disorder; or (c) a neuro-oncology related target, e.g., an antigen associated with a neuro- oncological disorder, e.g., HER2, or EGFR (e.g., EGFRvIII); (iii) the enzyme comprises a meganuclease, a zinc finger nuclease, a TALEN, a recombinase, integrase, a base editor, a Cas9, or a fragment thereof; (iv) the component of a gene editing system comprises one or more components of a CRISPR-Cas system, optionally wherein the one or more components of the CRISPR-Cas system comprises a Cas9, e.g., a Cas9 ortholog or a Cpf1, and a single guide RNA (sgRNA), wherein: (a) the sgRNA is located upstream (5’) of the cas9 enzyme; and / or (b) the sgRNA is located downstream (3’) of the cas9 enzyme; and / or (v) the RNAi agent (e.g., a dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA), modulates, e.g., inhibits, expression of, a CNS related gene, mRNA, and / or protein, optionally wherein the CNS related gene is chosen from SOD1, MAPT, APOE, HTT, C9ORF72, TDP-43, APP, BACE, SNCA, ATXN1, ATXN3, ATXN7, SCN1A-SCN5A, SCN8A-SCN11A, or a combination thereof.

25. The AAV particle of any one of claims 22-24, which comprises a viral genome comprising a promoter operably linked to the nucleic acid sequence encoding the payload, optionally wherein the promoter is chosen from human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent 201 321861031.1Attorney Docket Number: V2071-3046PCT protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a fragment, e.g., a truncation, or a functional variant thereof.

26. The AAV particle of claim 25, wherein the viral genome further comprises: (i) a polyadenylation (polyA) sequence; (ii) an inverted terminal repeat (ITR) sequence, optionally wherein the ITR sequence is positioned 5’ relative to the encoded payload (e.g., a 5’ ITR) and / or the ITR sequence is positioned 3’ relative to the encoded payload (e.g., a 3’ ITR); (iii) an enhancer; (iv) a Kozak sequence; (v) an intron; (vi) an exon; and / or (vii) a nucleotide sequence encoding a miR binding site, e.g., a miR binding site that modulates, e.g., reduces, expression of the antibody molecule encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed, optionally wherein the encoded miR binding site modulates, e.g., reduces, expression of the encoded antibody molecule in a cell or tissue of the DRG, liver, heart, hematopoietic lineage, or a combination thereof.

27. The AAV particle of claim 24 or 25, wherein the viral genome comprises: (i) at least 1-5 copies of the encoded miR binding site, e.g., at least 1, 2, 3, 4, or 5 copies; (ii) at least 3 copies of an encoded miR binding sites, optionally wherein: (a) all three copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise a different miR binding site; and / or (b) the 3 copies of the encoded miR binding sites are continuous (e.g., not separated by a spacer), or are separated by a spacer, optionally wherein the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to GATAGTTA; or (iii) at least 4 copies of an encoded miR binding site, optionally wherein (a) all four copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise a different miR binding site; and / or 202 321861031.1Attorney Docket Number: V2071-3046PCT (b) the 4 copies of the encoded miR binding sites are continuous (e.g., not separated by a spacer), or are separated by a spacer, optionally wherein the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to GATAGTTA.

28. The AAV particle of claim 26 or 27, wherein the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-1 binding site, a miR-142-3p, or a combination thereof, optionally wherein: (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (ii) the encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; (iii) the encoded miR-1 binding site comprises the nucleotide sequence of SEQ ID NO: 4679, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4679; and / or (iv) the encoded miR-142-3p binding site comprises the nucleotide sequence of SEQ ID NO: 4675, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, insertions, or deletions, but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4675.

29. The AAV particle of any one of claims 25-28, wherein the viral genome is: (i) single stranded; or (ii) self-complementary. 203 321861031.1Attorney Docket Number: V2071-3046PCT 30. The AAV5 capsid variant of any one of claims 1-17 or 21, the polynucleotide of claim 18 or 19, the peptide of claim 20, or AAV particle of any one of the preceding claims which is isolated, e.g., recombinant.

31. A vector comprising a polynucleotide encoding the AAV5 capsid variant of any one of claims 1- 27, 11, or 30, the polynucleotide of any one of claims 18, 19, or 30, or a polynucleotide encoding the peptide of claim 20 or 30.

32. A cell, e.g., a host cell, comprising the AAV5 capsid variant of any one of claims 1-17, 21, or 30, the polynucleotide of any one of claims 18, 19, or 30, a polynucleotide encoding the peptide of claim 20 or 30, the AAV particle of any one of claims 22-30, or the vector of claim 31, optionally wherein: (i) the cell is a mammalian cell or an insect cell; (ii) the cell is a cell of a brain region or a spinal cord region, optionally a cell of the caudate, motor cortex, putamen, thalamus, or cerebellum (e.g., the molecular and granule layer of the cerebellum); (iii) the cell is a cell of a muscle region and / or a heart region; and / or (iv) the cell is a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, oligodendrocyte, or a muscle cell (e.g., a cell of the heart, diaphragm, intercostal muscle, or quadriceps).

