AAV Capsid Variants and Uses Thereof

Abstract

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

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 307,742, filed February 8, 2022, and U.S. Provisional Application No. 63 / 339,574, filed May 9, 2022, the entire contents of each of which are incorporated herein by reference in their entirety.

[0002] Sequence Listing This application has been submitted electronically in XML format and contains a Sequence Listing, which is incorporated herein by reference in its entirety. The XML copy, created on January 24, 2023, is named V2071-1111PCT_SL.xml and is 2,233,613 bytes in size.

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

[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 due to their nonpathogenicity, low immunogenicity profile, low integration rate 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 use, and capsid neutralization by pre-existing neutralizing antibodies may prevent treatment of a large proportion of patients. For these reasons, considerable efforts have been made to obtain capsid variants with enhanced properties. Of the many approaches tested to date, significant progress has come from directed evolution of AAV capsids using in vitro or in vivo selection of capsid variants generated by capsid sequence randomization using either error-prone PCR, shuffling of various parent serotypes, or insertion of completely randomized short peptides at defined positions.

[0006] Attempts to provide AAV capsids with improved properties, such as improved tropism for target cells or tissues upon systemic administration, have met with limited success. Thus, there is a need for improved methods of producing AAV capsids and resulting AAV capsids for delivery of a desired payload to target cells or tissues, such as CNS cells or tissues, or muscle cells or tissues. Summary of the Invention

[0007] The present disclosure relates, at least in part, to compositions and methods for the production and use of AAV particles comprising AAV capsid polypeptides, e.g., AAV capsid variants (e.g., AAV5 capsid variants). In some embodiments, the AAV capsid variants have enhanced tropism for a tissue or cell, e.g., CNS tissue, CNS cells, cardiac cells, cardiac tissue, muscle cells, muscle tissue, liver cells, or liver tissue. Such tropism can be useful for delivering a payload, e.g., a payload described herein, to a cell or tissue for the treatment of a disorder, e.g., a neurological or neurodegenerative disorder, a muscular or neuromuscular disorder, or a neuro-oncological disorder.

[0008] Thus, in one aspect, the disclosure provides an AAV capsid variant, e.g., an AAV5 capsid variant, that comprises an amino acid other than T at position 577 (e.g., Y, N, or C) numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a Y at position 577 numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an N at position 577 numbered relative to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a C at position 577 numbered relative to SEQ ID NO: 138.

[0009] In another aspect, the disclosure provides an AAV capsid variant, e.g., a variant of a wild-type AAV5 capsid, comprising two or more amino acids replacing a threonine (T) at position 577, numbered relative to SEQ ID NO: 138. In some embodiments, an insertion of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids replaces the T at position 577, numbered relative to SEQ ID NO: 138. In some embodiments, an insertion of 8 amino acids replaces the T at position 577, numbered relative to SEQ ID NO: 138.

[0010] In another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising the formula [N2]-[N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5; (a) position X1 is Y, N, or C; (b) position X2 is P, K, T, or Q; (c) position X3 is A or P; (d) position X4 is E, S, or A; (e) position X5 is V, L, or E; and (ii) The amino acid sequence of [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK, and optionally the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii), and optionally, [N2]-[N3] occurs immediately after position 576, numbered relative to SEQ ID NO: 138, replacing position 577, numbered relative to SEQ ID NO: 138. In some embodiments, [N2] comprises a Y at position X1. In some embodiments, [N2] comprises a P at position X2. In some embodiments, [N2] comprises an A at position X3. In some embodiments, [N2] comprises an E at position X4. In some embodiments, [N2] comprises a V at position X5. In some embodiments, the amino acid sequence of [N3] is VQK. In some embodiments, numbered according to SEQ ID NO: 982, X1 of [N2] is located at position 577, X2 of [N2] is located at position 578, X3 of [N2] is located at position 579, X4 of [N2] is located at position 580, and X5 of [N2] is located at position 581. In some embodiments, [N2] is located at positions 577-581 numbered according to SEQ ID NO: 982. In some embodiments, [N3] is located at positions 582-584 numbered according to SEQ ID NO: 982. In some embodiments, [N2]-[N3] are located at positions 577-584 numbered according to SEQ ID NO: 982.

[0011] In some embodiments, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N3] consists of VQK. In some embodiments, [N2]-[N3] replaces the threonine (T) at position 577 of wild-type AAV5, e.g., SEQ ID NO: 138. In some embodiments, [N2]-[N3] replaces the threonine (T) at position 577 of wild-type AAV5, e.g., SEQ ID NO: 138, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1), and the amino acid sequence of [N3] consists of VQK. In some embodiments, [N2] is located at positions 577-581, numbered according to SEQ ID NO: 982. In some embodiments, [N3] is located at positions 582-584, numbered according to SEQ ID NO: 982. In some embodiments, [N2]-[N3] is located at positions 577-584, numbered according to SEQ ID NO: 982.

[0012] In another aspect, the present disclosure provides [N0], (i) wherein the amino acid sequence of [N0] comprises TNN, TNT, INN, TNS, NNN, or TNK; (ii) wherein the amino acid sequence of [N1] comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS; [N1], (iii) wherein the amino acid sequence of [N2] comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or the amino acid sequence of [N3] comprises YPAEV (SEQ ID NO: 11), YPPSL (SEQ ID NO: 12), NKAEV (SEQ ID NO: 13), YTAEV (SEQ ID NO: 14), YPAEE (SEQ ID NO: 15), YQAEV (SEQ ID NO: 16), YTPSL (SEQ ID NO: 17), YPAAV (SEQ ID NO: 18), NPAEV (SEQ ID NO: 19), or CPAEV (SEQ ID NO: 20). (iv) [N2] wherein the amino acid sequence of [N3] comprises VQK, EQK, VKK, VHK, VQQ, or LQK; and / or (v) [N4] wherein the amino acid sequence of [N4] comprises TA, PA, or NA; optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids (i) to (v); and optionally, [N0] is located immediately after position 570, numbered relative to SEQ ID NO: 138. In some embodiments, the amino acid sequence of [N0] is TNN. In some embodiments, the amino acid sequence of [N1] is QSS. In some embodiments, the amino acid sequence of [N2] is YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N3] is VQK. In some embodiments, the amino acid sequence of [N4] is TA. In some embodiments, the amino acid sequence of [N0] is TNN, the amino acid sequence of [N1] is QSS, the amino acid sequence of [N2] is YPAEV (SEQ ID NO: 1), the amino acid sequence of [N3] is VQK, and / or the amino acid sequence of [N4] is TA. In some embodiments, the amino acid sequence of [N0] is TNN, the amino acid sequence of [N1] is QSS, the amino acid sequence of [N2] is YPAEV (SEQ ID NO: 1), the amino acid sequence of [N3] is VQK, and the amino acid sequence of [N4] is TA.In any of these embodiments, [N0] is located immediately after position 570, as numbered relative to SEQ ID NO: 138. In any of these embodiments, [N0] replaces positions 571-573, as numbered relative to SEQ ID NO: 138 (e.g., T571, N572, and N573). In any of these embodiments, [N0] is located immediately after position 570, and [N0] is located immediately after position 571-573, as numbered relative to SEQ ID NO: 138 (e.g., T571, N572, and N573). In any of these embodiments, [N1] is located immediately after position 573, as numbered relative to SEQ ID NO: 138. In any of these embodiments, [N1] replaces positions 574-576, as numbered relative to SEQ ID NO: 138 (e.g., Q574, S575, and S576). In any of these embodiments, [N1] occurs immediately after position 573, and [N1] replaces positions 574-576 (e.g., Q574, S575, and S576) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2] occurs immediately after position 576, and [N2] replaces position 577 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2] occurs immediately after position 576, and [N2] replaces position 577 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2]-[N3] occur immediately after position 576, and [N2] replaces position 577 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2]-[N3] occur immediately after position 576, and [N2] replaces position 576 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2]-[N3] replaces position 577 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2]-[N3] occurs immediately after position 576, and [N2]-[N3] replaces position 577 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2]-[N3]-[N4] replaces positions 577-579 (e.g., T577, T578, and A579) numbered relative to SEQ ID NO: 138.In any of these embodiments, [N2]-[N3]-[N4] occurs immediately after position 576, and [N2]-[N3]-[N4] replaces positions 577-579, numbered relative to SEQ ID NO: 138 (e.g., T577, T578, and A579). In any of these embodiments, [N0]-[N1]-[N2]-[N3]-[N4] occurs immediately after position 570, numbered relative to SEQ ID NO: 138. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579, numbered relative to SEQ ID NO: 138 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579). In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is present immediately after position 570, and [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571 to 579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), numbered relative to SEQ ID NO: 138. For example, in some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533) and is located immediately after position 570, numbered relative to SEQ ID NO: 138, and [N2]-[N3] (YPAEVVQK (SEQ ID NO: 943)) replaces position 577, numbered relative to SEQ ID NO: 138 (e.g., replaces T577). In some embodiments, [N0] is located at positions 571-573, numbered according to SEQ ID NO: 982. In some embodiments, [N1] is located at positions 574-576, numbered according to SEQ ID NO: 982. In some embodiments, [N2] is located at positions 577-581, numbered according to SEQ ID NO: 982. In some embodiments, [N3] is located at positions 582-584, numbered according to SEQ ID NO: 982. In some embodiments, [N4] is located at positions 585-586, numbered according to SEQ ID NO: 982. In some embodiments, [N2]-[N3] are located at positions 577-584, numbered according to SEQ ID NO: 982.In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] are located at positions 571-586, numbered according to SEQ ID NO:982.

[0013] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising the formula [B]-[C], wherein (i) [B] comprises positions X1, X2, and X3; (a) position X1 is Q, T, S, A, I, L, or H; (b) position X2 is S, G, or A; (c) position X3 is S, K, L, R, or A; and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the foregoing amino acids in (i) and / or (ii); and further optionally, [B] is located immediately after position 573, numbered relative to SEQ ID NO: 138. In some embodiments, [B] comprises a Q at position X1. In some embodiments, [B] comprises an S at position X2. In some embodiments, [B] contains an S at position X3. In some embodiments, the amino acid sequence of [B] is QSS. In some embodiments, [B] is located immediately after position 573 relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [B] replaces positions 574-576 (e.g., Q574, S575, and S576) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [B] is located immediately after position 573, and [B] replaces positions 574-576 (e.g., Q574, S575, and S576) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [C] is located immediately after position 576 relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [C] replaces position 577 (e.g., T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [C] occurs immediately after position 576, and [C] replaces position 577 (e.g., T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [B]-[C] occurs immediately after position 573 relative to a reference sequence numbered according to SEQ ID NO: 138.In some embodiments, [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [B]-[C] is present immediately after position 573, and [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, numbered according to SEQ ID NO: 982, X1 of [B] is present at position 574, X2 of [B] is present at position 575, and X3 of [B] is present at position 576. In some embodiments, [B] is present at positions 574-576, numbered according to SEQ ID NO: 982. In some embodiments, [C] is present at positions 577-584, numbered according to SEQ ID NO: 982. In some embodiments, [B]-[C] is present at positions 574-584, numbered according to SEQ ID NO:982.

[0014] In another aspect, the disclosure provides a method for the preparation of a polypeptide comprising: (i) [A], wherein the amino acid sequence of [A] comprises TNN, TNT, INN, NNN, TNS, or TNK; (ii) [B], wherein the amino acid sequence of [B] comprises QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS; [B]; (iii) [C], wherein the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); and (iv) [D], wherein the amino acid sequence of TA or PA. and [D], optionally the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids (i) through (v), wherein optionally, [A] is located immediately after position 570, numbered relative to SEQ ID NO: 138, and [C] replaces position 577, numbered relative to SEQ ID NO: 138. In some embodiments, the amino acid sequence of [A] is TNN. In some embodiments, the amino acid sequence of [B] is QSS. In some embodiments, the amino acid sequence of [A] is TNN and the amino acid sequence of [B] is QSS. In some embodiments, the amino acid sequence of [A] is TNN, the amino acid sequence of [B] is QSS, and the amino acid sequence of [C] is YPAEVVQK (SEQ ID NO: 943). In some embodiments, the amino acid sequence of [A] is TNN, the amino acid sequence of [B] is QSS, the amino acid sequence of [C] is YPAEVVQK (SEQ ID NO:943), and the amino acid sequence of [D] is TA. In any of these embodiments, [A] is located immediately after position 570, as numbered relative to SEQ ID NO:138. In any of these embodiments, [A] replaces positions 571-573 (e.g., T571, N572, and N573), as numbered relative to SEQ ID NO:138. In any of these embodiments, [A] is located immediately after position 570, and [A] replaces positions 571-573 (e.g., T571, N572, and N573), as numbered relative to SEQ ID NO:138. In any of these embodiments, [B] is located immediately after position 573 relative to a reference sequence numbered according to SEQ ID NO:138.In any of these embodiments, [B] replaces positions 574-576 (e.g., Q574, S575, and S576) numbered relative to SEQ ID NO: 138. In any of these embodiments, [B] is located immediately after position 573, and [B] replaces positions 574-576 (e.g., Q574, S575, and S576) numbered relative to SEQ ID NO: 138. In any of these embodiments, [C] is located immediately after position 576, and [C] replaces position 577 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [C] is located immediately after position 576, and [C] replaces position 577 (e.g., T577) numbered relative to SEQ ID NO: 138. In any of these embodiments, [B]-[C] occurs immediately after position 573, as numbered relative to SEQ ID NO: 138. In any of these embodiments, [B]-[C] replaces positions 574-577, as numbered relative to SEQ ID NO: 138 (e.g., Q574, S575, S576, and T577). In any of these embodiments, [B]-[C] occurs immediately after position 573, and [B]-[C] replaces positions 574-577, as numbered relative to SEQ ID NO: 138 (e.g., Q574, S575, S576, and T577). In any of these embodiments, [C]-[D] occurs immediately after position 576, as numbered relative to SEQ ID NO: 138. In any of these embodiments, [C]-[D] replaces positions 577-579, numbered relative to SEQ ID NO: 138 (e.g., T577, T578, and A579). In any of these embodiments, [A]-[B]-[C]-[D] occurs immediately after position 570, numbered relative to SEQ ID NO: 138. In any of these embodiments, [A]-[B]-[C]-[D] replaces positions 571-579, numbered relative to SEQ ID NO: 138 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579).In any of these embodiments, [A]-[B]-[C]-[D] is located immediately after position 570, and [A]-[B]-[C]-[D] replaces positions 571-579, numbered relative to SEQ ID NO: 138 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579). For example, in some embodiments, [A]-[B]-[C]-[D] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), located immediately after position 570, numbered relative to SEQ ID NO: 138, and [C](YPAEVVQK (SEQ ID NO: 943)) replaces position 577, numbered relative to SEQ ID NO: 138 (e.g., replaces T577). In some embodiments, [A] is located at positions 571-573, numbered according to SEQ ID NO: 982. In some embodiments, [B] is present at positions 574-576, numbered according to SEQ ID NO: 982. In some embodiments, [C] is present at positions 577-584, numbered according to SEQ ID NO: 982. In some embodiments, [D] is present at positions 585-586, numbered according to SEQ ID NO: 982. In some embodiments, [A]-[B]-[C]-[D] are present at positions 571-586, numbered according to SEQ ID NO: 982.

[0015] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising the formula [N2]-[N3], wherein (i) [N2] comprises positions X1, X2, X3, X4, and X5, and (a) position X1 is Y or T, (b) position X2 is Q, T, P, or E, (c) position X3 is A, (d) position X4 is E or D, and (e) position X5 is V or E. (ii) [N3] comprises the amino acid sequence of VQK or VQN, and optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii), and further optionally, [N2]-[N3] occurs immediately after position 576, numbered relative to SEQ ID NO: 138, and replaces position 577, numbered relative to SEQ ID NO: 138. In some embodiments, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N3] consists of VQK. In some embodiments, [N2]-[N3] replaces position 577 (e.g., T577) of wild-type AAV5, e.g., SEQ ID NO: 138. In some embodiments, [N2]-[N3] replaces the threonine (T) at position 577 of wild-type AAV5, e.g., SEQ ID NO: 138, wherein the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1), and the amino acid sequence of [N3] consists of VQK. In some embodiments, numbered according to SEQ ID NO: 982, X1 of [N2] is at position 577, X2 of [N2] is at position 578, X3 of [N2] is at position 579, X4 of [N2] is at position 580, and X5 of [N2] is at position 581. In some embodiments, [N2] is at positions 577-581, numbered according to SEQ ID NO: 982. In some embodiments, [N3] is at positions 582-584, numbered according to SEQ ID NO: 982. In some embodiments, [N2]-[N3] are at positions 577-584, numbered according to SEQ ID NO: 982.

[0016] In another aspect, the disclosure provides an antibody comprising: (i) [N0] comprising the amino acid sequence of TNN, TNS, TNT, or TNK, [N0]; (ii) [N1] comprising the amino acid sequence of QSS, SLS, SLY, SAT, or QTS, [N1]; (iii) [N2] comprising the amino acid sequence of YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13), [N2]; (iv) [N3] comprising the amino acid sequence of VQK or VQN, [N3]; and / or or (v) an AAV capsid variant (e.g., an AAV5 capsid variant) comprising one, two, three, four, or all of [N4], wherein [N4] comprises the amino acid sequence of TA, PA, TD, NA, or PA; optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids of (i)-(v); and further optionally, [N0] occurs immediately after position 570, numbered relative to SEQ ID NO: 138, and [N2]-[N3] replace position 577, numbered relative to SEQ ID NO: 138. In any of these embodiments, [N0] occurs immediately after position 570, numbered relative to SEQ ID NO: 138. In any of these embodiments, [N0] replaces positions 571-573, numbered relative to SEQ ID NO: 138 (e.g., T571, N572, and N573). In any of these embodiments, [N0] occurs immediately after position 570, and [N0] replaces positions 571-573 (e.g., T571, N572, and N573) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N1] occurs immediately after position 573, and [N1] replaces positions 574-576 (e.g., Q574, S575, and S576) numbered relative to SEQ ID NO: 138. In any of these embodiments, [N1] occurs immediately after position 573, and [N1] replaces positions 574-576 (e.g., Q574, S575, and S576) numbered relative to SEQ ID NO: 138.In any of these embodiments, [N2] is located immediately after position 576, as numbered relative to SEQ ID NO: 138. In any of these embodiments, [N2] replaces position 577, as numbered relative to SEQ ID NO: 138 (e.g., T577). In any of these embodiments, [N2] is located immediately after position 576, and [N2] replaces position 577, as numbered relative to SEQ ID NO: 138 (e.g., T577). In any of these embodiments, [N2]-[N3] is located immediately after position 576, and [N2] replaces position 577, as numbered relative to SEQ ID NO: 138 (e.g., T577). In any of these embodiments, [N2]-[N3] is located immediately after position 576, and [N2]-[N3] replaces position 577, as numbered relative to SEQ ID NO: 138 (e.g., T577). In any of these embodiments, [N2]-[N3] is located immediately after position 576, and [N2]-[N3] replaces position 577, as numbered relative to SEQ ID NO: 138 (e.g., T577). In any of these embodiments, [N2]-[N3]-[N4] replaces positions 577-579, numbered relative to SEQ ID NO: 138 (e.g., T577, T578, and A579). In any of these embodiments, [N2]-[N3]-[N4] occurs immediately after position 576, and [N2]-[N3]-[N4] replaces positions 577-579, numbered relative to SEQ ID NO: 138 (e.g., T577, T578, and A579). In any of these embodiments, [N0]-[N1]-[N2]-[N3]-[N4] occurs immediately after position 570, numbered relative to SEQ ID NO: 138. In any of these embodiments, [N0]-[N1]-[N2]-[N3]-[N4] replace positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579) relative to a reference sequence numbered according to SEQ ID NO: 138.In any of these embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is present immediately after position 570, and [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [N0] is present at positions 571-573, numbered according to SEQ ID NO: 982. In some embodiments, [N1] is present at positions 574-576, numbered according to SEQ ID NO: 982. In some embodiments, [N2] is present at positions 577-581, numbered according to SEQ ID NO: 982. In some embodiments, [N3] is present at positions 582-584, numbered according to SEQ ID NO: 982. In some embodiments, [N4] is located at positions 585-586, numbered according to SEQ ID NO: 982. In some embodiments, [N2]-[N3] are located at positions 577-584, numbered according to SEQ ID NO: 982. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] are located at positions 571-586, numbered according to SEQ ID NO: 982.

[0017] In some embodiments, the amino acid sequence of [N0] is TNN, the amino acid sequence of [N1] is QSS, the amino acid sequence of [N2] is YPAEV (SEQ ID NO: 1), the amino acid sequence of [N3] is VQK, and / or the amino acid sequence of [N4] is TA. In some embodiments, the amino acid sequence of [N0] is TNN, the amino acid sequence of [N1] is QSS, the amino acid sequence of [N2] is YPAEV (SEQ ID NO: 1), the amino acid sequence of [N3] is VQK, and the amino acid sequence of [N4] is TA. In any of these embodiments, [N0]-[N1]-[N2]-[N3]-[N4] immediately follows position 570, numbered relative to SEQ ID NO: 138. In any of these embodiments, the amino acid sequence of [N2]-[N3] replaces position 577, numbered relative to SEQ ID NO: 138. For example, in some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533) and is located immediately after position 570, numbered relative to SEQ ID NO: 138, and [N2]-[N3] (YPAEVVQK (SEQ ID NO: 943)) replaces position 577, numbered relative to SEQ ID NO: 138 (e.g., replaces T577). In some embodiments, [N0] is located at positions 571-573, numbered according to SEQ ID NO: 982. In some embodiments, [N1] is located at positions 574-576, numbered according to SEQ ID NO: 982. In some embodiments, [N2] is located at positions 577-581, numbered according to SEQ ID NO: 982. In some embodiments, [N3] is located at positions 582-584, numbered according to SEQ ID NO: 982. In some embodiments, [N4] is located at positions 585-586, numbered according to SEQ ID NO: 982. In some embodiments, [N2]-[N3] are located at positions 577-584, numbered according to SEQ ID NO: 982. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] are located at positions 571-586, numbered according to SEQ ID NO: 982.

[0018] In another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising [B]-[C], wherein (i) [B] comprises positions X1, X2, and X3, (a) position X1 is Q or S, (b) position X2 is S, L, or A, and (c) position X3 is S, Y, or T, and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the foregoing amino acids in (i) and / or (ii), and further optionally, [B] is located immediately after position 573, numbered relative to SEQ ID NO: 138, and [C] replaces position 577, numbered relative to SEQ ID NO: 138. In some embodiments, [B] is QSS. In some embodiments, [C] consists of YPAEVVQK (SEQ ID NO:943) and is located immediately after position 576, as numbered relative to SEQ ID NO:138, and replaces position 577, as numbered relative to SEQ ID NO:138. In some embodiments, [B] is located immediately after position 573 relative to the reference sequence numbered according to SEQ ID NO:138. In some embodiments, [B] replaces positions 574-576 (e.g., Q574, S575, and S576) relative to the reference sequence numbered according to SEQ ID NO:138. In some embodiments, [B] is located immediately after position 573, and [B] replaces positions 574-576 (e.g., Q574, S575, and S576) relative to the reference sequence numbered according to SEQ ID NO:138. In some embodiments, [C] is located immediately after position 576 relative to the reference sequence numbered according to SEQ ID NO:138. In some embodiments, [C] replaces position 577 (e.g., T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [C] is located immediately after position 576, and [C] replaces position 577 (e.g., T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [B]-[C] is located immediately after position 573 relative to a reference sequence numbered according to SEQ ID NO: 138.In some embodiments, [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [B]-[C] is present immediately after position 573, and [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, numbered according to SEQ ID NO: 982, X1 of [B] is present at position 574, X2 of [B] is present at position 575, and X3 of [B] is present at position 576. In some embodiments, [B] is present at positions 574-576, numbered according to SEQ ID NO: 982. In some embodiments, [C] is present at positions 577-584, numbered according to SEQ ID NO: 982. In some embodiments, [B]-[C] is present at positions 574-584, numbered according to SEQ ID NO:982.

