AAV capsid variants and their use

Abstract

This 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 / 464,034 filed on 4 May 2023, U.S. Provisional Application No. 63 / 593,622 filed on 27 October 2023, and U.S. Provisional Application No. 63 / 564,320 filed on 12 March 2024, the entire contents of each of these applications being incorporated herein by reference.

[0002] Sequence List This application is filed together with an electronic sequence listing. The sequence listing file, named V2071-3015PCT_SL.xml, was created on April 3, 2024, and has a size of 5,493,507 bytes. The electronic information of the sequence listing is incorporated herein by reference in its entirety.

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

[0004] Gene delivery to the adult 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 a promising tool for clinical gene transduction due to their non-pathogenic nature, low immunogenicity profile, low integration rate into the host genome, and long-term transgene expression in non-dividing cells. However, the transduction efficiency of native AAV variants in certain organs is too low for clinical use, and capsid neutralization with existing neutralizing antibodies may hinder the treatment of the majority of patients. For these reasons, considerable effort has been made to obtain capsid variants with improved properties. Of the many approaches tested to date, significant advances have come from the directed evolution of AAV capsids using in vitro or in vivo selection of capsid variants produced by capsid sequence randomization, using either error-prone PCR, shuffling of various parental serotypes, or insertion of fully randomized short peptides at defined locations.

[0006] Attempts to provide AAV capsids with improved properties, such as improved tropism to target cells or tissues during systemic administration, have been limitedly successful. Therefore, there is a need for improved methods for producing AAV capsids and delivering the desired payload to target cells or tissues, such as CNS cells or tissues, or muscle cells or tissues. [Overview of the project]

[0007] This 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. In some embodiments, AAV capsid variants have enhanced tropism to tissues or cells, e.g., CNS tissue or CNS cells. Such tropism may be useful for delivering payloads, e.g., payloads described herein, to cells or tissues for the treatment of disorders, e.g., neuropathy or neurodegenerative disorders, muscular or neuromuscular disorders, or neurotumor disorders.

[0008] Accordingly, in one embodiment, the present disclosure provides an AAV capsid variant comprising (A) a modification in loop VIII, e.g., a substitution (e.g., a conservative substitution), and / or (B) an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein (i) optionally, [N1] comprises X1, X2, and X3, and at least one of X1, X2, or X3 is G; (ii) [N2] comprises an amino acid sequence of SPH; and (iii) [N3] comprises X4, X5, and X6, and at least one of X4, X5, or X6 is a basic amino acid, e.g., K or R. In some embodiments, loop VIII includes positions 587–599, numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581–593, numbered according to sequence number 138 or 6414. In some embodiments, position X4 of [N3] is K. In some embodiments, position X5 of [N3] is K. In some embodiments, [N3] is or contains SKA. In some embodiments, [N3] is or contains KSG. In some embodiments, [N2]-[N3] is located immediately after position 455, numbered according to sequence number 138, 981, or 982. In some embodiments, [N1] is located immediately after position 452, relative to the reference sequence numbered according to the amino acid sequence of sequence number 138, 981, or 982. In some embodiments, [N1] replaces positions 453–455 (e.g., G453, S454, and G455) with respect to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant includes H at position 454 and D at position 455, with respect to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant includes S at position 454 and G at position 455, with respect to SEQ ID NO: 138 or 981. In some embodiments, the eight-amino acid insertion replaces SG at positions 454–455, with respect to SEQ ID NO: 138.In some embodiments, the six amino acid insertions are located immediately after position 455, numbered according to sequence numbers 138, 981, or 982.

[0009] In another aspect, the present disclosure is (A)[A][B](SEQ ID NO: 4694), wherein (i)[A] comprises the amino acid sequence of GSGSPH(SEQ ID NO: 4695), and (ii)[B] comprises X1 X2 X3 X4 X5 X6 [A][B] and / or (B) provide an AAV capsid variant including modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), wherein (a) the X1 position is S, C, F, or V; (b) the X2 position is K, L, R, I, E, Y, V, or S; (c) the X3 position is A, R, L, G, I, Y, S, F, or W; (d) the X4 position is W, Q, R, G, L, V, S, or F; (e) the X5 position is N, Y, R, C, K, or L; (f) the X6 position is Q, G, K, R, T, L, or Y; and (g) the X7 position is Q, L, R, or V. In some embodiments, loop VIII includes positions 587–599, numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581–593, numbered according to sequence number 138 or 6414.

[0010] In yet another aspect, the present disclosure is (A)[A][B](Sequence ID 4699), wherein (i)[A] includes X1, X2, X3, X4, X5, and X6, (a) the X1 position is T, M, A, C, I, R, L, D, F, V, Q, N, or H, (b) the X2 position is I, P, E, N, D, S, A, T, M, or Q, (c) the X3 position is N, E, G, Y, W, M, T, I, K, Q, F, S, V, A, or L, (d) the X4 position is G, D, R, or E, (e) the X5 position is H, Q, N, or D, (f) the X6 position is D or R, and (ii)[B] The present invention provides an AAV capsid variant comprising [A][B] and / or (B) modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), wherein loop VIII optionally includes modifications such as loops 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or loops 581-593 numbered according to sequence numbers 138 or 6414.

[0011] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (A) an amino acid sequence having the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 6407), wherein (i) [N1] comprises positions X1, X2, and X3, with position X2 being S and position X3 being G, (ii) [N2] comprises the amino acid sequence SPH, and (iii) [N3] comprises positions X4, X5, and X6, with position X5 being K, and / or (B) a modification in loop VIII, e.g., a substitution (e.g., a conservative substitution). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NOs: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NOs: 138 or 6414. In some embodiments, [N1]-[N2]-[N3] are located immediately after position 452, numbered according to sequence number 138 or 982, and replace positions 453-455. In some embodiments, [N1]-[N2]-[N3] are or include GSGSPHSKA (sequence number 4697).

[0012] In another embodiment, the present disclosure provides an AAV capsid variant comprising (A) an amino acid sequence having the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 6408), wherein (i) [N1] comprises the X1, X2, and X3 positions, the X2 position being an amino acid other than S, the X3 position being an amino acid other than G, (ii) [N2] comprises the amino acid sequence SPH, and (iii) [N3] comprises the X4, X5, and X6 positions, the X4 position being K, and / or (B) a modification in loop VIII, e.g., a substitution (e.g., a conservative substitution). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NOs: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NOs: 138 or 6414. In some embodiments, [N1]-[N2]-[N3] are located immediately after position 452, numbered according to sequence number 138 or 982, and replace positions 453-455. In some embodiments, [N1]-[N2]-[N3] is or includes GHDSPHKSG (sequence number 4698).

[0013] In yet another aspect, the Disclosure comprises (A) formula [A]-[B] (sequence number 4696), where (i)[A] comprises GSGSPH (sequence number 4695), and (ii)[B] comprises X1, X2, X3, X4, and X5, where (a) the X1 position is S, I, F, V, C, Y, W, R, P, L, Q, M, K, or G, (b) the X2 position is K, M, R, F, V, C, P, Y, L, W, G, N, S, T, I, or A, (c) the X3 position is A, Y, L, R, W, C, T, F, H, I, P, M, K, S, V, G, Q, or N, and (d) the X4 position is Q, M, F, K, H, R, C, W, P, V, L, G, S, Y, I, A, T, The present invention provides an AAV capsid variant comprising the AAV capsid variant comprising the [A]-[B] and / or the (B) loop VIII, comprising an amino acid modification (e.g., a substitution) (e.g., a conservative substitution) of any of the above-mentioned amino acids in (a)-(e). In some embodiments, the loop VIII comprises positions 587-599, numbered according to SEQ ID NOs. 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NOs. 138 or 6414. In some embodiments, [A]-[B] is located immediately after position 452, and [A]-[B] replaces positions 453-457 (e.g., G453, S454, G455, Q456, N457) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid variant has increased tropism to liver cells or tissues compared to the tropism of the reference sequence containing the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid exhibits preferential transduction in the liver compared to transduction in the brain and / or dorsal root ganglia (DRG), for example, compared to SEQ ID NO: 138.

[0014] In another aspect, the Disclosure relates to (a) three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to Sequence ID No. 138, and (b) an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein [N1]-[N2]-[N3] is located in a hypervariable loop IV, and (i) [N1] includes X1, X2, and X3, and X1, X The present invention provides an AAV capsid variant comprising an amino acid sequence in which at least one of 2 or X3 is G, (ii)[N2] comprises the amino acid sequence of SPH, and (iii)[N3] comprises X4, X5, and X6, where at least one of X4, X5, or X6 is a basic amino acid, e.g., K or R, and the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203-736 of SEQ ID NO: 138.

[0015] In another embodiment, the Disclosure provides an AAV capsid variant comprising three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to Sequence ID No. 138, wherein the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to the amino acid sequence from positions 203 to 736 of Sequence ID No. 138. In some embodiments, the AAV capsid variant comprises an amino acid sequence having the following formula:[N1]-[N2]-[N3], where (i)[N1] comprises X1, X2, and X3, at least one of X1, X2, or X3 being G; (ii)[N2] comprises the amino acid sequence of SPH; (iii)[N3] comprises X4, X5, and X6, at least one of X4, X5, or X6 being a basic amino acid, e.g., K or R; and [N1]-[N2]-[N3] is located in the hypervariable loop IV.

[0016] In another embodiment, the Disclosure provides an AAV capsid variant comprising (a) three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138, and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV, wherein the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO: 138. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located immediately after amino acid 453, numbered according to SEQ ID NO: 982.

[0017] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (a) three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138, and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV, wherein the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO: 138. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located immediately after amino acid 455, numbered according to SEQ ID NO: 981.

[0018] In another aspect, the Disclosure relates to an AAV capsid variant which (i)(a) any amino acid sequence from any of the sequences provided in Tables 1, 2A, 2B, 13-19; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 13-19; (c) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 different amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 13-19; or (d) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), from any one of the sequences provided in Tables 1, 2A, 2B, 13-19. The present invention provides an AAV capsid variant comprising an acid sequence and / or (II)(i) the amino acid sequence of SEQ ID NO: 6419, (ii) an amino acid sequence comprising at least one or two but no more than three different amino acids relative to the amino acids of SEQ ID NO: 6419, (iii) an amino acid sequence comprising at least one or two modifications, e.g., substitutions (e.g., conservative substitutions), but no more than three modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 6419, or (iv) an amino acid sequence comprising at least three, four, five, six, or seven consecutive amino acids from SEQ ID NO: 6419, and optionally, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 590-596, numbered according to the amino acid sequences of SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the amino acid sequence is located in loop IV. In some embodiments, the amino acid sequence is located in loop VIII. In some embodiments, the amino acid sequence is located in loops IV and VIII. In some embodiments, the amino acid sequence is located immediately after positions 448, 452, 453, and 455 relative to a reference sequence numbered according to the amino acid sequence of sequence number 138 or 6414.In some embodiments, the amino acid sequence is located at positions 590, 592, 594, 595, and / or 596, numbered according to the amino acid sequence of SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the amino acid sequence is located at positions 594, 597, 598, and / or 599, numbered according to the amino acid sequence of SEQ ID NO: 981, 982, 6411, or 6412.

[0019] In yet another aspect, the Disclosure relates to an AAV capsid variant that (I)(a) any amino acid sequence from SEQ ID NOs. 945-980 or 985-986, (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from any one of SEQ ID NOs. 945-980 or 985-986, (c) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 different amino acids from any one of SEQ ID NOs. 945-980 or 985-986, (d) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), and / or (II) (II)(i) the amino acid sequence of SEQ ID NO: 6419, (ii) an amino acid sequence comprising at least one or two but no more than three different amino acids relative to the amino acid sequence of SEQ ID NO: 6419, (iii) an amino acid sequence comprising at least one or two modifications, e.g., substitutions (e.g., conservative substitutions), but no more than three modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 6419, or (iv) an AAV capsid variant comprising at least three, four, five, six, or seven consecutive amino acids from SEQ ID NO: 6419, wherein optionally, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 590-596, numbered according to the amino acid sequences of SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the amino acid sequence is located in loop IV. In some embodiments, the amino acid sequence is located in loop VIII. In some embodiments, the amino acid sequence is located in loops IV and VIII. In some embodiments, the amino acid sequence is located immediately after positions 448, 452, 453, and 455 of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence is located at positions 590, 592, 594, 595, and / or 596 of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981, 982, 6411, or 6412.In some embodiments, the amino acid sequence is present at position 594, 597, 598, and / or 599 numbered according to the amino acid sequence of SEQ ID NO: 981, 982, 6411, or 6412.

[0020] In yet another aspect, the Disclosure relates to an AAV capsid variant comprising (I) (a) any amino acid sequence of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, and (b) at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909 (c) an amino acid sequence containing an acid, (d) an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids for any one of the amino acid sequences of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, or (c) an amino acid sequence containing at least 1 The present invention provides an AAV capsid variant comprising: (i) an amino acid sequence having 2 or 3 but 4 or fewer modifications, e.g., substitutions (e.g., conservative substitutions); and / or (ii) the amino acid sequence of SEQ ID NO: 6419; (ii) an amino acid sequence having at least 1 or 2 but 3 or fewer different amino acids relative to the amino acid sequence of SEQ ID NO: 6419; (iii) an amino acid sequence having at least 1 or 2 modifications, e.g., substitutions (e.g., conservative substitutions), but 3 or fewer modifications, e.g., substitutions (e.g., conservative substitutions); or (iv) an amino acid sequence comprising at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID NO: 6419, wherein optionally, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 590-596, numbered according to the amino acid sequences of SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the amino acid sequence is located in loop IV. In some embodiments, the amino acid sequence is located in loop VIII. In some embodiments, the amino acid sequence is located in loops IV and VIII. In some embodiments, the amino acid sequence is located immediately after positions 448, 452, 453, and 455 of a reference sequence numbered according to the amino acid sequence of sequence number 138 or 6414.In some embodiments, the amino acid sequence is present at positions 590, 592, 594, 595, and / or 596 numbered according to the amino acid sequence of SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the amino acid sequence is present at positions 594, 597, 598, and / or 599 numbered according to the amino acid sequence of SEQ ID NO: 981, 982, 6411, or 6412.

[0021] In yet another aspect, the disclosure provides a polynucleotide encoding an AAV capsid variant described herein. In some embodiments, the polynucleotide comprises (i) a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, such as substitutions (e.g., conservative substitutions), but no more than 10 modifications, such as substitutions (e.g., conservative substitutions), with respect to the nucleotide sequence of SEQ ID NO: 3 or 942, (ii) a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, different nucleotides with respect to the nucleotide sequence of SEQ ID NO: 3 or 942, or (iii) the nucleotide sequence of SEQ ID NO: 3 or 942, or a nucleotide sequence that is substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0022] In yet another aspect, the Disclosure relates to an AAV capsid variant comprising an amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein (i) 3 consecutive amino acids comprise SPH, (ii) 4 consecutive amino acids comprise SPHS (SEQ ID NO: 4700), (iii) 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 4701), or (iv) 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941), and the AAV capsid variant also comprises (a) SEQ ID NO: 138 The present invention provides an AAV capsid variant comprising: (a) a VP1 protein containing the amino acid sequence of SEQ ID NO: 981; (b) a VP2 protein containing the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981; (c) a VP3 protein containing the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) an AAV capsid variant comprising 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). In some embodiments, the amino acid sequence is located immediately after position 455, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions). In some embodiments, loop VIII includes positions 587–599, numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581–593, numbered according to sequence number 138 or 6414.

[0023] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising one or two but no more than three substitutions to the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the AAV capsid variant comprises (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981, (b) a VP2 protein comprising the amino acid sequence at positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981, (c) a VP3 protein comprising the amino acid sequence at positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981, 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). In some embodiments, the amino acid sequence is located immediately after position 455, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant includes modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions). In some embodiments, loop VIII includes positions 587–599, numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581–593, numbered according to sequence number 138 or 6414.

[0024] In another aspect, the Disclosure relates to an AAV capsid variant comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein (i) 3 consecutive amino acids comprise HDS, (ii) 4 consecutive amino acids comprise HDSP (SEQ ID NO: 4702), (iii) 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 4703), and / or (iv) 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2), and the AAV capsid variant comprises (a) SEQ ID NO: 138 or SEQ ID NO: 9 The present invention provides an AAV capsid variant comprising: (b) a VP1 protein containing an 82-amino acid sequence; (c) a VP2 protein containing an amino acid sequence at positions 138-736 of SEQ ID NO: 138 or 138-742 of SEQ ID NO: 982; (d) a VP3 protein containing an amino acid sequence 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). In some embodiments, the amino acid sequence is located immediately after position 453, numbered according to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant includes modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions). In some embodiments, loop VIII includes positions 587–599, numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581–593, numbered according to sequence number 138 or 6414.

[0025] In another embodiment, the Disclosure provides an AAV capsid variant comprising one or two but no more than three substitutions to the amino acid sequence of HDSPHK (SEQ ID NO: 2), 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 at positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982, (c) a VP3 protein comprising the amino acid sequence at positions 203-736 of SEQ ID NO: 138 or positions 203-742 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). In some embodiments, the AAV capsid variant comprises modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions). In some embodiments, loop VIII includes positions 587–599, numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581–593, numbered according to sequence number 138 or 6414.

[0026] In yet another aspect, the Disclosure provides peptides comprising: (a) any amino acid sequence from among the sequences provided in Tables 1, 2A, 2B, 13-19, or 33; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 13-19, or 33; (c) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 different amino acids for any one of the sequences provided in Tables 1, 2A, 2B, 13-19, or 33; or (d) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), for any one of the sequences provided in Tables 1, 2A, 2B, 13-19, or 33.

[0027] In another aspect, the present disclosure provides a peptide comprising (a) any amino acid sequence from SEQ ID NOs: 945-980 or 985-986, (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from any one of SEQ ID NOs: 945-980 or 985-986, (c) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 different amino acids from any one of SEQ ID NOs: 945-980 or 985-986, or (d) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 modifications, e.g., substitutions (e.g., substitutions) from any one of SEQ ID NOs: 945-980 or 985-986.

[0028] In another aspect, the Disclosure may include (a) any amino acid sequence of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 2, 200, 201, 941, 943, 943, 204, The present invention provides an amino acid sequence comprising at least one, two, or three but no more than four different amino acids for any one amino acid sequence among 208, 404, or 903-909, or (d) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), for any one amino acid sequence among Sequence ID No. 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, e.g., substitutions (e.g., conservative substitutions).

[0029] In yet another aspect, the disclosure provides a peptide comprising (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), (ii) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), (iii) an amino acid sequence comprising at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), or (iv) at least three, four, or five consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0030] In yet another aspect, the Disclosure provides a peptide encoded by (i) the nucleotide sequence of SEQ ID NO: 942, or a nucleotide sequence substantially identical thereto (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or (ii) a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942, or (iii) a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 10 modifications, e.g., substitutions (e.g., conservative substitutions).

[0031] In yet another aspect, the Disclosure provides a peptide comprising a nucleotide sequence encoding the peptide, comprising: (i) the nucleotide sequence of SEQ ID NO: 942, or a nucleotide sequence substantially identical thereto (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); (ii) a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942; or (iii) a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 10 modifications, e.g., substitutions (e.g., conservative substitutions).

[0032] In another aspect, the Disclosure provides a peptide comprising (i) the amino acid sequence of HDSPHK(SEQ ID NO: 2), (ii) an amino acid sequence of HDSPHK(SEQ ID NO: 2) comprising at least one, two, or three but no more than four different amino acids, (iii) an amino acid sequence of HDSPHK(SEQ ID NO: 2) comprising at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), or (iv) at least three, four, or five consecutive amino acids from the amino acid sequence of HDSPHK(SEQ ID NO: 2).

[0033] In yet another aspect, the Disclosure provides a peptide encoded by (i) the nucleotide sequence of SEQ ID NO: 3, 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 comprising at least 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3, and (iii) a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 10 modifications, e.g., substitutions (e.g., conservative substitutions).

[0034] In another aspect, the Disclosure provides a peptide comprising a nucleotide sequence encoding the peptide, comprising: (i) the nucleotide sequence of SEQ ID NO: 3, 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 comprising at least 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3; or (iii) a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 10 modifications, e.g., substitutions (e.g., conservative substitutions).

[0035] In yet another aspect, the Disclosure relates to polynucleotides encoding AAV capsid variants, which include (I) (a) any amino acid sequence from any of the sequences provided in Tables 1, 2A, 2B, 13-19; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 13-19; (c) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 different amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 13-19; or (d) at least 1, 2, or 3 but no more than 4 modifications, e.g., substitutions (e.g., The present invention provides a polynucleotide encoding an AAV capsid variant, comprising an amino acid sequence including (conservative substitutions), and / or (II) (i) any amino acid sequence from among the sequences provided in Table 33, (ii) an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids for any one of the amino acid sequences provided in Table 33, (iii) an amino acid sequence containing at least 1, 2, or 3 modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), or (iv) a polynucleotide encoding an AAV capsid variant containing at least 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive amino acids from any one of the amino acid sequences in Table 33. In some embodiments, the amino acid sequences of (a), (b), (c), and / or (d) are located immediately after positions 448, 449, 450, 451, 452, 453, 454, or 455 of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 500-511 of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0036] In yet another aspect, the Disclosure relates to a polynucleotide encoding an AAV capsid variant, wherein the AAV capsid variant comprises (I) (a) the amino acid sequence of SPHSKA (SEQ ID NO: 941), (b) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 different amino acids relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), (c) an amino acid sequence comprising at least 1, 2, or 3 modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), or (d) at least 3, 4, 5, 6, 7, 8, or 9 consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941), and / or ( II) Provided are polynucleotides encoding an AAV capsid variant, comprising (i) any amino acid sequence from among the sequences provided in Table 33, (ii) an amino acid sequence containing at least one, two, or three but no more than four different amino acids for any one amino acid sequence from among the amino acid sequences provided in Table 33, (iii) an amino acid sequence containing at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), for any one amino acid sequence from among the amino acid sequences of Table 33. In some embodiments, the amino acid sequences of (a), (b), (c), and / or (d) are located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138. In some embodiments, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 500–511, numbered according to the amino acid sequence of sequence number 981 or 982.