33. A method of making an AAV particle, comprising (i) providing a host cell comprising a viral genome; and (ii) incubating the host cell under conditions suitable to enclose the viral genome in the AAV5 capsid variant of any one of claims 1-17, 21, or 30, or an AAV capsid variant encoded by the polynucleotide of any one of claims 18, 19, or 30; thereby making the AAV particle.

34. A pharmaceutical composition comprising the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30, and a pharmaceutically acceptable excipient.

35. A method of delivering a payload to a cell or tissue (e.g., a cell of the central nervous system (CNS) or a tissue of the CNS; a muscle cell or a muscle tissue; or a heart cell or a heart tissue), comprising administering an effective amount of the pharmaceutical composition of claim 34, the AAV particle of any one of claims 20-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30. 204 321861031.1Attorney Docket Number: V2071-3046PCT 36. The method of claim 35, wherein the cell is: (i) a cell of a brain region or a or a spinal cord region, optionally a cell of the t caudate, motor cortex, putamen, thalamus, cerebellum (e.g., the molecular and granule layer of the cerebellum), or a combination thereof; (ii) is a cell of the heart, e.g., a heart atrium or a heart ventricle; (iii) is a cell of the muscle (e.g., a cell of the quadriceps, diaphragm, or intercostal muscle); (iv) a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, or an oligodendrocyte; (v) in a subject, optionally wherein the subject has, has been diagnosed with having, or is at risk of having a genetic disorder (e.g., a monogenic disorder or a polygenic disorder), a neurological disorder (e.g., a neurodegenerative disorder), a neuro-oncological disorder, a muscular disorder, a muscular dystrophy, or a neuromuscular disorder.

37. A method of treating a subject having or diagnosed with having a genetic disorder, e.g., a monogenic disorder or a polygenic disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30; thereby treating the subject.

38. A method of treating a subject having or diagnosed with having a neurological disorder, e.g., a neurodegenerative disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30; thereby treating the subject.

39. A method of treating a subject having or diagnosed with having a muscular disorder, a muscular dystrophy, or a neuromuscular disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30; thereby treating the subject.

40. A method of treating a subject having or diagnosed with having a neuro-oncological disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30; thereby treating the subject. 205 321861031.1Attorney Docket Number: V2071-3046PCT 41. The method of any one of claims 36-40, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, muscular disorder, muscular dystrophy, neuromuscular disorder, or neuro-oncological disorder is Duchenne muscular dystrophy (DMD), Limb-Girdle Muscular Dystrophy (LGMD2A), Becker muscular dystrophy (BMD), congenital muscular dystrophy, Facioscapulohumeral muscular dystrophy, titinopathy, Emery Dreifuss muscular dystrophy, X-linked myotubular myopathy, Huntington’s Disease, Amyotrophic Lateral Sclerosis (ALS), Gaucher Disease, Dementia with Lewy Bodies, Parkinson’s disease, Spinal Muscular Atrophy, Alzheimer’s Disease, a leukodystrophy (e.g., Alexander disease, autosomal dominant leukodystrophy with autonomic diseases (ADLD)), Canavan disease, cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, Refsum disease, or a cancer (e.g., a HER2 / neu positive cancer or a glioblastoma).

42. The method of any one of claims 37-41, wherein treating comprises prevention of progression of the disease or disorder in the subject.

43. The method of any one of claims 36-42, wherein the subject is a human.

44. The method of any one of claims 37-43, wherein the AAV particle is administered to the subject: (i) intravenously, via intra-cisterna magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly; (ii) via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration; (iii) intravenously; or (iv) intramuscularly.

45. The pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30, for use in a method of delivering a payload to a cell or tissue.

46. The pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30, for use in a method of treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, a muscular dystrophy, a neuromuscular disorder, or a neuro-oncological disorder. 206 321861031.1Attorney Docket Number: V2071-3046PCT 47. The pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30, for use in the manufacture of a medicament.

48. Use of the pharmaceutical composition of claim 44, the AAV particle of any one of claims 32-40, an AAV particle comprising the AAV capsid variant of any one of claims 1-27, 31, or 40, or an AAV particle comprising the peptide of claim 30 or 40, in the manufacture of a medicament.

49. Use of the pharmaceutical composition of claim 34, the AAV particle of any one of claims 22-30, an AAV particle comprising the AAV capsid variant of any one of claims 1-17, 21, or 30, or an AAV particle comprising the peptide of claim 20 or 30, in the manufacture of a medicament for treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, a muscular dystrophy, a neuromuscular disorder, or a neuro-oncological disorder. 207 321861031.1

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