[0019] In yet another aspect, the present disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising one, two, three, four, or all of: (i) [A], [A] comprising the amino acid sequence of TNN, TNS, TNT, or TNK; (ii) [B], [B] comprising the amino acid sequence of QSS, SLY, SAT, or SLS; (iii) [C], [C] comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); or (iv) [D], [D] comprising the amino acid sequence of TA, TD, NA, or PA; optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids (i) through (v); and further optionally, [A] is located immediately after position 570, numbered relative to SEQ ID NO: 138, and [C] replaces position 577, numbered relative to SEQ ID NO: 138. In any of these embodiments, [A] is located immediately after position 570, numbered relative to SEQ ID NO: 138. In any of these embodiments, [A] replaces positions 571-573, numbered relative to SEQ ID NO: 138 (e.g., T571, N572, and N573). In any of these embodiments, [A] is located immediately after position 570, and [A] replaces positions 571-573, numbered relative to SEQ ID NO: 138 (e.g., T571, N572, and N573). In any of these embodiments, [B] is located immediately after position 573, relative to the reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [B] replaces positions 574-576, numbered relative to the reference sequence numbered according to SEQ ID NO: 138 (e.g., Q574, S575, and S576). In any of these embodiments, [B] is present immediately after position 573, and [B] replaces positions 574-576 (e.g., Q574, S575, and S576) relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [C] is present immediately after position 576 relative to a reference sequence numbered according to SEQ ID NO: 138.In any of these embodiments, [C] replaces position 577 (e.g., T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [C] is located immediately after position 576, and [C] replaces position 577 (e.g., T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [B]-[C] is located immediately after position 573 relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [B]-[C] replace positions 574-577 (e.g., Q574, S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [B]-[C] occurs immediately after position 573, and [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [C]-[D] occurs immediately after position 576 relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [C]-[D] replaces positions 577-579 (e.g., T577, T578, and A579) relative to a reference sequence numbered according to SEQ ID NO: 138. In any of these embodiments, [C]-[D] occurs immediately after position 576, and [C]-[D] replaces positions 577-579 (e.g., T577, T578, and A579) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [A] is present at positions 571-573, numbered according to SEQ ID NO: 982. In some embodiments, [B] is present at positions 574-576, numbered according to SEQ ID NO: 982. In some embodiments, [C] is present at positions 577-584, numbered according to SEQ ID NO: 982. In some embodiments, [D] is present at positions 585-586, numbered according to SEQ ID NO: 982. In some embodiments, [A]-[B]-[C]-[D] are present at positions 571-586, numbered according to SEQ ID NO: 982.

[0020] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising [K1]-[K2], wherein (i) [K1] comprises LSY or LYY; and (ii) [K2] comprises positions X1, X2, X3, and X4, wherein (a) position X1 is Q, T, or P; (b) position X2 is A; (c) position X3 is E or D; and (d) position X4 is V or E; and optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the foregoing amino acids in (i) and / or (ii). In some embodiments, [K1]-[K2] are located immediately after position 574 relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1]-[K2] replace positions 575-577 (e.g., S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1]-[K2] are located immediately after position 574, and [K1]-[K2] replace positions 575-577 (e.g., S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138.

[0021] In yet another aspect, the present disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising one, two, three, four, or all of: (i) [K0] comprising TNNS (SEQ ID NO: 14); (ii) [K1] comprising LSY or LYY; (iii) [K2] comprising QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19); (iv) [K3] comprising VQK or VQN; and (v) [K4] comprising TA, TD, NA, or PA; optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids (i) through (v). In some embodiments, [K0] is located immediately after position 570 relative to the reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K0] replaces positions 571-574 (e.g., T571, N572, N573, and Q574) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K0] is located immediately after position 570, and [K0] replaces positions 571-574 (e.g., T571, N572, N573, and Q574) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1] is located immediately after position 574 relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1] replaces positions 575-577 (e.g., S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1] occurs immediately after position 574, and [K1] replaces positions 575-577 (e.g., S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1]-[K2]-[K3] occurs immediately after position 574 relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1]-[K2]-[K3] replaces positions 575-577 (e.g., S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138.In some embodiments, [K1]-[K2]-[K3] occurs immediately after position 574, and [K1]-[K2]-[K3] replaces positions 575-577 (e.g., S575, S576, and T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1]-[K2]-[K3]-[K4] occurs immediately after position 574 relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1]-[K2]-[K3]-[K4] replaces positions 575-579 (e.g., S575, S576, T577, T578, and A579) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K1]-[K2]-[K3]-[K4] occurs immediately after position 574, and [K1]-[K2]-[K3]-[K4] replaces positions 575-579 (e.g., S575, S576, T577, T578, and A579) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K0]-[K1]-[K2]-[K3]-[K4] occurs immediately after position 570 relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K0]-[K1]-[K2]-[K3]-[K4] replace positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and T579) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, [K0]-[K1]-[K2]-[K3]-[K4] is located immediately after position 570, and [K0]-[K1]-[K2]-[K3]-[K4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and T579) relative to a reference sequence numbered according to SEQ ID NO: 138.

[0022] In yet another aspect, the disclosure provides a method for producing a medicament for a medicament comprising: (a) any of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (c) any of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (d) an amino acid sequence that includes one, two, or three, but not more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20.

[0023] In yet another aspect, the disclosure provides a method for the production of a medicament for the preparation of a medicament for the production ... 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, or 1610-1624; (c) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214 , 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583 to 1587, 1590, 1591 to 1593, 1598 to 1608, or 1610 to 1624, or (d) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences set forth in SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254 , 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, or 1610-1624.

[0024] In another aspect, the present disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of any of SEQ ID NOs: 943 or 2064-2080; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous amino acids from any one of SEQ ID NOs: 943 or 2064-2080; (c) an amino acid sequence that comprises 1, 2, or 3, but not more than 4, amino acids that differ from the amino acid sequence of any one of SEQ ID NOs: 943 or 2064-2080; or (d) an amino acid sequence that includes 1, 2, or 3, but not more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943 or 2064-2080.

[0025] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising the amino acid sequence of SEQ ID NO: 943. In some embodiments, the amino acid sequence of SEQ ID NO: 943 occurs immediately after position 576 relative to a reference sequence numbered according to SEQ ID NO: 138 or 982. In some embodiments, the amino acid sequence of SEQ ID NO: 943 replaces position 577 (e.g., replaces T577) relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence of SEQ ID NO: 943 occurs immediately after position 576, and the amino acid sequence of SEQ ID NO: 943 replaces position 577 (e.g., replaces T577) relative to a reference sequence numbered according to SEQ ID NO: 138.

[0026] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising YPAEVVQK (SEQ ID NO: 943), which occurs immediately after position 576 numbered relative to SEQ ID NO: 138 or 982. In some embodiments, the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) replaces position 577 numbered relative to SEQ ID NO: 138 (e.g., replaces T577).

[0027] In yet another aspect, the present disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising YPAEVVQK (SEQ ID NO: 943), which replaces position 577 numbered relative to SEQ ID NO: 138 (e.g., replaces T577).

[0028] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising YPAEVVQK (SEQ ID NO: 943), which occurs immediately after position 576 numbered relative to SEQ ID NO: 138, and YPAEVVQK (SEQ ID NO: 943) replaces position 577 numbered relative to SEQ ID NO: 138 (e.g., replaces T577).

[0029] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) that includes an amino acid Y at position 577 and further includes the amino acid sequence of PAEVVQK (SEQ ID NO: 20) located immediately after position 577, numbered relative to SEQ ID NO: 138.

[0030] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising the amino acid sequence of PAEVVQK (SEQ ID NO:20), which comprises an amino acid Y at position 577 and occurs immediately after position 577, as numbered relative to SEQ ID NO:982. In some embodiments, the AAV capsid variant further comprises the amino acid sequence of SEQ ID NO:739, or an amino acid sequence at least 95% (e.g., at least 96, 97, 98, or 99%) identical thereto. In some embodiments, the AAV capsid variant further comprises the amino acid sequence of SEQ ID NO:738, or an amino acid sequence at least 95% (e.g., at least 96, 97, 98, or 99%) identical thereto. In some embodiments, the AAV capsid variant further comprises the amino acid sequence of SEQ ID NO:982, or an amino acid sequence at least 95% (e.g., at least 96, 97, 98, or 99%) identical thereto.

[0031] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising the amino acid sequence of PAEVVQK (SEQ ID NO: 20) at positions 578-584, numbered relative to SEQ ID NO: 982, consisting of amino acid Y at position 577 and PAEVVQK at positions 578-584. In some embodiments, the AAV capsid variant further comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% (e.g., at least 96, 97, 98, or 99%) identical thereto. In some embodiments, the AAV capsid variant further comprises the amino acid sequence of SEQ ID NO: 738, or an amino acid sequence at least 95% (e.g., at least 96, 97, 98, or 99%) identical thereto. In some embodiments, the AAV capsid variant further comprises the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence at least 95% (e.g., at least 96, 97, 98, or 99%) identical thereto.

[0032] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), which occurs immediately after position 570 numbered relative to SEQ ID NO: 138 or 982. In some embodiments, the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) replaces position 577 numbered relative to SEQ ID NO: 138 (e.g., replaces T577).

[0033] In yet another aspect, the present disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), wherein YPAEVVQK (SEQ ID NO: 943) replaces position 577 numbered relative to SEQ ID NO: 138 (e.g., replaces T577).

[0034] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), which occurs immediately after position 570 numbered relative to SEQ ID NO: 138, and YPAEVVQK (SEQ ID NO: 943) replacing position 577 numbered relative to SEQ ID NO: 138 (e.g., replacing T577).

[0035] In yet another aspect, the present disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), located at positions 571 to 586, numbered according to SEQ ID NO: 982.

[0036] In another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising the amino acid sequence of SEQ ID NO: 982. In another aspect, the disclosure provides an AAV capsid variant consisting of the amino acid sequence of SEQ ID NO: 982.

[0037] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 984. In another aspect, the 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.

[0038] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of positions 193 to 731 of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). In some embodiments, the AAV capsid variant comprises the amino acid sequence of positions 193 to 731 of SEQ ID NO: 982.

[0039] In yet another aspect, the disclosure provides an AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739.

[0040] In yet another aspect, the disclosure provides peptides comprising: (a) an amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (c) an amino acid sequence that comprises 1, 2, or 3, but not more than 4, different amino acids relative to the amino acid sequence of any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (d) an amino acid sequence that includes 1, 2, or 3, but not more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20.

[0041] In yet another aspect, the disclosure provides a peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). In yet another aspect, the disclosure provides (i) an amino acid sequence that includes one, two, or three, but not more than four, amino acids that differ from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), (ii) an amino acid sequence that includes one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), or (iii) a peptide that includes at least 3, 4, 5, 6, or 7 contiguous amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).

[0042] In yet another aspect, the disclosure provides peptides encoded by the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In yet another aspect, the disclosure provides peptides encoded by (i) a nucleotide sequence that includes 1, 2, 3, 4, 5, 6, or 7, but not more than 10, different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944, or (ii) a nucleotide sequence that includes 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944.

[0043] In yet another aspect, the 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); (ii) a nucleotide sequence that includes 1, 2, 3, 4, 5, 6, or 7, but not more than 10, different nucleotides relative to the nucleotide sequence of SEQ ID NO:944; or (iii) a nucleotide sequence that includes 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO:944.

[0044] In another aspect, the disclosure provides a polynucleotide encoding an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the encoded AAV capsid variant has (a) an amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20. (c) an amino acid sequence that contains one, two, or three, but not more than four, amino acids that differ from the amino acid sequence of any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (d) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, from the amino acid sequence of any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20.

[0045] In yet another aspect, the disclosure provides a polynucleotide encoding an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the encoded AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). In yet another aspect, the disclosure provides a polynucleotide encoding an AAV capsid variant, wherein the encoded AAV capsid variant comprises (i) an amino acid sequence that includes one, two, or three, but not more than four, amino acids that differ from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), (ii) an amino acid sequence that includes one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), or (iii) at least 3, 4, 5, 6, or 7 contiguous amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).

[0046] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid polypeptide described herein, e.g., an AAV capsid variant (e.g., an AAV5 capsid variant). 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.

[0047] In yet another aspect, the present disclosure provides methods for producing AAV particles comprising an AAV capsid polypeptide, e.g., an AAV capsid variant (e.g., an AAV5 capsid variant), described herein. In some embodiments, the method includes providing a host cell comprising a viral genome and incubating the host cell under conditions suitable for encapsulating the viral genome into an AAV capsid variant, e.g., an AAV capsid variant described herein, thereby producing AAV particles.

[0048] In yet another aspect, the present disclosure provides a method for delivering a payload to a cell or tissue (e.g., a CNS cell, CNS tissue, muscle cell, or muscle tissue), the method comprising administering an effective amount of AAV particles comprising an AAV capsid variant described herein (e.g., an AAV5 capsid variant).

[0049] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with a genetic disorder, e.g., a monogenic or polygenic disorder, comprising administering an effective amount of AAV particles comprising an AAV capsid variant described herein (e.g., an AAV5 capsid variant).

[0050] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with a neurological disorder, e.g., a neurodegenerative disorder, comprising administering an effective amount of AAV particles comprising an AAV capsid variant described herein (e.g., an AAV5 capsid variant).

[0051] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with a muscle or neuromuscular disorder, the method comprising administering an effective amount of AAV particles comprising an AAV capsid variant described herein (e.g., an AAV5 capsid variant).

[0052] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with a cardiac disorder, e.g., a cardiac disorder described herein (e.g., cardiomyopathy (e.g., arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or hypertrophic cardiomyopathy), congestive heart failure, tachycardia (e.g., catecholamine-induced polymorphic ventricular tachycardia), ischemic heart disease, and / or myocardial infarction). The method comprises administering an effective amount of AAV particles comprising an AAV capsid variant described herein (e.g., an AAV5 capsid variant).

[0053] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with a neuro-oncology disorder, the method comprising administering an effective amount of AAV particles comprising an AAV capsid variant described herein (e.g., an AAV5 capsid variant).

[0054] 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 which equivalents are intended to be encompassed by the embodiments listed below.

[0055] Enumeration of Embodiments 1. The following formula: An AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence comprising [N2]-[N3], (i) [N2] comprises positions X1, X2, X3, X4, and X5; (a) position X1 is Y, N, C, or T; (b) position X2 is P, E, K, T, or Q; (c) position X3 is A or P; (d) position X4 is E, S, D, or A; (e) position X5 is V, L, or E; (ii) [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK; or The AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii).

[0056] 2. The following formula: An AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence comprising [N2]-[N3], (i) [N2] comprises positions X1, X2, X3, X4, and X5; (a) position X1 is Y, N, or C; (b) position X2 is P, K, T, or Q; (c) position X3 is A or P; (d) position X4 is E, S, or A; (e) position X5 is V, L, or E; (ii) [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK; or The AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii).

[0057] 3.(i) [N0], including TNN, TNT, INN, TNS, NNN, or TNK; (ii) including QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS, [N1]; (iii) [N2] comprising YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11); (iv) [N3], including VQK, EQK, VKK, VHK, VQQ, or LQK; and (v) An AAV capsid variant (e.g., an AAV5 capsid variant) containing one, two, three, four, or all of [N4], including TA, PA, or NA, Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) to (v).

[0058] 4. (a) X1 is Y or N, (b) position X2 is P, T, or Q; (c) X3 is A; (d) position X4 is E or S, and / or (e) The AAV capsid variant of embodiment 1 or 2, wherein position X5 is V or L.

[0059] 5. The AAV capsid variant of any one of embodiments 1, 2, or 4, wherein [N2] comprises YP, NK, YT, YQ, NP, CP, TH, AE, PS, AA, AS, PA, PP, KA, TA, QA, TP, HA, EV, SL, EE, AV, or SH.

[0060] 6. The AAV capsid variant of any one of embodiments 1, 2, 4, or 5, wherein [N2] comprises YPA, YPP, NKA, YTA, YQA, YTP, NPA, CPA, THA, PAE, PPS, KAE, TAE, QAE, TPS, PAA, HAS, AEV, PSL, AEE, or AAV.

[0061] 7. The AAV capsid variant of any one of embodiments 1-2 or 4-6, wherein [N2] comprises YPAE (SEQ ID NO:21), YPPS (SEQ ID NO:22), NKAE (SEQ ID NO:23), YTAE (SEQ ID NO:24), YQAE (SEQ ID NO:25), YTPS (SEQ ID NO:26), YPAA (SEQ ID NO:27), NPAE (SEQ ID NO:28), CPAE (SEQ ID NO:29), THAS (SEQ ID NO:30), PAEV (SEQ ID NO:17), PPSL (SEQ ID NO:31), KAEV (SEQ ID NO:32), TAEV (SEQ ID NO:16), PAEE (SEQ ID NO:18), QAEV (SEQ ID NO:15), TPSL (SEQ ID NO:33), PAAV (SEQ ID NO:34), or QAEE (SEQ ID NO:35).

[0062] 8. The AAV capsid variant of any one of embodiments 1 to 7, wherein [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11).

[0063] 9. An AAV capsid variant described in any one of embodiments 1-2 or 4-8, wherein [N3] comprises the amino acid sequence of VQK, EQK, or VKK. 10. The AAV capsid variant of any one of embodiments 1-2 or 4-9, wherein [N3] comprises VQK.

[0064] 11. The AAV capsid variant of any one of embodiments 1-2 or 4-9, wherein [N3] comprises EQK. 12. An AAV capsid variant described in any one of embodiments 1-2 or 4-9, wherein [N3] comprises VKK.

[0065] 13. An AAV capsid variant described in any one of embodiments 1 to 12, wherein [N2] is or comprises the amino acid sequence of YPAEV (sequence number 1), and [N3] is or comprises the amino acid sequence of VQK.

[0066] 14. (i) [N2] is or comprises the amino acid sequence of YTPSL (SEQ ID NO: 7), and [N3] is or comprises the amino acid sequence of VQK; (ii) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2), and [N3] is or comprises the amino acid sequence of VQK; (iii) [N2] is or comprises the amino acid sequence of YPPS (SEQ ID NO: 2)L, and [N3] is or comprises the amino acid sequence of EQK; or (iv) An AAV capsid variant described in any one of embodiments 1 to 12, wherein [N2] is or comprises the amino acid sequence of YPPSL (sequence number 2), and [N3] is or comprises the amino acid sequence of VKK.

[0067] 15.[N2]-[N3] (i) AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46), (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); The AAV capsid variant of any one of embodiments 1 to 2 or 4 to 14, comprising:

[0068] 16.[N2]-[N3] (i) PAEVVQK (SEQ ID NO: 20), PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48), TAEVVQK (SEQ ID NO: 49), PAEVEQK (SEQ ID NO: 50), PAEEVQK (SEQ ID NO: 51), QAEVVQK (SEQ ID NO: 52), TPSLVQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61), or QAEEVQK (SEQ ID NO: 62), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); The AAV capsid variant of any one of embodiments 1 to 2 or 4 to 15, comprising:

[0069] 17.[N2]-[N3] (i) YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948), YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSLVKK ( SEQ ID NO: 954), YPAEVVKK (SEQ ID NO: 955), YPAEVVHK (SEQ ID NO: 956), YPAAVVQK (SEQ ID NO: 957), NPAEVVQK (SEQ ID NO: 958), YPAEVVQQ (SEQ ID NO: 959), CPAEVVQK (SEQ ID NO: 960), YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963), (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 17. An AAV capsid variant according to any one of embodiments 1 to 16, which is or comprises:

[0070] 18. The AAV capsid variant of any one of embodiments 1 to 17, further comprising one, two, three, or all of the following amino acids, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982: an amino acid other than Q at position 574 (e.g., T, S, A, I, L, or H), an amino acid other than S at position 575 (e.g., G, A, or R), and / or an amino acid other than S at position 576 (e.g., K, L, R, A, or T).

[0071] 19. (i) Q at position 574, S at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) T at position 574, S at position 575, and / or L at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) S at position 574, S at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) Q at position 574, S at position 575, and / or R at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (v) Q at position 574, S at position 575, and / or K at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (vi) A at position 574, G at position 575, and / or A at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (vii) I at position 574, G at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (viii) Q at position 574, A at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ix) A at position 574, S at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (x) L at position 574, G at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xi) Q at position 574, S at position 575, and / or T at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xii) H at position 574, S at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xiii) L at position 574, S at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or (xiv) Q at position 574, R at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 18. The AAV capsid variant of any one of embodiments 1 to 17, further comprising:

[0072] 20. [N1] is further included, and [N1] is X D , X E , and X F Including rank, (a)X D The position is Q, T, S, A, I, L, or H, (b)X E The position is S, G, A, or R, (c)X F The position is S, K, L, R, A, or T, 20. An AAV capsid variant according to any one of embodiments 1 to 19, wherein the AAV capsid variant optionally comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) to (c).

[0073] 21. The AAV capsid variant of embodiment 20, wherein [N1] comprises SK, SL, SS, SR, GA, GS, AS, ST, RS, QS, TS, AG, IG, QA, LG, HS, LS, or QR.

[0074] 22. The AAV capsid variant of any one of embodiments 3, 20, or 21, wherein [N1] is or comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS.

[0075] 23.[N1]-[N2] (i) SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64), SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68), GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70), STNKA (SEQ ID NO: 71), SSYTA (SEQ ID NO: 72), SSYQA (SEQ ID NO: 73), SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77), or SSTHA (SEQ ID NO: 78); (ii) an amino acid sequence comprising any part of the amino acid sequences in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 23. An AAV capsid variant according to any one of embodiments 20 to 22, comprising:

[0076] 24.[N1]-[N2] (i) SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81), SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84), GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95), (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant described in any one of embodiments 20 to 23, comprising:

[0077] 25.[N1]-[N2] (i) QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SEQ ID NO:108), SSSYTAEV (SEQ ID NO:109), TSLYPAEE (SEQ ID NO:110), ASSYQAEV (SEQ ID NO:111), QSSYTPSL (SEQ ID NO:112), QSRYPAEE (SEQ ID NO:113), LSSYQAEV (SEQ ID NO:114), HSSYPAAV (SEQ ID NO:115), QSSNPAEV (SEQ ID NO:116), QSSYTAEV (SEQ ID NO:117), TSLCPAEV (SEQ ID NO:118), QRSYTAEV (SEQ ID NO:119), or QSSYQAEE (SEQ ID NO:120), (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 25. The AAV capsid variant of any one of embodiments 3 or 20 to 24, which is or comprises:

[0078] 26.[N1]-[N2]-[N3] (i) SSYPAEVVQ (SEQ ID NO: 121), SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125), GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127), ASYPAEVVQ (SEQ ID NO: 128), STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO: 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVVQ (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134), SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140), SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145), RSYTAEVVQ (SEQ ID NO: 146), SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 26. An AAV capsid variant according to any one of embodiments 20 to 25, comprising:

[0079] 27.[N1]-[N2]-[N3] (i) QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 27. The AAV capsid variant of any one of embodiments 3 or 20 to 26, which is or comprises:

[0080] 28. [N0] is further included, and [N0] is X A , X B , and X C Including rank, (a)X A The position is T, I, or N, (b)X B The rank is N, (c)X C The position is N, T, S, or K, 28. An AAV capsid variant according to any one of embodiments 1 to 27, optionally comprising an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) to (c).