[0037] In another embodiment, the present disclosure relates to a polynucleotide encoding an AAV capsid variant, wherein the AAV capsid variant comprises (I) (a) the amino acid sequence of HDSPHK (SEQ ID NO: 2), (b) an amino acid sequence comprising at least 1, 2, or 3 but no more than 4 different amino acids relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), (c) an amino acid sequence comprising at least 1, 2, or 3 modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 4 modifications, e.g., substitutions (e.g., conservative substitutions), or (d) at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2), and / or (II) (i) any amino acid sequence from the sequences provided in Table 33, (ii) an amino acid sequence from the sequences provided in Table 33 (iii) an amino acid sequence containing at least one, two, or three but no more than four different amino acids for any one amino acid sequence in any of the sequences in the column; (iii) an amino acid sequence containing at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than four modifications, e.g., substitutions (e.g., conservative substitutions) for any one amino acid sequence in any of the sequences in Table 33; or (iv) a polynucleotide encoding an AAV capsid variant containing at least three, four, five, six, seven, eight, nine, ten, or eleven consecutive amino acids from any one of the amino acid sequences in Table 33, and optionally, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 500-511, numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. In some embodiments, the amino acid sequences of (a), (b), (c), and / or (d) are located immediately after position 453 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 500–511, numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0038] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPH, wherein the amino acid sequence is located immediately after position 455, numbered according to any one of the amino acid sequences of SEQ ID NOs. 5-10, 36-59, 138, 981, 982, or 6409-6413, and / or (ii) a modification in loop VIII, e.g., a substitution (e.g., a conservative substitution). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NOs. 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NOs. 138 or 6414.

[0039] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, and / or (ii) modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NO: 138 or 6414.

[0040] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 981 or 6411, and / or (ii) modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NO: 138 or 6414.

[0041] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411, and (ii) one, two, three, four, or all of the amino acids other than H at position 590, S at position 592, Q at position 594, A at position 595, and / or Q at position 596, numbered according to SEQ ID NO: 981 or 6411. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0042] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411; and (ii) an amino acid other than H at position 590, S at position 592, Q at position 594, A at position 595, and Q at position 596, numbered according to SEQ ID NO: 981 or 6411. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0043] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411; and (ii) one, two, three, four, or all of the amino acids R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 981 or 6411, or a substitution thereof, e.g., a conservative substitution. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0044] In yet another aspect, the Disclosure provides an AAV capsid variant comprising (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411, and (ii) one, two, three, four, or all of the amino acids R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 981 or 6411, or a substitution thereof, such as a conservative substitution.

[0045] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411; and (ii) an amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 981 or 6411. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0046] In yet another aspect, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411, and (ii) an amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981 or 6411.

[0047] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411, and (ii) one, two, three, four, or all of the amino acids other than H at position 584, S at position 586, Q at position 588, A at position 589, and / or Q at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0048] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411; and (ii) an amino acid other than H at position 584, S at position 586, Q at position 588, A at position 589, and Q at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0049] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411; and (ii) one, two, three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138 or 6414, or a substitution thereof, e.g., a conservative substitution. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0050] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 6411; and (ii) an amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

[0051] In yet another aspect, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411, and (ii) an amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414.

[0052] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412, and / or (ii) a modification in loop VIII, e.g., a substitution (e.g., a conservative substitution). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0053] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412, and (ii) one, two, three, four, or all of the amino acids other than H at position 590, S at position 592, Q at position 594, A at position 595, and / or Q at position 596, numbered according to SEQ ID NO: 982 or 6412. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0054] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK(SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412, and (ii) an amino acid other than H at position 590, S at position 592, Q at position 594, A at position 595, and Q at position 596, numbered according to SEQ ID NO: 982 or 6412. In some embodiments, the amino acid sequence of HDSPHK(SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0055] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412; and (ii) one, two, three, four, or all of the amino acids R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 982 or 6412, or a substitution thereof, e.g., a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0056] In yet another aspect, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412, and (ii) one, two, three, four, or all of the amino acids R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 982 or 6412, or a substitution thereof, such as a conservative substitution.

[0057] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK(SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412; and (ii) an amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 982 or 6412. In some embodiments, the amino acid sequence of HDSPHK(SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0058] In yet another aspect, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412, and (ii) an amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 982 or 6412.

[0059] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412, and (ii) one, two, three, four, or all of the amino acids other than H at position 584, S at position 586, Q at position 588, A at position 589, and / or Q at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0060] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412, and (ii) an amino acid other than H at position 584, S at position 586, Q at position 588, A at position 589, and Q at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0061] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412; and (ii) one, two, three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138 or 6414, or a substitution thereof, e.g., a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0062] In yet another aspect, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412, and (ii) one, two, three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138 or 6414, or a substitution thereof, such as a conservative substitution.

[0063] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, 982, or 6412; and (ii) an amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0064] In yet another aspect, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412, and (ii) an amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414.

[0065] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) one, two, three, or all of the amino acids other than Q at position 594, A at position 597, Q at position 598, and / or T at position 599, numbered according to SEQ ID NO: 982 or 6413. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0066] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) an amino acid other than Q at position 594, A at position 597, Q at position 598, and T at position 599, numbered according to SEQ ID NO: 982 or 6413. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0067] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) one, two, three, or all of the amino acids K at position 594, S at position 597, S at position 598, and / or A at position 599, numbered according to SEQ ID NO: 982 or 6413, or a substitution thereof, e.g., a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0068] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) an amino acid K at position 594, S at position 597, S at position 598, and A at position 599, numbered according to SEQ ID NO: 982 or 6413. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0069] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) one, two, three, or all of the amino acids other than Q at position 588, A at position 591, Q at position 592, and / or T at position 593, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0070] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK(SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) an amino acid other than Q at position 588, A at position 591, Q at position 592, and T at position 593, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK(SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0071] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) one, two, three, or all of the amino acids K at position 588, S at position 591, S at position 592, and / or A at position 593, numbered according to SEQ ID NO: 138 or 6414, or a substitution thereof, e.g., a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0072] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982, and (ii) an amino acid K at position 588, S at position 591, S at position 592, and A at position 593, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0073] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 982, and / or (ii) a loop VIII including positions 587-599, numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

[0074] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located in loop IV with respect to the reference sequence of SEQ ID NO: 138, and / or (ii) modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, loop IV comprises positions 449-460, numbered according to SEQ ID NO: 138.

[0075] In yet another embodiment, the Disclosure provides an AAV capsid variant comprising (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located in loop IV with respect to the reference sequence of SEQ ID NO: 138, and / or (ii) a modification in loop VIII, e.g., a substitution (e.g., a conservative substitution). In some embodiments, loop VIII comprises positions 587-599, numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, loop IV comprises positions 449-460, numbered according to SEQ ID NO: 138.

[0076] In yet another embodiment, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6411.

[0077] In yet another embodiment, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412.

[0078] In yet another embodiment, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6413.

[0079] In yet another embodiment, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6414.

[0080] In yet another aspect, the present disclosure provides AAV capsid variants comprising one, two, three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138 or 6414, or substitutions thereof, such as conservative substitutions.

[0081] In yet another aspect, the present disclosure provides an AAV capsid variant comprising amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414.

[0082] In yet another embodiment, the disclosure provides AAV particles comprising the AAV capsid variants described herein. In some embodiments, the AAV particles include a nucleic acid sequence encoding a payload. In some embodiments, the AAV particles further include a viral genome comprising a promoter operably ligated to the nucleic acid encoding the payload.

[0083] In yet another aspect, the Disclosure provides a method for producing AAV particles comprising the AAV capsid variant described herein. The method comprises providing a host cell containing a viral genome and incubating the host cell under conditions suitable for encapsulating the viral genome in an AAV capsid variant, such as the AAV capsid variant described herein, thereby producing AAV particles.

[0084] In yet another aspect, the Disclosure provides a method for delivering a payload to cells or tissues (e.g., CNS cells, CNS tissue, hepatocytes, or hepatic tissue). The method comprises administering an effective amount of AAV particles containing the AAV capsid variant described herein.

[0085] In yet another aspect, the Disclosure provides a method for treating a subject who has or has been diagnosed with a genetic disorder, such as a monogenic or polygenic disorder. The method comprises administering an effective amount of AAV particles containing the AAV capsid variant described herein to the subject.

[0086] In yet another aspect, the Disclosure provides a method for treating a subject having or diagnosed with a neurological disorder, such as a neurodegenerative disorder. The method comprises administering an effective amount of AAV particles containing the AAV capsid variant described herein.

[0087] In yet another aspect, the Disclosure provides a method for treating a subject having or diagnosed with a neurotumor disorder. The method comprises administering an effective amount of AAV particles containing the AAV capsid variant described herein.

[0088] Those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments of the invention described herein simply by using standard experiments. Such equivalents are intended to be encompassed by the embodiments listed below.

[0089] Enumerated embodiments 1. AAV capsid variant, (A) Modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), which optionally include loop VIII having positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414, and / or (B) The following formula: contains an amino acid sequence having [N1]-[N2]-[N3], in which, (i) Optionally, [N1] includes X1, X2, and X3, and at least one of X1, X2, or X3 is G. (ii)[N2] contains the amino acid sequence of SPH, (iii) The AAV capsid variant wherein [N3] comprises X4, X5, and X6, and at least one of X4, X5, or X6 is a basic amino acid, e.g., K or R.

[0090] 2. The AAV capsid variant according to Embodiment 1, wherein X4, X5, or both of [N3] are K.

[0091] 3. An AAV capsid variant according to Embodiment 1 or 2, wherein X4, X5, or X6 of [N3] is R.

[0092] 4. (a) The X4th position of [N3] is K, S, A, V, T, G, F, W, V, N, or R, (b) The X5 position of [N3] is S, K, T, F, I, L, Y, H, M, or R, and / or (c) The 6th letter of X in [N3] is G, A, R, M, I, N, T, Y, D, P, V, L, E, W, N, Q, K, or S. Optionally, the AAV capsid variant according to any one of Embodiments 1 to 3 includes an amino acid modification, e.g., a conservative substitution, among the amino acids in (a) to (c).

[0093] 5. An AAV capsid variant according to any one of Embodiments 1 to 4, wherein [N3] includes SK, KA, KS, AR, RM, VK, AS, SR, VK, KR, KK, KN, VR, RS, RK, KT, TS, KF, FG, KI, IG, KL, LG, TT, TY, KY, YG, KD, KP, TR, RG, VR, GA, SL, SS, FL, WK, SA, RA, LR, KW, RR, GK, TK, NK, AK, KV, KG, KH, KM, TG, SE, SV, SW, SN, HG, SQ, LW, MG, MA, or SG.

[0094] 6. An AAV capsid variant according to any one of Embodiments 1 to 5, wherein [N3] is SKA, KSG, ARM, VKS, ASR, VKI, KKN, VRM, RKA, KTS, KFG, KIG, KLG, KTT, KTY, KYG, SKD, SKP, TRG, VRG, KRG, GAR, KSA, KSR, SKL, SRA, SKR, SLR, SRG, SSR, FLR, SKW, SKS, WKA, VRR, SKV, SKT, SKG, GKA, TKA, NKA, SKL, SKN, AKA, KTG, KSL, KSE, KSV, KSW, KSN, KHG, KSQ, KSK, KLW, WKG, KMG, KMA, or RSG, or includes the same.

[0095] 7. [N2]-[N3] are SPHSK (sequence number 4701), SPHKS (sequence number 4704), SPHAR (sequence number 4705), SPHVK (sequence number 4706), SPHAS (sequence number 4707), SPHKK (sequence number 4708), SPHVR (sequence number 4709), SPHRK (sequence number 4710), SPHKT (sequence number 4711), SPHKF (sequence number 4712), SPHKI (sequence number 4713), SPHKL (sequence number 4714), SPHKY (sequence number 4715), SPHTR (sequence number 4716), SPHKR (sequence number 47 17) An AAV capsid variant according to any one of Embodiments 1 to 6, comprising SPHGA (SEQ ID NO: 4718), SPHSR (SEQ ID NO: 4719), SPHSL (SEQ ID NO: 4720), SPHSS (SEQ ID NO: 4721), SPHFL (SEQ ID NO: 4722), SPHWK (SEQ ID NO: 4723), SPHGK (SEQ ID NO: 4724), SPHTK (SEQ ID NO: 4725), SPHNK (SEQ ID NO: 4726), SPHAK (SEQ ID NO: 4727), SPHKH (SEQ ID NO: 4728), SPHKM (SEQ ID NO: 4729), or SPHRS (SEQ ID NO: 4730).

[0096] 8. [N2]-[N3] is, (i) SPHSKA (SEQ ID NO: 941), SPHKSG (SEQ ID NO: 946), SPHARM (SEQ ID NO: 947), SPHVKS (SEQ ID NO: 948), SPHASR (SEQ ID NO: 949), SPHVKI (SEQ ID NO: 950), SPHKKN (SEQ ID NO: 954), SPHVRM (SEQ ID NO: 955), SPHRKA (SEQ ID NO: 956), SPHKFG (SEQ ID NO: 957), SPHKIG (SEQ ID NO: 958), SPHKLG (SEQ ID NO: 959), SPHKTS (SEQ ID NO: 963), SPHKTT (SEQ ID NO: 964), SPHKTY (SEQ ID NO: 964) Column number 965), SPHKYG (sequence number 966), SPHSKD (sequence number 967), SPHSKP (sequence number 968), SPHTRG (sequence number 972), SPHVRG (sequence number 973), SPHKRG (sequence number 974), SPHGAR (sequence number 975), SPHKSA (sequence number 977), SPHKSR (sequence number 951), SPHSKL (sequence number 960), SPHSRA (sequence number 969), SPHSKR (sequence number 978), SPHSLR (sequence number 952), SPHSRG (sequence number 961), SPH SSR (SEQ ID NO: 970), SPHFLR (SEQ ID NO: 979), SPHSKW (SEQ ID NO: 953), SPHSKS (SEQ ID NO: 962), SPHWKA (SEQ ID NO: 971), SPHVRR (SEQ ID NO: 980), SPHSKT (SEQ ID NO: 4731), SPHSKG (SEQ ID NO: 4732), SPHGKA (SEQ ID NO: 4733), SPHNKA (SEQ ID NO: 4734), SPHSKN (SEQ ID NO: 4735), SPHAKA (SEQ ID NO: 4736), SPHSKV (SEQ ID NO: 4737), SPHKTG (SEQ ID NO: 4738), SPHTKA (SEQ ID NO: 4739), SPHKSL (SEQ ID NO: 4740), SPHKSE (SEQ ID NO: 4741), SPHKSV (SEQ ID NO: 4742), SPHKSW (SEQ ID NO: 4743), SPHKSN (SEQ ID NO: 4744), SPHKHG (SEQ ID NO: 4745), SPHKSQ (SEQ ID NO: 4746), SPHKSK (SEQ ID NO: 4747), SPHKLW (SEQ ID NO: 4748), SPHWKG (SEQ ID NO: 4749), SPHKMG (SEQ ID NO: 4750), SPHKMA (SEQ ID NO: 4751), or SPHRSG (SEQ ID NO: 976), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 1 to 7, wherein the amino acid sequence in any one of the amino acid sequences in (i) contains one, two, or three but no more than four different amino acids.

[0097] 9. An AAV capsid variant according to any one of Embodiments 1 to 8, comprising an amino acid other than G at position 453 (e.g., V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C), an amino acid other than S at position 454 (V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q), and / or G at position 455 (e.g., C, L, D, E, Y, H, V, A, N, P, or S), numbered according to any one of Sequence IDs 5 to 10, 36 to 59, 138, 981, 982, or 6409 to 6414.

[0098] 10. An AAV capsid variant according to any one of Embodiments 1 to 8, comprising amino acid G at position 453, amino acid S at position 454, and amino acid G at position 455, numbered according to Sequence ID No. 138 or 981.

[0099] 11. An AAV capsid variant according to any one of Embodiments 1 to 9, comprising amino acid G at position 453, amino acid H at position 454, and amino acid D at position 455, numbered according to Sequence ID No. 138 or 982.

[0100] 12. An AAV capsid variant according to any one of Embodiments 1 to 11, wherein [N1] comprises X1, X2, and X3, and at least one of X1, X2, or X3 is G.

[0101] 13. (a) The X1 position of [N1] is G, V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C. (b) The X2 position of [N1] is S, V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q, and / or (c) The third letter of X in [N1] is G, C, L, D, E, Y, H, V, A, N, P, or S. An AAV capsid variant according to any one of Embodiments 1 to 12, wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the amino acids in (a) to (c).

[0102] 14. An AAV capsid variant according to any one of Embodiments 1 to 13, wherein [N1] includes GS, SG, GH, HD, GQ, QD, VS, CS, GR, RG, QS, SH, MS, RN, TS, IS, GP, ES, SS, GN, AS, NS, LS, GG, KS, GT, PS, RS, GI, WS, DS, ID, GL, DA, DG, ME, EN, KN, KE, AI, NG, PG, TG, SV, IG, LG, AG, EG, SA, YD, HE, HG, RD, ND, PD, MG, QV, DD, HN, HP, GY, GM, GD, or HS.

[0103] 15. An AAV capsid variant according to any one of Embodiments 1 to 14, wherein [N1] is GSG, GHD, GQD, VSG, CSG, GRG, CSH, GQS, GSH, RVG, GSC, GLL, GDD, GHE, GNY, MSG, RNG, TSG, ISG, GPG, ESG, SSG, GNG, ASG, NSG, LSG, GGG, KSG, HSG, GTG, PSG, GSV, RSG, GIG, WSG, DSG, IDG, GLG, DAG, DGG, MEG, ENG, GSA, KNG, KEG, AIG, GYD, GHG, GRD, GND, GPD, GMG, GQV, GHN, GHP, or GHS, or includes them.

[0104] 16. [N1]-[N2] is, (i)SGSPH (sequence number 4752), HDSPH (sequence number 4703), QDSPH (sequence number 4753), RGSPH (sequence number 4754), SHSPH (sequence number 4755), QSSPH (sequence number 4756), DDSPH (sequence number 4757), HESPH (sequence number 4758), NYSPH (sequence number 4759), VGSPH (sequence number 4760), SCSPH (sequence number 4761), LLSPH (sequence number 4762), NGSPH (sequence number 4763), PGSPH (sequence number 4764), GGSPH (sequence number 4765), TGSPH (sequence number 4766), SVSPH (sequence number) Number 4767), IGSPH (sequence number 4768), DGSPH (sequence number 4769), LGSPH (sequence number 4770), AGSPH (sequence number 4771), EGSPH (sequence number 4772), SASPH (sequence number 4773), YDSPH (sequence number 4774), HGSPH (sequence number 4775), RDSPH (sequence number 4776), NDSPH (sequence number 4777), PDSPH (sequence number 4778), MGSPH (sequence number 4779), QVSPH (sequence number 4780), HNSPH (sequence number 4781), HPSPH (sequence number 4782), or HSSPH (sequence number 4783), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any two, three, or four amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 1 to 15, comprising an amino acid sequence containing one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i).

[0105] 17. [N1]-[N2] is, (i) GSGSPH (SEQ ID NO: 4695), GHDSPH (SEQ ID NO: 4784), GQDSPH (SEQ ID NO: 4785), VSGSPH (SEQ ID NO: 4786), CSGSPH (SEQ ID NO: 4787), GRGSPH (SEQ ID NO: 4788), CSHSPH (SEQ ID NO: 4789), GQSSPH (SEQ ID NO: 4790), GSHSPH (SEQ ID NO: 4791), GDDSPH (SEQ ID NO: 4792), GHESPH (SEQ ID NO: 4793), GNYSPH (SEQ ID NO: 4794), RVGSPH (SEQ ID NO: 4795), GSCSPH (SEQ ID NO: 4796) ), GLLSPH (sequence number 4797), MSGSPH (sequence number 4798), RNGSPH (sequence number 4799), TSGSPH (sequence number 4800), ISGSPH (sequence number 4801), GPGSPH (sequence number 4802), ESGSPH (sequence number 4803), SSGSPH (sequence number 4804), GNGSPH (sequence number 4805), ASGSPH (sequence number 4806), NSGSPH (sequence number 4807), LSGSPH (sequence number 4808), GGGSPH (sequence number 4809), KSGSPH (sequence number 4810), HSGSPH (SEQ ID NO: 4811), GTGSPH (SEQ ID NO: 4812), PSGSPH (SEQ ID NO: 4813), GSVSPH (SEQ ID NO: 4814), RSGSPH (SEQ ID NO: 4815), GIGSPH (SEQ ID NO: 4816), WSGSPH (SEQ ID NO: 4817), DSGSPH (SEQ ID NO: 4818), IDGSPH (SEQ ID NO: 4819), GLGSPH (SEQ ID NO: 4820), DAGSPH (SEQ ID NO: 4821), DGGSPH (SEQ ID NO: 4822), MEGSPH (SEQ ID NO: 4823), ENGSPH (SEQ ID NO: 4824), GS ASPH (SEQ ID NO: 4825), KNGSPH (SEQ ID NO: 4826), KEGSPH (SEQ ID NO: 4827), AIGSPH (SEQ ID NO: 4828), GYDSPH (SEQ ID NO: 4829), GHGSPH (SEQ ID NO: 4830), GRDSPH (SEQ ID NO: 4831), GNDSPH (SEQ ID NO: 4832), GPDSPH (SEQ ID NO: 4833), GMGSPH (SEQ ID NO: 4834), GQVSPH (SEQ ID NO: 4835), GHNSPH (SEQ ID NO: 4836), GHPSPH (SEQ ID NO: 4837), or GHSSPH (SEQ ID NO: 4838), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 1 to 16, wherein the amino acid sequence in any one of the amino acid sequences in (i) contains one, two, or three but no more than four different amino acids, or contains such a sequence.