[0081] 29. The AAV capsid variant of embodiment 28, wherein [N0] comprises TN, IN, NN, NT, NS, or NK. 30. The AAV capsid variant of embodiment 3, 28, or 29, wherein [N0] is or comprises TNN, TNT, INN, TNS, NNN, or TNK.

[0082] 31.[N0]-[N1] is (i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201), (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 31. An AAV capsid variant according to any one of embodiments 3 or 28 to 30, which is or comprises:

[0083] 32.[N0]-[N1]-[N2]-[N3] is (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTA SSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524), TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), ​​TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSRYPAEEV QK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 5 51), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557), TNNQSSYTAEVVKK (SEQ ID NO: 558), TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562), or TNKQASYPAEVVQK (SEQ ID NO: 563), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids thereof, e.g., consecutive amino acids thereof; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 32. The AAV capsid variant of any one of embodiments 3 or 28 to 31, which is or comprises:

[0084] 33. The AAV capsid variant of any one of embodiments 3 or 32, wherein [N0]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (sequence number 500).

[0085] 34. The AAV capsid variant of embodiment 3 or 32, wherein [N0]-[N1]-[N2]-[N3] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), or INNQSSYPAEVVQK (SEQ ID NO: 543).

[0086] 35. [N4] is further included, and [N4] is X G and X H Including rank, (a)X G The position is T, P, or N, (b)X H The rank is A, 35. An AAV capsid variant according to any one of embodiments 1 to 34, wherein the AAV capsid variant optionally comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) or (b).

[0087] 36. The AAV capsid variant of embodiment 35, wherein [N4] is or comprises TA, PA, or NA. 37.[N3]-[N4] (i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); (ii) an amino acid sequence comprising any part of the amino acid sequences in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 37. The AAV capsid variant of any one of embodiments 3, 35 or 36, which is or comprises:

[0088] 38.[N0]-[N1]-[N2]-[N3]-[N4] (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 119) 4), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583), TNTASSYQAEVVQKTA (SEQ ID NO: 1584 ), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142) , INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEVVQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), TNNQRSYTAEVVQKTA (SEQ ID NO: 1604),TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 38. An AAV capsid variant according to any one of embodiments 3 or 35 to 37, which is or comprises:

[0089] 39. An AAV capsid variant described in any one of embodiments 3 or 35 to 38, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (sequence number 1533).

[0090] 40. The AAV capsid variant of embodiment 3 or 35-38, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024).

[0091] 41. An AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence comprising the following formula: [B]-[C], (i) [B] comprises positions X1, X2, and X3; (a) position X1 is Q, T, S, A, I, L, or H; (b) position X2 is S, G, or A; (c) position X3 is S, K, L, R, or A; (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii).

[0092] 42. (i) [A] contains the amino acid sequence of TNN, TNT, INN, NNN, TNS, or TNK; (ii) [B] comprises the amino acid sequence QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS; (iii) [C], wherein [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), and (iv) [D] contains the amino acid sequence of TA or PA. an AAV capsid variant (e.g., an AAV5 capsid variant) comprising one, two, three, four, or all of: Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i)-(v); Further optionally, the AAV capsid variant, wherein [C] substitutes position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0093] 43.(a) Position X1 is Q, T, S, A, or H; (b) position X2 is S or G; (c) The AAV capsid variant of embodiment 41, wherein position X3 is S, K, L, or R.

[0094] 44. The AAV capsid variant of embodiment 41 or 43, wherein [B] comprises QS, TS, SS, AG, IG, QA, AS, LG, HS, SK, SL, SR, GA, or GS.

[0095] 45. An AAV capsid variant according to any one of embodiments 41 to 44, wherein [B] is or comprises QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS.

[0096] 46. ​​[B]-[C] (i) SSYPAEVVQK (SEQ ID NO: 572), SKYPAEVVQK (SEQ ID NO: 573), SLYPAEVVQK (SEQ ID NO: 574), SRYPAEVVQK (SEQ ID NO: 575), GAYPAEVVQK (SEQ ID NO: 576), GSYPAEVVQK (SEQ ID NO: 580), or ASYPAEVVQK (SEQ ID NO: 582); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 46. ​​An AAV capsid variant according to any one of embodiments 41 or 43 to 45, comprising:

[0097] 47.[B]-[C] (i) QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), or HSSYPAEVVQK (SEQ ID NO: 162), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 47. An AAV capsid variant according to any one of embodiments 41 to 46, which is or comprises:

[0098] 48. An AAV capsid variant described in any one of embodiments 41 to 47, wherein [B]-[C] is or comprises QSSYPAEVVQK (sequence number 150). 49. An AAV capsid variant described in any one of embodiments 41 to 47, wherein [B]-[C] is or comprises AGAYPAEVVQK (SEQ ID NO: 156), TSLYPAEVVQK (SEQ ID NO: 152), QSKYPAEVVQK (SEQ ID NO: 151), or QSRYPAEVVQK (SEQ ID NO: 154).

[0099] 50. The AAV capsid variant of any one of embodiments 1 to 49, further comprising one or both of an amino acid other than T at position 571 (e.g., I or N) and / or an amino acid other than N at position 573 (e.g., T, S, or K) relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0100] 51. (i) T at position 571, N at position 572, and / or N at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) a T at position 571, an N at position 572, and / or a T at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) an I at position 571, an N at position 572, and / or an N at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) T at position 571, N at position 572, and / or S at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (v) an N at position 571, an N at position 572, and / or an N at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or (vi) T at position 571, N at position 572, and / or K at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 50. The AAV capsid variant of any one of embodiments 1 to 49, further comprising:

[0101] 52. [A] is further included, and [A] is X A , X B , and X C Including rank, (a)X A The position is T, I, or N, (b)X B The rank is N, (c)X C The position is N, T, S, or K, Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) to (c).

[0102] 53. The AAV capsid variant of embodiment 52, wherein [A] comprises TN, IN, NN, NT, NS, or NK. 54. The AAV capsid variant of any one of embodiments 42, 52, or 53, wherein [A] is or comprises TNN, TNT, INN, NNN, TNS, or TNK.

[0103] 55. [A]-[B] (i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNHSS (SEQ ID NO: 194), INNQSS (SEQ ID NO: 196), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), or TNKQAS (SEQ ID NO: 201); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 55. An AAV capsid variant according to any one of embodiments 42 or 52 to 54, which is or comprises:

[0104] 56. [A]-[B]-[C] (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVV QK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNHSSYPAEVVQK (SEQ ID NO: 525), INNQSSYPAEVVQK (SEQ ID NO: 543), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNSTSLYPAEVVQK (SEQ ID NO: 556), or TNKQASYPAEVVQK (SEQ ID NO: 563), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 56. An AAV capsid variant according to any one of embodiments 42 or 52 to 55, which is or comprises:

[0105] 57. An AAV capsid variant described in any one of embodiments 42, or 52 to 54, wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (sequence number 500).

[0106] 58. An AAV capsid variant described in any one of embodiments 42 or 52 to 54, wherein [A]-[B]-[C] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNQSRYPAEVVQK (SEQ ID NO: 510), or INNQSSYPAEVVQK (SEQ ID NO: 543).

[0107] 59. (i) an amino acid other than T (e.g., P or N) at position 578 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, or (ii) an amino acid other than T (e.g., P or N) at position 585 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982 59. The AAV capsid variant of any one of embodiments 1 to 58, further comprising:

[0108] 60. (i) T at position 578 and / or A at position 579 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, or T at position 585 and / or A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982; (ii) a P at position 578 and / or an A at position 579 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, or a P at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982, or (iii) N at position 578 and / or A at position 579 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, or N at position 585 and / or A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982 59. The AAV capsid variant of any one of embodiments 1 to 58, further comprising:

[0109] 61. Further comprising [D], wherein [D] comprises positions X4 and X5; (a) position X4 is T or N; (b) X5 is A; 61. An AAV capsid variant according to any one of embodiments 41 to 60, optionally comprising an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) or (b).

[0110] 62. The AAV capsid variant of embodiment 42 or 61, wherein [D] is or comprises TA or PA. 63.[C]-[D] (i) YPAEVVQKTA (SEQ ID NO: 584) or YPAEVVQKPA (SEQ ID NO: 586), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 63. The AAV capsid variant of any one of embodiments 42, 61, or 62, which is or comprises:

[0111] 64.[A]-[B]-[C]-[D] (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 64. An AAV capsid variant according to any one of embodiments 42 or 61 to 63, which is or comprises:

[0112] 65. An AAV capsid variant described in any one of embodiments 42 or 61 to 64, wherein [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (sequence number 1533).

[0113] 66. An AAV capsid variant described in any one of embodiments 42 or 61 to 64, wherein [A]-[B]-[C]-[D] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024).

[0114] 67.Formula: An AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence comprising [N2]-[N3], (i) [N2] comprises positions X1, X2, X3, X4, and X5; (a) position X1 is Y or T; (b) position X2 is Q, T, P, or E; (c) X3 is A; (d) position X4 is E or D; (e) X5 is V or E; (ii) [N3] comprises the amino acid sequence of VQK or VQN; or The AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii).

[0115] 68.(i) Contains TNN, TNS, TNT, or TNK [N0]; (ii) including QSS, SLS, SLY, SAT, or QTS [N1]; (iii) [N2] comprising YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13); (iv) [N3] containing a VQK or VQN, and (v) TA, PA, TD, NA, or PA included [N4] an AAV capsid variant (e.g., an AAV5 capsid variant) comprising one, two, three, four, or all of: Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) to (v).

[0116] 69. The AAV capsid variant of embodiment 1 or 67, wherein [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV, AE, or AD.

[0117] 70. The AAV capsid variant of any one of embodiments 1, 67, or 69, wherein [N2] comprises YPA, YQA, YTA, TEA, QAE, TAE, PAE, EAE, PAD, AEV, AEE, or ADV.

[0118] 71. The AAV capsid variant of any one of embodiments 1, 67, 69 or 70, wherein [N2] comprises YPAE (SEQ ID NO: 21), YQAE (SEQ ID NO: 25), YTAE (SEQ ID NO: 24), TEAE (SEQ ID NO: 587), YPAD (SEQ ID NO: 588), QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), EAEV (SEQ ID NO: 590), or PADV (SEQ ID NO: 19).

[0119] 72. The AAV capsid variant of any one of embodiments 1 or 67 to 71, wherein [N2] is or comprises YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13).

[0120] 73. The AAV capsid variant of any one of embodiments 1 or 67 to 72, wherein [N3] comprises the amino acid sequence of VQK. 74.[N2]-[N3] (i) AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); The AAV capsid variant of any one of embodiments 1, 67, or 69 to 73, comprising:

[0121] 75.[N2]-[N3] (i) PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant according to any one of embodiments 1, 67, 69 to 74, comprising:

[0122] 76.[N2]-[N3] (i) YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 76. The AAV capsid variant of any one of embodiments 1 or 57 to 75, which is or comprises:

[0123] 77. An AAV capsid variant described in any one of embodiments 1 or 67 to 76, wherein [N2]-[N3] is or comprises YPAEVVQK (sequence number 943).

[0124] 78. An AAV capsid variant according to any one of embodiments 1 to 77, wherein [N2]-[N3] replaces position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0125] 79. The AAV capsid variant of any one of embodiments 1 or 67-78, further comprising one, two, three, or all of the following amino acids: an amino acid other than Q (e.g., S) at position 574, an amino acid other than S (e.g., L, A, or T) at position 575, and / or an amino acid other than S (e.g., Y or T) at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0126] 80. (i) Q at position 574, S at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) S at position 574, L at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) S at position 574, L at position 575, and / or Y at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) S at position 574, A at position 575, and / or T at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (v) Q at position 574, T at position 575, and / or S at position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 79. The AAV capsid variant of any one of embodiments 1 or 67 to 78, further comprising:

[0127] 81. [N1] is further included, and [N1] is X D , X E , and X F Including rank, (a)X D The place is Q or S, (b)X E is S, L, A, or T, (c)X F The position is S, Y, or T, 81. An AAV capsid variant described in any one of embodiments 1 or 67 to 80, optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) to (c).

[0128] 82. The AAV capsid variant of embodiment 81, wherein [N1] comprises QS, SL, SA, QT, LS, LY, AT, TS, or SS. 83. An AAV capsid variant according to any one of embodiments 68, 81, 82, wherein [N1] is or comprises QSS, SLS, SLY, SAT, or QTS.

[0129] 84.[N1]-[N2] (i) SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603), or TSTEA (SEQ ID NO: 605); (ii) an amino acid sequence comprising any part of the amino acid sequences in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 84. An AAV capsid variant according to any one of embodiments 81 to 83, comprising:

[0130] 85.[N1]-[N2] (i) SSYPAE (SEQ ID NO: 79), LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), ATYPAE (SEQ ID NO: 613), LSYPAE (SEQ ID NO: 616), TSTEAE (SEQ ID NO: 619), or LSYPAD (SEQ ID NO: 621); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 85. An AAV capsid variant according to any one of embodiments 81 to 84, comprising:

[0131] 86.[N1]-[N2] (i) QSSYPAEV (SEQ ID NO: 96), SLSYQAEV (SEQ ID NO: 622), SLSYTAEV (SEQ ID NO: 623), SLYYPAEV (SEQ ID NO: 624), SATYPAEV (SEQ ID NO: 625), SLSYPAEV (SEQ ID NO: 629), SLSYPAEE (SEQ ID NO: 632), QTSTEAEV (SEQ ID NO: 633), or SLSYPADV (SEQ ID NO: 634); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 86. An AAV capsid variant according to any one of embodiments 68 or 81 to 85, which is or comprises:

[0132] 87.[N1]-[N2]-[N3] (i) QSSYPAEVVQK (SEQ ID NO: 150), SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), SLSYPAEVVQK (SEQ ID NO: 642), SLSYPAEEVQK (SEQ ID NO: 643), SLSYPAEVVQN (SEQ ID NO: 644), QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 87. An AAV capsid variant according to any one of embodiments 68 or 81 to 86, which is or comprises:

[0133] 88. An AAV capsid variant described in any one of embodiments 68 or 81 to 87, wherein [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (sequence number 150).

[0134] 89. [N0] is further included, and [N0] is X A , X B , and X C Including rank, (a)X A The place is T, (b)X B The rank is N, (c)X C The position is N, T, S, or K, Optionally, the AAV capsid variant of any one of embodiments 1 or 67 to 88, wherein the AAV capsid comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) to (c).

[0135] 90. [N0] (i) contains TN, NS, NT, NN, or NK; and / or (ii) An AAV capsid variant described in embodiment 89 that is or comprises TNS, TNT, TNN, or TNK.

[0136] 91.[N0]-[N1] (i) TNNQSS (SEQ ID NO: 183), TNSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650), or TNKSAT (SEQ ID NO: 651); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 91. The AAV capsid variant of any one of embodiments 68, 89, or 90, which is or comprises:

[0137] 92.[N0]-[N1]-[N2]-[N3] (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant according to any one of embodiments 68 or 89 to 91, which is or comprises:

[0138] 93. An AAV capsid variant described in any one of embodiments 68 or 89 to 92, wherein [N0]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (sequence number 500).

[0139] 94. [N4] is further included, and [N4] is X G and X H Including rank, (a)X G The position is T, P, or N, (b)X H The place is A or D, Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) or (b).

[0140] 95. The AAV capsid variant of embodiment 94, wherein [N4] is or comprises TA, TD, PA, or NA. 96.[N3]-[N4] (i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); (ii) an amino acid sequence comprising any part of the amino acid sequences in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 96. The AAV capsid variant of embodiment 68, 94, or 95, which is or comprises:

[0141] 97.[N0]-[N1]-[N2]-[N3]-[N4] (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), TNNQTSTEAEVVQKTA (SEQ ID NO: 2074), TNKSATYPAEVVQKTA (SEQ ID NO: 2075), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 97. An AAV capsid variant according to any one of embodiments 68 or 94 to 96, which is or comprises:

[0142] 98. An AAV capsid variant described in any one of embodiments 68 or 94 to 97, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (sequence number 1533).

[0143] 99. An AAV capsid variant (e.g., an AAV5 capsid variant) comprising the formula [K1]-[K2], wherein: (i) [K1] includes LSY or LYY; (ii) [K2] includes X1, X2, X3, and X4; (a) position X1 is Q, T, or P; (b) X2 is A; (c) position X3 is E or D; (d) position X4 is V or E; Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii).

[0144] 100. (i) [K0], comprising TNNS (SEQ ID NO: 14); (ii) [K1], including LSY or LYY; (iii) [K2], comprising QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19); (iv) [K3], including VQK or VQN; (v) including TA, TD, NA, or PA, [K4] an AAV capsid variant (e.g., an AAV5 capsid variant) comprising one, two, three, four, or all of: Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) to (v).

[0145] 101. The AAV capsid variant of embodiment 99 or 100, wherein [K1] comprises LSY. 102. The AAV capsid variant of embodiment 99 or 101, wherein [K2] comprises QA, TA, PA, EV, EE, DV, AE, or AD.

[0146] 103. The AAV capsid variant of any one of embodiments 99, 101, or 102, wherein [K2] comprises QAE, TAE, PAE, PAD, AEV, AEE, or ADV.

[0147] 104. The AAV capsid variant of any one of embodiments 99 to 103, wherein [K2] is or comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19).

[0148] 105. An AAV capsid variant described in any one of embodiments 99 or 101 to 104, wherein [K1]-[K2] comprises LSYQA (sequence number 597), LSYTA (sequence number 598), LYYPA (sequence number 600), or LSYPA (sequence number 603).

[0149] 106.[K1]-[K2] (i) LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), LSYPAE (SEQ ID NO: 616), or LSYPAD (SEQ ID NO: 621); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant described in any one of embodiments 99 or 101 to 105, comprising:

[0150] 107.[K1]-[K2] (i) LSYQAEV (SEQ ID NO: 667), LSYTAEV (SEQ ID NO: 668), LYYPAEV (SEQ ID NO: 669), LSYPAEV (SEQ ID NO: 671), LSYPAEE (SEQ ID NO: 673), or LSYPADV (SEQ ID NO: 674); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant according to any one of embodiments 99 to 106, which is or comprises:

[0151] 108. The AAV capsid variant of any one of embodiments 99 to 107, further comprising an amino acid other than Q (e.g., S) at position 574 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0152] 109. The AAV capsid variant of any one of embodiments 99 to 108, further comprising an S at position 574 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0153] 110. An AAV capsid variant according to any one of embodiments 99 to 109, further comprising [K0], wherein [K0] is or comprises TNNS (SEQ ID NO: 14); an amino acid sequence comprising any part of its amino acid sequence, for example, any 2 or 3 amino acids, for example, consecutive amino acids; an amino acid sequence comprising 1, 2, or 3, but not more than 4, modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of TNNS (SEQ ID NO: 14); or an amino acid sequence comprising 1, 2, or 3, but not more than 4, different amino acids relative to the amino acid sequence of TNNS (SEQ ID NO: 14).

[0154] 111.[K0]-[K1] is (i) TNSLS (SEQ ID NO: 647) or TNSSLY (SEQ ID NO: 648), (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 111. The AAV capsid variant of embodiment 110, comprising:

[0155] 112.[K0]-[K1] is (i) TNSSLSY (SEQ ID NO: 676) or TNSSLYY (SEQ ID NO: 678), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 112. The AAV capsid variant of any one of embodiments 100, 110 or 111, which is or comprises:

[0156] 113.[K0]-[K1]-[K2] (i) TNSSLSYQA (SEQ ID NO: 679), TNSSLSYTA (SEQ ID NO: 681), TNSSLYYPA (SEQ ID NO: 682), or TNSSLSYPA (SEQ ID NO: 683); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant described in any one of embodiments 110 to 112, comprising:

[0157] 114.[K0]-[K1]-[K2] (i) TNSSLSYQAE (SEQ ID NO: 684), TNSSLSYTAE (SEQ ID NO: 685), TNSSLYYPAE (SEQ ID NO: 686), TNSSLSYPAE (SEQ ID NO: 687), or TNSSLSYPAD (SEQ ID NO: 689); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant described in any one of embodiments 110 to 113, comprising:

[0158] 115.[K0]-[K1]-[K2] (i) TNSSLSYQAEV (SEQ ID NO: 692), TNSSLSYTAEV (SEQ ID NO: 693), TNSSLYYPAEV (SEQ ID NO: 696), TNSSLSYPAEV (SEQ ID NO: 697), TNSSLSYPAEE (SEQ ID NO: 698), or TNSSLSYPADV (SEQ ID NO: 699); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 115. An AAV capsid variant according to any one of embodiments 100 or 110 to 114, which is or comprises:

[0159] 116. [K3] is further included, and [K3] is X A , X B , and XC Including rank, (a)X A The rank is V, (b)X B The place is Q, (c)X C The position is K or N, Optionally, the AAV capsid variant of any one of embodiments 99 to 115, wherein the AAV capsid comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) to (c).

[0160] 117. [K3] (i) contains VQ, QK, or QN; (ii) is or contains a VQK or VQN; An AAV capsid variant described in embodiment 116.

[0161] 118.[K2]-[K3] (i) QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), PAEVVQN (SEQ ID NO: 594), or PADVVQK (SEQ ID NO: 596); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 118. The AAV capsid variant of embodiment 100, 116, or 117, which is or comprises:

[0162] 119.[K1]-[K2]-[K3] (i) LSYQAEVVQK (SEQ ID NO: 700), LSYTAEVVQK (SEQ ID NO: 701), LYYPAEVVQK (SEQ ID NO: 702), LSYPAEVVQK (SEQ ID NO: 703), LSYPAEEVQK (SEQ ID NO: 704), LSYPAEVVQN (SEQ ID NO: 706), or LSYPADVVQK (SEQ ID NO: 708); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant according to embodiments 100 or 116 to 118, which is or comprises:

[0163] 120.[K0]-[K1]-[K2]-[K3] (i) TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), or TNSSLSYPADVVQK (SEQ ID NO: 665); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 120. An AAV capsid variant according to embodiment 100 or 116 to 119, which is or comprises:

[0164] 121. [K4] is further included, and [K4] is X D and X E Including rank, (a)X D The position is T, P, or N, (b)X E The place is A or D, Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) or (b).

[0165] 122. The AAV capsid variant of embodiment 100 or 121, wherein [K4] is or comprises TA, TD, PA, or NA. 123.[K3]-[K4] (i) VQKTA (SEQ ID NO: 564), VQKTD (SEQ ID NO: 714), VQNTA (SEQ ID NO: 715), VQKNA (SEQ ID NO: 570), or VQKPA (SEQ ID NO: 567); (ii) an amino acid sequence comprising any part of the amino acid sequences in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 123. The AAV capsid variant of any one of embodiments 100, 121, or 122, which is or comprises:

[0166] 124.[K0]-[K1]-[K2]-[K3]-[K4] (i) TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076), (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 124. An AAV capsid variant according to any one of embodiments 100 or 121 to 123, which is or comprises:

[0167] 125. An AAV capsid variant (e.g., an AAV5 capsid variant) comprising [B]-[C], (i) [B] comprises positions X1, X2, and X3; (a) position X1 is Q or S; (b) position X2 is S, L, or A; (c) position X3 is S, Y, or T; (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i) and / or (ii).

[0168] 126.(i) [A] containing TNN, TNS, TNT, or TNK; (ii) [B] containing QSS, SLY, SAT, or SLS; (iii) [C] containing YPAEVVQK (SEQ ID NO: 943), and (iv) an AAV capsid variant (e.g., an AAV5 capsid variant) containing one, two, three, four, or all of [D], including TA, TD, NA, or PA; Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (i)-(v); Further optionally, the AAV capsid variant, wherein [C] substitutes position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0169] 127. The AAV capsid variant of embodiment 125, wherein [B] comprises QS, SL, SA, LY, AT, LS, or SS. 128. An AAV capsid variant according to any one of embodiments 125 to 127, wherein [B] is or comprises QSS, SLY, SAT, or SLS.

[0170] 129. [B]-[C] (i) SSYPAEVVQK (SEQ ID NO: 572), LYYPAEVVQK (SEQ ID NO: 702), ATYPAEVVQK (SEQ ID NO: 718), or LSYPAEVVQK (SEQ ID NO: 703); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 129. The AAV capsid variant of any one of embodiments 125, 127, or 128, comprising:

[0171] 130.[B]-[C] (i) QSSYPAEVVQK (SEQ ID NO: 150), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), or SLSYPAEVVQK (SEQ ID NO: 642); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 130. An AAV capsid variant according to any one of embodiments 125 to 129, which is or comprises:

[0172] 131. The AAV capsid variant of embodiment 126 or 130, wherein [B]-[C] is or comprises QSSYPAEVVQK (sequence number 150). 132. The AAV capsid variant of any one of embodiments 67 to 98 or 125 to 131, further comprising an amino acid other than N (e.g., T, S, or K) at position 573 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0173] 133. (i) T at position 571, N at position 572, and / or N at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (ii) a T at position 571, an N at position 572, and / or a T at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (iii) T at position 571, N at position 572, and / or S at position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (iv) T at position 571, N at position 572, and / or K at position 573 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 The AAV capsid variant of any one of embodiments 67 to 98 or 125 to 131, further comprising:

[0174] 134. [A] is further included, and [A] is X A , X B , and X C Including rank, (a)X A The place is T, (b)X B The rank is N, (c)X C The position is N, T, S, or K, Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) to (c).

[0175] 135. [A] (i) includes TN, NS, NT, NK, or NN; (ii) is or contains TNN, TNS, TNT, or TNK; An AAV capsid variant according to embodiment 126 or 134.

[0176] 136. [A]-[B] (i) TNNQSS (SEQ ID NO: 183), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNSLS (SEQ ID NO: 647), or TNKSAT (SEQ ID NO: 651); (ii) an amino acid sequence comprising any part of the amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 136. The AAV capsid variant of any one of embodiments 126, 134, or 135, which is or comprises:

[0177] 137. [A]-[B]-[C] (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), or TNKSATYPAEVVQK (SEQ ID NO: 663); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); An AAV capsid variant according to any one of embodiments 126 or 134 to 136, which is or comprises:

[0178] 138. An AAV capsid variant described in any one of embodiments 126, or 134 to 137, wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (sequence number 500).

[0179] 139. The AAV capsid variant of any one of embodiments 67 to 98 or 125 to 138, further comprising one or both of an amino acid other than T at position 578 (e.g., P or N), and / or an amino acid other than A at position 579 (e.g., D), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0180] 140. (i) T at position 578 and / or A at position 579 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (ii) T at position 578 and / or D at position 579 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (iii) P at position 578 and / or A at position 579 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (iv) N at position 578 and / or A at position 579 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 The AAV capsid variant of any one of embodiments 67 to 98 or 125 to 138, further comprising:

[0181] 141. Further comprising [D], wherein [D] comprises positions X4 and X5; (a) position X4 is T, N, or P; (b) position X5 is A or D; Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforementioned amino acids in (a) or (b).

[0182] 142. The AAV capsid variant of embodiment 141, wherein [D] is or comprises TA, TD, NA, or PA. 143.[C]-[D] (i) YPAEVVQKTA (SEQ ID NO: 584), YPAEVVQKTD (SEQ ID NO: 719), YPAEVVQKNA (SEQ ID NO: 724), or YPAEVVQKPA (SEQ ID NO: 586); (ii) any part of the amino acid sequence in (i), e.g., an amino acid sequence comprising any of 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 143. The AAV capsid variant of embodiment 126, 141, or 142, which is or comprises:

[0183] 144. [A]-[B]-[C]-[D] (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNKSATYPAEVVQKTA (SEQ ID NO: 2075), (ii) an amino acid sequence comprising any part of the amino acid sequence in (ii)(i), e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, of any of them; (iii) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences in (i); 144. An AAV capsid variant according to any one of embodiments 126 or 141 to 143, which is or comprises:

[0184] 145. An AAV capsid variant described in any one of embodiments 126, or 141 to 144, wherein [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (sequence number 1533).

[0185] 146. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, or 140, wherein [N2]-[N3] are present within loop VIII, and optionally loop VIII comprises positions 571 to 592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571 to 599 numbered according to SEQ ID NO: 982.

[0186] 147. The AAV capsid variant of any one of embodiments 2, 15-40, 59, 60, 68, 79-98, 139, 137, or 146, wherein [N0], [N1], and / or [N4] are present within loop VIII, and optionally loop VIII comprises positions 571-592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571-599 numbered according to SEQ ID NO: 982.

[0187] 148. The AAV capsid variant of any one of embodiments 2, 15-40, 59, 60, 68, 79-98, 139, 140, 146, or 147, wherein [N0]-[N1]-[N2]-[N3]-[N4] are present within loop VIII, and optionally loop VIII comprises positions 571-592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571-599 numbered according to SEQ ID NO: 982.

[0188] 149. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 148, wherein [N2] is located immediately after position 576 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0189] 150. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 149, wherein [N2] replaces position 577 (e.g., T577) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0190] 151. The AAV capsid variant of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, or 146-150, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [N2] is located immediately after position 576 and [N2] replaces position 577 (e.g., T577).

[0191] 152. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 151, wherein [N2] corresponds to positions 577 to 581 of SEQ ID NO: 982 (e.g., Y577, P578, A579, E580, V581).

[0192] 153. The AAV capsid variant of any one of embodiments 1 to 152, comprising an amino acid other than T at position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0193] 154. The AAV capsid variant of any one of embodiments 1 to 153, comprising a Y at position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0194] 155. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 154, wherein, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, X1 of [N2] is present at position 577 (e.g., T577), and positions X2 to X5 of [N2] are present immediately after position 577.

[0195] 156. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 155, wherein X1 of [N2] corresponds to position 577 (e.g., Y577), X2 of [N2] corresponds to position 578 (e.g., P588), X3 of [N2] corresponds to position 579 (e.g., A579), X4 of [N2] corresponds to position 580 (e.g., E580), and X5 of [N2] corresponds to position 581 (e.g., V581) of SEQ ID NO: 982.

[0196] 157. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 156, wherein [N2]-[N3] is located immediately after position 576 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0197] 158. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 157, wherein [N2]-[N3] replaces position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0198] 159. The AAV capsid variant of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, or 146-158, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [N2]-[N3] occurs immediately after position 576, and [N2]-[N3] replaces position 577 (e.g., T577).

[0199] 160. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 159, wherein [N2]-[N3] correspond to positions 577 to 584 of SEQ ID NO: 982 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584).

[0200] 161. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 160, wherein [N2]-[N3]-[N4] are located immediately after position 576 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0201] 162. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 161, wherein [N2]-[N3]-[N4] replace positions 577 to 579 (e.g., T577, T578, and A579) relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0202] 163. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 162, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [N2]-[N3]-[N4] occurs immediately after position 576, and [N2]-[N3]-[N4] replaces positions 577 to 579 (e.g., T577, T578, and A579).

[0203] 164. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 163, wherein [N2]-[N3]-[N4] correspond to positions 577 to 586 of SEQ ID NO: 982 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586).

[0204] 165. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-164, wherein [N1] is located immediately after position 573 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0205] 166. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-165, wherein [N1] replaces positions 574 to 576 (e.g., Q574, S575, and S576) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0206] 167. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-166, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [N1] is located immediately after position 573, and [N1] replaces positions 574-576 (e.g., Q574, S575, and S576).

[0207] 168. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-167, wherein [N1] replaces positions 574 to 576 (e.g., Q574, S575, and S576) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0208] 169. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-168, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982, [N1] is located immediately after position 573, and [N1] replaces positions 574-576 (e.g., Q574, S575, and S576).

[0209] 170. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-169, wherein [N1] corresponds to positions 574 to 576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982.

[0210] 171. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-170, wherein [N1]-[N2]-[N3]-[N4] are located immediately after position 573 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0211] 172. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-171, wherein [N1]-[N2]-[N3]-[N4] replace positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579) relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0212] 173. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-171, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [N1]-[N2]-[N3]-[N4] occurs immediately after position 573, and [N1]-[N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579).

[0213] 174. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-173, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 574 to 586 of SEQ ID NO: 982 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586).

[0214] 175. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-174, wherein [N0] is located immediately after position 570 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0215] 176. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-175, wherein [N0] replaces positions 571 to 573 (e.g., T571, N572, and N573) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0216] 177. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-176, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [N0] is located immediately after position 570, and [N0] replaces positions 571-573 (e.g., T571, N572, and N573).

[0217] 178. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-177, wherein [N0] is located immediately after position 570 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0218] 179. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-178, wherein [N0] replaces positions 571 to 573 (e.g., T571, N572, and N573) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0219] 180. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-179, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982, [N0] is located immediately after position 570, and [N0] replaces positions 571-573 (e.g., T571, N572, and N573).

[0220] 181. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-181, wherein [N0] corresponds to positions 571 to 573 (e.g., T571, N572, and N573) of SEQ ID NO: 982.

[0221] 182. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-181, wherein [N0]-[N1]-[N2]-[N3]-[N4] are located immediately after position 570 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0222] 183. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-182, wherein [N0]-[N1]-[N2]-[N3]-[N4] replace positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579) relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0223] 184. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-183, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [N0]-[N1]-[N2]-[N3]-[N4] occurs immediately after position 570, and [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579).

[0224] 185. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-184, wherein [N0]-[N1]-[N2]-[N3]-[N4] correspond to positions 571 to 586 of SEQ ID NO: 982 (e.g., T571, N572, N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586).

[0225] 186. The AAV capsid variant of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, or 146-185, wherein [N4] is located immediately after position 584, numbered according to SEQ ID NO: 982.

[0226] 187. The AAV capsid variant of any one of embodiments 3, 31 to 40, 68, 94 to 98, 139, 140, or 146 to 186, wherein [N4] replaces positions 578 and 579, numbered according to SEQ ID NO: 138, or positions 585 and 586, numbered according to SEQ ID NO: 982.

[0227] 188. The AAV capsid variant of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, or 146-187, wherein [N4] is located immediately after position 584 and replaces positions 585 and 586, numbered according to SEQ ID NO: 982.

[0228] 189. (i) Numbered in accordance with SEQ ID NO. 982, X of [N0] A is present at position 571 and is X in [N0] B is present at position 572 and is X in [N0] C is at the 573rd position, (ii) X in [N1] numbered according to SEQ ID NO: 982 D is present at position 574 and is X in [N1] E is present at position 575 and is X in [N1] F is at position 576, (iii) numbered according to SEQ ID NO: 982, wherein X1 of [N2] is at position 577, X2 of [N2] is at position 578, X3 of [N2] is at position 579, X4 of [N2] is at position 580, and X5 of [N2] is at position 581; (iv) numbered according to SEQ ID NO: 982, wherein [N3] is present at positions 582 to 584; and / or (v) X numbered according to SEQ ID NO: 982 and [N4] G is present at position 585 and is X in [N4] H However, it is in 586th place. An AAV capsid variant described in any one of embodiments 3, 31-40, 68, 94-98, 139, 140, or 146-188.

[0229] 190. (i) Numbered according to SEQ ID NO: 982, [N0] is present at positions 571 to 573; (ii) numbered according to SEQ ID NO: 982, wherein [N1] is present at positions 574 to 576; (iii) numbered according to SEQ ID NO: 982, wherein [N2] is present at positions 577 to 581; (iv) numbered according to SEQ ID NO: 982, wherein [N3] is present at positions 582 to 584; (v) numbered according to SEQ ID NO: 982, wherein [N4] is present at positions 585-586; (vi) [N2]-[N3] are located at positions 577-584, numbered according to SEQ ID NO: 982; and / or (vii) numbered according to SEQ ID NO: 982, [N0]-[N1]-[N2]-[N3]-[N4] are present at positions 571 to 586; An AAV capsid variant according to any one of embodiments 3, 31-40, 68, 94-98, 139, 140, or 146-189.

[0230] 191. The AAV capsid variant of any one of embodiments 1 to 40, 59, 60, 67 to 98, 139, 140, or 146 to 190, wherein [N3] is located immediately after [N2].

[0231] 192. The AAV capsid variant of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, or 146-191, wherein [N4] is located immediately after [N3].

[0232] 193. The AAV capsid variant of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, or 146-192, comprising, from N-terminus to C-terminus, [N2]-[N3].

[0233] 194. The AAV capsid variant of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, or 146-193, comprising, from N-terminus to C-terminus, [N1]-[N2]-[N3].

[0234] 195. The AAV capsid variant of any one of embodiments 3, 18, 19, 28-40, 59, 60, 68, 89-98, 139, 140, or 146-194, comprising, from N-terminus to C-terminus, [N0]-[N1]-[N2]-[N3].

[0235] 196. The AAV capsid variant of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, or 146-195, comprising, from N-terminus to C-terminus, [N1]-[N2]-[N3]-[N4].

[0236] 197. The AAV capsid variant of any one of embodiments 3, 18, 19, 28-40, 59, 60, 68, 89-98, 139, 140, or 146-196, comprising, from N-terminus to C-terminus, [N0]-[N1]-[N2]-[N3]-[N4].

[0237] 198. The AAV capsid variant of any one of embodiments 41 to 66 or 125 to 145, wherein [B]-[C] is present within loop VIII, and optionally loop VIII comprises positions 571 to 592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571 to 599 numbered according to SEQ ID NO: 982.

[0238] 199. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198, wherein [A] and / or [D] are present within loop VIII, and optionally loop VIII comprises positions 571-592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571-599 numbered according to SEQ ID NO: 982.

[0239] 200. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, 198, or 199, wherein [A]-[B]-[C]-[D] are present within loop VIII, and optionally loop VIII comprises positions 571-592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571-599 numbered according to SEQ ID NO: 982.

[0240] 201. An AAV capsid variant described in any one of embodiments 41 to 66, 125 to 145, or 198 to 200, wherein [B] is located immediately after position 573 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0241] 202. An AAV capsid variant according to any one of embodiments 41 to 66, 125 to 145, or 198 to 201, wherein [B] replaces positions 574 to 576 (e.g., Q574, S575, and S576) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0242] 203. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 202, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [B] is present immediately after position 573, and [B] replaces positions 574 to 576 (e.g., Q574, S575, and S576).

[0243] 204. An AAV capsid variant described in any one of embodiments 41 to 66, 125 to 145, or 198 to 203, wherein [B] is located immediately after position 573 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0244] 205. An AAV capsid variant according to any one of embodiments 41 to 66, 125 to 145, or 198 to 204, wherein [B] replaces positions 574 to 576 (e.g., Q574, S575, and S576) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0245] 206. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 205, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982, [B] is present immediately after position 573, and [B] replaces positions 574 to 576 (e.g., Q574, S575, and S576).

[0246] 207. An AAV capsid variant described in any one of embodiments 41 to 66, 125 to 145, or 198 to 206, wherein [B] corresponds to positions 574 to 576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982.

[0247] 208. An AAV capsid variant described in any one of embodiments 41 to 66, 125 to 145, or 198 to 207, wherein [B]-[C] is located immediately after position 573 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0248] 209. An AAV capsid variant according to any one of embodiments 41 to 66, 125 to 145, or 198 to 208, wherein [B]-[C] replace positions 574 to 577 (e.g., Q574, S575, S576, and T577) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0249] 210. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 209, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [B]-[C] is located immediately after position 573, and [B]-[C] replaces positions 574 to 577 (e.g., Q574, S575, S576, and T577).

[0250] 211. An AAV capsid variant described in any one of embodiments 41 to 66, 125 to 145, or 198 to 210, wherein [B]-[C] correspond to positions 574 to 584 of SEQ ID NO: 982 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584).

[0251] 212. An AAV capsid variant described in any one of embodiments 41 to 66, 125 to 145, or 198 to 211, wherein [B]-[C]-[D] is located immediately after position 573 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0252] 213. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 212, wherein [B]-[C]-[D] replace positions 574 to 579 (e.g., Q574, S575, S576, T577, T578, and A579) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0253] 214. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 213, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [B]-[C]-[D] is present immediately after position 573, and [B]-[C]-[D] replaces positions 574 to 579 (e.g., Q574, S575, S576, T577, T578, and A579).

[0254] 215. An AAV capsid variant described in any one of embodiments 41 to 66, 125 to 145, or 198 to 214, wherein [B]-[C]-[D] correspond to positions 574 to 586 of SEQ ID NO: 982 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586).

[0255] 216. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 215, wherein [C] is located immediately after position 576 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0256] 217. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 216, wherein [C] replaces position 577 (e.g., T577) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0257] 218. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 217, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [C] is located immediately after position 576 and [C] replaces position 577 (e.g., T577).

[0258] 219. An AAV capsid variant according to any one of embodiments 41 to 66, 125 to 145, 198 to 218, wherein [C] corresponds to positions 577 to 584 of SEQ ID NO: 982 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584).

[0259] 220. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-219, wherein [A] is located immediately after position 570 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0260] 221. The AAV capsid variant of any one of embodiments 42, 52 to 66, 126, 134 to 145, or 198 to 220, wherein [A] replaces positions 571 to 573 (e.g., T571, N572, and N573) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0261] 222. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-221, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [A] is present immediately after position 570, and [A] replaces positions 571-573 (e.g., T571, N572, and N573).

[0262] 223. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-222, wherein [A] is located immediately after position 570 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0263] 224. The AAV capsid variant of any one of embodiments 42, 52 to 66, 126, 134 to 145, or 198 to 223, wherein [A] replaces positions 571 to 573 (e.g., T571, N572, and N573) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0264] 225. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-224, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982, [A] is present immediately after position 570, and [A] replaces positions 571-573 (e.g., T571, N572, and N573).

[0265] 226. The AAV capsid variant of any one of embodiments 42, 52 to 66, 126, 134 to 145, or 198 to 225, wherein [A] corresponds to positions 571 to 573 (e.g., T571, N572, and N573) of SEQ ID NO: 982.

[0266] 227. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-226, wherein [D] is located immediately after position 584, numbered according to SEQ ID NO: 982.

[0267] 228. An AAV capsid variant according to any one of embodiments 42, 52 to 66, 126, 134 to 145, or 198 to 227, wherein [D] replaces positions 578 and 579, numbered according to SEQ ID NO: 138, or replaces positions 585 and 586, numbered according to SEQ ID NO: 982.

[0268] 229. The AAV capsid variant of any one of embodiments 42, 52 to 66, 126, 134 to 145, or 198 to 228, wherein [D] is located immediately after position 584 and replaces positions 585 and 586, numbered according to SEQ ID NO: 982.

[0269] 230. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-229, wherein [A]-[B]-[C]-[D] are located immediately after position 570 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0270] 231. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-230, wherein [A]-[B]-[C]-[D] replace positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0271] 232. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-231, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [A]-[B]-[C]-[D] is present immediately after position 570, and [A]-[B]-[C]-[D] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579).

[0272] 233. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-232, wherein [A]-[B]-[C]-[D] correspond to positions 571 to 586 of SEQ ID NO: 982 (e.g., T571, N572, N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586).

[0273] 234. (i) Numbered in accordance with SEQ ID NO. 982, X in [A] A is present at position 571 and is an X in [A] B is present at position 572 and is an X in [A]. Cis at the 573rd position, (ii) numbered according to SEQ ID NO: 982, wherein X1 of [B] is at position 574, X2 of [B] is at position 575, and X3 of [B] is at position 576; (iii) numbered according to SEQ ID NO: 982, wherein [C] is present at positions 577 to 584; and / or (iv) An AAV capsid variant described in any one of embodiments 42, 52 to 66, 126, 134 to 145, or 198 to 233, wherein X4 of [D] is present at position 585 and X5 of [D] is present at position 586, numbered according to SEQ ID NO: 982.

[0274] 235. (i) Numbered according to SEQ ID NO: 982, wherein [A] is present at positions 571 to 573; (ii) numbered according to SEQ ID NO: 982, wherein [B] is present at positions 574 to 576; (iii) numbered according to SEQ ID NO: 982, wherein [C] is present at positions 577 to 584; (iv) numbered according to SEQ ID NO: 982, wherein [D] is present at positions 585-586; and / or (v) An AAV capsid variant described in any one of embodiments 42, 52 to 66, 126, 134 to 145, or 198 to 234, wherein [A]-[B]-[C]-[D] are present at positions 571 to 586, numbered according to SEQ ID NO: 982.

[0275] 236. The AAV capsid variant of any one of embodiments 41 to 66, 125 to 145, or 198 to 235, wherein [C] is located immediately after [B]. 237. The AAV capsid variant of any one of embodiments 42, 61-66, 126, 141-145, or 198-236, wherein [D] is present immediately after [C].

[0276] 238. The AAV capsid variant of any one of embodiments 41-66, 125-145, or 198-237, comprising, from N-terminus to C-terminus, [B]-[C]. 239. The AAV capsid variant of any one of embodiments 42, 52-66, 126, 134-145, or 198-238, comprising, from N-terminus to C-terminus, [A]-[B]-[C].

[0277] 240. The AAV capsid variant of any one of embodiments 42, 61-66, 126, 141-145, or 198-239, comprising, from N-terminus to C-terminus, [B]-[C]-[D].

[0278] 241. The AAV capsid variant of any one of embodiments 42, 61-66, 126, 141-145, or 198-240, comprising, from N-terminus to C-terminus, [A]-[B]-[C]-[D].

[0279] 242. The AAV capsid variant according to any one of embodiments 99 to 124, wherein [K1]-[K2] is present in loop VIII. 243. The AAV capsid variant of any one of embodiments 100, 92-124, or 242, wherein [K0], [K3], and / or [K4] are present within loop VIII, and optionally loop VIII comprises positions 571 to 592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571 to 599 numbered according to SEQ ID NO: 982.

[0280] 244. The AAV capsid variant of any one of embodiments 100, 92-124, 242, or 243, wherein [K0]-[K1]-[K2]-[K3]-[K4] are present within loop VIII, and optionally loop VIII comprises positions 571-592 numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)), or positions 571-599 numbered according to SEQ ID NO: 982.

[0281] 245. The AAV capsid variant of any one of embodiments 99 to 124 or 242 to 244, wherein [K1] is located immediately after position 574 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0282] 246. An AAV capsid variant according to any one of embodiments 99 to 124 or 242 to 245, wherein [K1] replaces positions 575 to 577 (e.g., S575, S576, and T577) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0283] 247. An AAV capsid variant according to any one of embodiments 99 to 124 or 242 to 246, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [K1] is located immediately after position 574, and [K1] replaces positions 575 to 577 (e.g., S575, S576, and T577).

[0284] 248. An AAV capsid variant according to any one of embodiments 100, 116-124, or 242-247, wherein [K1]-[K2]-[K3] are located immediately after position 574 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0285] 249. An AAV capsid variant according to any one of embodiments 100, 116 to 124, or 242 to 248, wherein [K1]-[K2]-[K3] replace positions 575 to 577 (e.g., S575, S576, and T577) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0286] 250. The AAV capsid variant of any one of embodiments 100, 116-124, or 242-249, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [K1]-[K2]-[K3] occurs immediately after position 574, and [K1]-[K2]-[K3] replaces positions 575 to 577 (e.g., S575, S576, and T577).