[0106] 18. [N1]-[N2]-[N3] is (i)SGSPHSK (SEQ ID NO: 4839), HDSPHKS (SEQ ID NO: 4840), SGSPHAR (SEQ ID NO: 4841), SGSPHVK (SEQ ID NO: 4842), QDSPHKS (SEQ ID NO: 4843), SGSPHKK (SEQ ID NO: 4844), SGSPHVR (SEQ ID NO: 4845), SGSPHAS (SEQ ID NO: 4846), SGSPHRK (SEQ ID NO: 4847), SGSPHKT (SEQ ID NO: 4848), SHSPHKS (SEQ ID NO: 4849), QSSPHRS (SEQ ID NO: 4850), RGSPHAS (SEQ ID NO: 4851), RGSPHSK (SEQ ID NO: 4849) SGSPHKF (SEQ ID NO: 4852), SGSPHKI (SEQ ID NO: 4854), SGSPHKL (SEQ ID NO: 4855), SGSPHKY (SEQ ID NO: 4856), SGSPHTR (SEQ ID NO: 4857), SHSPHKR (SEQ ID NO: 4858), SGSPHGA (SEQ ID NO: 4859), HDSPHKR (SEQ ID NO: 4860), DDSPHKS (SEQ ID NO: 4861), HESPHKS (SEQ ID NO: 4862), NYSPHKI (SEQ ID NO: 4863), SGSPHSR (SEQ ID NO: 4864), SGSPHSL (SEQ ID NO: 4865), SGSPHSS (SEQ ID NO: 4866), VGSPHSK (SEQ ID NO: 4867), SCSPHRK (SEQ ID NO: 4868), SGSPHFL (SEQ ID NO: 4869), LLSPHWK (SEQ ID NO: 4870), NGSPHSK (SEQ ID NO: 4871), PGSPHSK (SEQ ID NO: 4872), GGSPHSK (SEQ ID NO: 4873), TGSPHSK (SEQ ID NO: 4874), SVSPHGK (SEQ ID NO: 4875), SGSPHTK (SEQ ID NO: 4876), IGSPHSK (SEQ ID NO: 4877), DGSPHSK (SEQ ID NO: 4878), SGSPHNK (SEQ ID NO: 4879), LGS PHSK (SEQ ID NO: 4880), AGSPHSK (SEQ ID NO: 4881), EGSPHSK (SEQ ID NO: 4882), SASPHSK (SEQ ID NO: 4883), SGSPHAK (SEQ ID NO: 4884), HDSPHKI (SEQ ID NO: 4885), YDSPHKS (SEQ ID NO: 4886), HDSPHKT (SEQ ID NO: 4887), RGSPHKR (SEQ ID NO: 4888), HGSPHSK (SEQ ID NO: 4889), RDSPHKS (SEQ ID NO: 4890), NDSPHKS (SEQ ID NO: 4891), QDSPHKI (SEQ ID NO: 4892), PDSPHKI (SEQ ID NO: 4893),PDSPHKS (sequence code 4894), MGSPHSK (sequence code 4895), HDSPHKH (sequence code 4896), QVSPHKS (sequence code 4897), HNSPHKS (sequence code 4898), NGSPHKR (sequence code 4899), HDSPHKY (sequence code 4900), NDSPHKI (sequence code 4901), HDSPHKL (sequence code 4902), HPSPHWK (sequence code 4903), HDSPHKM (sequence code 4904), or HSSPHRS (sequence code 4905), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, or 6 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 1 to 17, comprising an amino acid sequence containing one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i).

[0107] 19. [N1]-[N2]-[N3] is (i) GSGSPHSKA (SEQ ID NO: 4697), GHDSPHKSG (SEQ ID NO: 4698), GSGSPHARM (SEQ ID NO: 4906), GSGSPHVKS (SEQ ID NO: 4907), GQDSPHKSG (SEQ ID NO: 4908), GSGSPHASR (SEQ ID NO: 4909), GSGSPHVKI (SEQ ID NO: 4910), GSGSPHKKN (SEQ ID NO: 4911), GSGSPHVRM (SEQ ID NO: 4912), VSGSPHSKA (SEQ ID NO: 4913), CSGSPHSKA (SEQ ID NO: 4914), GSGSPHRKA (SEQ ID NO: 4915), CS GSPHKTS (SEQ ID NO: 4916), CSHSPHKSG (SEQ ID NO: 4917), GQSSPHRSG (SEQ ID NO: 4918), GRGSPHASR (SEQ ID NO: 4919), GRGSPHSKA (SEQ ID NO: 4920), GSGSPHKFG (SEQ ID NO: 4921), GSGSPHKIG (SEQ ID NO: 4922), GSGSPHKLG (SEQ ID NO: 4923), GSGSPHKTS (SEQ ID NO: 4924), GSGSPHKTT (SEQ ID NO: 4925), GSGSPHKTY (SEQ ID NO: 4926), GSGSPHKYG (SEQ ID NO: 4927), GSGSPHSK D (SEQ ID NO: 4928), GSGSPHSKP (SEQ ID NO: 4929), GSGSPHTRG (SEQ ID NO: 4930), GSGSPHVRG (SEQ ID NO: 4931), GSHSPHKRG (SEQ ID NO: 4932), GSHSPHKSG (SEQ ID NO: 4933), VSGSPHASR (SEQ ID NO: 4934), VSGSPHGAR (SEQ ID NO: 4935), VGSPHKFG (SEQ ID NO: 4936), GHDSPHKRG (SEQ ID NO: 4937), GDDSPHKSG (SEQ ID NO: 4938), GHESPHKSA (SEQ ID NO: 4939), GHDSPHKSA (SEQ ID NO: 4938) 4940), GNYSPHKIG (SEQ ID NO: 4941), GHDSPHKSR (SEQ ID NO: 4942), GSGSPHSKL (SEQ ID NO: 4943), GSGSPHSRA (SEQ ID NO: 4944), GSGSPHSKR (SEQ ID NO: 4945), GSGSPHSLR (SEQ ID NO: 4946), GSGSPHSRG (SEQ ID NO: 4947), GSGSPHSSR (SEQ ID NO: 4948), RVGSPHSKA (SEQ ID NO: 4949), GSCSPHRKA (SEQ ID NO: 4950), GSGSPHFLR (SEQ ID NO: 4951), GSGSPHSKW (SEQ ID NO: 4952),GSGSPHSKS (SEQ ID NO: 4953), GLLSPHWKA (SEQ ID NO: 4954), GSGSPHVRR (SEQ ID NO: 4955), GSGSPHSKV (SEQ ID NO: 4956), MSGSPHSKA (SEQ ID NO: 4957), RNGSPHSKA (SEQ ID NO: 4958), TSGSPHSKA (SEQ ID NO: 4959), ISGSPHSKA (SEQ ID NO: 4960), GPGSPHSKA (SEQ ID NO: 4961), GSGSPHSKT (SEQ ID NO: 4962), ESGSPHSKA (SEQ ID NO: 4963), SSGSPHSKA (SEQ ID NO: 4964), GNGSPHSKA ( SEQ ID NO: 4965), ASGSPHSKA (SEQ ID NO: 4966), NSGSPHSKA (SEQ ID NO: 4967), LSGSPHSKA (SEQ ID NO: 4968), GGGSPHSKA (SEQ ID NO: 4969), KSGSPHSKA (SEQ ID NO: 4970), GGGSPHSKS (SEQ ID NO: 4971), GSGSPHSKG (SEQ ID NO: 4972), HSGSPHSKA (SEQ ID NO: 4973), GTGSPHSKA (SEQ ID NO: 4974), PSGSPHSKA (SEQ ID NO: 4975), GSVSPHGKA (SEQ ID NO: 4976), RSGSPHSKA (SEQ ID NO: 4977), GSGSPHTKA (SEQ ID NO: 4978), GIGSPHSKA (SEQ ID NO: 4979), WSGSPHSKA (SEQ ID NO: 4980), DSGSPHSKA (SEQ ID NO: 4981), IDGSPHSKA (SEQ ID NO: 4982), GSGSPHNKA (SEQ ID NO: 4983), GLGSPHSKS (SEQ ID NO: 4984), DAGSPHSKA (SEQ ID NO: 4985), DGGSPHSKA (SEQ ID NO: 4986), MEGSPHSKA (SEQ ID NO: 4987), ENGSPHSKA (SEQ ID NO: 4988), GSASPHSKA (SEQ ID NO: 4989), GNGSPHSKS ( SEQ ID NO: 4990), KNGSPHSKA (SEQ ID NO: 4991), KEGSPHSKA (SEQ ID NO: 4992), AIGSPHSKA (SEQ ID NO: 4993), GSGSPHSKN (SEQ ID NO: 4994), GSGSPHAKA (SEQ ID NO: 4995), GHDSPHKIG (SEQ ID NO: 4996), GYDSPHKSG (SEQ ID NO: 4997), GHESPHKSG (SEQ ID NO: 4998), GHDSPHKTG (SEQ ID NO: 4999), GRGSPHKRG (SEQ ID NO: 5000), GQDSPHKSG (SEQ ID NO: 4908), GHDSPHKSL (SEQ ID NO: 5001),GHGSPHSKA (SEQ ID NO: 5002), GHDSPHKSE (SEQ ID NO: 5003), VSGSPHSKA (SEQ ID NO: 4913), GRDSPHKSG (SEQ ID NO: 5004), GNDSPHKSV (SEQ ID NO: 5005), GQDSPHKIG (SEQ ID NO: 5006), GHDSPHKSV (SEQ ID NO: 5007), GPDSPHKIG (SEQ ID NO: 5008), GPDSPHKSG (SEQ ID NO: 5009), GHDSPHKSW (SEQ ID NO: 5010), GHDSPHKSN (SEQ ID NO: 5011), GMGSPHSKT (SEQ ID NO: 5012), GHDSPHKHG (SEQ ID NO: 5013), GQ VSPHKSG (SEQ ID NO: 5014), GDDSPHKSV (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016), GNGSPHKRG (SEQ ID NO: 5017), GHDSPHKYG (SEQ ID NO: 5018), GHDSPHKSQ (SEQ ID NO: 5019), GNDSPHKIG (SEQ ID NO: 5020), GHDSPHKSK (SEQ ID NO: 5021), GHDSPHKLW (SEQ ID NO: 5022), GHPSPHWKG (SEQ ID NO: 5023), GHDSPHKMG (SEQ ID NO: 5024), GHDSPHKMA (SEQ ID NO: 5025), or GHSSPHRSG (SEQ ID NO: 5026), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, or 8 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 1 to 18, wherein the amino acid sequence in any one of the amino acid sequences in (i) contains one, two, or three but no more than four different amino acids, or contains such a sequence.

[0108] 20. An AAV capsid variant according to any one of Embodiments 1 to 19, wherein [N3] comprises SK, KA, KS, or SG.

[0109] 21. An AAV capsid variant according to any one of Embodiments 1 to 20, wherein [N3] is SKA, KSG, or KYG, or includes them.

[0110] 22. An AAV capsid variant according to any one of Embodiments 1 to 21, wherein [N2]-[N3] includes SPHSK (SEQ ID NO: 4701), SPHKS (SEQ ID NO: 4704), or SPHKY (SEQ ID NO: 4715).

[0111] 23. An AAV capsid variant according to any one of Embodiments 1 to 22, wherein [N2]-[N3] is SPHSKA (SEQ ID NO: 941) or includes it.

[0112] 24. An AAV capsid variant according to any one of Embodiments 1 to 22, wherein [N2]-[N3] is SPHKSG (SEQ ID NO: 946) or includes it.

[0113] 25. An AAV capsid variant according to any one of Embodiments 1 to 22, wherein [N2]-[N3] is SPHKYG (SEQ ID NO: 966) or contains the same.

[0114] 26. An AAV capsid variant according to any one of Embodiments 1 to 25, wherein [N1] comprises GS, SG, GH, or HD.

[0115] 27. An AAV capsid variant according to any one of Embodiments 1 to 26, wherein [N1] is GSG or includes it.

[0116] 28. An AAV capsid variant according to any one of Embodiments 1 to 26, wherein [N1] is GHD or includes it.

[0117] 29. An AAV capsid variant according to any one of Embodiments 1 to 23 or 26 to 27, wherein [N1]-[N2]-[N3] includes SGSPHSK (SEQ ID NO: 4839).

[0118] 30. An AAV capsid variant according to any one of embodiments 1 to 22, 24, 26, or 28, wherein [N1]-[N2]-[N3] include HDSPHKS (SEQ ID NO: 4840).

[0119] 31. An AAV capsid variant according to any one of Embodiments 1 to 22 or 25 to 27, wherein [N1]-[N2]-[N3] includes SGSPHKYG (SEQ ID NO: 5027).

[0120] 32. An AAV capsid variant according to any one of Embodiments 1-8, 10, 12-23, 26-27, or 29, wherein [N1]-[N2]-[N3] is GSGSPHSKA (Sequence ID 4697) or includes it.

[0121] 33. An AAV capsid variant according to any one of Embodiments 1-9, 11-22, 24, 26, 28, or 30, wherein [N1]-[N2]-[N3] is GHDSPHKSG (SEQ ID NO: 4698) or includes it.

[0122] 34. An AAV capsid variant according to any one of Embodiments 1-8, 10, 12-22, 25-27, or 31, wherein [N1]-[N2]-[N3] is GSGSPHKYG (Sequence ID 4927) or includes it.

[0123] 35. An AAV capsid variant according to any one of Embodiments 1 to 34, wherein [N1]-[N2]-[N3] replaces positions 453-455, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0124] 36. An AAV capsid variant according to any one of Embodiments 1 to 35, comprising, with respect to a reference sequence numbered according to Sequence ID No. 138, an amino acid other than Q at position 456 (e.g., W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F), an amino acid other than N at position 457 (e.g., Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, I, M, Q, or L), an amino acid other than Q at position 458 (e.g., G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y), and / or an amino acid other than Q at position 459 (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V).

[0125] 37. For reference sequences numbered according to SEQ ID NOs. 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57, the amino acid other than Q at position 462 (e.g., W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F), and the amino acid other than N at position 463 (e.g., Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A) An AAV capsid variant according to any one of Embodiments 1 to 36, comprising an amino acid other than Q at position 464 (e.g., G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y), and / or an amino acid other than Q at position 465 (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V).

[0126] 38. (a) With respect to a reference sequence numbered according to Sequence ID No. 138, amino acid Q at position 456, amino acid N at position 457, amino acid Q at position 458, and / or amino acid Q at position 459, or (b) An AAV capsid variant according to any one of Embodiments 1 to 37, comprising amino acid Q at position 462, amino acid N at position 463, amino acid Q at position 464, and / or amino acid Q at position 465, with respect to a reference sequence numbered according to SEQ ID NOs. 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57.

[0127] 39. [N4] further includes, and [N4] includes X7 X8 X9 X10, (a) The X7th position is Q, W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F, (b) The X8th position is N, Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, I, M, Q, or L, (c) The 9th position of X is Q, G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y, (d) The X10th position is Q, H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V, Optionally, the AAV capsid variant according to any one of Embodiments 1 to 38 includes an amino acid modification, e.g., a conservative substitution, among the amino acids in (a) to (d).

[0128] 40. (a) The 7th position of X in [N4] is Q or R, (b) The X8th position of [N4] is either N or R, (c) The 9th X in [N4] is either Q or R, (d) The AAV capsid variant according to Embodiment 39, wherein the X10 position of [N4] is Q, L, or R.

[0129] 41. [N4] ga, (i) QNQQ (SEQ ID NO: 5028), WNQQ (SEQ ID NO: 5029), QYYV (SEQ ID NO: 5030), RRQQ (SEQ ID NO: 5031), GCGQ (SEQ ID NO: 5032), LRQQ (SEQ ID NO: 5033), RNQQ (SEQ ID NO: 5034), VNQQ (SEQ ID NO: 5035), FRLQ (SEQ ID NO: 5036), FNQQ (SEQ ID NO: 5037), LLQQ (SEQ ID NO: 5038), SNQQ (SEQ ID NO: 5039), RLQQ (SEQ ID NO: 5040), LNQQ (SEQ ID NO: 5041), QRKL (SEQ ID NO: 5042), LRRQ (SEQ ID NO: 5043), QRLR ( SEQ ID NOs: 5044, QRRL (SEQ ID NOs: 5045), RRLQ (SEQ ID NOs: 5046), RLRQ (SEQ ID NOs: 5047), SKRQ (SEQ ID NOs: 5048), QLYR (SEQ ID NOs: 5049), QLTV (SEQ ID NOs: 5050), QNKQ (SEQ ID NOs: 5051), KNQQ (SEQ ID NOs: 5052), QKQQ (SEQ ID NOs: 5053), QTQQ (SEQ ID NOs: 5054), QNHQ (SEQ ID NOs: 5055), QHQQ (SEQ ID NOs: 5056), QNQH (SEQ ID NOs: 5057), QHRQ (SEQ ID NOs: 5058), LTQQ (SEQ ID NOs: 5059), QNQW (SEQ ID NOs: 5060) QNTH (sequence number 5061), RRRQ (sequence number 5062), QYQQ (sequence number 5063), QNDQ (sequence number 5064), QNRH (sequence number 5065), RDQQ (sequence number 5066), PNLQ (sequence number 5067), HVRQ (sequence number 5068), PNQH (sequence number 5069), HNQQ (sequence number 5070), QSQQ (sequence number 5071), QPAK (sequence number 5072), QNLA (sequence number 5073), QNQL (sequence number 5074), QGQQ (sequence number 5075), LNRQ (sequence number 5076), QNPP (distribution) Column number 5077), QNLQ (sequence number 5078), QDQE (sequence number 5079), QDQQ (sequence number 5080), HWQQ (sequence number 5081), PNQQ (sequence number 5082), PEQQ (sequence number 5083), QRTM (sequence number 5084), LHQH (sequence number 5085), QHRI (sequence number 5086), QYIH (sequence number 5087), QKFE (sequence number 5088), QFPS (sequence number 5089), QNPL (sequence number 5090), QAIK (sequence number 5091), QNRQ (sequence number 5092), QYQH (sequence number 5093),QNPQ (sequence number 5094), QHQL (sequence number 5095), QSPP (sequence number 5096), QAKL (sequence number 5097), KSQQ (sequence number 5098), QDRP (sequence number 5099), QNLG (sequence number 5100), QAFH (sequence number 5101), QNAQ (sequence number 5102), HNQL (sequence number 5103), QKLN (sequence number 5104), QNVQ (sequence number 5105), QAQQ (sequence number 5106), QTPP (sequence number 5107), QPPA (sequence number 5108), QERP (sequence number 5109), QDLQ (array (Sequence number 5110), QAMH (Sequence number 5111), QHPS (Sequence number 5112), PGLQ (Sequence number 5113), QGIR (Sequence number 5114), QAPA (Sequence number 5115), QIPP (Sequence number 5116), QTQL (Sequence number 5117), QAPS (Sequence number 5118), QNTY (Sequence number 5119), QDKQ (Sequence number 5120), QNHL (Sequence number 5121), QIGM (Sequence number 5122), LNKQ (Sequence number 5123), PNQL (Sequence number 5124), QLQQ (Sequence number 5125), QRMS (Sequence number 5126), QGIL (SEQ ID NO: 5127), QDRQ (SEQ ID NO: 5128), RDWQ (SEQ ID NO: 5129), QERS (SEQ ID NO: 5130), QNYQ (SEQ ID NO: 5131), QRTC (SEQ ID NO: 5132), QIGH (SEQ ID NO: 5133), QGAI (SEQ ID NO: 5134), QVPP (SEQ ID NO: 5135), QVQQ (SEQ ID NO: 5136), LMRQ (SEQ ID NO: 5137), QYSV (SEQ ID NO: 5138), QAIT (SEQ ID NO: 5139), QKTL (SEQ ID NO: 5140), QLHH (SEQ ID NO: 5141), QNII (SEQ ID NO: 5142), QGHH (SEQ ID NO: 5142) (Sequence number 5143), QSKV (Sequence number 5144), QLPS (Sequence number 5145), IGKQ (Sequence number 5146), QAIH (Sequence number 5147), QHGL (Sequence number 5148), QFMC (Sequence number 5149), QNQM (Sequence number 5150), QHLQ (Sequence number 5151), QPAR (Sequence number 5152), QSLQ (Sequence number 5153), QSQL (Sequence number 5154), HSQQ (Sequence number 5155), QMPS (Sequence number 5156), QGSL (Sequence number 5157), QVPA (Sequence number 5158), HYQQ (Sequence number 5159),QVPS (SEQ code 5160), RGEQ (SEQ code 5161), PGQQ (SEQ code 5162), LEQQ (SEQ code 5163), QNQS (SEQ code 5164), QKVI (SEQ code 5165), QNND (SEQ code 5166), QSVH (SEQ code 5167), QPLG (SEQ code 5168), HNQE (SEQ code 5169), QIQQ (SEQ code 5170), QVRN (SEQ code 5171), PSNQ (SEQ code 5172), QVGH (SEQ code 5173), QRDI (SEQ code 5174), QMPN (SEQ code 5175), RGLQ (SEQ code) (Sequence number 5176), PSLQ (Sequence number 5177), QRDQ (Sequence number 5178), QAKG (Sequence number 5179), QSAH (Sequence number 5180), QSTM (Sequence number 5181), QREM (Sequence number 5182), QYRA (Sequence number 5183), QRQQ (Sequence number 5184), QWQQ (Sequence number 5185), QRMN (Sequence number 5186), GDSQ (Sequence number 5187), QKIS (Sequence number 5188), PSMQ (Sequence number 5189), SPRQ (Sequence number 5190), MEQQ (Sequence number 5191), QYQN (Sequence number 5192), QIRQ (sequence number 5193), QSVQ (sequence number 5194), RSQQ (sequence number 5195), QNKL (sequence number 5196), QIQH (sequence number 5197), PRQQ (sequence number 5198), HTQQ (sequence number 5199), QRQH (sequence number 5200), RNQE (sequence number 5201), QSKQ (sequence number 5202), QNQP (sequence number 5203), QSPQ (sequence number 5204), QTRQ (sequence number 5205), QNLH (sequence number 5206), QNQE (sequence number 5207), LNQP (sequence number 5208), QNQD (sequence number) (Sequence number 5209), QNLL (Sequence number 5210), QLVI (Sequence number 5211), RTQE (Sequence number 5212), QTHQ (Sequence number 5213), QDQH (Sequence number 5214), QSQH (Sequence number 5215), VRQQ (Sequence number 5216), AWQQ (Sequence number 5217), QSVP (Sequence number 5218), QNIQ (Sequence number 5219), LDQQ (Sequence number 5220), PDQQ (Sequence number 5221), ESQQ (Sequence number 5222), QRQL (Sequence number 5223), QIIV (Sequence number 5224), QKQS (Sequence number 5225),QSHQ (sequence number 5226), QFVV (sequence number 5227), QSQP (sequence number 5228), QNEQ (sequence number 5229), INQQ (sequence number 5230), RNRQ (sequence number 5231), RDQK (sequence number 5232), QWKR (sequence number 5233), ENRQ (sequence number 5234), QTQP (sequence number 5235), QKQL (sequence number 5236), RNQL (sequence number 5237), ISIQ (sequence number 5238), QTVC (sequence number 5239), QQIM (sequence number 5240), LNHQ (sequence number 5241), QNQA (sequence number 5242), QMIH (sequence number 5243), RNHQ (sequence number 5244), or QKMN (sequence number 5245), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any two or three amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 39 or 40, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0130] 42. [N1]-[N2]-[N3]-[N4] is (i) Any amino acid sequence from sequence numbers 1800 to 2241, (ii) An amino acid sequence containing any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 39 to 41, wherein the amino acid sequence in any one of the amino acid sequences in (i) contains one, two, or three but no more than four different amino acids, or contains such a sequence.

[0131] 43. An AAV capsid variant according to any one of Embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is GSGSPHSKAQNQQ (Sequence ID 1801) or includes it.

[0132] 44. An AAV capsid variant according to any one of Embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is GHDSPHKSGQNQQ (SEQ ID NO: 1800) or includes it.

[0133] 45. An AAV capsid variant according to any one of Embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is GSGSPHKYGQNQQT (SEQ ID NO: 910) or includes it.

[0134] 46. ​​An AAV capsid variant according to any one of Embodiments 1 to 45, comprising an amino acid other than T at position 450 (e.g., S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G), an amino acid other than I at position 451 (e.g., M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L), and / or an amino acid other than N at position 452 (e.g., M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S) with respect to a reference sequence numbered according to any one of Sequence IDs 5 to 10, 36 to 59, 138, 981, 982, or 6409 to 6414.

[0135] 47. An AAV capsid variant according to any one of Embodiments 1 to 46, comprising amino acid T at position 450, amino acid I at position 451, and / or amino acid N at position 452, relative to a reference sequence numbered according to any one of Sequence ID No. 138, 981, or 982.

[0136] 48. Further including [N0], where [N0] includes XA, XB and XC, (a) Position XA is T, S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G, (b) The XB position is I, M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L, (c) The XC position is N, M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S. Optionally, the AAV capsid variant according to any one of Embodiments 1 to 47 includes an amino acid modification, e.g., a conservative substitution, among the amino acids in (a) to (c).

[0137] 49.[N0] is TIN, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW, ANN, IPE, ADM, IEY, ADY, IET, MEW, CEY, R IN, MEI, LEY, ADW, IEI, DIM, FEQ, MEF, CDQ, LPE, IEN, MES, AEI, VEY, IIN, TSN, IEV, MEM, AEV, MDA, VEW , AEQ, LEW, MEL, MET, MEA, IES, MEV, CEI, ATN, MDG, QEV, ADQ, NMN, IEM, ISN, TGN, QQQ, HDW, IEG, TII, T FP, TEK, EIN, TVN, TFN, SIN, TER, TSY, ELH, AIN, SVN, TDN, TFH, TVH, TEN, TSS, TID, TCN, NIN, TEH, AEM, AAV capsid variant according to Embodiment 48, which is AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TIY, TFS, TES, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, NAD, TIT, NCV, TIR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV, SDI, NSI, NSL, EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, NNL, or any of these dipeptides, or comprising them.

[0138] 50.[N0]-[N1]-[N2]-[N3]-[N4] is, (i) Any one amino acid sequence from sequence numbers 2242 to 2886, (ii) An amino acid sequence containing any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 48 or 49, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0139] 51. An AAV capsid variant according to any one of Embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is TINGSGSPHSKAQNQQ (Sequence ID 2242) or includes it.

[0140] 52. An AAV capsid variant according to any one of Embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is TINGHDSPHKSGQNQQ (Sequence ID 2243) or includes it.

[0141] 53. An AAV capsid variant according to any one of Embodiments 48 to 52, wherein [N0]-[N1]-[N2]-[N3]-[N4] is TINGSGSPHKYGQNQQT (Sequence ID 5246) or includes it.

[0142] 54. An AAV capsid variant according to any one of Embodiments 1 to 53, wherein [N1]-[N2]-[N3] are present in Loop IV.

[0143] 55. An AAV capsid variant according to any one of embodiments 48 to 54, wherein [N0] and [N4] are present in loop IV.

[0144] 56. An AAV capsid variant according to any one of embodiments 48 to 55, wherein [N0] is located immediately after position 449 with respect to a reference sequence numbered according to the amino acid sequence of sequence number 138.

[0145] 57. An AAV capsid variant according to any one of embodiments 48 to 56, wherein [N0] is located immediately after position 449 of a reference sequence numbered according to any one of the amino acid sequences among sequence numbers 5 to 10, 36 to 59, 981, 982, or 6409 to 6413.

[0146] 58. An AAV capsid variant according to any one of embodiments 48 to 57, wherein [N0] replaces positions 450, 451, and 452 (e.g., T450, I451, and N452) of a reference sequence numbered according to sequence number 138.

[0147] 59. An AAV capsid variant according to any one of embodiments 48 to 58, wherein [N0] replaces positions 450 to 452 (e.g., T450, I451, and N452) in a reference sequence numbered according to any one of sequence numbers 5 to 10, 36 to 59, 981, 982, or 6409 to 6413.

[0148] 60. An AAV capsid variant according to any one of embodiments 48 to 59, wherein [N0] corresponds to position 450 to 452 of any one of sequence numbers 5 to 10, 36 to 59, 138, 981, 982, or 6409 to 6414.

[0149] 61. An AAV capsid variant according to any one of embodiments 48 to 60, wherein [N0] is located immediately after position 449, and [N0] replaces positions 450 to 452 (e.g., T450, I451, and N452) in a reference sequence numbered according to sequence number 138.

[0150] 62. An AAV capsid variant according to any one of embodiments 48 to 61, wherein [N0] is located immediately after position 449, and [N0] replaces positions 450 to 452 (e.g., T450, I451, and N452) in a reference sequence numbered according to any one of sequence numbers 5 to 10, 36 to 59, 981, 982, or 6409 to 6413.

[0151] 63. An AAV capsid variant according to any one of Embodiments 1 to 62, wherein [N1] is located immediately after position 452 with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0152] 64. An AAV capsid variant according to any one of Embodiments 1 to 63, wherein [N1] is located immediately after position 452 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0153] 65. An AAV capsid variant according to any one of Embodiments 1 to 61, wherein [N1] replaces positions 453 to 455 (e.g., G453, S454, and G455) in a reference sequence numbered according to Sequence ID No. 138.

[0154] 66. An AAV capsid variant according to any one of Embodiments 1 to 64, wherein [N1] replaces position 453 (e.g., G453) in a reference sequence numbered according to sequence number 138.

[0155] 67. An AAV capsid variant according to any one of Embodiments 1 to 65, wherein [N1] replaces positions 453 to 455 (e.g., G453, S454, and G455) in a reference sequence numbered according to Sequence ID No. 981.

[0156] 68. An AAV capsid variant according to any one of Embodiments 1 to 65 or 67, wherein [N1] replaces positions 453 to 455 in a reference sequence numbered according to sequence number 982.

[0157] 69. An AAV capsid variant according to any one of embodiments 1 to 65, 67, or 68, wherein [N1] is located immediately after position 452, and [N1] replaces positions 453 to 455 (e.g., G453, S454, and G455) in a reference sequence numbered according to sequence number 138.

[0158] 70. An AAV capsid variant according to any one of embodiments 1 to 64 or 66, wherein [N1] is located immediately after position 452, and [N1] replaces position 453 (e.g., G453) in a reference sequence numbered according to sequence number 138.

[0159] 71. An AAV capsid variant according to any one of embodiments 1 to 64, 66, or 70, wherein [N1] is located immediately after position 452, and [N1] replaces positions 453-455 with respect to a reference sequence numbered according to sequence number 981 or 982.

[0160] 72. An AAV capsid variant according to any one of Embodiments 1 to 71, wherein [N1] corresponds to position 453 to 455 of any one of sequence numbers 5 to 10, 36 to 59, 981, 982, or 6409 to 6413.

[0161] 73. An AAV capsid variant according to any one of Embodiments 1 to 72, comprising an amino acid other than S at position 454 and / or an amino acid other than G at position 455, numbered according to Sequence ID No. 138, 981, or 982.

[0162] 74. An AAV capsid variant according to any one of Embodiments 1 to 73, comprising amino acid H at position 454 and amino acid D at position 455, numbered according to Sequence ID No. 138 or 982.

[0163] 75. An AAV capsid variant according to any one of Embodiments 1 to 74, comprising substitutions at position 454 (e.g., S454H) and / or substitutions at position 455 (e.g., G455D), numbered according to Sequence ID No. 138.

[0164] An AAV capsid variant according to any one of Embodiments 1 to 75, comprising amino acid H at position 76,454 and amino acid D at position 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately after position 455 with respect to a reference sequence numbered according to SEQ ID NO: 138.

[0165] 77. An AAV capsid variant according to any one of Embodiments 1 to 76, comprising amino acid H at position 454 and amino acid D at position 455 with respect to a reference sequence numbered according to Sequence ID No. 982.

[0166] An AAV capsid variant according to any one of Embodiments 1 to 77, comprising amino acid H at position 78,454 and amino acid D at position 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455 with respect to a reference sequence numbered according to SEQ ID NO: 982.

[0167] 79. An AAV capsid variant according to any one of Embodiments 1 to 72, comprising amino acid S at position 454 and amino acid G at position 455 with respect to a reference sequence numbered according to Sequence ID No. 138.

[0168] An AAV capsid variant according to any one of Embodiments 1 to 72 or 79, comprising amino acid S at position 80,454 and amino acid G at position 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455 with respect to a reference sequence numbered according to SEQ ID NO: 138.

[0169] 81. An AAV capsid variant according to any one of embodiments 1 to 72, 79, or 80, comprising amino acid S at position 454 and amino acid G at position 455 with respect to a reference sequence numbered according to sequence number 981.

[0170] An AAV capsid variant according to any one of embodiments 1 to 72 or 79 to 81, comprising amino acid S at position 82,454 and amino acid G at position 455, and further comprising the amino acid sequence SPHSKA (sequence number 941) immediately after position 455 with respect to a reference sequence numbered according to sequence number 981.

[0171] 83.[N2] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV capsid variant according to any one of Embodiments 1 to 82.

[0172] 84. An AAV capsid variant according to any one of Embodiments 1 to 83, wherein [N2] corresponds to positions 456 to 458 of sequence number 981 or 982 (e.g., S456, P457, H458).

[0173] 85. An AAV capsid variant according to any one of Embodiments 1 to 83, wherein [N2] corresponds to position 456 to 458 (e.g., S456, P457, H458) of any one of sequence numbers 5 to 10, 36 to 59, or 6409 to 6413.

[0174] 86. An AAV capsid variant according to any one of Embodiments 1 to 85, wherein [N2]-[N3] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0175] 87. An AAV capsid variant according to any one of Embodiments 1 to 86, wherein [N2] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0176] 88. An AAV capsid variant according to any one of Embodiments 1 to 87, wherein [N2]-[N3] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0177] 89. An AAV capsid variant according to any one of Embodiments 1 to 88, wherein [N2]-[N3] corresponds to positions 456-461 of Sequence ID No. 981 (e.g., S456, P457, H458, S459, K460, A461).

[0178] 90. An AAV capsid variant according to any one of Embodiments 1 to 88, wherein [N2]-[N3] corresponds to positions 456-461 of Sequence ID No. 982 (e.g., S456, P457, H458, K459, S460, G461).

[0179] 91. An AAV capsid variant according to any one of Embodiments 1 to 90, wherein [N2] is located immediately after [N1].

[0180] 92. An AAV capsid variant according to any one of embodiments 1 to 64, 66, 70, or 71, wherein [N3] is present immediately after [N2] and replaces positions 454 and 455 (e.g., S454 and G455) as numbered according to sequence number 138.

[0181] 93. An AAV capsid variant according to any one of Embodiments 1-1-64, 66, 70, 71, or 92, wherein [N3] is located immediately after [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455) as numbered according to Sequence ID No. 138.

[0182] An AAV capsid variant according to any one of embodiments 39 to 93, wherein 94.[N4] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0183] An AAV capsid variant according to any one of embodiments 39 to 94, wherein 95.[N4] replaces positions 456 to 459 (e.g., Q456, N457, Q458, and Q459) of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0184] An AAV capsid variant according to any one of embodiments 39 to 95, wherein 96.[N4] corresponds to positions 462 to 465 of sequence number 981 or 982 (e.g., Q462, N463, Q464, Q465).

[0185] 97. An AAV capsid variant according to any one of embodiments 39 to 96, wherein [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459) of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0186] 98. An AAV capsid variant according to any one of embodiments 39 to 97, wherein [N2]-[N3]-[N4] is located immediately after position 455, and [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459) in a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0187] An AAV capsid variant according to any one of embodiments 39 to 98, wherein 99.[N2]-[N3]-[N4] corresponds to positions 456-465 of sequence number 981 (for example, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0188] An AAV capsid variant according to any one of embodiments 39 to 98, wherein 100.[N2]-[N3]-[N4] corresponds to positions 456-465 of sequence number 982 (e.g., S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0189] 101. An AAV capsid variant according to any one of embodiments 39 to 98, wherein [N2]-[N3]-[N4] corresponds to position 456-465 of any one of sequence numbers 5-10, 36-59, and 6409-6413.

[0190] An AAV capsid variant according to any one of Embodiments 39 to 101, wherein 102.[N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459) of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0191] 103. An AAV capsid variant according to any one of Embodiments 39 to 102, wherein [N1]-[N2]-[N3]-[N4] is located immediately after position 452, and [N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459) in a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0192] 104. An AAV capsid variant according to any one of embodiments 39 to 99, 102, or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of sequence number 981 (for example, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0193] 105. An AAV capsid variant according to any one of embodiments 39-98, 100, 102, or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of sequence number 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0194] 106. An AAV capsid variant according to any one of embodiments 39-98, 102, or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of any one of sequence numbers 5-10, 36-59, or 6409-6413.

[0195] 107. An AAV capsid variant according to any one of Embodiments 1 to 99 or 102 to 104, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 of Sequence ID No. 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0196] 108. An AAV capsid variant according to any one of embodiments 1 to 98, 100, 102, 103, or 105, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 of sequence number 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461).

[0197] 109. An AAV capsid variant according to any one of embodiments 39-98, 102, 103, or 106, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 of any one of sequence numbers 5-10, 36-59, or 6409-6413.

[0198] An AAV capsid variant according to any one of Embodiments 48 to 109, wherein 110.[N0]-[N1]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459) of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0199] 111. An AAV capsid variant according to any one of embodiments 48 to 110, wherein [N0]-[N1]-[N2]-[N3]-[N4] is located immediately after position 449, and [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459) in a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0200] 112. An AAV capsid variant according to any one of embodiments 48-99, 102-104, or 106, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of sequence number 981 (e.g., T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0201] 113. An AAV capsid variant according to any one of embodiments 48-98, 100, 102, 103, 105, or 108, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of sequence number 982 (e.g., T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0202] 114. An AAV capsid variant according to any one of embodiments 48-98, 102, 103, 106, or 109, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of any one of sequence numbers 5-10, 36-59, or 6409-6413.

[0203] An AAV capsid variant according to any one of embodiments 39 to 114, wherein 115.[N4] replaces positions 462 to 465 (e.g., Q462, N463, Q464, and Q465) of a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982.

[0204] 116. An AAV capsid variant according to any one of embodiments 39 to 115, wherein [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465) of a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982.

[0205] 117. An AAV capsid variant according to any one of embodiments 39 to 116, wherein [N2]-[N3]-[N4] is located immediately after position 455, and [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0206] 118. An AAV capsid variant according to any one of Embodiments 1 to 117, wherein [N3] is located immediately after [N2].

[0207] 119. An AAV capsid variant according to any one of Embodiments 1 to 118, comprising [N2]-[N3] from the N-terminus to the C-terminus.

[0208] 120. An AAV capsid variant according to any one of Embodiments 1 to 119, comprising [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0209] 121. An AAV capsid variant according to any one of embodiments 48 to 120, comprising [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0210] 122. An AAV capsid variant according to any one of embodiments 39 to 121, comprising [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0211] 123. An AAV capsid variant according to any one of embodiments 48 to 122, comprising [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0212] 124. An AAV capsid variant according to any one of the prior embodiments, numbered according to the amino acid sequence of Sequence ID No. 138, with another amino acid (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S) at position 460 (T).

[0213] 125. An AAV capsid variant according to any one of the prior embodiments, comprising amino acid N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S at position 460, numbered according to the amino acid sequence of Sequence ID No. 138.

[0214] 126. An AAV capsid variant according to any one of the prior embodiments, numbered according to any one amino acid sequence of SEQ ID NOs. 5-10, 36-59, 981, 982, or 6409-6413, wherein the T at position 466 contains another amino acid (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S).

[0215] 127. An AAV capsid variant according to any one of the prior embodiments, comprising amino acid N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S at position 466, numbered according to any one of the amino acid sequences among SEQ ID NOs. 5-10, 36-59, 981, 982, or 6409-6413.

[0216] 128. An AAV capsid variant according to any one of the prior embodiments, numbered according to one of the amino acid sequences of SEQ ID NOs. 36-59, 138, 981, or 982, comprising another amino acid (e.g., E, N, or T) at position 449 (K).

[0217] 129. An AAV capsid variant according to any one of the prior embodiments, comprising amino E, N, or T at position 449, numbered according to one of the amino acid sequences of SEQ ID NOs. 5-10, 36-59, 138, 981, 982, or 6409-6414.

[0218] 130. AAV capsid variant, (A) Modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), which optionally include loop VIII having positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414, and / or (B)[A][B](Sequence ID 4694) (i)[A] contains the amino acid sequence GSGSPH (SEQ ID NO: 4695), (ii)[B] includes X1 X2 X3 X4 X5 X6 X7, (a) The X1st position is S, C, F, or V, (b) The X2 position is K, L, R, I, E, Y, V, or S, (c) The third letter of X is A, R, L, G, I, Y, S, F, or W. (d) The 4th position is W, Q, R, G, L, V, S, or F, (e) The 5th position of X is N, Y, R, C, K, or L, (f) The 6th position of X is Q, G, K, R, T, L, or Y, (g) The 7th position of X is Q, L, R, or V, including [A][B], Optionally, the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, among the amino acids in (a) to (g).

[0219] 131. (a) X1st place is S, (b) The X2 position is K or L, (c) The 3rd position is A, R, or L, (d) The 4th position in X is Q or R, (e) The 5th position of X is N or R, (f) The 6th position of X is Q or R, (g) The AAV capsid variant according to Embodiment 130, wherein the X7 position is Q, L, or R.