[0287] 251. An AAV capsid variant according to any one of embodiments 100, 121-124, or 242-250, wherein [K1]-[K2]-[K3]-[K4] are located immediately after position 574 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0288] 252. The AAV capsid variant of any one of embodiments 100, 121 to 124, or 242 to 251, wherein [K1]-[K2]-[K3]-[K4] replace positions 575 to 579 (e.g., S575, S576, T577, T578, and A579) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0289] 253. The AAV capsid variant of any one of embodiments 100, 121 to 124, or 242 to 252, wherein [K1]-[K2]-[K3]-[K4] is located immediately after position 574, and [K1]-[K2]-[K3]-[K4] replaces positions 575 to 579 (e.g., S575, S576, T577, T578, and A579) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0290] 254. The AAV capsid variant of any one of embodiments 100, 110-124, or 242-253, wherein [K0] is located immediately after position 570 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0291] 255. The AAV capsid variant of any one of embodiments 100, 110-124, or 242-254, wherein [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0292] 256. The AAV capsid variant of any one of embodiments 100, 110-124, or 242-255, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [K0] is located immediately after position 570, and [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574).

[0293] 257. An AAV capsid variant according to any one of embodiments 100, 121 to 124, or 242 to 256, wherein [K0]-[K1]-[K2]-[K3]-[K4] are located immediately after position 570 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0294] 258. The AAV capsid variant of any one of embodiments 100, 121 to 124, or 242 to 257, wherein [K0]-[K1]-[K2]-[K3]-[K4] replace positions 571 to 579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579) relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0295] 259. The AAV capsid variant of any one of embodiments 100, 121-124, or 242-258, wherein, relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, [K0]-[K1]-[K2]-[K3]-[K4] occurs immediately after position 570, and [K0]-[K1]-[K2]-[K3]-[K4] replaces positions 571 to 579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579).

[0296] 260. The AAV capsid variant of any one of embodiments 100, 116-124, or 242-259, wherein [K3] is located immediately after [K2]. 261. The AAV capsid variant of any one of embodiments 100, 121-124, or 242-260, wherein [K4] is located immediately after [K3].

[0297] 262. The AAV capsid variant of any one of embodiments 100, 121-124, or 242-261, comprising, from N-terminus to C-terminus, [K1]-[K2]. 263. The AAV capsid variant of any one of embodiments 100, 116-124, or 242-262, comprising, from N-terminus to C-terminus, [K1]-[K2]-[K3].

[0298] 264. The AAV capsid variant of any one of embodiments 100, 116-124, or 242-263, comprising, from N-terminus to C-terminus, [K0]-[K1]-[K2]-[K3].

[0299] 265. The AAV capsid variant of any one of embodiments 100, 121-124, or 242-264, comprising, from N-terminus to C-terminus, [K1]-[K2]-[K3]-[K4].

[0300] 266. The AAV capsid variant of any one of embodiments 100, 121-124, or 242-265, comprising, from N-terminus to C-terminus, [K0]-[K1]-[K2]-[K3]-[K4].

[0301] 267. (a) An amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (c) an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (d) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20. AAV capsid variants (e.g., AAV5 capsid variants), including:

[0302] 268. (a) any amino acid sequence selected from SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, or 1610-1624; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, or 1610-1624; (c) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences set forth in SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583 to 1587, 1590, 1591 to 1593, 1598 to 1608, or 1610 to 1624; or (d) an amino acid sequence containing one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences set forth in SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583 to 1587, 1590, 1591 to 1593, 1598 to 1608, or 1610 to 1624. AAV capsid variants (e.g., AAV5 capsid variants), including:

[0303] 269. (a) the amino acid sequence of any one of SEQ ID NOs: 943 and 2064 to 2080; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 943 or 2064-2080; (c) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences of SEQ ID NOs: 943 or 2064 to 2080; or (d) an amino acid sequence containing one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences of SEQ ID NOs: 943 or 2064 to 2080; AAV capsid variants (e.g., AAV5 capsid variants), including:

[0304] 270. (a) the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, or 1591; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, or 1591; (c) an amino acid sequence that contains one, two, or three, but not more than four, different amino acids from the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, or 1591; or (d) an amino acid sequence containing one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, or 1591. AAV capsid variants (e.g., AAV5 capsid variants), including:

[0305] 271. The AAV capsid variant of any one of embodiments 267-270, comprising at least 3, 4, 5, 6, or 7 consecutive amino acids from any one of SEQ ID NOs: 943 or 946-966.

[0306] 272. The AAV capsid variant of embodiments 267-271, wherein the three consecutive amino acids comprise YPA. 273. The AAV capsid variant of embodiments 267-272, wherein the four consecutive amino acids comprise YPAE (SEQ ID NO: 21).

[0307] 274. The AAV capsid variant of embodiments 267-273, wherein the five consecutive amino acids comprise YPAEV (SEQ ID NO: 1). 275. The AAV capsid variant of embodiments 267-274, wherein the 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725).

[0308] 276. The AAV capsid variant of embodiments 267-275, wherein the 7 consecutive amino acids comprise YPAEVVQ (sequence number 726). 277. The AAV capsid variant of embodiments 267-276, wherein the amino acid sequence comprises YPAEVVQK (sequence number 943).

[0309] 278.(i) The three consecutive amino acids include YTP; (ii) the four consecutive amino acids comprise YTPS (SEQ ID NO: 26); (iii) the five consecutive amino acids comprise YTPSL (SEQ ID NO: 7); (iv) the 6 contiguous amino acids comprise YTPSLV (SEQ ID NO: 727); (v) the seven consecutive amino acids comprise YTPSLVQ (SEQ ID NO: 728), and / or (vi) the amino acid sequence comprises YTPSLVQK (SEQ ID NO: 952); An AAV capsid variant described in any one of embodiments 267, 268, or 270.

[0310] 279. (i) The three consecutive amino acids comprise YPP; (ii) the four consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the five consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 contiguous amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the seven contiguous amino acids comprise YPPSLVQ (SEQ ID NO: 732), and / or (vi) the amino acid sequence comprises YPPSLVQK (SEQ ID NO: 946); An AAV capsid variant described in any one of embodiments 267, 268, or 270.

[0311] 280. (i) The three consecutive amino acids comprise YPP; (ii) the four consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the five consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 contiguous amino acids comprise YPPSLE (SEQ ID NO: 733); (v) the seven contiguous amino acids comprise YPPSLEQ (SEQ ID NO: 734), and / or (vi) the amino acid sequence comprises YPPSLEQK (SEQ ID NO: 953); An AAV capsid variant described in any one of embodiments 267, 268, or 270.

[0312] 281. (i) The three consecutive amino acids comprise YPP; (ii) the four consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the five consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 contiguous amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the 7 contiguous amino acids comprise YPPSLVK (SEQ ID NO: 735), and / or (vi) the amino acid sequence comprises YPPSLVKK (SEQ ID NO: 954); An AAV capsid variant described in any one of embodiments 267, 268, or 270.

[0313] 282. The AAV capsid variant of any one of embodiments 267 to 277, comprising an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).

[0314] 283. The AAV capsid variant of any one of embodiments 267, 268, 270, or 278-281, comprising an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids relative to the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, or 1591.

[0315] 284. The AAV capsid variant of any one of embodiments 267, 268, 270, or 378-281, comprising an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids relative to the amino acid sequence of any of SEQ ID NOs: 946, 952, 953, or 954.

[0316] 285. The AAV capsid variant of any one of embodiments 267-277 or 282, comprising an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).

[0317] 286. The AAV capsid variant of any one of embodiments 267, 268, 270, 278-281, or 283, comprising an amino acid sequence containing one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, or 1591.

[0318] 287. The AAV capsid variant of any one of embodiments 267, 268, 270, 278-281, or 284, comprising an amino acid sequence containing one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 946, 952, 953, or 954.

[0319] 288. (i) A nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but no more than 10 modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; or (ii) a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7 but not more than 10 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944. 286. The AAV capsid variant of any one of embodiments 267-277, 282, or 285, comprising an amino acid sequence encoded by:

[0320] 289. The nucleotide sequence encoding the amino acid sequence is (i) a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but no more than 10 modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; or (ii) a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7 but not more than 10 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944. 289. The AAV capsid variant of any one of embodiments 267-277, 282, 285, or 289, comprising:

[0321] 290. (a) an amino acid sequence selected from SEQ ID NOs: 2024 to 2063; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 2024-2063; (c) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences of SEQ ID NOs: 2024 to 2063; or (d) an amino acid sequence containing one, two, or three, but not more than four modifications, such as substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences of SEQ ID NOs: 2024 to 2063; 268. The AAV capsid variant of embodiment 267, comprising:

[0322] 291. With respect to any one of the amino acid sequences of SEQ ID NOs: 2024 to 2063, the amino acid sequence containing 1, 2, or 3, but not more than 4, different amino acids, wherein the different amino acids are at the following positions: (i) position 1, wherein the different amino acid is T or L; (ii) position 2, wherein the different amino acid is N, L, K, A, T, or P; (iii) position 3, wherein the different amino acid is N, K, L, A, Y, or S; (iv) position 4, wherein the different amino acid is Q, L, T, S, F, Y, K, or A; (v) position 5, wherein the different amino acid is S, H, A, M, Q, T, V, or F; (vi) position 6, wherein the different amino acid is S, P, V, A, Q, L, T, N, or M; (vii) position 7, wherein the different amino acid is Y, H, S, V, A, L, or T; (viii) position 8, wherein the different amino acid is D, P, A, Q, F, L, S, H, or M; (ix) position 9, wherein the different amino acid is F, A, L, D, or Q; (x) position 10, wherein the different amino acid is T, E, I, or S; (xi) position 11, wherein the different amino acid is V, A, N, or S; (xii) position 12, wherein the different amino acid is V, L, or P; (xiii) position 13, wherein the different amino acid is Q, E, or P; (xiv) position 14, wherein the different amino acid is K, N, S, or L; (xv) position 15, wherein the different amino acid is T, V, M, or L; and / or (xvi) position 16, wherein the different amino acid is A, G, or R. 291. The AAV capsid variant of embodiment 267 or 290, wherein the AAV capsid variant is present in one or more of:

[0323] 292. (a) any one of the amino acid sequences of SEQ ID NOs: 1632 to 2023; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1632-2023; (c) an amino acid sequence containing one, two, or three, but not more than four, different amino acids from any one of the amino acid sequences of SEQ ID NOs: 1632 to 2023; or (d) an amino acid sequence containing one, two, or three, but not more than four modifications, such as substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences of SEQ ID NOs: 1632 to 2023; 268. The AAV capsid variant of embodiment 267, comprising:

[0324] 293. With respect to any one of the amino acid sequences of SEQ ID NOs: 1632 to 2023, the amino acid sequence containing 1, 2, or 3, but not more than 4, different amino acids, wherein the different amino acids are at the following positions: (i) position 1, wherein the different amino acid is T, G, N, S, E, L, Y, V, or I; (ii) position 2, wherein the different amino acid is D, N, K, E, V, G, R, L, H, F, P, T, A, S, I, or Y; (iii) position 3, wherein the different amino acid is Y, N, K, T, W, Q, M, V, C, A, L, F, H, G, R, S, or P; (iv) position 4, wherein the different amino acid is H, Q, P, E, R, K, A, S, V, L, T, D, I, G, M, or N; (v) position 5, wherein the different amino acid is R, S, K, N, H, G, W, A, P, V, Q, Y, L, or F; (vi) position 6, wherein the different amino acid is G, S, F, R, W, H, I, C, M, A, Y, K, N, Q, V, P, E, D, T, or L; (vii) position 7, wherein the different amino acid is D, Y, S, I, H, F, P, K, R, G, L, Q, A, M, T, N, V, W, C, or E; (viii) position 8, wherein the different amino acid is P, L, Q, T, W, V, G, K, I, Y, N, H, R, D, S, M, A, F, or E; (ix) position 9, wherein the different amino acid is A, R, T, Q, S, M, L, E, K, V, G, D, N, H, F, P, or I; (x) position 10, wherein the different amino acid is K, E, Q, H, V, G, R, S, P, I, N, M, A, L, D, or T; (xi) position 11, wherein the different amino acid is V, A, E, N, R, L, M, T, Q, S, K, C, G, D, Y, P, H, F, or I; (xii) position 12, wherein the different amino acid is V, P, L, S, T, N, A, G, K, R, I, H, E, Q, or M; (xiii) position 13, wherein the different amino acid is Q, K, N, A, H, R, T, V, E, I, P, G, S, or L; (xiv) position 14, wherein the different amino acid is K, E, I, Y, Q, R, G, D, L, N, or S; (xv) position 15, wherein the different amino acid is S, T, N, Q, I, P, E, G, K, M, or H; and / or (xvi) position 16, wherein the different amino acid is A, D, L, Y, Q, or T. 293. The AAV capsid variant of embodiment 268 or 292, wherein the AAV capsid variant is present in one or more of:

[0325] 294. The AAV capsid variant of any one of embodiments 267 to 293, wherein the amino acid sequence is present in loop VIII. 295. The AAV capsid variant of any one of embodiments 267 to 294, wherein the amino acid sequence is located immediately after position 570, 571, 572, 573, 574, 575, or 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0326] 296. The AAV capsid variant of any one of embodiments 267 to 295, wherein the amino acid sequence replaces one, two, three, four, five, or all of positions 571, 572, 573, 574, 575, and / or 576 (e.g., positions T571, N572, N573, Q574, S575, S576, T577, T578, and / or A579) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0327] 297. The AAV capsid variant of any one of embodiments 267 to 296, wherein the amino acid sequence is located immediately after position 576 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0328] 298. The AAV capsid variant of any one of embodiments 267 to 297, comprising an amino acid residue other than T at position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0329] 299. The AAV capsid variant of any one of embodiments 267 to 298, comprising an amino acid Y at position 577 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0330] 300. The AAV capsid variant of any one of embodiments 267 to 299, comprising the substitution T577Y, numbered according to SEQ ID NO: 138. 301. The AAV capsid variant of embodiment 298 or 299, wherein the amino acid sequence is or comprises YPAEVVQK (SEQ ID NO: 943) and starts at position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.

[0331] 302. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-301, further comprising the amino acid sequence of PAEVVQK (SEQ ID NO: 20), numbered relative to SEQ ID NO: 138, and including an amino acid other than T at position 577 and located immediately following position 577.

[0332] 303. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-302, further comprising the amino acid sequence of PAEVVQK (SEQ ID NO: 20), numbered relative to SEQ ID NO: 138, and including the amino acid Y at position 577 and immediately following position 577.

[0333] 304. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-303, further comprising the amino acid sequence of PAEVVQK (SEQ ID NO: 20), numbered relative to SEQ ID NO: 982, including the amino acid Y at position 577 and located immediately after position 577 (e.g., at positions 578-584).

[0334] 305. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-304, comprising the amino acid sequence YPAEVVQK (SEQ ID NO: 943), wherein said amino acid sequence replaces position 577 (e.g., T577) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0335] 306. The amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the amino acid sequence is (i) immediately following position 576; (ii) replacing position 577 (e.g., T577); The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-305, wherein (i) and (ii) are numbered relative to SEQ ID NO: 138.

[0336] 307. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-306, further comprising an amino acid other than T (e.g., I) at position 571, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982.

[0337] 308. The AAV capsid variant of any one of embodiments 267-277, 272, 275, 278, 289, or 294-307, further comprising an I at position 571, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982.

[0338] 309. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-308, further comprising one, two, or all of the following: an amino acid other than Q (e.g., A or T) at position 574, an amino acid other than S (e.g., G) at position 575, and / or an amino acid other than S (e.g., A, L, K, or R) at position 576, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982.

[0339] 310.(i) A at position 574, G at position 575, and A at position 576, numbered relative to SEQ ID NO: 138 or 982, or (ii) T at position 574 and L at position 576, numbered relative to SEQ ID NO: 138 or 982 289, 294-309. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-309, further comprising: 311.(i) K at position 576, numbered relative to SEQ ID NO: 138 or 982, or (ii) R at position 576, numbered relative to SEQ ID NO: 138 or 982 The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-309, further comprising: 312.(i) A at position 574, G at position 575, A at position 576, and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20) immediately following position 577, numbered according to SEQ ID NO: 138 or 982 The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-310, comprising:

[0340] 313.(i) T at position 574, L at position 576, and Y at position 577, numbered according to SEQ ID NO: 138 or 982, and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20) immediately following position 577, numbered according to SEQ ID NO: 138 or 982 The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, or 294-310, comprising:

[0341] 314.(i) K at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982, and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20) immediately following position 577, numbered according to SEQ ID NO: 138 or 982 The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, 294-309, or 311, comprising:

[0342] 315.(i) R at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982, and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20) immediately following position 577, numbered according to SEQ ID NO: 138 or 982 The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, 295-309, or 311, comprising:

[0343] 316.(i) I at position 571 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982, and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20) immediately following position 577, numbered according to SEQ ID NO: 138 or 982 An AAV capsid variant according to any one of embodiments 267 to 277, 282, 285, 288, 289, 294 to 308, comprising:

[0344] 317. The AAV capsid variant of any one of embodiments 267, 268, 270, 278, 283, 284, 286, or 287, all numbered according to SEQ ID NO: 138 or 982, comprising a Y at position 577 and the amino acid sequence TPSLVQK (SEQ ID NO: 53) located immediately after position 577.

[0345] 318. The AAV capsid variant of any one of embodiments 267, 268, 270, 279, 283, 284, 286, or 287, all numbered according to SEQ ID NO: 138 or 982, comprising a Y at position 577 and the amino acid sequence PPSLVQK (SEQ ID NO: 47) located immediately after position 577.

[0346] 319. The AAV capsid variant of any one of embodiments 267, 268, 270, 280, 283, 284, 286, or 287, all numbered according to SEQ ID NO: 138 or 982, comprising a Y at position 577 and the amino acid sequence PPSLEQK (SEQ ID NO: 54) located immediately after position 577.

[0347] 320. The AAV capsid variant of any one of embodiments 267, 268, 270, 281, 283, 284, 286, or 287, all numbered according to SEQ ID NO: 138 or 982, comprising a Y at position 577 and the amino acid sequence PPSLVKK (SEQ ID NO: 55) located immediately after position 577.

[0348] 321. The AAV capsid variant of any one of the preceding embodiments, further comprising a modification, e.g., an insertion, a substitution (e.g., a conservative substitution), and / or a deletion, in loops I, II, IV, and / or VI.

[0349] 322. The AAV capsid variant of any one of the preceding embodiments, comprising an amino acid sequence that includes at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but no 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.

[0350] 323. The AAV capsid variant of any one of the preceding embodiments, comprising an amino acid sequence that includes at least 1, 2, or 3, but no more than 30, 20, or 10, different amino acids relative to the amino acid sequence of SEQ ID NO: 138.

[0351] 324. The AAV capsid variant of any one of the preceding embodiments, comprising the amino acid sequence of SEQ ID NO: 138, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0352] 325. The AAV capsid variant of any one of the preceding embodiments, comprising the amino acid sequence of SEQ ID NO: 138. 326. The AAV capsid variant of any one of the preceding embodiments, comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 137, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0353] 327. 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 having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0354] 328. The AAV capsid variant of any one of the preceding embodiments, comprising a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof. 329. The AAV capsid variant of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, or 321-328, comprising an amino acid sequence corresponding to positions 137-731 of SEQ ID NO: 982, e.g., VP2, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0355] 330. The AAV capsid variant of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, or 321-329, comprising an amino acid sequence corresponding to positions 193-731 of SEQ ID NO: 982, e.g., VP3, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0356] 331. The AAV capsid variant of any one of embodiments 1 to 321, comprising an amino acid sequence corresponding to positions 137 to 724 of SEQ ID NO: 138, e.g., VP2, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0357] 332. The AAV capsid variant of any one of embodiments 1 to 321, comprising an amino acid sequence corresponding to positions 193 to 724 of SEQ ID NO: 138, e.g., VP3, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0358] 333. An amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), (i) the three consecutive amino acids include YPA; (ii) the four consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the five consecutive amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the 6 contiguous amino acids comprise YPAEVV (SEQ ID NO: 725); (v) the seven contiguous amino acids comprise YPAEVVQ (SEQ ID NO: 726); An AAV capsid variant described in any one of embodiments 267 to 277, 282, 285, 288, 289, 294 to 306, or 321 to 328, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 739.

[0359] 334. An amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), (i) the three consecutive amino acids include YPA; (ii) the four consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the five consecutive amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the 6 contiguous amino acids comprise YPAEVV (SEQ ID NO: 725); (v) the seven contiguous amino acids comprise YPAEVVQ (SEQ ID NO: 726); 333. The AAV capsid variant of any one of embodiments 267 to 277, 282, 285, 288, 289, 294 to 306, 321 to 328, or 333, 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 to 724 of SEQ ID NO: 138 or positions 137 to 731 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193 to 724 of SEQ ID NO: 138 or positions 193 to 731 of SEQ ID NO: 982; or (d) an amino acid sequence having 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) to (c).

[0360] 335. The AAV capsid variant comprises one, two, or three, but not more than four, different amino acids relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), (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 to 724 of SEQ ID NO: 138 or positions 137 to 731 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193 to 724 of SEQ ID NO: 138 or positions 193 to 731 of SEQ ID NO: 982, or (d) an amino acid sequence having at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a) to (c). The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, or 334, comprising:

[0361] 336. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-335, comprising one, two, or three, but not more than four, different amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence with at least 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 739.

[0362] 337. The AAV capsid variant of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-336, comprising one or two, but not more than three, substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises an amino acid sequence that is 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.

[0363] 338. The AAV capsid variant of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-337, comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0364] 339. The AAV capsid variant of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-338, comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence having at least 95% identity thereto.

[0365] 340. The AAV capsid variant of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-339, comprising the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence having at least 98% identity thereto.

[0366] 341. The AAV capsid variant of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-340, comprising an amino acid sequence containing at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but no 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.

[0367] 342. The AAV capsid variant of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-341, comprising an amino acid sequence that contains at least 1, 2, or 3, but no more than 30, 20, or 10, different amino acids relative to the amino acid sequence of SEQ ID NO: 982.

[0368] 343. The AAV capsid variant of any one of the preceding embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-342, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0369] 344. The AAV capsid variant of any one of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant is codon-optimized. 345. An AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence according to any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-342, 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.

[0370] 346. An AAV capsid variant (e.g., an AAV5 capsid variant) comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).

[0371] 347. The AAV capsid variant of embodiment 346, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739. 348. An AAV capsid variant (e.g., an AAV5 capsid variant) comprising the amino acid sequence of SEQ ID NO: 982.

[0372] 349. An AAV capsid variant (e.g., an AAV5 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.

[0373] 350. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-349, having increased tropism for CNS cells or tissue, e.g., brain cells, brain tissue, spinal cord cells, or spinal cord tissue, compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.

[0374] 351. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-350, having increased tropism for CNS cells or tissue, e.g., brain cells, brain tissue, spinal cord cells, or spinal cord tissue, compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.

[0375] 352. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-351, having increased tropism for CNS cells or tissue, e.g., brain cells, brain tissue, spinal cord cells, or spinal cord tissue, compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 139.

[0376] 353. A brain region, e.g., the temporal cortex, the perirhinal cortex, the globus pallidus, the putamen, the caudate nucleus, the thalamus, the hippocampus, the geniculate nucleus, the Purkinje layer, the deep cerebellar nuclei, and / or the cerebellum, is transduced, and optionally the level of transduction is compared to a reference sequence of SEQ ID NO: 139, as measured, for example, by an assay, e.g., an immunohistochemistry assay, or a qPCR assay, e.g., as described in Example 2. or at least 1.5, 2.2, 2.4, 2.5, 2.6, 2.7, 3.0, 3.2, 3.5, 3.7, 4.0, 4.2, 4.5, 4.7, 4.9, 5, 10, 15, 20, 25, 30, 35 times greater than the AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-352.

[0377] 354. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-353, which is enriched in the brain by at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65 times as compared to the reference sequence of SEQ ID NO: 138, as measured, for example, by an assay as described in Example 1.