[0220] 132.[B] is, (i) SLLWNQQ (SEQ ID NO: 5247), SKAQYYV (SEQ ID NO: 5248), SKLRRQQ (SEQ ID NO: 5249), SIWQNQQ (SEQ ID NO: 5250), SKAGCGQ (SEQ ID NO: 5251), SRAQNQQ (SEQ ID NO: 5252), SKRLRQQ (SEQ ID NO: 5253), SLRRNQQ (SEQ ID NO: 5254), SRGRNQQ (SEQ ID NO: 5255), SEIVNQ Q (sequence number 5256), SSRRNQQ (sequence number 5257), CLLQNQQ (sequence number 5258), SKAFRLQ (sequence number 5259), CLAQNQQ (sequence number 5260), FLRQNQQ (sequence number 5261), SLRFNQQ (sequence number 5262), SYLRNQQ (sequence number 5263), CSLQNQQ (sequence number 5264), VLWQNQQ (sequence number 5265) ), SKWLLQQ (sequence number 5266), SLWSNQQ (sequence number 5267), SKRRLQQ (sequence number 5268), SVYLNQQ (sequence number 5269), SLWLNQQ (sequence number 5270), SKAQRKL (sequence number 5271), SKALRRQ (sequence number 5272), SKAQRLR (sequence number 5273), SKAQNQQ (sequence number 5274), SKAQRRL ( SEQ ID NO: 5275), SKARRQQ (SEQ ID NO: 5276), SKARRLQ (SEQ ID NO: 5277), SKSRRQQ (SEQ ID NO: 5278), SKARLRQ (SEQ ID NO: 5279), SKASKRQ (SEQ ID NO: 5280), VRRQNQQ (SEQ ID NO: 5281), SKAQLYR (SEQ ID NO: 5282), SLFRNQQ (SEQ ID NO: 5283), SKAQLTV (SEQ ID NO: 5284), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, or 6 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 130 or 131, comprising an amino acid sequence containing one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i).

[0221] 133.[A][B] is, (i) GSGSPHSLLWNQQ (SEQ ID NO: 5285), GSGSPHSKAQYYV (SEQ ID NO: 2060), GSGSPHSKLRRQQ (SEQ ID NO: 2061), GSGSPHSIWQNQQ (SEQ ID NO: 5286), GSGSPHSKAGCGQ (SEQ ID NO: 2062), GSGSPHSRAQNQQ (SEQ ID NO: 2063), GSGSPHSKRLRQQ (SEQ ID NO: 2064), GSGSPHSLRRNQQ (SEQ ID NO: 2065), GSGSPHSRGRNQQ (SEQ ID NO: 2066), GGSPHSEI VNQQ (SEQ ID NO: 5287), GSGSPHSSRRNQQ (SEQ ID NO: 2067), GSGSPHCLLQNQQ (SEQ ID NO: 5288), GSGSPHSKAFRLQ (SEQ ID NO: 2068), GSGSPHCLAQNQQ (SEQ ID NO: 5289), GSGSPHFLRQNQQ (SEQ ID NO: 2070), GSGSPHSLRFNQQ (SEQ ID NO: 2071), GSGSPHSYLRNQQ (SEQ ID NO: 5290), GSGSPHCSLQNQQ (SEQ ID NO: 5291), GSGSPHVLWQNQQ (SEQ ID NO: 5292 ), GSGSPHSKWLLQQ (Sequence ID 2072), GSGSPHSLWSNQQ (Sequence ID 5293), GSGSPHSKRRLQQ (Sequence ID 2073), GSGSPHSVYLNQQ (Sequence ID 5294), GSGSPHSLWLNQQ (Sequence ID 5295), GSGSPHSKAQRKL (Sequence ID 2074), GSGSPHSKALRRQ (Sequence ID 2075), GSGSPHSKAQRLR (Sequence ID 2076), GSGSPHSKAQNQQ (Sequence ID 1801), GSGSPHSKAQR RL (SEQ ID NO: 2077), GSGSPHSKARRQQ (SEQ ID NO: 2078), GSGSPHSKARRLQ (SEQ ID NO: 2079), GSGSPHSKSRRQQ (SEQ ID NO: 2080), GSGSPHSKARLRQ (SEQ ID NO: 2082), GSGSPHSKASKRQ (SEQ ID NO: 2083), GSGSPHVRRQNQQ (SEQ ID NO: 2084), GSGSPHSKAQLYR (SEQ ID NO: 2085), GSGSPHSLFRNQQ (SEQ ID NO: 5296), GSGSPHSKAQLTV (SEQ ID NO: 2086), (ii) An amino acid sequence containing any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 130 to 132, comprising an amino acid sequence containing one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i).

[0222] 134. An AAV capsid variant according to any one of Embodiments 130 to 133, further comprising one, two, or all of the following: an amino acid other than T at position 450 (e.g., S, Y, or G), an amino acid other than I at position 451 (e.g., M or L), and / or an amino acid other than N at position 452 (e.g., S), with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0223] 135. An AAV capsid variant according to any one of embodiments 130 to 134, further comprising S at position 450 and M at position 451, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0224] 136. An AAV capsid variant according to any one of embodiments 130 to 134, further comprising Y at position 450, L at position 451, and S at position 452, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0225] 137. An AAV capsid variant according to any one of embodiments 130 to 134, further comprising G at position 450, L at position 451, and S at position 452, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0226] 138. An AAV capsid variant according to any one of embodiments 130 to 137, wherein [A] and [B] are present in loop IV.

[0227] 139.[A] is located immediately after position 452 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV capsid variant according to any one of embodiments 130 to 138.

[0228] 140. An AAV capsid variant according to any one of Embodiments 130 to 139, wherein [A] replaces positions 453 to 455 (e.g., G453, S454, G455) with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0229] 141. An AAV capsid variant according to any one of Embodiments 130 to 140, wherein [A] is located immediately after position 452, and [A] replaces positions 453 to 455 (e.g., G453, S454, G455) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0230] 142. An AAV capsid variant according to any one of embodiments 130 to 141, wherein [B] is located immediately after [A].

[0231] 143.[B] is an AAV capsid variant according to any one of Embodiments 130 to 142, wherein it replaces positions 456 to 459 (e.g., Q456, N457, Q458, Q459) with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0232] 144. An AAV capsid variant according to any one of Embodiments 130 to 143, wherein [A][B] replaces positions 453 to 459 (e.g., G453, S454, G455, Q456, N457, Q458, Q459) of a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0233] 145. An AAV capsid variant according to any one of Embodiments 130 to 144, wherein [A][B] is located immediately after position 452, and [A][B] replaces positions 453 to 459 (e.g., G453, S454, G455, Q456, N457, Q458, Q459) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0234] 146. An AAV capsid variant according to any one of embodiments 130 to 145, comprising [A] and [B] from the N-terminus to the C-terminus.

[0235] 147. AAV capsid, (A) Modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), which optionally include loop VIII having positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414, and / or (B)[A][B](Sequence ID 4699) (i)[A] includes X1 X2 X3 X4 X5 X6, (a) The X1 position is T, M, A, C, I, R, L, D, F, V, Q, N, or H, (b) The X2 position is I, P, E, N, D, S, A, T, M, or Q, (c) The third position of X is N, E, G, Y, W, M, T, I, K, Q, F, S, V, A, or L. (d) The 4th position is G, D, R, or E, (e) The 5th position of X is H, Q, N, or D, (f) The 6th position of X is D or R, Optionally, the AAV capsid variant includes any of the above amino acid modifications in (a) to (f), such as a conservative substitution. (ii)[B] is the AAV capsid containing SPHKSG (SEQ ID NO: 946).

[0236] 148. (a) The X1 position is T, M, A, or I, (b) The X2 position is E, I or D, (c) The third position of X is N, Q, Y, I, M, or V, (d) The 4th place in X is G, (e) The 5th position in X is H, (f) The AAV capsid according to Embodiment 147, wherein position X6 is D.

[0237] 149.[A] is, (i) TINGHD (SEQ ID NO: 5297), MPEGHD (SEQ ID NO: 5298), MEGGHD (SEQ ID NO: 5299), MEYGHD (SEQ ID NO: 5300), AEWGHD (SEQ ID NO: 5301), CEWGHD (SEQ ID NO: 5302), ANNGQD (SEQ ID NO: 5303), IPEGHD (SEQ ID NO: 5304), ADMGHD (SEQ ID NO: 5305), IEYGHD (SEQ ID NO: 5306), ADYGHD (SEQ ID NO: 5307), IETGHD (SEQ ID NO: 5308), MEWGHD (SEQ ID NO: 5309), CEYGHD (SEQ ID NO: 5310), R INGHD (SEQ ID NO: 5311), MEIGHD (SEQ ID NO: 5312), LEYGHD (SEQ ID NO: 5313), ADWGHD (SEQ ID NO: 5314), IEIGHD (SEQ ID NO: 5315), TIKDND (SEQ ID NO: 5316), DIMGHD (SEQ ID NO: 5317), FEQGHD (SEQ ID NO: 5318), MEFGHD (SEQ ID NO: 5319), CDQGHD (SEQ ID NO: 5320), LPEGHD (SEQ ID NO: 5321), IENGHD (SEQ ID NO: 5322), MESGHD (SEQ ID NO: 5323), AEIGHD (SEQ ID NO: 5324), VEYGHD (SEQ ID NO: 5325), TSNGDD (SEQ ID NO: 5326), IEGGHD (SEQ ID NO: 5327), MEMGHD (SEQ ID NO: 5328), AEVGHD (SEQ ID NO: 5329), MDAGHD (SEQ ID NO: 5330), VEWGHD (SEQ ID NO: 5331), AEQGHD (SEQ ID NO: 5332), LEWGHD (SEQ ID NO: 5333), MELGHD (SEQ ID NO: 5334), METGHD (SEQ ID NO: 5335), MEAGHD (SEQ ID NO: 5336), TINRQR (SEQ ID NO: 5337), IESGHD (SEQ ID NO: 5338), TAKDHD (SEQ ID NO: 5335) 5339), MEVGHD (SEQ ID NO: 5340), CEIGHD (SEQ ID NO: 5341), ATNGHD (SEQ ID NO: 5342), MDGGHD (SEQ ID NO: 5343), QEVGHD (SEQ ID NO: 5344), ADQGHD (SEQ ID NO: 5345), NMNGHD (SEQ ID NO: 5346), TPWEHD (SEQ ID NO: 5347), IEMGHD (SEQ ID NO: 5348), TANEHD (SEQ ID NO: 5349), QQQGHD (SEQ ID NO: 5350), TPQDHD (SEQ ID NO: 5351), HDWGHD (SEQ ID NO: 5352), IEGGHD (SEQ ID NO: 5353) (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 147 or 148, comprising an amino acid sequence containing one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i).

[0238] 150.[A][B] (i)TINGHDSPHKR (SEQ ID NO: 5354), MPEGHDSPHKS (SEQ ID NO: 5355), MEGGHDSPHKS (SEQ ID NO: 5356), MEYGHDSPHKS (SEQ ID NO: 5357), AEWGHDSPHKS (SEQ ID NO: 5358), CEWGHDSPHKS (SEQ ID NO: 5359), ANNGQDSPHKS (SEQ ID NO: 5360), IPEGHDSPHKS (SEQ ID NO: 5361), ADMGHDSPHKS (SEQ ID NO: 5362), IEYGHDSPHKS (SEQ ID NO: 5363), ADYGHDSPHKS (SEQ ID NO: 5364), IET GHDSPHKS (SEQ ID NO: 5365), MEWGHDSPHKS (SEQ ID NO: 5366), CEYGHDSPHKS (SEQ ID NO: 5367), RINGHDSPHKS (SEQ ID NO: 5368), MEIGHDSPHKS (SEQ ID NO: 5369), LEYGHDSPHKS (SEQ ID NO: 5370), ADWGHDSPHKS (SEQ ID NO: 5371), IEIGHDSPHKS (SEQ ID NO: 5372), TIKDNDSPHKS (SEQ ID NO: 5373), DIMGHDSPHKS (SEQ ID NO: 5374), FEQGHDSPHKS (SEQ ID NO: 5375), MEFGHDSPH KS (Sequence No. 5376), CDQGHDSPHKS (Sequence No. 5377), LPEGHDSPHKS (Sequence No. 5378), IENGHDSPHKS (Sequence No. 5379), MESGHDSPHKS (Sequence No. 5380), AEIGHDSPHKS (Sequence No. 5381), VEYGHDSPHKS (Sequence No. 5382), TSNGDDSPHKS (Sequence No. 5383), IEVGHDSPHKS (Sequence No. 5384), MEMGHDSPHKS (Sequence No. 5385), AEVGHDSPHKS (Sequence No. 5386), MDAGHDSPHKS (Sequence No. (Sequence No. 5387), VEWGHDSPHKS (Sequence No. 5388), AEQGHDSPHKS (Sequence No. 5389), LEWGHDSPHKS (Sequence No. 5390), MELGHDSPHKS (Sequence No. 5391), METGHDSPHKS (Sequence No. 5392), MEAGHDSPHKS (Sequence No. 5393), TINRQRSPHKS (Sequence No. 5394), IESGHDSPHKS (Sequence No. 5395), TAKDHDSPHKS (Sequence No. 5396), MEVGHDSPHKS (Sequence No. 5397), CEIGHDSPHKS (Sequence No. 5398),ATNGHDSPHKS (SEQ ID NO: 5399), MDGGHDSPHKS (SEQ ID NO: 5400), QEVGHDSPHKS (SEQ ID NO: 5401), ADQGHDSPHKS (SEQ ID NO: 5402), NMNGHDSPHKS (SEQ ID NO: 5403), TPWEHDSPHKS (SEQ ID NO: 5404), IEMGHDSPHKS (SEQ ID NO: 5405), TANEHDSPHKS (SEQ ID NO: 5406), TINGHDSPHKS (SEQ ID NO: 5407), QQQGHDSPHKS (SEQ ID NO: 5408), TPQDHDSPHKS (SEQ ID NO: 5409), HDWGHDSPHKS (SEQ ID NO: 5410), IEGGHDSPHKS (SEQ ID NO: 5411), (ii) An amino acid sequence containing any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 147 to 149, comprising an amino acid sequence containing one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i).

[0239] 151. An AAV capsid variant according to any one of Embodiments 147 to 150, further comprising one, two, three, four, or all of the following, with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138: an amino acid other than Q at position 456 (e.g., R or L), an amino acid other than N at position 457 (e.g., H, K, or R), an amino acid other than Q at position 458 (e.g., R or T), an amino acid other than Q at position 459 (H), and / or an amino acid other than T at position 460 (N or S).

[0240] 152. An AAV capsid variant according to any one of embodiments 147 to 151, further comprising an R at position 456 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0241] 153. An AAV capsid variant according to any one of embodiments 147 to 151, further comprising L at position 456 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0242] 154. An AAV capsid variant according to any one of Embodiments 147 to 153, further comprising H at position 457 and R at position 458 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0243] 155. An AAV capsid variant according to any one of Embodiments 147 to 153, further comprising a K at position 457 and an N at position 460, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0244] 156. An AAV capsid variant according to any one of Embodiments 147 to 153, further comprising a T at position 458, an H at position 459, and an S at position 460, relative to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0245] 157. An AAV capsid variant according to any one of Embodiments 147 to 151, further comprising R at position 456, R at position 457, and R at position 458, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0246] 158. An AAV capsid variant according to any one of embodiments 147 to 157, wherein [A] and [B] are present in loop IV.

[0247] 159.[A] is located immediately after position 449 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV capsid variant according to any one of Embodiments 147 to 158.

[0248] The AAV capsid variant according to any one of Embodiments 147 to 159, wherein 160. [A] replaces positions 450 to 453 (for example, T450, I451, N452, G453) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0249] The AAV capsid variant according to any one of Embodiments 147 to 160, wherein 161. [A] is present immediately after position 449, and [A] replaces positions 450 to 453 (for example, T450, I451, N452, G453) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0250] The AAV capsid variant according to any one of Embodiments 147 to 161, wherein 162. [A][B] replaces positions 450 to 455 (for example, T450, I451, N45G453, S454, G455) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0251] The AAV capsid variant according to any one of Embodiments 147 to 162, wherein 163. [A][B] is present immediately after position 449, and [A][B] replaces positions 450 to 455 (for example, T450, I451, N452, G453, S454, G455) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0252] The AAV capsid variant according to any one of Embodiments 147 to 163, wherein 164. [B] is present immediately after [A], and [B] replaces positions 454 and 455 (for example, S454 and G455) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0253] The AAV capsid variant according to any one of Embodiments 147 to 164, wherein 165. [B] is present immediately after position 455 with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.

[0254] 166. An AAV capsid variant according to any one of embodiments 147 to 165, wherein [B] exists immediately after [A].

[0255] 167. An AAV capsid variant according to any one of embodiments 147 to 166, comprising [A][B] from the N-terminus to the C-terminus.

[0256] 168. An AAV capsid variant, comprising: (A) A modification in loop VIII, such as a substitution (e.g., a conservative substitution), optionally, wherein loop VIII is numbered according to SEQ ID NO: 981, 982, 6411, or 6412, and the modification includes positions 587 to 599, or is numbered according to SEQ ID NO: 138 or 6414, and includes positions 581 to 593, and / or (B) An amino acid sequence (SEQ ID NO: 6407) having the following formula: [N1]-[N2]-[N3], wherein (i) [N1] includes positions X1, X2, and X3, position X2 is S, and position X3 is G, (ii) [N2] includes the amino acid sequence SPH, (iii) [N3] includes positions X4, X5, and X6, and position X5 is K, said AAV capsid variant.

[0257] 169. (i) X4 of [N3] is S, T, N, or A, (ii) X5 of [N3] is A, V, T, S, G, R, L, or N, Optionally, said AAV capsid variant according to embodiment 16,8 includes an amino acid modification, such as a conservative substitution, of any of the above amino acids in (i) or (ii).

[0258] 170. An AAV capsid variant according to embodiment 168 or 169, wherein X4 is S and / or X5 is A.

[0259] 171. An AAV capsid variant according to any one of Embodiments 168 to 170, wherein [N3] comprises SK, TK, NK, AK, KA, KV, KT, KS, KG, KR, KL, or KN.

[0260] 172. An AAV capsid variant according to any one of Embodiments 168 to 171, wherein [N3] is SKA, SKV, SKT, SKS, SKG, SKR, TKA, NKA, SKL, SKN, or AKA, or includes them.

[0261] 173. An AAV capsid variant according to any one of embodiments 168 to 172, wherein [N3] is or includes an SKA.

[0262] 174. An AAV capsid variant according to any one of Embodiments 168 to 173, wherein [N2]-[N3] includes SPHSK (SEQ ID NO: 4701), SPHTK (SEQ ID NO: 4725), SPHNK (SEQ ID NO: 4726), or SPHAK (SEQ ID NO: 4727).

[0263] 175. [N2]-[N3] (i) SPHSKA (sequence code 941), SPHSKV (sequence code 4737), SPHSKT (sequence code 4731), SPHSKS (sequence code 962), SPHSKG (sequence code 4732), SPHSKR (sequence code 978), SPHTKA (sequence code 4739), SPHNKA (sequence code 4734), SPHSKL (sequence code 960), SPHSKN (sequence code 4735), or SPHAKA (sequence code 4736), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 168 to 174, wherein the amino acid sequence in any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0264] 176. An AAV capsid variant according to any one of embodiments 168 to 175, wherein [N2]-[N3] is SPHSKA (SEQ ID NO: 941) or includes it.

[0265] 177. An AAV capsid variant according to any one of Embodiments 168 to 176, comprising an amino acid other than G at position 453, numbered according to Sequence ID No. 138 or 981 (e.g., M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D).

[0266] 178. An AAV capsid variant according to any one of embodiments 168 to 177, comprising amino acid G at position 453, numbered according to Sequence ID No. 138 or 981.

[0267] 179. An AAV capsid variant according to any one of Embodiments 168 to 178, wherein X1 of [N1] is selected from G, M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D, and optionally the AAV capsid variant includes an amino acid modification of any of the amino acids, e.g., a conservative substitution.

[0268] 180. An AAV capsid variant according to any one of Embodiments 168 to 179, wherein [N1] includes SG, GS, MS, TS, IS, ES, SS, AS, NS, VS, LS, KS, HS, PS, RS, WS, or DS.

[0269] 181. The AAV capsid variant according to any one of embodiments 168 to 180, wherein [N1] is GSG, MSG, TSG, ISG, ESG, SSG, ASG, NSG, VSG, LSG, KSG, HSG, PSG, RSG, WSG, or DSG, or includes them.

[0270] 182. The AAV capsid variant according to any one of embodiments 168 to 181, wherein [N1] is GSG or includes it.

[0271] 183. The AAV capsid variant according to any one of embodiments 168 to 182, wherein [N1]-[N2] includes SGSPH (SEQ ID NO: 4752).

[0272] 184. [N1]-[N2] is (i) GSGSPH (SEQ ID NO: 4695), MSGSPH (SEQ ID NO: 4798), TSGSPH (SEQ ID NO: 4800), ISGSPH (SEQ ID NO: 4801), ESGSPH (SEQ ID NO: 4803), SSGSPH (SEQ ID NO: 4804), ASGSPH (SEQ ID NO: 4806), NSGSPH (SEQ ID NO: 4807), VSGSPH (SEQ ID NO: 4786), LSGSPH (SEQ ID NO: 4808), KSGSPH (SEQ ID NO: 4810), HSGSPH (SEQ ID NO: 4811), PSGSPH (SEQ ID NO: 4813), RSGSPH (SEQ ID NO: 4815), WSGSPH (SEQ ID NO: 4817), DSGSPH (SEQ ID NO: 4818), (ii) An amino acid sequence including any part of the amino acid sequences in (i), for example, any 2, 3, 4, or 5 amino acids of them, for example, consecutive amino acids, (iii) An amino acid sequence including 1, 2, or 3 but no more than 4 modifications, for example, substitutions (for example, conservative substitutions), insertions, or deletions, with respect to any of the amino acid sequences in (i), or (iv) An AAV capsid variant according to any one of Embodiments 168 to 183, wherein the amino acid sequence contains one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i), or contains such a sequence.

[0273] 185. [N1]-[N2]-[N3] is, (i) GSGSPHSKA (SEQ ID NO: 4697), GSGSPHSKV (SEQ ID NO: 4956), MSGSPHSKA (SEQ ID NO: 4957), TSGSPHSKA (SEQ ID NO: 4959), ISGSPHSKA (SEQ ID NO: 4960), GSGSPHSKT (SEQ ID NO: 4962), ESGSPHSKA (SEQ ID NO: 4963), SSGSPHSKA (SEQ ID NO: 4964), GSGSPHSKS (SEQ ID NO: 4953), ASGSPHSKA (SEQ ID NO: 4966), NSGSPHSKA (SEQ ID NO: 4967), VSGSPHSKA (SEQ ID NO: 4913), LSGSPHSKA (SEQ ID NO: 4968), KSGSPHSKA (SEQ ID NO: 4970), GSGSPHSKG (SEQ ID NO: 4972), GSGSPHSKR (SEQ ID NO: 4945), HSGSPHSKA (SEQ ID NO: 4973), PSGSPHSKA (SEQ ID NO: 4975), RSGSPHSKA (SEQ ID NO: 4977), GSGSPHTKA (SEQ ID NO: 4978), WSGSPHSKA (SEQ ID NO: 4980), DSGSPHSKA (SEQ ID NO: 4981), GSGSPHNKA (SEQ ID NO: 4983), GSGSPHSKL (SEQ ID NO: 4943), GSGSPHSKN (SEQ ID NO: 4994), or GSGSPHAKA (SEQ ID NO: 4995), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 168 to 184, wherein the amino acid sequence in any one of the amino acid sequences in (i) contains one, two, or three but no more than four different amino acids, or contains such a sequence.

[0274] 186. An AAV capsid variant according to any one of embodiments 168 to 185, wherein [N1]-[N2]-[N3] is GSGSPHSKA (SEQ ID NO: 4697) or includes it.

[0275] 187. For a reference sequence numbered according to Sequence ID No. 138, remove any amino acid other than Q at position 456 (e.g., R, P, H, L, K, I, G, S, M, or E), any amino acid other than N at position 457 (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M), and any amino acid other than Q at position 458 (e.g., R, L, A, P, H, T, I, F, K) An AAV capsid variant according to any one of Embodiments 168 to 186, comprising an amino acid other than Q at position 459 (e.g., H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G), and / or an amino acid other than T at position 460 (e.g., I, N, S, H, R, L, D, Y, A, or Q).

[0276] 188. For a reference sequence numbered according to sequence number 981, remove any amino acid other than Q at position 462 (e.g., R, P, H, L, K, I, G, S, M, or E), any amino acid other than N at position 463 (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M), and any amino acid other than Q at position 464 (e.g., R, L, A, P, H, T, I, F, K) An AAV capsid variant according to any one of Embodiments 168 to 187, comprising an amino acid other than Q at position 465 (e.g., H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G), and / or an amino acid other than T at position 466 (e.g., I, N, S, H, R, L, D, Y, A, or Q).

[0277] 189. An AAV capsid variant according to any one of Embodiments 168 to 188, comprising amino acid Q at position 456, amino acid N at position 457, amino acid Q at position 458, amino acid Q at position 459, and / or amino acid T at position 460, relative to a reference sequence numbered according to Sequence ID No. 138.

[0278] 190. An AAV capsid variant according to any one of Embodiments 168 to 189, comprising amino acid Q at position 462, amino acid N at position 463, amino acid Q at position 464, amino acid Q at position 465, and / or amino acid T at position 466, numbered according to Sequence ID No. 981.

[0279] 191. Further including [N4], where [N4] includes X7, X8, X9, X10, and X11, (a) X7 is Q, R, P, H, L, K, I, G, S, M, or E, (b) X8 is N, D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M, (c)X9 is Q, R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, D, (d) X10 is Q, H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G, (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q, An AAV capsid variant according to any one of Embodiments 168 to 190, wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the amino acids in (a) to (e).

[0280] 192.[N4] is, (i) QNQQT (SEQ ID NO: 5412), QNRHT (SEQ ID NO: 5413), RDQQT (SEQ ID NO: 5414), PNLQT (SEQ ID NO: 5415), HVRQT (SEQ ID NO: 5416), PNQHT (SEQ ID NO: 5417), QSQQT (SEQ ID NO: 5418), QNQQI (SEQ ID NO: 5419), QPAKT (SEQ ID NO: 5420), QTQQN (SEQ ID NO: 5421), QNLAT (SEQ ID NO: 5422), QNQLT (SEQ ID NO: 5423), QGQQT (SEQ ID NO: 5424), LNRQS (SEQ ID NO: 5425), HNQQT (SEQ ID NO: 5426), QNPPT (SEQ ID NO: 5427), QNLQT (SEQ ID NO: 5428), QYQQT (SEQ ID NO: 5429), QDQET (SEQ ID NO: 5430), QNHQT (SEQ ID NO: 5431), QDQQT (SEQ ID NO: 5432), HWQQT (SEQ ID NO: 5433), PNQQT (SEQ ID NO: 5434), QNQLI (SEQ ID NO: 5435), PEQQT (SEQ ID NO: 5436), QRTMT (SEQ ID NO: 5437), QNQQH (SEQ ID NO: 5438), LHQHT (SEQ ID NO: 5439), QHRIT (SEQ ID NO: 5440), QYIHT (SEQ ID NO: 5441), QKFET (SEQ ID NO: 5442 ), QFPST (SEQ ID NO: 5443), HNQQR (SEQ ID NO: 5444), QAIKT (SEQ ID NO: 5445), QNRQT (SEQ ID NO: 5446), QYQHT (SEQ ID NO: 5447), QNPQS (SEQ ID NO: 5448), QHQLT (SEQ ID NO: 5449), QSPPT (SEQ ID NO: 5450), QAKLT (SEQ ID NO: 5451), KSQQT (SEQ ID NO: 5452), QDRPT (SEQ ID NO: 5453), QSQQL (SEQ ID NO: 5454), QAFHT (SEQ ID NO: 5455), QKQQD (SEQ ID NO: 5456), QNAQT (SEQ ID NO: 5457), HNQLT (SEQ ID NO: 5457) Column number 5458), QNQQY (sequence number 5459), QKLNT (sequence number 5460), QNVQT (sequence number 5461), QAQQT (sequence number 5462), QNLQA (sequence number 5463), QTPPT (sequence number 5464), QYQHA (sequence number 5465), QGQQA (sequence number 5466), QPPAT (sequence number 5467), QERPT (sequence number 5468), QDLQT (sequence number 5469), QAMHT (sequence number 5470), LNQQT (sequence number 5471), QHPST (sequence number 5472), PGLQT (sequence number 5473),QGIRT (SEQ ID NO: 5474), QAPAT (SEQ ID NO: 5475), QSQQI (SEQ ID NO: 5476), QIPPT (SEQ ID NO: 5477), QTQLT (SEQ ID NO: 5478), QAPST (SEQ ID NO: 5479), QNTYA (SEQ ID NO: 5480), QNQHI (SEQ ID NO: 5481), QNHLT (SEQ ID NO: 5482), QIGMT (SEQ ID NO: 5483), LNKQT (SEQ ID NO: 5484), QLQQT (SEQ ID NO: 5485), QRMST (SEQ ID NO: 5486), QGILT (SEQ ID NO: 5487), QDRQT (SEQ ID NO: 5488), RDWQT (SEQ ID NO: 5488) Number 5489), QNTHD (SEQ ID NO: 5490), PNLQI (SEQ ID NO: 5491), QERST (SEQ ID NO: 5492), QNYQT (SEQ ID NO: 5493), QRTCT (SEQ ID NO: 5494), QIGHT (SEQ ID NO: 5495), QGAIT (SEQ ID NO: 5496), QVPPT (SEQ ID NO: 5497), QVQQI (SEQ ID NO: 5498), LMRQT (SEQ ID NO: 5499), QYSVT (SEQ ID NO: 5500), QAITT (SEQ ID NO: 5501), QKTLT (SEQ ID NO: 5502), QNQWT (SEQ ID NO: 5503), QLHHT (SEQ ID NO: 5504), QNIII (SEQ ID NO: 5505), QGHHT (SEQ ID NO: 5506), QSKVT (SEQ ID NO: 5507), QLPST (SEQ ID NO: 5508), IGKQT (SEQ ID NO: 5509), QAIHT (SEQ ID NO: 5510), QHGLT (SEQ ID NO: 5511), QFMCT (SEQ ID NO: 5512), QHLQT (SEQ ID NO: 5513), QNHQN (SEQ ID NO: 5514), QPART (SEQ ID NO: 5515), QSLQT (SEQ ID NO: 5516), QSQLT (SEQ ID NO: 5517), QDRQS (SEQ ID NO: 5518), QMPST (SEQ ID NO: 5519), QGSLT (SEQ ID NO: 5519) Number 5520), QVPAT (sequence number 5521), QDKQT (sequence number 5522), HYQQT (sequence number 5523), QVPST (sequence number 5524), RGEQT (sequence number 5525), PGQQT (sequence number 5526), ​​QSLQI (sequence number 5527), LEQQT (sequence number 5528), QNQST (sequence number 5529), QKVIT (sequence number 5530), QNNDQ (sequence number 5531), QSVHT (sequence number 5532), QPLGT (sequence number 5533), HNQET (sequence number 5534), QNLQI (sequence number 5535),QIQQT (sequence number 5536), QVRNT (sequence number 5537), PSNQT (sequence number 5538), QVGHT (sequence number 5539), QRDIT (sequence number 5540), QMPNT (sequence number 5541), RGLQT ​​(sequence number 5542), QKQQT (sequence number 5543), PSLQT (sequence number 5544), QRDQT (sequence number 5545), QAKGT (sequence number 5546), QSAHT (sequence number 5547), QSTMT (sequence number 5548), QREMT (sequence number 5549), QYRAT (sequence number QWQQT (sequence number 5551), QRMNT (sequence number 5552), GDSQT (sequence number 5553), QKIST (sequence number 5554), PSMQT (sequence number 5555), SPRQT (sequence number 5556), MEQQT (sequence number 5557), QYQNT (sequence number 5558), QHQQT (sequence number 5559), INQQT (sequence number 5560), PNQQH (sequence number 5561), ENRQT (sequence number 5562), QTQQA (sequence number 5563), or QNQAT (sequence number 5564), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any two, three, or four amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 191, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0281] 193.[N1]-[N2]-[N3]-[N4] is, (i) One of the amino acid sequences from sequence number 200 or 2887-3076, (ii) An amino acid sequence containing any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 191 or 192, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0282] 194. An AAV capsid variant according to any one of Embodiments 191 to 193, wherein [N1]-[N2]-[N3]-[N4] is GSGSPHSKAQNQQT (Sequence ID 200) or includes it.

[0283] 195. An AAV capsid variant according to any one of Embodiments 191 to 193, wherein [N1]-[N2]-[N3]-[N4] is VSGSPHSKAQNQQT (SEQ ID NO: 903) or includes it.

[0284] 196. An AAV capsid variant according to any one of Embodiments 168 to 195, comprising, with respect to a reference sequence numbered according to Sequence ID No. 138 or 981, an amino acid other than K at position 449 (e.g., T, E, or N), an amino acid other than T at position 450 (e.g., S, E, A, N, V, Q, or G), an amino acid other than I at position 451 (e.g., F, E, V, L, D, S, C, T, A, N, H, R, G, or W), and / or an amino acid other than N at position 452 (e.g., I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G).

[0285] 197. An AAV capsid variant according to any one of Embodiments 168 to 196, comprising amino acid K at position 449, amino acid T at position 450, amino acid I at position 451, and / or amino acid N at position 452, relative to a reference sequence numbered according to Sequence ID No. 138 or 981.

[0286] 198. [N0] further includes, and [N0] is X A , X B , X C , and X D Includes, (a)X A However, it is K, T, E, or N, (b)X b However, it is T, S, E, A, N, V, Q, or G, (c)X C However, it is I, F, E, V, L, D, S, C, T, A, N, H, R, G, or W. (d)X D However, it is N, I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G. An AAV capsid variant according to any one of Embodiments 168 to 197, wherein the AAV capsid variant optionally includes an amino acid modification, e.g., a conservative substitution, among the amino acids in (a) to (d).

[0287] 199.[N0] is, (i) KTII (sequence number 5565), KTFP (sequence number 5566), KTEK (sequence number 5567), KTVN (sequence number 5568), KTFN (sequence number 5569), KTIN (sequence number 5570), TTIN (sequence number 5571), KSIN (sequence number 5572), KTER (sequence number 5573), KELH (sequence number 5574), KAIN (sequence number 5575), KTDN (sequence number 5576), KTFH (sequence number 5577), KTSN (sequence number 5578), ETIN (sequence number 5579), NTIN (sequence number 5580), KTEN ( SEQ ID NO: 5581), KTSS (SEQ ID NO: 5582), KTCN (SEQ ID NO: 5583), KTEH (SEQ ID NO: 5584), KAEM (SEQ ID NO: 5585), KATN (SEQ ID NO: 5586), KAIK (SEQ ID NO: 5587), KTDK (SEQ ID NO: 5588), KTFK (SEQ ID NO: 5589), KSDQ (SEQ ID NO: 5590), KTEI (SEQ ID NO: 5591), KTID (SEQ ID NO: 5592), KNTN (SEQ ID NO: 5593), KTET (SEQ ID NO: 5594), KTEL (SEQ ID NO: 5595), KNIN (SEQ ID NO: 5596), KTEA (SEQ ID NO: 5597) ), KTAN (sequence number 5598), NTIY (sequence number 5599), KTFS (sequence number 5600), KTES (sequence number 5601), KTTN (sequence number 5602), KTED (sequence number 5603), KTNN (sequence number 5604), KEVH (sequence number 5605), KTIS (sequence number 5606), KTVR (sequence number 5607), KTDR (sequence number 5608), ETIK (sequence number 5609), KNHI (sequence number 5610), KESD (sequence number 5611), KTIK (sequence number 5612), KTDL (sequence number 5613), KTVP (distribution Column number 5614), KTVI (sequence number 5615), KAEH (sequence number 5616), KNCL (sequence number 5617), KTVK (sequence number 5618), KNAD (sequence number 5619), KTIT (sequence number 5620), KNCV (sequence number 5621), KNAL (sequence number 5622), KVIN (sequence number 5623), KTEF (sequence number 5624), KTRE (sequence number 5625), KQGE (sequence number 5626), KSEK (sequence number 5627), KNVN (sequence number 5628), KGGE (sequence number 5629), KEFV (sequence number 5630),KSDK (SEQ ID NO: 5631), KTEQ (SEQ ID NO: 5632), KEVQ (SEQ ID NO: 5633), KTEY (SEQ ID NO: 5634), KNCW (SEQ ID NO: 5635), KTDV (SEQ ID NO: 5636), KSDI (SEQ ID NO: 5637), KNSI (SEQ ID NO: 5638), KNSL (SEQ ID NO: 5639), KEVV (SEQ ID NO: 5640), KTEP (SEQ ID NO: 5641), KSEL (SEQ ID NO: 5642), KTWQ (SEQ ID NO: 5643), KTEV (SEQ ID NO: 5644), KAVN (SEQ ID NO: 5631) 5645), KGVL (sequence number 5646), KTEG (sequence number 5647), KTRD (sequence number 5648), KTGN (sequence number 5649), KNAI (sequence number 5650), KAEN (sequence number 5651), KAET (sequence number 5652), KTVH (sequence number 5653), KETA (sequence number 5654), KNNL (sequence number 5655), EAIN (sequence number 5656), KSLN (sequence number 5657), KTIP (sequence number 5658), or KTIH (sequence number 5659), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any two or three amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 198, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0288] 200.[N0]-[N1]-[N2]-[N3]-[N4] is, (i) One amino acid sequence from sequence numbers 3239-3526 or 3591-3605, (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 198 or 199, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0289] 201. An AAV capsid variant according to any one of Embodiments 198 to 200, wherein [N0]-[N1]-[N2]-[N3]-[N4] is KTINGSGSPHSKAQNQQT (SEQ ID NO: 5660) or includes it.

[0290] 202. An AAV capsid variant according to any one of Embodiments 198 to 200, wherein [N0]-[N1]-[N2]-[N3]-[N4] is KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589) or includes it.

[0291] 203. AAV capsid variant, (A) Modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), which optionally include loop VIII having positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414, and / or (B) The following formula: contains an amino acid sequence having [N1]-[N2]-[N3] (SEQ ID NO: 6408), in which, (i)[N1] includes positions X1, X2, and X3, with position X2 being an amino acid other than S, and position X3 being an amino acid other than G. (ii)[N2] contains the amino acid sequence SPH, (iii) The AAV capsid variant wherein [N3] includes positions X4, X5, and X6, and the position X4 is K.

[0292] 204. (i) X5 of [N3] is S, I, T, R, H, Y, L, or M, (ii) X6 of [N3] is G, A, L, E, V, R, W, N, Q, or K, The AAV capsid variant according to Embodiment 203, wherein the AAV capsid variant optionally includes an amino acid modification of any of the amino acids in (i) or (ii), for example, a conservative substitution.

[0293] 205. An AAV capsid variant according to embodiment 203 or 204, wherein X5 is S and / or X6 is G.

[0294] 206. An AAV capsid variant according to any one of embodiments 203 to 205, wherein [N3] includes KS, KI, KT, KR, KH, KY, KL, KM, SG, IG, TG, RG, SA, SL, SE, SV, SR, SW, SN, HG, YG, SQ, IV, SK, LW, MG, or MA.

[0295] 207. An AAV capsid variant according to any one of embodiments 203 to 206, wherein [N3] is KSG, KIG, KTG, KRG, KSA, KSL, KSE, KSV, KSR, KSW, KSN, KHG, KYG, KSQ, KIV, KSK, KLW, KMG, or KMA, or includes them.

[0296] 208. An AAV capsid variant according to any one of embodiments 203 to 207, wherein [N3] is KSG or includes it.

[0297] 209. An AAV capsid variant according to any one of Embodiments 203 to 208, wherein [N2]-[N3] includes SPHKS (SEQ ID NO: 4704), SPHKI (SEQ ID NO: 4713), SPHKT (SEQ ID NO: 4711), SPHKR (SEQ ID NO: 4717), NPHKS (SEQ ID NO: 5661), SPHKH (SEQ ID NO: 4728), SPHKY (SEQ ID NO: 4715), SPHKL (SEQ ID NO: 4714), or SPHKM (SEQ ID NO: 4729).

[0298] 210. [N2]-[N3] (i) SPHKSG (sequence number 946), SPHKIG (sequence number 958), SPHKTG (sequence number 4738), SPHKRG (sequence number 974), NPHKSG (sequence number 5662), SPHKSA (sequence number 977), SPHKSL (sequence number 4740), SPHKSE (sequence number 4741), SPHKSV (sequence number 4742), SPHKSR (sequence number 951), SPHKSW (sequence number 4743), SPHKSN (sequence number 4744), SPHKHG (sequence number 4745), SPHKYG (sequence number 966), SPHKSQ (sequence number 4746), SPHKIV (sequence number 5663), SPHKSK (sequence number 4747), SPHKLW (sequence number 4748), SPHKMG (sequence number 4750), or SPHKMA (sequence number 4751), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 203 to 209, wherein the amino acid sequence in any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0299] 211. An AAV capsid variant according to any one of embodiments 203 to 210, wherein [N2]-[N3] is SPHKSG (SEQ ID NO: 946) or includes it.

[0300] 212. An AAV capsid variant according to any one of embodiments 203 to 211, comprising an amino acid other than G at position 453, numbered according to Sequence ID No. 138 or 981 (e.g., A, K, W, R, L, I, M, N, T, E, Q, Y, H, F, or V).

[0301] 213. An AAV capsid variant according to any one of embodiments 203 to 212, comprising amino acid G at position 453, numbered according to Sequence ID No. 138 or 981.

[0302] 214. (i) The X1 position of [N1] is G, A, K, W, R, L, I, M, N, T, E, Q, Y, H, F, or V, (ii) The X2 position of [N1] is H, Y, R, Q, N, P, or D, (iii) The X3 position of [N1] is D, E, G, V, or N, An AAV capsid variant according to any one of Embodiments 203 to 214, wherein the AAV capsid variant optionally includes an amino acid modification of any of the amino acids in (i), (ii), or (iii), such as a conservative substitution.

[0303] 215. An AAV capsid variant according to any one of embodiments 203 to 214, wherein the X2 position of [N1] is H and the X3 position of [N1] is D.

[0304] 216. An AAV capsid variant according to any one of embodiments 203 to 215, wherein the X1 position of [N1] is G, the X2 position of [N1] is H, and the X3 position of [N1] is D.