[0378] 355. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-354, which is enriched in the brain by at least about 10, 12, 15, 17, 20, 25, 30, 35, 40, 45, 50, 55, 60, 61, 62, 63, 64, or 65-fold compared to the reference sequence of SEQ ID NO: 138, as measured, for example, by an assay such as that described in Example 1.

[0379] 356. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-355, which is enriched in the brain of at least two to three species, e.g., non-human primates and rodents (e.g., rats and / or mice), for example, compared to the reference sequence of SEQ ID NO: 138.

[0380] 357. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-356, which is enriched by at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, 30, 35, 40, or 45-fold in the brain of at least two to three species, e.g., non-human primates and rodents (e.g., rats and / or mice), compared to the reference sequence of SEQ ID NO: 138, as measured, e.g., by an assay such as that described in Examples 1, 2, 4, and 5.

[0381] 358. The AAV capsid variant of embodiment 356 or 357, wherein the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, rat, and / or mouse (e.g., BALB / c mouse).

[0382] 359. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-358, which is enriched in the brain by at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 125, 150, 175, 200, or 225-fold compared to the reference sequence of SEQ ID NO: 982, as measured, for example, by an assay such as that described in Example 4.

[0383] 360. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-359, which delivers increased levels of payload to a brain region, and optionally, the level of said payload is increased by at least 20, 25, 30, 35 fold compared to the reference sequence of SEQ ID NO: 139, e.g., as measured by an assay, e.g., a qRT-PCR or qPCR assay (e.g., as described in Example 2).

[0384] 361. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-360, which delivers increased levels of viral genomes to a brain region, and optionally, the level of viral genomes is increased by at least 1.5, 2.2, 2.4, 2.5, 2.6, 2.7, 3.0, 3.2, 3.5, 3.7, 4.0, 4.2, 4.5, 4.7, 4.9, or 5-fold compared to the reference sequence of SEQ ID NO: 139, e.g., as measured by an assay, e.g., a qRT-PCR or qPCR assay (e.g., as described in Example 2).

[0385] 362. The AAV capsid variant of any one of embodiments 350-361, wherein the brain region is the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate nucleus, thalamus, hippocampus, geniculate nucleus, Purkinje layer, deep cerebellar nuclei, cerebellum, or a combination thereof.

[0386] 363. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-362, which is enriched in the spinal cord region by at least about 3, 3.5, 4.0, 4.5, 5, 5.0, 6.0, or 6.5-fold compared to the reference sequence of SEQ ID NO: 139, e.g., as measured by an assay such as that described in Example 2.

[0387] 364. The AAV capsid variant of any one of embodiments 363, wherein the spinal region is the cervical region, the lumbar region, the thoracic region, or a combination thereof. 365. The AAV capsid variant of any one of the preceding embodiments, which exhibits preferential transduction in brain regions compared to transduction in the dorsal root ganglia (DRG).

[0388] 366. An AAV capsid variant according to any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-365, capable of transducing neuronal cells.

[0389] 367. The AAV capsid variant of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-366, which is capable of transducing non-neuronal cells, e.g., glial cells (e.g., oligodendrocytes).

[0390] 368. An AAV capsid variant according to any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, or 294-367, which exhibits preferential transduction in brain regions compared to transduction in the liver.

[0391] 369. The AAV capsid variant of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, or 321-349, having increased tropism for cardiac cells or tissues, e.g., ventricles or atria, compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.

[0392] 370. The AAV capsid variant of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, or 369, having increased tropism for cardiac cells or tissues, e.g., ventricles or atria, compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 139.

[0393] 371. The AAV capsid variant of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, 369, or 370, which delivers increased levels of payload to the cardiac region, and optionally, the level of said payload is increased by at least 1.5, 2, or 2.5 fold compared to the reference sequence of SEQ ID NO: 139, e.g., as measured by an assay, e.g., an IHC assay or an RT-ddPCR assay (e.g., as described in Example 2).

[0394] 372. The AAV capsid variant of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, or 369-371, having increased tropism for cardiac cells or tissues, e.g., ventricles or atria, compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.

[0395] 373. The AAV capsid variant of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, or 369-372, which is enriched in the heart by at least about 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50-fold compared to the reference sequence of SEQ ID NO: 982, as measured, for example, by an assay such as that described in Example 4.

[0396] 374. The AAV capsid variant of any one of embodiments 267, 290, 291, 321-328, 331, 332, or 344, having an increased tropism for muscle cells or tissues compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.

[0397] 375. The AAV capsid variant of any one of embodiments 267, 290, 291, 321-328, 331, 332, 344, or 374, which is enriched in muscle by at least about 2, 3, 4, 5, 10, 15, 20, 25, 30, or 35-fold compared to the reference sequence of SEQ ID NO: 982, e.g., as measured by an assay such as that described in Example 4.

[0398] 376. The AAV capsid variant of embodiment 374 or 375, wherein the muscle cell or tissue is myocardium (e.g., ventricle or atrium, or both), quadriceps, or both.

[0399] 377. The AAV capsid variant of any one of embodiments 267, 292, 293, 321-328, 331, 332, or 344, having increased tropism for liver cells or tissues compared to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.

[0400] 378. The AAV capsid variant of any one of embodiments 267, 292, 293, 321-328, 331, 332, 344, or 377, which is enriched in the liver by at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 130, 140, 150, 160, 170, 180, 185, or 190-fold compared to the reference sequence of SEQ ID NO: 982, as measured, for example, by an assay such as that described in Example 4.

[0401] 379. A polynucleotide encoding the AAV capsid variant of any one of embodiments 1 to 378. 380. (i) A nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but not more than 10 modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; (ii) a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944; or (iii) the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). 380. The polynucleotide of embodiment 379, comprising:

[0402] 381. The polynucleotide of embodiment 379 or 380, comprising the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0403] 382. A polynucleotide encoding an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 984.

[0404] 383. A polynucleotide encoding an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the encoded AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.

[0405] 384. A polynucleotide encoding an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the encoded AAV capsid variant is: (a) any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (c) an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (d) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20. The polynucleotide comprising:

[0406] 385. A polynucleotide encoding an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the encoded AAV capsid variant is: (i) the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence that contains 1, 2, or 3, but not more than 4, amino acids that differ from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); (iii) an amino acid sequence containing one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); or (iv) at least 3, 4, 5, 6, or 7 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). The polynucleotide comprising:

[0407] 386. (i) The nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); (ii) a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944; or (iii) a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. 386. The polynucleotide of embodiment 384 or 385, comprising:

[0408] 387.AAV capsid variants, (i) the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; (ii) an amino acid sequence that has one, two, or three, but not more than four, amino acids that differ from the amino acid sequence of SEQ ID NO: 982; or (iii) an amino acid sequence containing 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. 387. The polynucleotide of any one of embodiments 384 to 386, comprising:

[0409] 388. The polynucleotide of any one of embodiments 384 to 387, comprising the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0410] 389. The polynucleotide of any one of embodiments 384 to 388, comprising a nucleotide sequence that is codon-optimized. 390. A peptide, (a) any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (c) an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (d) an amino acid sequence that contains one, two, or three, but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20. The peptide comprising:

[0411] 391. A peptide, (i) the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence that contains 1, 2, or 3, but not more than 4, amino acids that differ from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); (iii) an amino acid sequence containing one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); or (iv) at least 3, 4, 5, 6, or 7 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). The peptide comprising:

[0412] 392. A peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 393. A peptide, (i) the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); or (ii) a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7 but not more than 10 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944; (iii) a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. The peptide comprising:

[0413] 394. A peptide, wherein the nucleotide sequence encoding said peptide is: (i) the nucleotide sequence of SEQ ID NO: 944, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); (ii) a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944; or (iii) a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 944. The peptide comprising:

[0414] 395. An AAV capsid variant (e.g., an AAV5 capsid variant) comprising a peptide according to any one of embodiments 390 to 394. 396. An AAV capsid variant (e.g., an AAV5 capsid variant) encoded by a polynucleotide according to any one of embodiments 382 to 389.

[0415] 397. An AAV particle comprising an AAV capsid variant described in any one of embodiments 1 to 378, 395, or 396. 398. The AAV particle of embodiment 399, comprising a nucleotide sequence encoding a payload.

[0416] 399. The AAV particle of embodiment 398, wherein the encoded payload comprises a therapeutic protein or a functional variant thereof, an antibody or antibody fragment, an enzyme, a component of a gene editing system, an RNAi agent (e.g., dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA), or a combination thereof.

[0417] 400. The AAV particle of embodiment 399, wherein the therapeutic protein or functional variant thereof, e.g., recombinant protein, is associated with (e.g., is abnormally expressed in) a neurological or neurodegenerative disorder, a muscular or neuromuscular disorder, or a neuro-oncological disorder.

[0418] 401. The AAV particle of embodiment 399 or 400, wherein the therapeutic protein or functional variant thereof is selected from apolipoprotein E (APOE) (e.g., ApoE2, ApoE3, and / or ApoE4), human motor neuron survival (SMN) 1 or SMN2, glucocerebrosidase (GBA1), aromatic L-amino acid decarboxylase (AADC), aspartoacylase (ASPA), tripeptidyl peptidase I (CLN2), beta-galactosidase (GLB1), N-sulfoglucosamine sulfohydrolase (SGSH), N-acetyl-alpha-glucosaminidase (NAGLU), iduronate 2-sulfatase (IDS), intracellular cholesterol transporter (NPC1), gigaxonin (GAN), or a combination thereof.

[0419] 402. The antibody or antibody-binding fragment is (i) CNS-related targets, e.g., antigens associated with neurological or neurodegenerative disorders, e.g., β-amyloid, APOE, tau, SOD1, TDP-43, huntingtin (HTT), and / or synuclein; (ii) a muscle- or neuromuscular-related target, e.g., an antigen associated with a muscle disorder or a neuromuscular disorder; or (iii) neuro-oncology-associated targets, e.g., antigens associated with neuro-oncology disorders, e.g., HER2, or EGFR (e.g., EGFRvIII). 399. The AAV particle of embodiment 399, which binds to

[0420] 403. The AAV particle of embodiment 399, wherein the enzyme comprises a meganuclease, zinc finger nuclease, TALEN, recombinase, integrase, base editor, Cas9, or a fragment thereof.

[0421] 404. The AAV particle of embodiment 399, wherein the components of the gene editing system include one or more components of a CRISPR-Cas system. 405. The one or more components of the CRISPR-Cas system include Cas9, e.g., a Cas9 ortholog or Cpf1, and a single guide RNA (sgRNA), and optionally: (i) the sgRNA is located upstream (5') of the Cas9 enzyme; or (ii) the sgRNA is located downstream (3') of the Cas9 enzyme; An AAV particle described in embodiment 404.

[0422] 406. The AAV particle of embodiment 399, wherein the RNAi agent (e.g., dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA) regulates, e.g., inhibits, the expression of a CNS-related gene, mRNA, and / or protein.

[0423] 407. The AAV particle of embodiment 406, wherein the CNS-related gene is selected from SOD1, MAPT, APOE, HTT, C9ORF72, TDP-43, APP, BACE, SNCA, ATXN1, ATXN3, ATXN7, SCN1A to SCN5A, SCN8A to SCN11A, or a combination thereof.

[0424] 408. An AAV particle described in any one of embodiments 397 to 407, comprising a viral genome comprising a promoter operably linked to a nucleic acid sequence encoding the payload.

[0425] 409. The promoter is selected from the group consisting of human elongation factor 1 α-subunit (EF1α), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA) and its derivatives 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), beta-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), cardiovascular promoters (e.g., αMHC, cTnT, and CMV-MLC2k), liver promoters (e.g., hAAT, TBG), skeletal muscle promoters (e.g., desmin, MCK, C512) or functional fragments, e.g., truncated forms, or functional variants thereof.

[0426] 410. The AAV particle of embodiment 408 or 409, wherein the promoter is an EF-1a promoter variant, for example a truncated EF-1a promoter. 411. The promoter is any one of SEQ ID NOs: 2100, 2101, 2103, 2104, 2108, 2109, 2111-2120, or any one of the nucleotide sequences provided in Table 8; SEQ ID NOs: 2100, 2101, 2103, 2104, 2108, 2109, 2111-2120, or any one of the nucleotide sequences provided in Table 8; 411. The AAV particle of any one of embodiments 408 to 410, wherein the AAV particle comprises a nucleotide sequence containing 10 or fewer modifications, e.g., substitutions, insertions, or deletions, or a nucleotide sequence having 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, 2111-2120, or any one of the nucleotide sequences provided in Table 8.

[0427] 412. The AAV particle of any one of embodiments 408 to 411, wherein the viral genome further comprises a polyA signal sequence. 413. An AAV particle described in any one of embodiments 408 to 412, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.

[0428] 414. An AAV particle described in any one of embodiments 408 to 413, wherein the viral genome comprises an ITR sequence located 5' to the nucleic acid sequence encoding the payload.

[0429] 415. An AAV particle described in any one of embodiments 408 to 414, wherein the viral genome comprises an ITR sequence located 3' to the nucleic acid sequence encoding the payload.

[0430] 416. An AAV particle described in any one of embodiments 408 to 415, wherein the viral genome comprises an ITR sequence located 5' to the payload and an ITR sequence located 3' to the nucleic acid sequence encoding the payload.

[0431] 417. An AAV particle described in any one of embodiments 408 to 416, wherein the viral genome further comprises an enhancer, a Kozak sequence, an intron region, and / or an exon region.

[0432] 418. An AAV particle described in any one of embodiments 408 to 417, wherein the viral genome further comprises a nucleotide sequence encoding an miR binding site, e.g., an miR binding site that regulates, e.g., reduces, expression of the payload encoded by the viral genome in cells or tissues in which the corresponding miRNA is expressed.

[0433] 419. The AAV particle of embodiment 418, wherein the encoded miRNA binding site is complementary, e.g., fully complementary or partially complementary, to an miRNA expressed in cells or tissues of DRG, liver, heart, hematopoietic, or a combination thereof.

[0434] 420. The AAV particle of embodiment 418 or 419, wherein the encoded miR binding site regulates, e.g., reduces, expression of the encoded antibody molecule in cells or tissues of, for example, the DRG, liver, heart, hematopoietic system, or a combination thereof.

[0435] 421. An AAV particle described in any one of embodiments 408 to 420, wherein the viral genome comprises at least 1 to 5 copies of the encoded miR binding site, for example at least 1, 2, 3, 4, or 5 copies.

[0436] 422. An AAV particle described in any one of embodiments 408 to 421, wherein the viral genome comprises at least three copies of the encoded miR binding site, and optionally, all three copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise different miR binding sites.

[0437] 423. The AAV particle of embodiment 422, wherein the three copies of the encoded miR binding site are contiguous (e.g., not separated by a spacer). 424. The AAV particle of embodiment 422, wherein three copies of the encoded miR binding site are separated by a spacer, and optionally, the spacer comprises the nucleotide sequence of GATAGTTA or a nucleotide sequence having one, two, or three modifications, e.g., substitutions, insertions, or deletions, but not more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA.

[0438] 425. An AAV particle described in any one of embodiments 408 to 424, wherein the viral genome comprises at least four copies of the encoded miR binding site, and optionally, all four copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise different miR binding sites.

[0439] 426. The AAV particle of embodiment 425, wherein the four copies of the encoded miR binding site are contiguous (e.g., not separated by a spacer). 427. The AAV particle of embodiment 425, wherein the four copies of the encoded miR binding site are separated by a spacer, and optionally the spacer comprises a nucleotide sequence of GATAGTTA or a nucleotide sequence having one, two, or three modifications, e.g., substitutions, insertions, or deletions, but not more than four modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA.

[0440] 428. 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; and optionally, (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4675; An AAV particle described in embodiments 408 to 427.

[0441] 429. An AAV particle described in any one of embodiments 408 to 428, wherein the viral genome comprises an encoded miR122 binding site. 430. The AAV particle of any one of embodiments 408 to 429, wherein the viral genome comprises at least 1 to 5 copies, e.g., 1, 2, or 3 copies, of the miR122 binding site, optionally wherein each copy is contiguous (e.g., not separated by a spacer) or each copy is separated by a spacer, and optionally wherein the spacer comprises the nucleotide sequence GATAGTTA, or a nucleotide sequence having 1, 2, or 3 modifications, e.g., substitutions, insertions, or deletions, but not more than 4 modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA.

[0442] 431. The AAV particle of embodiment 429 or 430, wherein the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673.

[0443] 432. The viral genome is (A)(i) a first encoded miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (ii) a first spacer comprising a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than four modifications, e.g., substitutions (e.g., conservative 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673. contains, or (B)(i) a first encoded miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (ii) a first spacer comprising a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than four modifications, e.g., substitutions (e.g., conservative 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673; (iv) a second spacer comprising a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than four modifications, e.g., substitutions (e.g., conservative 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673. 432. An AAV particle according to any one of embodiments 408 to 431, comprising:

[0444] 433. An AAV particle described in any one of embodiments 408 to 432, wherein the viral genome comprises an encoded miR183 binding site. 434. An AAV particle according to any one of embodiments 408 to 433, wherein the viral genome comprises at least 1 to 5 copies, e.g., 1, 2, or 3 copies, of the miR183 binding site, optionally wherein each copy is contiguous (e.g., not separated by a spacer) or each copy is separated by a spacer, and optionally wherein the spacer comprises the nucleotide sequence GATAGTTA, or a nucleotide sequence having 1, 2, or 3 modifications, e.g., substitutions, insertions, or deletions, but not more than 4 modifications, e.g., substitutions, insertions, or deletions, relative to GATAGTTA.

[0445] 435. The AAV particle of embodiment 433 or 434, wherein the encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4673.

[0446] 436. The viral genome is (A)(i) a first encoded miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; (ii) a first spacer comprising a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions, insertions, or deletions, but not 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676. contains, or (B)(i) a first encoded miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; (ii) a first spacer comprising a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions, insertions, or deletions, but not 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676; (iv) a second spacer comprising a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, two, or three modifications, e.g., substitutions, insertions, or deletions, but not 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 thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, insertions, or deletions, but not more than 10 modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4676. 436. An AAV particle according to any one of embodiments 408 to 435, comprising:

[0447] 437. An AAV particle described in any one of embodiments 408 to 436, wherein the viral genome comprises an encoded miR122 binding site and a miR-1 binding site. 438. An AAV particle described in any one of embodiments 408 to 437, wherein the viral genome is single-stranded or self-complementary.

[0448] 439. An AAV particle described in any one of embodiments 408 to 438, wherein the viral genome further comprises a nucleotide sequence encoding a Rep protein, e.g., a nonstructural protein, and the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 protein and a Rep52 protein).

[0449] 440. An AAV particle described in any one of embodiments 397 to 439, wherein the AAV particle further comprises a nucleotide sequence encoding a Rep protein, e.g., a nonstructural protein, and the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 protein and a Rep52 protein).

[0450] 441. The AAV particle of embodiment 439 or 440, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene.

[0451] 442. The AAV particle of any one of embodiments 408 to 441, wherein the viral genome further comprises a nucleotide sequence encoding an AAV capsid variant of any one of embodiments 1 to 364, 381, or 382.

[0452] 443. The AAV particle of any one of embodiments 397 to 442, wherein the AAV particle further comprises a nucleotide sequence encoding an AAV capsid variant of any one of embodiments 1 to 364, 381, or 382.

[0453] 444. The AAV capsid variant, polynucleotide, peptide, or AAV particle of any one of the preceding embodiments, which is isolated, e.g., recombinant. 445. A vector comprising a polynucleotide encoding an AAV capsid variant of any one of embodiments 1 to 378, 395, 396, or 444, a polynucleotide of any one of embodiments 379 to 389, or 444, or a polynucleotide encoding a peptide of any one of embodiments 390 to 394, or 444.

[0454] 446. A cell, e.g., a host cell, comprising an AAV capsid variant according to any one of embodiments 1 to 378, 395, 396, or 444, a polynucleotide according to any one of embodiments 379 to 389, or 444, a peptide according to any one of embodiments 390 to 394, or 444, an AAV particle according to any one of embodiments 397 to 444, or a vector according to embodiment 445.

[0455] 447. The cell according to embodiment 446, wherein the cell is a mammalian cell or an insect cell. 448. The cell of embodiment 446 or 447, wherein the cell is a cell of a brain region or a spinal cord region, optionally a cell of the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate nucleus, thalamus, hippocampus, geniculate nucleus, Purkinje layer, deep cerebellar nuclei, cerebellum, cervical spinal cord, thoracic spinal cord, lumbar spinal cord, or a combination thereof.

[0456] 449. The cell of any one of embodiments 446 to 448, wherein the cell is a neuron, sensory neuron, motor neuron, astrocyte, glial cell, oligodendrocyte, or muscle cell (e.g., a cardiac, diaphragm, or quadriceps cell).

[0457] 450. A method for producing AAV particles, comprising: (i) providing a host cell containing a viral genome; (ii) incubating the host cells under conditions suitable for packaging the viral genome into an AAV capsid variant of any one of embodiments 1 to 378, 395, 396, or 444, or an AAV capsid variant encoded by a polynucleotide of any one of embodiments 379 to 389, or 444; This method thereby produces the AAV particles.

[0458] 451. The method of embodiment 450, further comprising, prior to step (i), introducing into the host cell a first nucleic acid molecule comprising the viral genome. 452. The method of embodiment 450 or 451, wherein the host cell comprises a second nucleic acid encoding the capsid variant.

[0459] 453. The method of embodiment 452, wherein the second nucleic acid molecule is introduced into the host cell before, simultaneously with, or after the first nucleic acid molecule.

[0460] 454. A pharmaceutical composition comprising an AAV particle according to any one of embodiments 397 to 444, an AAV particle comprising a capsid variant according to any one of embodiments 1 to 378, 395, 396, or 444, an AAV particle comprising a peptide according to any one of embodiments 390 to 394, or 444, and a pharmaceutically acceptable excipient.

[0461] 455. A method for delivering a payload to a cell or tissue (e.g., a CNS cell, CNS tissue, cardiac cell, cardiac tissue, muscle cell, muscle tissue, liver cell, or liver tissue), comprising administering an effective amount of a pharmaceutical composition described in embodiment 454, an AAV particle described in any one of embodiments 397 to 444, an AAV particle comprising a capsid variant described in any one of embodiments 1 to 378, 395, 396, or 444, or an AAV particle comprising a peptide described in any one of embodiments 390 to 394 or 444.

[0462] 456. The method of embodiment 455, wherein the cell is a cell of a brain region or a spinal cord region, optionally a cell of the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate nucleus, thalamus, hippocampus, geniculate nucleus, Purkinje layer, deep cerebellar nuclei, cerebellum, cervical spinal cord region, thoracic spinal cord region, lumbar spinal cord region, or a combination thereof.

[0463] 457. The method of embodiment 455, wherein the cells are cardiac, e.g., atrial or ventricular, cells. 458. The method of embodiment 455, wherein the cell is a muscle cell (e.g., a quadriceps cell) or a liver cell.

[0464] 459. The method of embodiment 455 or 456, wherein the cell is a neuron, sensory neuron, motor neuron, astrocyte, glial cell, or oligodendrocyte. 460. The method of any one of embodiments 455-459, wherein the cell or tissue is in a subject.

[0465] 461. The method of embodiment 460, wherein the subject has, has been diagnosed with, or is at risk of having a genetic disorder, such as a monogenic or polygenic disorder. 462. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with, or is at risk of having a neurological disorder, e.g., a neurodegenerative disorder.

[0466] 463. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with, or is at risk of having a myopathy or neuromuscular disorder. 464. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with, or is at risk of having a neuro-oncology disorder.

[0467] 465. A method for treating a subject having or diagnosed as having a genetic disorder, such as a monogenic or polygenic disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454, the AAV particle of any one of embodiments 397-444, the AAV particle comprising a capsid variant of any one of embodiments 1-378, 395, 396, or 444, or the AAV particle comprising a peptide of any one of embodiments 390-394 or 444.