[0305] 217. An AAV capsid variant according to any one of embodiments 203 to 216, wherein [N1] includes GH, HD, GY, GR, GQ, AH, GN, KH, GP, WH, RH, LH, IH, MH, GD, NH, TH, EH, QH, YH, HH, FH, VH, YD, HE, RG, QD, RD, ND, PD, QV, DD, HN, or NG.

[0306] 218. An AAV capsid variant according to any one of Embodiments 203 to 217, wherein [N1] is GHD, GYD, GHE, GRG, GQD, GRD, AHD, GND, KHD, GPD, WHD, RHD, LHD, GQV, IHD, MHD, GDD, GHN, NHD, THD, GNG, EHD, QHD, YHD, HHD, FHD, or VHD, or includes them.

[0307] 219. An AAV capsid variant according to any one of embodiments 203 to 218, wherein [N1] is GHD or includes it.

[0308] 220. An AAV capsid variant according to any one of embodiments 203 to 219, wherein [N1]-[N2] includes HDSPH (sequence number 4703).

[0309] 221. [N1]-[N2], (i) GHDSPH (SEQ ID NO: 4784), GYDSPH (SEQ ID NO: 4829), GHESPH (SEQ ID NO: 4793), GRGSPH (SEQ ID NO: 4788), GHDNPH (SEQ ID NO: 5664), GQDSPH (SEQ ID NO: 4785), GRDSPH (SEQ ID NO: 4831), AHDSPH (SEQ ID NO: 5665), GNDSPH (SEQ ID NO: 4832), KHDSPH (SEQ ID NO: 5666), GPDSPH (SEQ ID NO: 4833), WHDSPH (SEQ ID NO: 5667), RHDSPH (SEQ ID NO: 5668), LHDSPH (SEQ ID NO: 5669), GQVSPH (sequence number 4835), IHDSPH (sequence number 5670), MHDSPH (sequence number 5671), GDDSPH (sequence number 4792), GHNSPH (sequence number 4836), NHDSPH (sequence number 5672), THDSPH (sequence number 5673), GNGSPH (sequence number 4805), EHDSPH (sequence number 5674), QHDSPH (sequence number 5675), YHDSPH (sequence number 5676), HHDSPH (sequence number 5677), FHDSPH (sequence number 5678), or VHDSPH (sequence number 5679), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 203 to 220, wherein the amino acid sequence in any one of the amino acid sequences in (i) contains one, two, or three but no more than four different amino acids, or contains such a sequence.

[0310] 222.[N1]-[N2]-[N3] is, (i) GHDSPHKSG (SEQ ID NO: 4698), GHDSPHKIG (SEQ ID NO: 4996), GYDSPHKSG (SEQ ID NO: 4997), GHESPHKSG (SEQ ID NO: 4998), GHDSPHKTG (SEQ ID NO: 4999), GRGSPHKRG (SEQ ID NO: 5000), GHDNPHKSG (SEQ ID NO: 5680), GQDSPHKSG (SEQ ID NO: 4908), GHDSPHKSA (SEQ ID NO: 4940), GHDSPHKSL (SEQ ID NO: 5001), GHDSPHKSE (SEQ ID NO: 5003), GRDSPHKSG (SEQ ID NO: 5004), AH DSPHKSG (SEQ ID NO: 5681), GNDSPHKSV (SEQ ID NO: 5005), AHDSPHKIG (SEQ ID NO: 5682), GHESPHKSA (SEQ ID NO: 4939), GQDSPHKIG (SEQ ID NO: 5006), GHDSPHKSV (SEQ ID NO: 5007), GHDSPHKSR (SEQ ID NO: 4942), KHDSPHKSG (SEQ ID NO: 5683), GPDSPHKIG (SEQ ID NO: 5008), GPDSPHKSG (SEQ ID NO: 5009), GHDSPHKSW (SEQ ID NO: 5010), WHDSPHKSG (SEQ ID NO: 5684), RHDSPHKS G (SEQ ID NO: 5685), GHDSPHKSN (SEQ ID NO: 5011), GHDSPHKRG (SEQ ID NO: 4937), GHDSPHKHG (SEQ ID NO: 5013), LHDSPHKSG (SEQ ID NO: 5686), GQVSPHKSG (SEQ ID NO: 5014), IHDSPHKSG (SEQ ID NO: 5687), MHDSPHKSG (SEQ ID NO: 5688), GDDSPHKSV (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016), NHDSPHKSG (SEQ ID NO: 5689), THDSPHKSG (SEQ ID NO: 5690), GNGSPHKRG (SEQ ID NO: 5017), EHDSPHKSG (sequence number 5691), GHDSPHKYG (sequence number 5018), GHDSPHKSQ (sequence number 5019), QHDSPHKSG (sequence number 5692), RHDSPHKIV (sequence number 5693), YHDSPHKSG (sequence number 5694), GNDSPHKIG (sequence number 5020), HHDSPHKSG (sequence number 5695), GHDSPHKSK (sequence number 5021), FHDSPHKSG (sequence number 5696), GHDSPHKLW (sequence number 5022), VHDSPHKSG (sequence number 5697),GHDSPHKMG (sequence number 5024), GHDSPHKMA (sequence number 5025), or GDDSPHKSG (sequence number 4938), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 203 to 221, wherein the amino acid sequence in any one of the amino acid sequences in (i) contains one, two, or three but no more than four different amino acids, or contains such a sequence.

[0311] 223. An AAV capsid variant according to any one of Embodiments 203 to 222, wherein [N1]-[N2]-[N3] is GHDSPHKSG (SEQ ID NO: 4698) or includes it.

[0312] 224. An AAV capsid variant according to any one of Embodiments 203 to 223, comprising, with respect to a reference sequence numbered according to Sequence ID No. 138, an amino acid other than Q at position 456 (e.g., R, P, H, K, L, V, A, E, or I), an amino acid other than N at position 457 (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q, or M), an amino acid other than Q at position 458 (e.g., R, V, K, P, Y, H, L, I, E, or M), an amino acid other than Q at position 459 (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N), and / or an amino acid other than T at position 460 (e.g., A, E, K, S, I, P, G, or N).

[0313] 225. An AAV capsid variant according to any one of Embodiments 203 to 224, comprising, with respect to a reference sequence numbered according to Sequence ID No. 982, an amino acid other than Q at position 462 (e.g., R, P, H, K, L, V, A, E, or I), an amino acid other than N at position 463 (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q, or M), an amino acid other than Q at position 464 (e.g., R, V, K, P, Y, H, L, I, E, or M), an amino acid other than Q at position 465 (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N), and / or an amino acid other than T at position 466 (e.g., A, E, K, S, I, P, G, or N).

[0314] 226. An AAV capsid variant according to any one of Embodiments 203 to 225, comprising amino acid Q at position 456, amino acid N at position 457, amino acid Q at position 458, amino acid Q at position 459, and / or amino acid T at position 460, relative to a reference sequence numbered according to Sequence ID No. 138.

[0315] 227. An AAV capsid variant according to any one of Embodiments 203 to 226, comprising amino acid Q at position 462, amino acid N at position 463, amino acid Q at position 464, amino acid Q at position 465, and / or amino acid T at position 466, relative to a reference sequence numbered according to Sequence ID No. 138.

[0316] 228. Further including [N4], where [N4] includes X7, X8, X9, X10, and X11, (a) X7 is Q, R, P, H, L, K, I, G, S, M, or E, (b) X8 is N, D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M, (c)X9 is Q, R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, D, (d) X10 is Q, H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G, (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q, An AAV capsid variant according to any one of embodiments 203 to 227, wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the amino acids in (a) to (e).

[0317] 229.[N4] ga, (i) QNQQT (SEQ ID NO: 5412), QIRQT (SEQ ID NO: 5698), QNQHA (SEQ ID NO: 5699), QKQQT (SEQ ID NO: 5543), QSVQT (SEQ ID NO: 5700), RSQQT (SEQ ID NO: 5701), QNKLE (SEQ ID NO: 5702), QNQQK (SEQ ID NO: 5703), QHQQA (SEQ ID NO: 5704), QIQHT (SEQ ID NO: 5705), PRQQT (SEQ ID NO: 5706), HTQQT (SEQ ID NO: 5707), QRQHT (SEQ ID NO: 5708), QSQQT (SEQ ID NO: 5418), QNQQS (SEQ ID NO: 5709), RNQET (SEQ ID NO: 5710), QTQLT (SEQ ID NO: 5478), KNQQT (SEQ ID NO: 5711), QDQQT (SEQ ID NO: 5432), HNQQT (SEQ ID NO: 5426), QNQLT (SEQ ID NO: 5423), QTQQT (SEQ ID NO: 5712), QTQQI (SEQ ID NO: 5713), QSKQA (SEQ ID NO: 5714), QNQPP (SEQ ID NO: 5715), QSPQT (SEQ ID NO: 5716), QNYQT (SEQ ID NO: 5493), QNHQT (SEQ ID NO: 5431), QNRQT (SEQ ID NO: 5446), QNQQG (SEQ ID NO: 5717), QNHLT (SEQ ID NO: 5482) ), QYQHT (SEQ ID NO: 5447), QNQWT (SEQ ID NO: 5503), QNQHT (SEQ ID NO: 5718), QTRQT (SEQ ID NO: 5719), QNLHT (SEQ ID NO: 5720), LNQQT (SEQ ID NO: 5471), QNQET (SEQ ID NO: 5721), QHLQT (SEQ ID NO: 5513), LNQPT (SEQ ID NO: 5722), QNQDT (SEQ ID NO: 5723), RNQQT (SEQ ID NO: 5724), QNLLT (SEQ ID NO: 5725), QLVIT (SEQ ID NO: 5726), RTQET (SEQ ID NO: 5727), QTHQT (SEQ ID NO: 5728), QNQPA (SEQ ID NO: 5728) Column number 5729), QDQHT ​​(sequence number 5730), QSQHT (sequence number 5731), RNQQI (sequence number 5732), VRQQT (sequence number 5733), QNQHS (sequence number 5734), AWQQT (sequence number 5735), QSVPT (sequence number 5736), QNIQP (sequence number 5737), QNHLN (sequence number 5738), LDQQT (sequence number 5739), PDQQS (sequence number 5740), ESQQT (sequence number 5741), QNKQT (sequence number 5742), QRQLT (sequence number 5743), QIIVT (sequence number 5744),QKQST (SEQ ID NO: 5745), QSHQT (SEQ ID NO: 5746), QFVVT (SEQ ID NO: 5747), QNLQT (SEQ ID NO: 5428), QNQQI (SEQ ID NO: 5419), QSQPT (SEQ ID NO: 5748), QNEQT (SEQ ID NO: 5749), QSLQT (SEQ ID NO: 5516), RNRQT (SEQ ID NO: 5750), QSKQT (SEQ ID NO: 5751), QNPLT (SEQ ID NO: 5752), RDQKT (SEQ ID NO: 5753), HNQQN (SEQ ID NO: 5754), QWKRT (SEQ ID NO: 5755), QSQQI (SEQ ID NO: 5476), QAQQT (SEQ ID NO: 5462), QNHQI (SEQ ID NO: 5756), QNQQA (SEQ ID NO: 5757), QNQLN (SEQ ID NO: 5757) Number 5758), QTQPT (SEQ ID NO: 5759), INQQT (SEQ ID NO: 5560), QKQLT (SEQ ID NO: 5760), RNQLA (SEQ ID NO: 5761), RNQQS (SEQ ID NO: 5762), ISIQT (SEQ ID NO: 5763), QNQQN (SEQ ID NO: 5764), QSQQS (SEQ ID NO: 5765), QTVCT (SEQ ID NO: 5766), QYQQI (SEQ ID NO: 5767), QQIMT (SEQ ID NO: 5768), QNEQS (SEQ ID NO: 5769), LNHQT (SEQ ID NO: 5770), QMIHT (SEQ ID NO: 5771), RNHQS (SEQ ID NO: 5772), QKMNT (SEQ ID NO: 5773), QSQQN (SEQ ID NO: 5774), QYQHA (SEQ ID NO: 5465), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any two, three, or four amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 228, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0318] 230.[N1]-[N2]-[N3]-[N4] is, (i) One of the amino acid sequences from sequence number 201 or 3160-3237, (ii) An amino acid sequence containing any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 228 or 229, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0319] 231. An AAV capsid variant according to any one of Embodiments 228 to 230, wherein [N1]-[N2]-[N3]-[N4] is GHDSPHKSGQNQQT (Sequence ID 201) or includes it.

[0320] 232. An AAV capsid variant according to any one of Embodiments 203 to 231, comprising, with respect to a reference sequence numbered according to Sequence ID No. 138 or 982, an amino acid other than K at position 449 (e.g., T), an amino acid other than T at position 450 (e.g., A, S, I, V, N, E, Y, C, G, W, or Q), an amino acid other than I at position 451 (e.g., E, V, S, T, N, D, C, G, Q, L, P, A), and / or an amino acid other than N at position 452 (e.g., S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R).

[0321] 233. An AAV capsid variant according to any one of Embodiments 203 to 232, comprising amino acid K at position 449, amino acid T at position 450, amino acid I at position 451, and / or amino acid N at position 452, relative to a reference sequence numbered according to Sequence ID No. 138 or 982.

[0322] further comprising 234.[N0], wherein [N0] is X A , X B , X C , and X D and comprising (a) X A is K or T, (b) X b is T, A, S, I, V, N, E, Y, C, G, W, or Q, (c) X C is I, E, V, S, T, N, D, C, G, Q, L, P, A, (d) X D is N, S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R, Optionally, the AAV capsid variant comprises an amino acid modification of any of the amino acids in (a)-(d), such as a conservative substitution, and is the AAV capsid variant according to any one of Embodiments 203-233.

[0323] 235. [N0] is (i) KAIN (sequence number 5575), KTIN (sequence number 5570), KTES (sequence number 5601), TTIN (sequence number 5571), KSIN (sequence number 5572), KTVN (sequence number 5568), KSIY (sequence number 5775), KTSN (sequence number 5578), KTTN (sequence number 5602), KIIN (sequence number 5776), KTIS (sequence number 5606), KAII (sequence number 5777), KTIK (sequence number 5612), KTEF (sequence number 5624), KTIT (sequence number 5620), KTNN (sequence number 5604), KTID ( SEQ ID NO: 5592), KAIS (SEQ ID NO: 5778), KTVD (SEQ ID NO: 5779), KTIE (SEQ ID NO: 5780), KTEG (SEQ ID NO: 5647), KVIN (SEQ ID NO: 5623), KAVN (SEQ ID NO: 5645), KTIY (SEQ ID NO: 5781), KTDN (SEQ ID NO: 5576), KTCN (SEQ ID NO: 5583), KNVV (SEQ ID NO: 5782), KTEL (SEQ ID NO: 5595), KTDA (SEQ ID NO: 5783), KTEV (SEQ ID NO: 5644), KSEL (SEQ ID NO: 5642), KTEM (SEQ ID NO: 5784), KTEQ (SEQ ID NO: 5632) ), KTII (sequence number 5565), KIVN (sequence number 5785), KTEK (sequence number 5567), KTEN (sequence number 5581), KIGN (sequence number 5786), KEVM (sequence number 5787), KYQV (sequence number 5788), KTEA (sequence number 5597), KATN (sequence number 5586), KTEH (sequence number 5584), KTVE (sequence number 5789), KAID (sequence number 5790), KTIM (sequence number 5791), KEVG (sequence number 5792), KSEM (sequence number 5793), KAQQ (sequence number 5794), KCGE (distribution Column number 5795), KASN (sequence number 5796), KTET (sequence number 5594), KTIG (sequence number 5797), KTDP (sequence number 5798), KELV (sequence number 5799), KELM (sequence number 5800), KNEI (sequence number 5801), KTPN (sequence number 5802), KITN (sequence number 5803), KTDI (sequence number 5804), KTDQ (sequence number 5805), KGIN (sequence number 5806), KSEI (sequence number 5807), KSEK (sequence number 5627), KWSA (sequence number 5808), KELA (sequence number 5809),KQTQ (SEQ ID NO: 5810), KGAD (SEQ ID NO: 5811), KVGE (SEQ ID NO: 5812), KANE (SEQ ID NO: 5813), KTDT (SEQ ID NO: 5814), KTCI (SEQ ID NO: 5815), KELR (SEQ ID NO: 5816), KCQI (SEQ ID NO: 5817), KGVM (SEQ ID NO: 5818), KACD (SEQ ID NO: 5819), KNEL (SEQ ID NO: 5820), KAAE (SEQ ID NO: 5821), KG QN (sequence number 5822), KNEF (sequence number 5823), KTSI (sequence number 5824), KAEH (sequence number 5616), KCDQ (sequence number 5825), KEIL (sequence number 5826), KTER (sequence number 5573), KNAI (sequence number 5650), KTDK (sequence number 5588), KTPD (sequence number 5827), KTIH (sequence number 5659), or KTEI (sequence number 5591), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any two or three amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 234, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0324] 236.[N0]-[N1]-[N2]-[N3]-[N4] is, (i) Any one amino acid sequence from sequence numbers 3606 to 3836, (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to Embodiment 234 or 235, wherein any one of the amino acid sequences in (i) is an amino acid sequence containing one, two, or three but no more than four different amino acids, or contains such a sequence.

[0325] 237. An AAV capsid variant according to any one of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is KTINGHDSPHKSGQNQQT (SEQ ID NO: 5828) or includes it.

[0326] 238. An AAV capsid variant according to any one of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754) or includes it.

[0327] 239. An AAV capsid variant according to any one of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241) or includes it.

[0328] 240. An AAV capsid variant according to any one of embodiments 168 to 239, wherein [N1]-[N2]-[N3] are present in loop IV.

[0329] 241. An AAV capsid variant according to any one of embodiments 198-202 or 234-240, wherein [N0] and [N4] are present in loop IV.

[0330] An AAV capsid variant according to any one of Embodiments 198-202 or 234-241, wherein 242.[N0] is located immediately after position 448 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982.

[0331] An AAV capsid variant according to any one of Embodiments 198-202 or 234-242, wherein 243.[N0] replaces positions 449-452 (e.g., K449, T450, I451, and N452) in a reference sequence numbered according to sequence number 138, 981, or 982.

[0332] An AAV capsid variant according to any one of Embodiments 198-202 or 234-243, wherein 244.[N0] is located immediately after position 448, and [N0] replaces positions 449-452 (e.g., K449, T450, I451, and N452) with respect to a reference sequence numbered according to sequence numbers 138, 981, or 982.

[0333] 245. An AAV capsid variant according to any one of Embodiments 198-202 or 234-244, wherein [N0] corresponds to positions 449-452 (e.g., K449, T450, I451, and N452) of any one of Sequence IDs 138, 981, or 982.

[0334] An AAV capsid variant according to any one of embodiments 168 to 245, wherein 246.[N1] is located immediately after position 452 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982.

[0335] 247. An AAV capsid variant according to any one of embodiments 168 to 246, wherein [N1] replaces positions 453 to 455 (e.g., G453, S454, and G455) in a reference sequence numbered according to sequence number 138, 981, or 982.

[0336] An AAV capsid variant according to any one of embodiments 168 to 246, wherein 248.[N1] replaces position 453 (e.g., G453) in a reference sequence numbered according to sequence number 138, 981, or 982.

[0337] 249. (i) The X1 position of [N1] replaces the 453 position (for example, G453), (ii) The X2 position of [N1] corresponds to the 454 position (for example, S454), (iii) The X3rd position of [N1] corresponds to the 455th position (for example, G455), (i), (ii), and (iii) are AAV capsid variants according to any one of embodiments 168-177, 179-181, 183-185, 187-193, 195-200, 202, or 240-246, numbered according to sequence number 138 or sequence number 981.

[0338] 250. (i) The X1 position of [N1] corresponds to the 453rd position (for example, G453), (ii) The X2 position of [N1] corresponds to the 454 position (for example, S454), (iii) The X3rd position of [N1] corresponds to the 455th position (for example, G455), AAV capsid variants according to any one of embodiments 168-176, 178-201, or 240-246, wherein (i), (ii), and (iii) are numbered according to sequence number 138 or sequence number 981.

[0339] 251. (i) The X1 position of [N1] corresponds to the 453rd position (for example, G453), (ii) The X2 position of [N1] replaces the 454 position (for example, S454), (iii) The 3rd position of X in [N1] replaces the 455th position (for example, G455), AAV capsid variant according to any one of Embodiments 203 to 248, wherein (i), (ii), and (iii) are numbered according to Sequence ID No. 138 or Sequence ID No. 982.

[0340] An AAV capsid variant according to any one of embodiments 203 to 248 or 251, wherein 252.[N1] corresponds to positions 453 to 455 of sequence number 982 (e.g., G453, H454, D455).

[0341] An AAV capsid variant according to any one of embodiments 168-176, 178-201, 240-247, or 250, wherein 253.[N1] corresponds to positions 453-455 of sequence number 138 or 981 (e.g., G453, S454, G455).

[0342] An AAV capsid variant according to any one of Embodiments 168 to 253, wherein 254.[N2] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982.

[0343] An AAV capsid variant according to any one of Embodiments 168 to 254, wherein 255.[N2] corresponds to positions 456 to 458 of Sequence ID No. 981 or 982 (e.g., S456, P457, and H458).

[0344] An AAV capsid variant according to any one of Embodiments 168 to 254, wherein 256.[N2] corresponds to positions 456 to 458 (e.g., S456, P457, and H458) of any one of Sequence IDs 5 to 10, 36 to 59, or 6409 to 6413.

[0345] 257. An AAV capsid variant according to any one of embodiments 168 to 256, wherein [N2] is located immediately after [N1].