[0468] 466. A method for treating a subject having or diagnosed as having a neurological disorder, e.g., a neurodegenerative disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454, an AAV particle of any one of embodiments 397-444, an AAV particle comprising a capsid variant of any one of embodiments 1-378, 395, 396, or 444, or an AAV particle comprising a peptide of any one of embodiments 390-394 or 444.

[0469] 467. A method for treating a subject having or diagnosed as having a muscle or neuromuscular disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454, an AAV particle of any one of embodiments 397-444, an AAV particle comprising a capsid variant of any one of embodiments 1-378, 395, 396, or 444, or an AAV particle comprising a peptide of any one of embodiments 390-394 or 444.

[0470] 468. A method for treating a subject having or diagnosed as having a neuro-oncology disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454, the AAV particle of any one of embodiments 397-444, the AAV particle comprising a capsid variant of any one of embodiments 1-378, 395, 396, or 444, or the AAV particle comprising a peptide of any one of embodiments 390-394 or 444.

[0471] 469. The method of any one of embodiments 465-468, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, myopathy, neuromuscular disorder, or neuro-oncological disorder is Huntington's disease, amyotrophic lateral sclerosis (ALS), Gaucher disease, dementia with Lewy bodies, Parkinson's disease, spinal muscular atrophy, Alzheimer's disease, leukodystrophy (e.g., Alexander disease, autosomal dominant leukodystrophy with autonomic dysfunction (ADLD), Canavan disease, cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, or Refsum disease), or cancer (e.g., HER2 / neu-positive cancer or glioblastoma).

[0472] 470. The method of any one of embodiments 465-469, wherein treating comprises preventing the progression of said disease or said disorder in said subject. 471. The method of any one of embodiments 460-470, wherein the subject is a human.

[0473] 472. The method of any one of embodiments 465 to 471, wherein the AAV particles are administered to the subject intravenously, via intracisternal injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly.

[0474] 473. The method of any one of embodiments 465 to 472, wherein the AAV particles are administered to the subject, for example, via focused ultrasound (FUS) with intravenous administration of microbubbles (FUS-MB) or via MRI-guided FUS with intravenous administration.

[0475] 474. The method of any one of embodiments 465 to 472, wherein the AAV particles are administered intravenously to the subject. 475. The method of any one of embodiments 465 to 475, wherein administration of the AAV particles results in a decrease in the presence, level, and / or activity of a gene, mRNA, protein, or a combination thereof.

[0476] 476. The method of any one of embodiments 465-475, wherein administration of the AAV particles results in an increase in the presence, level, and / or activity of a gene, mRNA, protein, or a combination thereof.

[0477] 477. A pharmaceutical composition according to embodiment 454, an AAV particle according to any one of embodiments 397 to 444, an AAV particle comprising a capsid variant according to any one of embodiments 1 to 378, 395, 396, or 444, or an AAV particle comprising a peptide according to any one of embodiments 390 to 394 or 444, for use in a method for delivering a payload to a cell or tissue.

[0478] 478. A pharmaceutical composition according to embodiment 454, an AAV particle according to any one of embodiments 397 to 444, an AAV particle comprising a capsid variant according to any one of embodiments 1 to 378, 395, 396, or 444, or an AAV particle comprising a peptide according to any one of embodiments 390 to 394, or 444, for use in a method for treating a genetic, neurological, neurodegenerative, myopathic, neuromuscular, or neuro-oncological disorder.

[0479] 479. A pharmaceutical composition according to embodiment 454, an AAV particle according to any one of embodiments 397 to 444, an AAV particle comprising a capsid variant according to any one of embodiments 1 to 378, 395, 396, or 444, or an AAV particle comprising a peptide according to any one of embodiments 390 to 394 or 444, an AAV particle comprising a peptide according to any one of embodiments 376 to 380, or 430, for use in the manufacture of a medicament.

[0480] 480. Use of a pharmaceutical composition according to embodiment 454, an AAV particle according to any one of embodiments 397 to 444, an AAV particle comprising a capsid variant according to any one of embodiments 1 to 378, 395, 396, or 444, or an AAV particle comprising a peptide according to any one of embodiments 390 to 394, or 444, in the manufacture of a medicament.

[0481] 481. Use of the pharmaceutical composition of embodiment 454, the AAV particle of any one of embodiments 397 to 444, the AAV particle comprising a capsid variant of any one of embodiments 1 to 378, 395, 396, or 444, or the AAV particle comprising a peptide of any one of embodiments 390 to 394, or 444, in the manufacture of a medicament for treating a genetic, neurological, neurodegenerative, myopathic, neuromuscular, or neuro-oncological disorder.

[0482] The details of one or more embodiments of the present disclosure are set forth in the accompanying description below. Other features, objects, and advantages of the present disclosure will become apparent from the specification. As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Certain terms are defined in the definitions section and throughout. [Brief explanation of the drawings]

[0483] [Figure 1A] Immunohistochemistry images from various CNS and peripheral tissues isolated from NHP (cynomolgus monkey) 28 days after intravenous administration of AAV particles containing the TTN-002 capsid variant (top panel) or AAV9 control capsid (bottom panel), and a self-complementary genome encoding the payload fused to an HA tag driven by a heterologous constitutive promoter, are shown. From left to right, the cerebellum (Purkinje layer), spinal cord (cervical), cortex (temporal), and brainstem are shown. [Figure 1B]Immunohistochemistry images from various CNS and peripheral tissues isolated from NHP (cynomolgus monkey) 28 days after intravenous administration of AAV particles containing the TTN-002 capsid variant (top panel) or AAV9 control capsid (bottom panel), and a self-complementary genome encoding the payload fused to an HA tag driven by a heterologous constitutive promoter, are shown. From left to right, the globus pallidus, hippocampus, thalamus, putamen, and dentate nucleus are shown. [Figure 1C] Immunohistochemistry images from various CNS and peripheral tissues isolated from NHP (cynomolgus monkey) 28 days after intravenous administration of AAV particles containing the TTN-002 capsid variant (top panel) or AAV9 control capsid (bottom panel), and a self-complementary genome encoding the payload fused to an HA tag driven by a heterologous constitutive promoter, are shown. From left to right, the whole brain (Level H), the whole brain (Level K), and the cerebellum are shown. [Figure 1D] Immunohistochemistry images from various CNS and peripheral tissues isolated from NHP (cynomolgus monkey) 28 days after intravenous administration of AAV particles containing the TTN-002 capsid variant (top panel) or AAV9 control capsid (bottom panel), and a self-complementary genome encoding the payload fused to an HA tag driven by a heterologous constitutive promoter, are shown. From left to right, the spinal cord (thoracic), DRG (thoracic), liver, and heart are shown. DETAILED DESCRIPTION OF THE INVENTION

[0484] Described herein are, among other things, compositions comprising AAV capsid variants, e.g., the AAV capsid variants described herein, as well as methods of making and using them. Generally, AAV capsid variants have enhanced tropism for delivery of a payload to a cell or tissue, e.g., a CNS tissue, a cardiac cell, a cardiac tissue, a myocyte, a muscle tissue, a hepatocyte, or a hepatic tissue.

[0485] As shown in the Examples herein below, certain AAV capsid variants described herein exhibit multiple advantages over wild-type AAV5 and / or wild-type AAV9, including (i) increased penetration across the blood-brain barrier following intravenous administration, (ii) broader distribution throughout multiple brain regions, e.g., the frontal cortex, sensory cortex, motor cortex, putamen, thalamus, cerebellar cortex, dentate nucleus, caudate nucleus, and / or hippocampus, (iii) increased payload expression in multiple brain regions, (iv) broader distribution in one or more peripheral tissues, e.g., the heart, muscle, and / or liver, and / or (v) increased payload expression in one or more peripheral tissues. Without wishing to be bound by theory, it is believed that these advantages may be due, in part, to dissemination of the AAV capsid variants via the cerebral vasculature. In some embodiments, the AAV capsids described herein enhance delivery of a payload to multiple regions of the brain, including, for example, the frontal cortex, sensory cortex, motor cortex, putamen, thalamus, cerebellar cortex, dentate nucleus, caudate nucleus, and / or hippocampus, hi some embodiments, the AAV capsids described herein enhance delivery of a payload to the heart, muscle, and / or liver.

[0486] In some embodiments, the AAV capsid variants disclosed herein include a modification of loop VIII of AAV5, e.g., at a position between 571 and 579, e.g., at position 577, numbered relative to SEQ ID NO: 138. Without wishing to be bound by theory, in some embodiments, the aforementioned region of the AAV5 capsid (e.g., a position between 571 and 579, e.g., position 577) is believed to be a surface-exposed position in the AAV5 capsid that projects above the three-fold axis of symmetry, 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 incorporated herein 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, numbered according to SEQ ID NO: 138 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)). In some embodiments, loop VIII (e.g., VR-VIII) comprises positions 571-599, numbered according to SEQ ID NO: 982 (e.g., amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)). In some embodiments, loop VIII or variable region VIII (VR-VIII) is as described in Govindasamy et al. (supra), the contents of which are incorporated herein by reference in their entirety.

[0487] Several approaches have been used to produce AAV capsids with enhanced tropism for cells or tissues, such as CNS cells or tissues. One approach involves co-infecting 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 tissues (Lisowski et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 2014 506:382-386) with adenovirus to induce exponential replication of infectious AAV DNA. Another approach involved the use of cell-specific CRE transgenic mice that allow viral DNA recombination specifically in astrocytes, followed by recovery of CRE-recombined capsid variants (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 incorporated herein by reference). Other approaches apply high-throughput DNA synthesis, multiplexing, sequencing technologies, and machine learning to evaluate viral DNA sequencing reads in different tissues and engineer variant capsids. These approaches differ from the approach disclosed herein.

[0488] Capsid generation methods known in the art have several limitations. 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 tissues do not exhibit similar properties in larger animals. The aforementioned transduction-specific approaches are not compatible with large animal studies for the following reasons: 1) many tissues of interest (e.g., the CNS) are not easily accessible for adenoviral co-infection; 2) specific adenoviral tropism itself biases library distribution; and 3) large animals are typically not amenable to transgenesis or genetic manipulation and do not express CRE recombinase in defined cell types.

[0489] 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 accompanying 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, driving capsid mRNA expression in the absence of helper virus co-infection. Without wishing to be bound by theory, this RNA-driven selection is thought to increase selective pressure favoring capsid variants that transduce specific cell types. The TRACER platform enables the generation of AAV capsid libraries without the need for transgenic animals or helper virus co-infection, thereby achieving specific recovery and subcloning of capsid mRNA expressed in transduced cells. Without wishing to be bound by theory, because mRNA transcription is a hallmark of complete transduction, it is believed that the method disclosed herein allows for the identification of fully infectious AAV capsid variants, and in addition to its increased stringency, this method allows for the identification of capsids with enhanced tropism for specific cell types using libraries designed to express CAP mRNA under the control of any cell-specific promoter, such as, but not limited to, the synapsin-1 promoter (neurons), the GFAP promoter (astrocytes), the TBG promoter (liver), the CAMK promoter (skeletal muscle), or the MYH6 promoter (cardiomyocytes). Described herein are AAV capsid variants generated using the TRACER method that exhibit enhanced tropism for, for example, CNS cells, CNS tissue, muscle cells, or muscle tissue.

[0490] The AAV particles and payloads of the present disclosure can be delivered to one or more target cells, tissues, organs, or organisms. In some embodiments, the AAV particles of the present disclosure exhibit enhanced tropism for target cell types, tissues, or organs. As a non-limiting example, the AAV particles may have enhanced tropism for cells and tissues of the central nervous system or peripheral nervous system (CNS and PNS, respectively). In some embodiments, the AAV particles of the present disclosure may additionally or alternatively exhibit reduced tropism for cell types, tissues, or organs.

[0491] In some embodiments, AAV particles are used as biological tools due to their relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integrating into the host genome and without replication, and their relatively benign immunogenic profile. The viral genome can be engineered to contain minimal components for the assembly of functional recombinant viruses or viral particles loaded with a desired payload or engineered to express or deliver a desired payload to specific tissues.

[0492] In some embodiments, the AAV particle is a naturally occurring (e.g., wild-type) AAV or 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 3' ends and provide origins of replication for the viral genome. In some embodiments, the AAV viral genome typically contains two ITR sequences. These ITRs have a characteristic T-shaped hairpin structure defined by self-complementary regions (145 nt in wild-type AAV) at the 5' and 3' ends of the ssDNA that form an energetically stable double-stranded region. The double-stranded hairpin structure has multiple functions, including, but not limited to, acting as an origin of DNA replication by serving as a primer for the endogenous DNA polymerase complex of the host viral replicating cell.

[0493] In some embodiments, the wild-type AAV viral genome further comprises nucleotide sequences for two open reading frames: one for four nonstructural Rep proteins (Rep78, Rep68, Rep52, and Rep40, encoded by Rep genes) and one for three capsid, or structural, proteins (VP1, VP2, and VP3, encoded by capsid or Cap genes). The Rep proteins are used for replication and packaging, while the capsid proteins assemble to create the protein shell of AAV or AAV capsid polypeptides, e.g., AAV capsid variants. Alternative splicing and alternative start codons and promoters result in the production of four different Rep proteins from a single open reading frame and the production of three capsid proteins from a single open reading frame. While this varies depending on the AAV serotype, for example, for AAV5 (SEQ ID NOS: 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, with respect to the amino acid sequence of SEQ ID NO: 982, VP1 includes amino acids 1-731, VP2 includes amino acids 137-731, and VP3 includes amino acids 193-731. In other words, VP1 is the full-length capsid sequence, and VP2 and VP3 are shorter components. As a result, a sequence change within the VP3 region will result in a change to both VP1 and VP2, but because VP3 is the shortest of the three, the percent difference compared to the parent sequence will be greatest for VP3. While this discussion is focused on amino acid sequences, the same discussion applies to the nucleic acid sequences encoding these proteins. The three capsid proteins assemble together to create the AAV capsid protein. Without wishing to be bound by theory, AAV capsid proteins typically comprise a molar ratio of VP1:VP2:VP3 of 1:1:10.

[0494] The AAV particles of the present disclosure may be recombinantly produced and may be based on an adeno-associated virus (AAV) reference sequence. In addition to single-stranded AAV viral genomes (e.g., ssAAV), the present disclosure also provides self-complementary AAV (scAAV) viral genomes. The scAAV viral genome contains DNA strands that anneal together to form double-stranded DNA. By omitting second-strand synthesis, scAAV allows for rapid expression in transduced cells. In some embodiments, the AAV particles of the present disclosure are scAAV. In some embodiments, the AAV particles of the present disclosure are ssAAV.

[0495] Methods for producing and / or modifying AAV particles have been disclosed in the art, such as pseudotyped AAV particles (PCT Patent Publication Nos. WO200028004, WO200123001, WO2004112727, WO2005005610, and WO2005072364, the contents of each of which are incorporated herein by reference in their entirety).

[0496] As described herein, the AAV particles of the present disclosure, comprising an AAV capsid variant and a viral genome, have enhanced tropism for a cell type or tissue, e.g., a CNS cell type, region, or tissue.

[0497] peptide Disclosed herein are peptides and related AAV particles, including AAV capsid variants and peptides, for enhanced or improved transduction of target tissues (e.g., cells of the CNS or PNS). In some embodiments, the peptides are isolated, e.g., recombinant peptides. In some embodiments, the nucleic acids encoding the peptides are isolated, e.g., recombinant nucleic acids.

[0498] In some embodiments, the peptide may increase the distribution of AAV particles to cells, regions, or tissues of the CNS. Cells of the CNS may be brain support cells, such as neurons (e.g., excitatory, inhibitory, motor, sensory, autonomic, sympathetic, parasympathetic, Purkinje, Betz, etc.), glial cells (e.g., microglia, astrocytes, oligodendrocytes), and / or immune cells (e.g., T cells). Tissues of the CNS may be, but are not limited to, the cortex (e.g., frontal, parietal, occipital, temporal), thalamus, hypothalamus, striatum, putamen, caudate nucleus, hippocampus, entorhinal cortex, basal ganglia, or deep cerebellar nuclei. In some embodiments, the CNS tissue is the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate nucleus, thalamus, hippocampus, geniculate nucleus, Purkinje layer, deep cerebellar nuclei, cerebellum, cervical spinal cord, thoracic spinal cord, or lumbar spinal cord.

[0499] In some embodiments, the peptide can increase the distribution of AAV particles to cells, regions, or tissues of the PNS, such as, but not limited to, the dorsal root ganglion (DRG).

[0500] In some embodiments, the peptides can increase the distribution of AAV particles to the CNS (e.g., cortex) after intravenous administration. In some embodiments, the peptides can increase the distribution of AAV particles to the CNS (e.g., cortex) after, for example, focused ultrasound (FUS) with intravenous administration of microbubbles (FUS-MB) or MRI-guided FUS with intravenous administration.

[0501] In some embodiments, the peptides can increase the distribution of AAV particles to the PNS (e.g., DRG) after intravenous administration. In some embodiments, the peptides can increase the distribution of AAV particles to the PNS (e.g., DRG) after, for example, focused ultrasound (FUS) with intravenous administration of microbubbles (FUS-MB) or MRI-guided FUS with intravenous administration.

[0502] In some embodiments, the peptide can increase the distribution of AAV particles to cells, regions, or tissues of the heart, such as the atria or ventricles. In some embodiments, the peptide can increase the distribution of AAV particles to cells, regions, or tissues of the heart after intravenous administration.

[0503] In some embodiments, the peptide can increase the distribution of AAV particles to muscle cells, regions, or tissues. In some embodiments, the muscle is myocardium (e.g., atrium or ventricle) or quadriceps. In some embodiments, the peptide can increase the distribution of AAV particles to muscle cells, regions, or tissues after intravenous administration.

[0504] In some embodiments, the peptide can increase the distribution of AAV particles to cells, regions, or tissues of the liver. In some embodiments, the peptide can increase the distribution of AAV particles to cells, regions, or tissues of the liver after intravenous administration.

[0505] The length of the peptides can vary. In some embodiments, the peptides are about 3 to about 20 amino acids in length. By way of non-limiting example, the peptides 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, the peptides comprise about 6-12 amino acids in length, e.g., about 9 amino acids in length. In some embodiments, the peptides comprise about 7-11 amino acids in length, e.g., about 8 amino acids in length. In some embodiments, the peptides comprise about 5-10 amino acids in length, e.g., about 7 amino acids in length. In some embodiments, the peptide comprises about 4-9 amino acids in length, for example, about 6 amino acids in length.

[0506] In some embodiments, the peptide may comprise a sequence set forth in Table 1 (e.g., comprising any of the amino acid sequences of SEQ ID NOs: 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590-1593, 1598-1624, or 2064-2079). In some embodiments, the peptide may comprise a sequence set forth in Table 2A or 2B. In some embodiments, the peptide may comprise a sequence set forth in Table 9 or 15-20. In some embodiments, the peptide is isolated, e.g., recombinant.

[0507] [Table 1]

[0508] [Table 2]

[0509] [Table 3]

[0510] In some embodiments, the peptides described herein comprise an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5, and [N3] comprises an amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, position X1 of [N2] is Y, N, C, or T. In some embodiments, position X2 of [N2] is P, E, K, T, or Q. In some embodiments, position X3 of [N2] is A or P. In some embodiments, position X4 of [N2] is E, S, D, or A. In some embodiments, position X5 of [N2] is V, L, or E. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises an E at position X4. In some embodiments, [N2] comprises a V at position X5. In some embodiments, the amino acid sequence of [N3] comprises VQK. In some embodiments, the amino acid sequence of [N3] consists of VQK.

[0511] In some embodiments, the peptides described herein comprise an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5, and [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, [N3] comprises the amino acid sequence of VQK, EQK, or VKK. In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, [N3] consists of the amino acid sequence VQK. In some embodiments, position X1 of [N2] is Y, N, or C. In some embodiments, position X1 of [N2] is Y or N. In some embodiments, position X2 of [N2] is P, K, T, or Q. In some embodiments, position X2 of [N2] is P, T, or Q. In some embodiments, position X3 of [N2] is A or P. In some embodiments, position X3 of [N2] is A. In some embodiments, position X4 of [N2] is E, S, or A. In some embodiments, position X5 of [N2] is V, L, or E. In some embodiments, position X5 of [N2] is V or L. In some embodiments, [N2] contains Y at position X1. In some embodiments, [N2] contains P at position X2. In some embodiments, [N2] contains A at position X3. In some embodiments, [N2] contains E at position X4. In some embodiments, [N2] contains V at position X5. In some embodiments, [N2] contains YPA, YPP, NKA, YTA, YQA, YTP, NPA, CPA, THA, PAE, PPS, KAE, TAE, QAE, TPS, PAA, HAS, AEV, PSL, AEE, or AAV.In some embodiments, [N2] comprises YPAE (SEQ ID NO:21), YPPS (SEQ ID NO:22), NKAE (SEQ ID NO:23), YTAE (SEQ ID NO:24), YQAE (SEQ ID NO:25), YTPS (SEQ ID NO:26), YPAA (SEQ ID NO:27), NPAE (SEQ ID NO:28), CPAE (SEQ ID NO:29), THAS (SEQ ID NO:30), PAEV (SEQ ID NO:17), PPSL (SEQ ID NO:31), KAEV (SEQ ID NO:32), TAEV (SEQ ID NO:16), PAEE (SEQ ID NO:18), QAEV (SEQ ID NO:15), TPSL (SEQ ID NO:33), PAAV (SEQ ID NO:34), or QAEE (SEQ ID NO:35). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11). In some embodiments, [N2] comprises the amino acid sequence of YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises the amino acid sequence of AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46).In some embodiments, [N2]-[N3] comprises the amino acid sequence PAEVVQK (SEQ ID NO:20), PPSLVQK (SEQ ID NO:47), KAEVVQK (SEQ ID NO:48), TAEVVQK (SEQ ID NO:49), PAEVEQK (SEQ ID NO:50), PAEEVQK (SEQ ID NO:51), QAEVVQK (SEQ ID NO:52), TPSLVQK (SEQ ID NO:53), PPSLEQK (SEQ ID NO:54), PPSLVKK (SEQ ID NO:55), PAEVVKK (SEQ ID NO:56), PAEVVHK (SEQ ID NO:57), PAAVVQK (SEQ ID NO:58), PAEVVQQ (SEQ ID NO:59), TAEVVKK (SEQ ID NO:60), PAEVLQK (SEQ ID NO:61), or QAEEVQK (SEQ ID NO:62). In some embodiments, [N2]-[N3] is selected from the group consisting of YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948), YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSLVKK (SEQ ID NO: 954), YPAEVVKK (SEQ ID NO: 955), YPAEVVHK (SEQ ID NO: 956), YPAAVVQK (SEQ ID NO: 957), NPAEVVQK (SEQ ID NO: 958), YPAEVVQQ (SEQ ID NO: 959), CPAEVVQK (SEQ ID NO: 960), YPAEEVQK (SEQ ID NO: 961), YQAEVVQK (SEQ ID NO: 962), YTPSLVQK (SEQ ID NO: 963), YPPSLEQK (SEQ ID NO: 964), YPPSLVKK (SEQ ID NO: 965), YPAEVVKK (SEQ ID NO: 966), YPAEVVHK (SEQ ID NO: 967), YPAAVVQK (SEQ ID NO: 968), NPAEVVQK (SEQ ID NO: 969), YPAEVVQK (SEQ ID NO: 970), YPAEVVQK (SEQ ID NO: 971), YPAEVVQK (SEQ ID NO: 972), YPAEVVQK (SEQ ID NO: 973), YPAEV SEQ ID NO: 960), YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963); an amino acid sequence comprising any portion of any of these aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., contiguous amino acids); an amino acid sequence comprising 1, 2, or 3, but not more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising 1, 2, or 3, but not more than 4, different amino acids relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943).In some embodiments, [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0512] In some embodiments, the peptide comprising an amino acid sequence comprising the formula [N2]-[N3] is X D , X E , and X F In some embodiments, X in [N1] further comprises D Positions X, S, A, I, L, or H. In some embodiments, X in [N1] E Positions X in [N1] are S, G, A, or R. In some embodiments, X in [N1] is S, G, A, or R. FIn some embodiments, [N1] is or comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS. In some embodiments, the amino acid sequence of [N1] is QSS. In some embodiments, [N1]-[N2] comprises SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64), SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68), GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70), STNKA (SEQ ID NO: 71), SSYTA (SEQ ID NO: 72), SSYQA (SEQ ID NO: 73), SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77), or SSTHA (SEQ ID NO: 78). In some embodiments, [N1]-[N2] comprises SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81), SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84), GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95).In some embodiments, [N1]-[N2] is selected from the group consisting of QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), LSSYQAEV (SEQ ID NO: 115), LSSYQAEV (SEQ ID NO: 116), LSSYQAEV (SEQ ID NO: 117), LSSYQAEV (SEQ ID NO: 118), LSSYQAEV (SEQ ID NO: 119), LSSYQAEV (SEQ ID NO: 120), LSSYQAEV (SEQ ID NO: 121), LSSYQAEV (SEQ ID NO: 122), LSSYQAEV (SEQ ID NO: 123), LSSYQAEV (SEQ ID NO: 124), LSSYQAEV (SEQ ID NO: 125), LSSYQ 114), HSSYPAAV (SEQ ID NO:115), QSSNPAEV (SEQ ID NO:116), QSSYTAEV (SEQ ID NO:117), TSLCPAEV (SEQ ID NO:118), QRSYTAEV (SEQ ID NO:119), or QSSYQAEE (SEQ ID NO:120); an amino acid sequence comprising any portion of any of these aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., contiguous amino acids); an amino acid sequence comprising one, two, or three, but not more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three, but not more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [N1]-[N2] is QSSYPAEV (SEQ ID NO:96).In some embodiments, [N1]-[N2]-[N3] is selected from the group consisting of SSYPAEVVQ (SEQ ID NO: 121), SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125), GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127), ASYPAEVVQ (SEQ ID NO: 128), STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO: 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVV Q (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134), SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140), SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145), RSYTAEVVQ (SEQ ID NO: 146), SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149).In some embodiments, [N1]-[N2]-[N3] is selected from the group consisting of QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYP AEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 1 71), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); an amino acid sequence that includes any portion of any of the foregoing amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., contiguous amino acids); an amino acid sequence that includes 1, 2, or 3, but not more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the foregoing amino acid sequences; or an amino acid sequence that includes 1, 2, or 3, but not more than 4, different amino acids relative to any one of the foregoing amino acid sequences.In some embodiments, the amino acid sequence of [N1]-[N2]-[N3] is QSSYPAEVVQK (SEQ ID NO: 150).

[0513] In some embodiments, the peptide comprising an amino acid sequence comprising the formula [N2]-[N3] further comprises [N0], wherein [N0] is X A , X B , and X C In some embodiments, X in [N0] A The X position in [NO] is T, I, or N. In some embodiments, the X B In some embodiments, the X position of [N0] is N. CIn some embodiments, [N0] is N, T, S, or K. In some embodiments, [N0] comprises TN, IN, NN, NT, NS, or NK. In some embodiments, [N0] is or comprises TNN, TNT, INN, TNS, NNN, or TNK. In some embodiments, the amino acid sequence of [N0] is TNN. In some embodiments, [N0]-[N1] is selected from the group consisting of TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 1 98), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201); an amino acid sequence comprising any portion of any of these aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., contiguous amino acids); an amino acid sequence comprising 1, 2, or 3, but not more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising 1, 2, or 3, but not more than 4, different amino acids relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1] is TNNQSS (SEQ ID NO: 183). In some embodiments, [N0]-[N1]-[N2]-[N3] is selected from the group consisting of TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514),TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524), TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), ​​TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533) , TNNQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 551 ), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557), TNNQSSYTAEVVKK (SEQ ID NO: 558), TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562), or TNKQASYPAEVVQK (SEQ ID NO: 563); any of the foregoing amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3] is or comprises an amino acid sequence comprising any portion of any (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., contiguous amino acids); an amino acid sequence comprising 1, 2, or 3, but not more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the foregoing amino acid sequences; or an amino acid sequence comprising 1, 2, or 3, but not more than 4, different amino acids relative to any one of the foregoing amino acid sequences.TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0514] In some embodiments, the peptide comprising an amino acid sequence comprising the formula [N2]-[N3] is G and X H In some embodiments, the X in [N4] further comprises G In some embodiments, the X in [N4] is T, P, or N. G In some embodiments, the X position of [N4] is T. HIn some embodiments, [N4] is TA, PA, or NA. In some embodiments, [N4] is TA. In some embodiments, [N3]-[N4] is or comprises VQKTA (SEQ ID NO:564), EQKTA (SEQ ID NO:565), VKKTA (SEQ ID NO:566), VQKPA (SEQ ID NO:567), VHKTA (SEQ ID NO:568), VQQTA (SEQ ID NO:569), VQKNA (SEQ ID NO:570), or LQKTA (SEQ ID NO:571); an amino acid sequence comprising any portion (e.g., any 2, 3, or 4 amino acids, e.g., contiguous amino acids) of any of these aforesaid amino acid sequences; an amino acid sequence comprising 1, 2, or 3, but not more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising 1, 2, or 3, but not more than 4, different amino acids relative to any one of the aforesaid amino acid sequences. In some embodiments, [N3]-[N4] is VQKTA (SEQ ID NO: 564). In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1539). 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583),TNTASSYQAEVVQKTA (SEQ ID NO: 1584), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQS KYPAEVVHKTA (SEQ ID NO: 1453), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNSSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEV VQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), TNNQRSYTAEVVQKTA (SEQ ID NO: 1604), TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); any portion (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 69, 69, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids (e.g., consecutive amino acids); an amino acid sequence that contains 1, 2, or 3, but not more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the foregoing amino acid sequences; or an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids relative to any one of the foregoing amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0515] In some embodiments, a peptide described herein comprises the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5, and [N3] comprises the amino acid sequence VQK or VQN. In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, position X1 of [N2] is Y or T. In some embodiments, position X2 of [N2] is Q, T, P, or E. In some embodiments, position X3 of [N2] is A. In some embodiments, position X4 of [N2] is E or D. In some embodiments, position X4 of [N2] is E or D. In some embodiments, position X5 of [N2] is V or E. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises a V at the X5 position. In some embodiments, [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV, AE, or AD. In some embodiments, [N2] comprises YPA, YQA, YTA, TEA, QAE, TAE, PAE, EAE, PAD, AEV, AEE, or ADV. In some embodiments, [N2] comprises YPAE (SEQ ID NO:21), YQAE (SEQ ID NO:25), YTAE (SEQ ID NO:24), TEAE (SEQ ID NO:587), YPAD (SEQ ID NO:588), QAEV (SEQ ID NO:15), TAEV (SEQ ID NO:16), PAEV (SEQ ID NO:17), PAEE (SEQ ID NO:18), EAEV (SEQ ID NO:590), or PADV (SEQ ID NO:19). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13). In some embodiments, [N2] is YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprise AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593).In some embodiments, [N2]-[N3] comprises PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596). In some embodiments, [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966); an amino acid sequence including any portion (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., contiguous amino acids) of any of these aforesaid amino acid sequences; an amino acid sequence including 1, 2, or 3, but not more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence including 1, 2, or 3, but not more than 4 different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943).

[0516] In some embodiments, the peptide comprising an amino acid sequence comprising the formula [N2]-[N3] is X D , X E , and X F In some embodiments, X in [N1] further comprises D In some embodiments, the X position in [N1] is Q or S. E In some embodiments, the X in [N1] is S, L, A, or T. FIn some embodiments, [N1] is or comprises QSS, SLS, SLY, SAT, or QTS. In some embodiments, [N1] is QSS. In some embodiments, [N1]-[N2] comprise SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603), or TSTEA (SEQ ID NO: 605). In some embodiments, [N1]-[N2] comprises SSYPAE (SEQ ID NO: 79), LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), ATYPAE (SEQ ID NO: 613), LSYPAE (SEQ ID NO: 616), TSTEAE (SEQ ID NO: 619), or LSYPAD (SEQ ID NO: 621). In some embodiments, [N1]-[N2] is or comprises QSSYPAEV (SEQ ID NO: 96), SLSYQAEV (SEQ ID NO: 622), SLSYTAEV (SEQ ID NO: 623), SLYYPAEV (SEQ ID NO: 624), SATYPAEV (SEQ ID NO: 625), SLSYPAEV (SEQ ID NO: 629), SLSYPAEE (SEQ ID NO: 632), QTSTEAEV (SEQ ID NO: 633), or SLSYPADV (SEQ ID NO: 634); an amino acid sequence including any portion (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., contiguous amino acids) of any of these afores...

Claims

Claim 1: An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, An AAV capsid variant, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) in the variable region (VR-VIII).

2. An AAV capsid variant as described in claim 1, numbered relative to sequence number 982, wherein amino acid Y is present at position 577 and the amino acid sequence of PAEVVQK (sequence number 20) is present at positions 578 to 584.

3. An AAV capsid variant described in claim 1, wherein VR-VIII comprises positions 571 to 599 of sequence number 982.

4. The following formula: An adeno-associated virus (AAV) capsid variant comprising an amino acid sequence having [N2]-[N3], (i) [N2] comprises positions X1, X2, X3, X4, and X5; (a) position X1 is Y, N, or C; (b) position X2 is P, K, T, or Q; (c) position X3 is A or P; (d) position X4 is E, S, or A; (e) position X5 is V, L, or E; (ii) [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK; The AAV capsid variant, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% identical thereto.

5. (i) [N2] comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11), and / or (ii) [N2]-[N3] is selected from the group consisting of YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948), YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPS LVKK (SEQ ID NO:954), YPAEVVKK (SEQ ID NO:955), YPAEVVHK (SEQ ID NO:956), YPAAVVQK (SEQ ID NO:957), NPAEVVQK (SEQ ID NO:958), YPAEVVQQ (SEQ ID NO:959), CPAEVVQK (SEQ ID NO:960), YTAEVVKK (SEQ ID NO:961), YPAEVLQK (SEQ ID NO:962), or YQAEEVQK (SEQ ID NO:963), The AAV capsid variant of claim 4.

6. (i) Further comprising [N1], wherein [N1] is X Ｄ , X Ｅ , and X Ｆ Including rank, (a) X Ｄ the position is Q, T, S, A, I, L, or H; (b) X Ｅ position is S, G, A, or R; (c) X Ｆ positions are S, K, L, R, A, or T; (ii) further comprising [N0], wherein [N0] comprises positions XA, XB, and XC; (a) position X A is T, I, or N; (b) position X B is N; (c) position X C is N, T, S, or K; and / or (iii) further comprising [N4], wherein [N4] comprises positions X G and X H ; (a) position X G is T, P, or N; (b) the X H position is A; The AAV capsid variant of claim 4.

7. (i) [N1] comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS; (ii) [N0] comprises TNN, TNT, INN, TNS, NNN, or TNK; and / or (iii) [N4] comprises TA, PA, or NA; The AAV capsid variant of claim 6.

8. (i) [N1]-[N2] is selected from the group consisting of QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAE V (SEQ ID NO:108), SSSYTAEV (SEQ ID NO:109), TSLYPAEE (SEQ ID NO:110), ASSYQAEV (SEQ ID NO:111), QSSYTPSL (SEQ ID NO:112), QSRYPAEE (SEQ ID NO:113), LSSYQAEV (SEQ ID NO:114), HSSYPAAV (SEQ ID NO:115), QSSNPAEV (SEQ ID NO:116), QSSYTAEV (SEQ ID NO:117), TSLCPAEV (SEQ ID NO:118), QRSYTAEV (SEQ ID NO:119), or QSSYQAEE (SEQ ID NO:120), (ii) [N1]-[N2]-[N3] is selected from the group consisting of QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), Sequence number 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSY QAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182), (iii) [N0]-[N1] is TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201), (iv) [N0]-[N1]-[N2]-[N3] is TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVV QK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524), TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), ​​TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TN NQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 549) sequence number 551), NNNQSRYPAEVVQK (SEQ ID NO:552), TNNQSSYTAEVVQK (SEQ ID NO:553), TNNTSLCPAEVVQK (SEQ ID NO:554), TNSTSLYPAEVVQK (SEQ ID NO:556), TNNQRSYTAEVVQK (SEQ ID NO:557), TNNQSSYTAEVVKK (SEQ ID NO:558), TNNHSSYPAEVLQK (SEQ ID NO:560), TNNQSSYQAEEVQK (SEQ ID NO:562), or TNKQASYPAEVVQK (SEQ ID NO:563), (v) [N3]-[N4] comprise VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); and / or (vi) [N0] -[N1] -[N2] -[N3] -[N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 111 2), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583 ), TNTASSYQAEVVQKTA (SEQ ID NO: 1584), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453) , TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEVVQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605),TNNQRSYTAEVVQKTA (SEQ ID NO: 1604), TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587), The AAV capsid variant of claim 7. (i) [N2]-[N3] is present in loop VIII, and loop VIII comprises positions 571 to 599 of SEQ ID NO: 982; (ii) [N0], [N1], and [N4] are present in loop VIII, and loop VIII comprises positions 571 to 599 of SEQ ID NO: 982; (iii) X numbered according to SEQ ID NO: 982 and [NO] Ａ is present at position 571, and X in [N0] Ｂ is present at position 572, and X in [N0] Ｃ is present at position 573, (iv) X in [N1] numbered according to SEQ ID NO: 982 Ｄ is present at position 574, and X in [N1] Ｅ is present at position 575, and X in [N1] Ｆ is present at position 576, (v) numbered according to SEQ ID NO: 982, X1 of [N2] is present at position 577, X2 of [N2] is present at position 578, X3 of [N2] is present at position 579, X4 of [N2] is present at position 580, and X5 of [N2] is present at position 581; (vi) numbered according to SEQ ID NO: 982, wherein [N3] is present at positions 582 to 584; and / or (vii) X in [N4] numbered according to SEQ ID NO: 982 Ｇ is present at position 585, and X in [N4] Ｈ is located at 586th position. The AAV capsid variant of claim 8.

10. An adeno-associated virus (AAV) capsid variant, comprising: (a) an amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (c) an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20. The AAV capsid variant comprising:

11. (i) the at least three consecutive amino acids include YPA; (ii) the at least four consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the at least five contiguous amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the at least 6 contiguous amino acids comprise YPAEVV (SEQ ID NO: 725); (v) the at least 7 contiguous amino acids comprise YPAEVVQ (SEQ ID NO: 726); and / or (vi) the amino acid sequence comprises YPAEVVQK (SEQ ID NO: 943); The AAV capsid variant of claim 10. (i) the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO:943), or an amino acid sequence that includes one, two, or three, but not more than four, different amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO:943); (ii) the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:944, or a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, nucleotides that differ from the nucleotide sequence of SEQ ID NO:944; (iii) the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO:944, or a nucleotide sequence that contains at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, different nucleotides relative to the nucleotide sequence of SEQ ID NO:944; and / or (iv) numbered relative to SEQ ID NO: 982, the amino acid Y is present at position 577 and the amino acid sequence of PAEVVQK (SEQ ID NO: 20) is present at positions 578-584; The AAV capsid variant of claim 10. (i) comprising an amino acid sequence at least 98% identical to SEQ ID NO: 739; (ii) comprises at least 95%, or at least 98%, of the amino acid sequence of SEQ ID NO: 738; and / or (iii) comprises at least 95%, or at least 98%, of the amino acid sequence set forth in SEQ ID NO: 982; An AAV capsid variant according to any one of claims 1 to 12. (i) the amino acid sequence of SEQ ID NO: 739, (ii) the amino acid sequence of SEQ ID NO: 738, and / or (iii) the amino acid sequence of SEQ ID NO: 982 The AAV capsid variant of any one of claims 1 to 12, comprising: (i) the amino acid sequence of SEQ ID NO: 739, (ii) the amino acid sequence of SEQ ID NO: 738, and / or (iii) the amino acid sequence of SEQ ID NO: 982 Adeno-associated virus (AAV) capsid variants, including:

16. The AAV capsid variant is has increased tropism for brain cells or brain tissue compared to an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 138; An AAV capsid variant according to any one of claims 1 to 12 and 15.

17. A polynucleotide encoding the AAV capsid variant of any one of claims 1 to 12 and 15.

18. 18. The polynucleotide of claim 17, comprising the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.

19. A peptide, (a) an amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, or 15-20; or (c) an amino acid sequence that contains 1, 2, or 3, but not more than 4, different amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 9, or 15-20. The peptide comprising:

20. An AAV particle comprising the AAV capsid variant of any one of claims 1 to 12 and 15.

21. comprising a nucleotide sequence encoding a payload, The AAV particle of claim 20, wherein the encoded payload comprises a protein, an antibody, an enzyme, a component of a gene editing system, or an inhibitory RNA. (i) a 5' inverted terminal repeat (ITR) sequence, and / or a 3' ITR; (ii) a promoter operably linked to a nucleic acid sequence encoding the payload; (iii) an enhancer, (iv) Kozak sequence, (v) introns, (vi) exons, (vii) a nucleotide sequence encoding a microRNA (miR) binding site, and / or (viii) a polyadenylation sequence (polyA) sequence; 22. The AAV particle of claim 21, further comprising:

23. A vector comprising a polynucleotide encoding the AAV capsid variant of any one of claims 1 to 12 and 15.

24. A cell comprising an AAV capsid variant according to any one of claims 1 to 12 and 15, optionally comprising: (i) the cell is a mammalian cell or an insect cell; (ii) the cell is a cell of the brain or spinal cord region; and / or (iii) The cell is a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, an oligodendrocyte, or a muscle cell.

25. 1. A method of producing AAV particles, comprising: (i) providing a host cell comprising a viral genome and a polynucleotide encoding the AAV capsid variant of any one of claims 1 to 12 and 15; (ii) incubating the host cells under conditions suitable for packaging the viral genome into the AAV capsid variant; This method thereby produces the AAV particles.

26. 21. A pharmaceutical composition comprising the AAV particles of claim 20 and a pharmaceutically acceptable excipient.

27. ​​A pharmaceutical composition for use in delivering a payload to a cell or tissue, comprising an AAV particle described in claim 20.

28. The cells (i) a cell of a brain or spinal cord region, optionally a cell of the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate nucleus, thalamus, hippocampus, geniculate nucleus, Purkinje layer, deep cerebellar nuclei, cerebellum, cervical spinal cord region, thoracic spinal cord region, lumbar spinal cord region, or a combination thereof; (ii) a cardiac cell; (iii) a muscle cell; (iv) a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, or an oligodendrocyte; and / or (v) in a subject, wherein the subject has, has been diagnosed with, or is at risk of having a genetic disorder, a neurological disorder, a neurodegenerative disorder, a neuro-oncological disorder, a muscle disorder, or a neuromuscular disorder; 28. The pharmaceutical composition of claim 27.

29. The pharmaceutical composition of claim 28, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, muscle disorder, neuromuscular disorder, or neuro-oncological disorder is Huntington's disease, amyotrophic lateral sclerosis (ALS), Gaucher disease, dementia with Lewy bodies, Parkinson's disease, spinal muscular atrophy, Alzheimer's disease, leukodystrophy, Alexander disease, autosomal dominant leukodystrophy with autonomic dysfunction (ADLD), Canavan disease, cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, or Refsum disease, cancer, HER2 / neu-positive cancer, or glioblastoma.

30. The pharmaceutical composition of claim 27, formulated for intravenous administration, intracisternal injection (ICM), intracerebral administration, intrathecal administration, intraventricular administration, intraparenchymal administration, or intramuscular administration.

31. Use of the AAV particles described in claim 20 in the manufacture of a pharmaceutical for delivery of a payload to a cell or tissue.

32. The cells (i) a cell of a brain or spinal cord region, optionally a cell of the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate nucleus, thalamus, hippocampus, geniculate nucleus, Purkinje layer, deep cerebellar nuclei, cerebellum, cervical spinal cord region, thoracic spinal cord region, lumbar spinal cord region, or a combination thereof; (ii) a cardiac cell; (iii) a muscle cell; (iv) a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, or an oligodendrocyte; and / or (v) in a subject, wherein the subject has, has been diagnosed with, or is at risk of having a genetic disorder, a neurological disorder, a neurodegenerative disorder, a neuro-oncological disorder, a muscle disorder, or a neuromuscular disorder; 32. The use according to claim 31.

33. The use of claim 32, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, muscle disorder, neuromuscular disorder, or neuro-oncological disorder is Huntington's disease, amyotrophic lateral sclerosis (ALS), Gaucher disease, dementia with Lewy bodies, Parkinson's disease, spinal muscular atrophy, Alzheimer's disease, leukodystrophy, Alexander disease, autosomal dominant leukodystrophy with autonomic dysfunction (ADLD), Canavan disease, cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, or Refsum disease, cancer, HER2 / neu positive cancer, or glioblastoma.

34. The use of claim 31, wherein the AAV particles are formulated for intravenous administration, intracisternal injection (ICM), intracerebral administration, intrathecal administration, intraventricular administration, intraparenchymal administration, or intramuscular administration.

35. A pharmaceutical composition for use in treating a subject having or diagnosed with a genetic disorder, a neurological disorder, a neurodegenerative disorder, a neuro-oncological disorder, a muscle disorder, or a neuromuscular disorder, comprising the AAV particles of claim 20. (i) the genetic disorder, the neurological disorder, the neurodegenerative disorder, the myopathic disorder, the neuromuscular disorder, or the neuro-oncological disorder is Huntington's disease, amyotrophic lateral sclerosis (ALS), Gaucher disease, dementia with Lewy bodies, Parkinson's disease, spinal muscular atrophy, Alzheimer's disease, leukodystrophy, Alexander disease, autosomal dominant leukodystrophy with autonomic dysfunction (ADLD), Canavan disease, cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, or Refsum disease, cancer, HER2 / neu-positive cancer, or glioblastoma; and / or (ii) the pharmaceutical composition is formulated for intravenous administration, intramuscular administration, intracerebral administration, intrathecal administration, intraventricular administration, intraparenchymal administration, or intracisternal injection (ICM); 36. The pharmaceutical composition of claim 35.

37. Use of the AAV particles described in claim 20 in the manufacture of a pharmaceutical for treating a subject having or diagnosed as having a genetic disorder, a neurological disorder, a neurodegenerative disorder, a neuro-oncological disorder, a muscle disorder, or a neuromuscular disorder. (i) the genetic disorder, the neurological disorder, the neurodegenerative disorder, the myopathic disorder, the neuromuscular disorder, or the neuro-oncological disorder is Huntington's disease, amyotrophic lateral sclerosis (ALS), Gaucher disease, dementia with Lewy bodies, Parkinson's disease, spinal muscular atrophy, Alzheimer's disease, leukodystrophy, Alexander disease, autosomal dominant leukodystrophy with autonomic dysfunction (ADLD), Canavan disease, cerebrotendinous xanthomatosis (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, or Refsum disease, cancer, HER2 / neu-positive cancer, or glioblastoma; and / or (ii) the AAV particles are formulated for intravenous administration, intramuscular administration, intracerebral administration, intrathecal administration, intracerebroventricular administration, intraparenchymal administration, or intracisternal injection (ICM); 38. The use according to claim 37.