[0346] An AAV capsid variant according to any one of embodiments 168-202, 240-247, or 249-257, wherein 258.[N3] corresponds to positions 459-460 of sequence number 981 (e.g., S459, K460, A461).

[0347] An AAV capsid variant according to any one of embodiments 168-202, 240-247, 249-257, wherein 259.[N3] corresponds to positions 459-460 of sequence numbers 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, or 59 (e.g., S459, K460, A461).

[0348] An AAV capsid variant according to any one of embodiments 168 to 259, wherein 260.[N2]-[N3] is located immediately after position 455 with respect to a reference sequence numbered according to any one of the amino acid sequences of sequence numbers 138, 981, or 982.

[0349] An AAV capsid variant according to any one of embodiments 168 to 259, wherein 261.[N2]-[N3] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of sequence number 981.

[0350] 262. An AAV capsid variant according to any one of embodiments 168 to 261, wherein [N2]-[N3] corresponds to positions 456-461 of sequence number 981 (e.g., S456, P457, H458, S459, K460, A461).

[0351] 263. An AAV capsid variant according to any one of embodiments 168 to 262, wherein [N2]-[N3] corresponds to position 456-461 (e.g., S456, P457, H458, S459, K460, A461) of any one of sequence numbers 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, or 59.

[0352] An AAV capsid variant according to any one of embodiments 203-257 or 259-261, wherein 264.[N3] corresponds to positions 459-460 of sequence number 982 (e.g., K459, S460, G461).

[0353] 265.[N3] corresponds to positions 459-460 of sequence number 37 (e.g., K459, S460, G461), an AAV capsid variant according to any one of embodiments 203-257 or 259-261.

[0354] An AAV capsid variant according to any one of embodiments 203 to 265, wherein 266.[N2]-[N3] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of sequence number 982.

[0355] An AAV capsid variant according to any one of embodiments 203-246, 248, 252, 255, 257, 260, 263-266, wherein 267.[N3] replaces the 454th and 455th positions (e.g., S454 and G455) numbered according to sequence number 138.

[0356] An AAV capsid variant according to any one of embodiments 203-246, 248, 252, 255, 257, 260, 263-267, wherein 268.[N3] is present immediately after [N2] and replaces the 454th and 455th positions (e.g., S454 and G455) numbered according to sequence number 138.

[0357] 269. An AAV capsid variant according to any one of embodiments 203-246, 248, 252, 255, 257, 260, 263-268, wherein [N3] is located immediately after [N1]-[N2] and replaces the 454th and 455th positions (e.g., S454 and G455) numbered according to sequence number 138.

[0358] An AAV capsid variant according to any one of embodiments 203-257, 260, 264-269, wherein 270.[N2]-[N3] corresponds to positions 456-461 of sequence number 982 (e.g., S456, P457, H458, K459, S460, G461).

[0359] 271. An AAV capsid variant according to any one of embodiments 203-257, 260, 264-270, wherein [N2]-[N3] corresponds to positions 456-461 of sequence number 37 (e.g., S456, P457, H458, K459, S460, G461).

[0360] An AAV capsid variant according to any one of embodiments 191-202 or 228-271, wherein 272.[N4] is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of sequence number 138.

[0361] An AAV capsid variant according to any one of Embodiments 191-202 or 228-272, wherein 273.[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) of a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0362] An AAV capsid variant according to any one of Embodiments 191-202 or 228-273, wherein 274.[N4] corresponds to positions 462-466 ​​of Sequence ID No. 981 or 982 (e.g., Q462, N463, Q464, Q465, and T466).

[0363] An AAV capsid variant according to any one of Embodiments 191-202 or 228-273, wherein 275.[N4] corresponds to position 462-466 ​​of any one of Sequence IDs 5-10, 36-59, or 6409-6413.

[0364] An AAV capsid variant according to any one of embodiments 191-202 or 228-274, wherein 276.[N4] corresponds to positions 456-460 of sequence number 138 (e.g., Q456, N457, Q458, Q459, and T460).

[0365] An AAV capsid variant according to any one of Embodiments 191-202 or 228-276, wherein 277.[N2]-[N3]-[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0366] 278. An AAV capsid variant according to any one of Embodiments 191-202 or 228-277, wherein [N2]-[N3]-[N4] is located immediately after position 455 and replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0367] An AAV capsid variant according to any one of Embodiments 191-202 or 228-278, wherein 279.[N1]-[N2]-[N3]-[N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460) of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0368] 280. An AAV capsid variant according to any one of Embodiments 191-202 or 228-279, wherein [N1]-[N2]-[N3]-[N4] is located immediately after position 452, and [N1]-[N2]-[N3]-[N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0369] 281. An AAV capsid variant according to any one of embodiments 191-202, 240-247, 249, 250, 253-263, 266, or 272-280, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 of sequence number 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, and T466).

[0370] 282. An AAV capsid variant according to any one of embodiments 168-202, 240-247, 249, 250, 253-263, 266, or 272-280, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 of sequence number 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0371] 283. An AAV capsid variant according to any one of embodiments 228-257, 260, 261, 264-282, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 of sequence number 982 (for example, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466).

[0372] 284. An AAV capsid variant according to any one of embodiments 203-257, 260, 261, 264-283, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 of sequence number 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461).

[0373] 285. An AAV capsid variant according to any one of embodiments 228-257, 260, 261, 264-282, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 of any one of sequence numbers 5-10, 36-59, or 6409-6413.

[0374] An AAV capsid variant according to any one of Embodiments 198-202 or 234-286, wherein 286.[N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460) of a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0375] 287. An AAV capsid variant according to any one of Embodiments 198-202 or 234-286, wherein [N0]-[N1]-[N2]-[N3]-[N4] is located immediately after position 448, and [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0376] 288. An AAV capsid variant according to any one of embodiments 198-202, 240-247, 249, 250, 253-263, 266, 272-281, 286, or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of sequence number 981 (e.g., K449, T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466).

[0377] 289. An AAV capsid variant according to any one of embodiments 234-257, 260, 261, 264-284, 286, or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of sequence number 982 (e.g., K449, T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466).

[0378] An AAV capsid variant according to any one of embodiments 234-257, 260, 261, 264-284, 286, or 287, wherein 290.[N0]-[N1]-[N2]-[N3]-[N4] corresponds to position 449-466 of any one of sequence numbers 5-10, 36-59, or 6409-6413.

[0379] An AAV capsid variant according to any one of Embodiments 191-202 or 228-290, wherein 291.[N4] is located immediately after position 461 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0380] An AAV capsid variant according to any one of Embodiments 191-202 or 228-291, wherein 292.[N4] replaces positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) of a reference sequence numbered according to the amino acid sequence of Sequence ID No. 981 or 982.

[0381] An AAV capsid variant according to any one of Embodiments 191-202 or 228-292, wherein 293.[N2]-[N3]-[N4] replaces positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0382] 294. An AAV capsid variant according to any one of Embodiments 191-202 or 228-293, wherein [N2]-[N3]-[N4] is located immediately after position 455, and [N2]-[N3]-[N4] replaces positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0383] 295. An AAV capsid variant according to any one of embodiments 168 to 294, comprising [N2]-[N3] from the N-terminus to the C-terminus.

[0384] 296. An AAV capsid variant according to any one of embodiments 168 to 295, comprising [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0385] 297. An AAV capsid variant according to any one of embodiments 168 to 296, comprising [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0386] 298. An AAV capsid variant according to any one of embodiments 168 to 297, comprising [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0387] 299. An AAV capsid variant according to any one of Embodiments 168 to 298, comprising [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0388] 300. AAV capsid variant, (A) Modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), which optionally include loop VIII having positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414, and / or (B) Formula [A]-[B] (Sequence ID 4696) is included, and in the formula, (i)[A] contains GSGSPH (sequence number 4695), (ii)[B] includes X1, X2, X3, X4, and X5, (a) The X1 position is S, I, F, V, C, Y, W, R, P, L, Q, M, K, or G, (b) The X2 position is K, M, R, F, V, C, P, Y, L, W, G, N, S, T, I, or A, (c) The third letter of X is A, Y, L, R, W, C, T, F, H, I, P, M, K, S, V, G, Q, or N. (d) The 4th position of X is Q, M, F, K, H, R, C, W, P, V, L, G, S, Y, I, A, T, D, N, or E, (e) The 5th position of X is A, N, Y, R, K, L, I, M, Q, S, C, W, F, T, G, V, or P. Optionally, the AAV capsid variant includes any of the above-mentioned amino acid modifications in (a) to (e), such as a conservative substitution.

[0389] 301. (a) The X1 position is S, L, R, V, or P, (b) The X2 position is K, C, F, L, P, R, S, or V, (c) The third position of X is A, C, F, I, K, L, M, P, R, T, W, or Y, (d) The 4th position of X is Q, R, S, T, C, F, K, L, P, or Y, (e) The 5th position of X is N, R, S, T, K, M, Q, or Y, The AAV capsid variant according to Embodiment 300, wherein the AAV capsid variant optionally includes an amino acid modification, e.g., a conservative substitution, among the amino acids in (a) to (e).

[0390] 302. YY、SLY、SKP、SRF、SRM、SVK、SWA、SLW、SFR、SKK、SYA、SCS、SGA、SFP、SFF、SMC、 SKT, SGK, FYR, CRV, YGI, VNC, SLA, WSY, RWL, PSC, SSW, SKG, VPW, SGC, STT, PKR, SKC, WVP, SFW, RIK, SKM, LRW, LPT, SYM, LLC, RCC, LCV, SYL, QGC, MAF, SFQ, S LC、RPW、RPR、SCP、SVR、SLP、VYH、SYT、LVY、YRY、SWL、CPA、SPP、RWT、PRK、PFV 、SKS、WVA、SKV、CAL、SSC、SKN、LCT、STC、SKQ、KSG、SYY、SLT、SCQ、FPF、SVF、GR Y、AQA、AQN、YMN、AFY、LKR、RHR、AQK、WRL、CRN、TCN、FFI、AQY、WQN、YFM、ARQ、 HQN、IRR、YQN、YWN、AFS、FWN、AQC、MRN、KKN、APN、WKN、ARW、RPN、KVF、AFN、ACS 、RLW、SRN、CPN、ACN、FRQ、PFN、FGN、CQN、LFW、TRK、KRN、RQN、VQN、IQN、AQR、P FR、AWN、RSY、LQN、WLN、RRA、AQT、GCT、RYT、TPN、ARM、CFL、PQN、WSN、FKN、KQN、 APR、RYN、MIC、TQN、WKS、AAR、LTR、IRG、LVN、FQN、ACQ、WGL、ILR、QIN、ACI、AL R、AHA、CLN、AFV、AQF、RCN、MPC、KTS、PYN、AQS、TRN、LKN、AQM、CTN、PDN、RNY、A CR, CSV, ARI, LPK, SEQ, VRM, NSR, RKR, ARN, QRP, RVV, GQN, YSN, QSN, AKG, CTS, FEN, AKK, KAQ, MYM, KAF, KLK, KRH, KWR, RCR, FTC, KFF, VWQ, KYF, KAR, CHQ, PW Q、KIR、YYQ、LYW、KPK、RFW、RMR、VKK、WAP、LWK、FRP、KKV、YAF、KAC、KRL、CSR、R CP、GAC、KFR、FFG、MCQ、KLF、KTR、GKR、YRQ、RVQ、GIQ、NCQ、KPF、LAW、KRS、SYQ、An AAV capsid variant according to Embodiment 300 or 301, comprising WLQ, KRR, KGC, KRY, GCQ, FTP, TTC, KRQ, KCF, VPQ, FWS, KFK, IKQ, KAP, FRY, KMI, RWQ, PTQ, KWK, YMR, KAA, LCQ, CCQ, CVQ, KLT, KLC, YLV, AFQ, KWG, KIL, FQI, KAL, KAH, LCL, PRQ, CPQ, VRY, VRC, KMP, KKT, LPY, YHQ, YTR, VYQ, RYQ, WLK, PAQ, MCT, PPD, WTQ, RKQ, KCS, FVQ, KLP, KSE, VAQ, LYQ, KVR, ALQ, SCT, KNS, KRK, CTQ, TCL, YAR, KQR, KRV, SGQ, YYS, LTC, CQS, KAK, KPQ, PFQ, KCT, or VFE.,

[0391] 303.[B] includes SKAQ (sequence number 5829), SMYM (sequence number 5830), SKAF (sequence number 5831), SKLK (sequence number 5832), SKRH (sequence number 5833), SKWR (sequence number 5834), SRCR (sequence number 5835), SFTC (sequence number 5836), SKFF (sequence number 5837), IVWQ (sequence number 5838), SKYF (sequence number 5839), SKAR (sequence number 5840), SCHQ (sequence number 5841), FPWQ (sequence number 5842), SKIR (sequence number 5843), VYYQ (sequence number 5844), SLYW (SEQ ID NO: 5845), SKPK (SEQ ID NO: 5846), SRFW (SEQ ID NO: 5847), SRMR (SEQ ID NO: 5848), SVKK (SEQ ID NO: 5849), SWAP (SEQ ID NO: 5850), SLWK (SEQ ID NO: 5851), SFRP (SEQ ID NO: 5852), SKKV (SEQ ID NO: 5853), SYAF (SEQ ID NO: 5854), SKAC (SEQ ID NO: 5855), SKRL (SEQ ID NO: 5856), SCSR (SEQ ID NO: 5857), SRCP (SEQ ID NO: 5858), SGAC (SEQ ID NO: 5859), SKFR (SEQ ID NO: 5860), SFPF (SEQ ID NO: 5849) 861), SFFG (SEQ ID NO: 5862), SMCQ (SEQ ID NO: 5863), SKLF (SEQ ID NO: 5864), SKTR (SEQ ID NO: 5865), SGKR (SEQ ID NO: 5866), FYRQ (SEQ ID NO: 5867), CRVQ (SEQ ID NO: 5868), YGIQ (SEQ ID NO: 5869), VNCQ (SEQ ID NO: 5870), SKPF (SEQ ID NO: 5871), SLAW (SEQ ID NO: 5872), SKRS (SEQ ID NO: 5873), WSYQ (SEQ ID NO: 5874), RWLQ (SEQ ID NO: 5875), PSCQ (SEQ ID NO: 5876), SSWL (SEQ ID NO: 5877), SKRR ( SEQ ID NOs: 5878, SKGC (SEQ ID NOs: 5879), VPWQ (SEQ ID NOs: 5880), SKRY (SEQ ID NOs: 5881), SGCQ (SEQ ID NOs: 5882), SFTP (SEQ ID NOs: 5883), STTC (SEQ ID NOs: 5884), PKRQ (SEQ ID NOs: 5885), SKCF (SEQ ID NOs: 5886), WVPQ (SEQ ID NOs: 5887), SFWS (SEQ ID NOs: 5888), SKFK (SEQ ID NOs: 5889), RIKQ (SEQ ID NOs: 5890), SKAP (SEQ ID NOs: 5891), SFRY (SEQ ID NOs: 5892), SKMI (SEQ ID NOs: 5893), LRWQ (SEQ ID NOs: 5894),LPTQ (SEQ ID NO: 5895), SKWK (SEQ ID NO: 5896), SYMR (SEQ ID NO: 5897), SKAA (SEQ ID NO: 5898), LLCQ (SEQ ID NO: 5899), RCCQ (SEQ ID NO: 5900), LCVQ (SEQ ID NO: 5901), SKLT (SEQ ID NO: 5902), SKLC (SEQ ID NO: 5903), SYLV (SEQ ID NO: 5904), QGCQ (SEQ ID NO: 5905), MAFQ (SEQ ID NO: 5906), SKWG (SEQ ID NO: 5907), SKIL (SEQ ID NO: 5908), SFQI (SEQ ID NO: 5909), SKAL (SEQ ID NO: 5910), SKAH (SEQ ID NO: 5906) Number 5911), SLCL (sequence number 5912), RPWQ (sequence number 5913), RPRQ (sequence number 5914), SCPQ (sequence number 5915), SVRY (sequence number 5916), SVRC (sequence number 5917), SKMP (sequence number 5918), SKKT (sequence number 5919), SLPY (sequence number 5920), VYHQ (sequence number 5921), SYTR (sequence number 5922), LVYQ (sequence number 5923), YRYQ (sequence number 5924), SWLK (sequence number 5925), CPAQ (sequence number 5926), SMCT (sequence number 5927), SPPD (SEQ ID NO: 5928), SKRN (SEQ ID NO: 5929), RWTQ (SEQ ID NO: 5930), PRKQ (SEQ ID NO: 5931), SKCS (SEQ ID NO: 5932), PFVQ (SEQ ID NO: 5933), SKLP (SEQ ID NO: 5934), SKSE (SEQ ID NO: 5935), WVAQ (SEQ ID NO: 5936), SLYQ (SEQ ID NO: 5937), SKVR (SEQ ID NO: 5938), CALQ (SEQ ID NO: 5939), SSCT (SEQ ID NO: 5940), SKNS (SEQ ID NO: 5941), SKRK (SEQ ID NO: 5942), LCTQ (SEQ ID NO: 5943), STCL (SEQ ID NO: 5943) Number 5944), SYAR (sequence number 5945), SKQR (sequence number 5946), SKRV (sequence number 5947), KSGQ (sequence number 5948), SYYS (sequence number 5949), SLTC (sequence number 5950), SCQS (sequence number 5951), SKAK (sequence number 5952), SKPQ (sequence number 5953), FPFQ (sequence number 5954), SKCT (sequence number 5955), SVFE (sequence number 5956), GRYQ (sequence number 5957), KAQA (sequence number 5958), KAQN (sequence number 5959), MYMN (sequence number 5960),KAFY (sequence number 5961), KLKR (sequence number 5962), KRHR (sequence number 5963), KAQK (sequence number 5964), KWRL (sequence number 5965), RCRN (sequence number 5966), FTCN (sequence number 5967), KFFI (sequence number 5968), KAQY (sequence number 5969), VWQN (sequence number 5970), KYFM (sequence number 5971), KARQ (sequence number 5972), CHQN (sequence number 5973), PWQN (sequence number 5974), KIRR (sequence number 5975), YYQN (sequence number 5976), LYWN (sequence number) Number 5977), KPKR (SEQ ID NO: 5978), KAFS (SEQ ID NO: 5979), RFWN (SEQ ID NO: 5980), KAQC (SEQ ID NO: 5981), RMRN (SEQ ID NO: 5982), VKKN (SEQ ID NO: 5983), WAPN (SEQ ID NO: 5984), LWKN (SEQ ID NO: 5985), KARW (SEQ ID NO: 5986), FRPN (SEQ ID NO: 5987), KKVF (SEQ ID NO: 5988), YAFN (SEQ ID NO: 5989), KACS (SEQ ID NO: 5990), KRLW (SEQ ID NO: 5991), CSRN (SEQ ID NO: 5992), RCPN (SEQ ID NO: 5993), GACN (sequence number 5994), KFRQ (sequence number 5995), FPFN (sequence number 5996), FFGN (sequence number 5997), MCQN (sequence number 5998), KLFW (sequence number 5999), KTRK (sequence number 6000), GKRN (sequence number 6001), YRQN (sequence number 6002), RVQN (sequence number 6003), GIQN (sequence number 6004), KAQR (sequence number 6005), NCQN (sequence number 6006), KPFR (sequence number 6007), LAWN (sequence number 6008), KRSY (sequence number 6009), SYQN (sequence number) Number 6010), WLQN (sequence number 6011), SCQN (sequence number 6012), SWLN (sequence number 6013), KRRA (sequence number 6014), KAQT (sequence number 6015), KGCT (sequence number 6016), KRYT (sequence number 6017), GCQN (sequence number 6018), FTPN (sequence number 6019), TTCN (sequence number 6020), KARM (sequence number 6021), KRQN (sequence number 6022), KCFL (sequence number 6023), VPQN (sequence number 6024), FWSN (sequence number 6025), KFKN (sequence number 6026),IKQN (sequence number 6027), KAPR (sequence number 6028), FRYN (sequence number 6029), KMIC (sequence number 6030), RWQN (sequence number 6031), PTQN (sequence number 6032), KWKS (sequence number 6033), YMRN (sequence number 6034), KAAR (sequence number 6035), LCQN (sequence number 6036), CCQN (sequence number 6037), CVQN (sequence number 6038), KLTR (sequence number 6039), KLCT (sequence number 6040), KIRG (sequence number 6041), YLVN (sequence number 6042), AFQN (sequence number) Number 6043), KACQ (SEQ ID NO: 6044), KWGL (SEQ ID NO: 6045), KILR (SEQ ID NO: 6046), FQIN (SEQ ID NO: 6047), KACI (SEQ ID NO: 6048), KALR (SEQ ID NO: 6049), KAHA (SEQ ID NO: 6050), LCLN (SEQ ID NO: 6051), KAFV (SEQ ID NO: 6052), PRQN (SEQ ID NO: 6053), CPQN (SEQ ID NO: 6054), KAQF (SEQ ID NO: 6055), VRYN (SEQ ID NO: 6056), VRCN (SEQ ID NO: 6057), KMPC (SEQ ID NO: 6058), KKTS (SEQ ID NO: 6059), LPYN (sequence code 6060), YHQN (sequence code 6061), KAQS (sequence code 6062), YTRN (sequence code 6063), VYQN (sequence code 6064), RYQN (sequence code 6065), WLKN (sequence code 6066), KAQM (sequence code 6067), PAQN (sequence code 6068), MCTN (sequence code 6069), PPDN (sequence code 6070), KRNY (sequence code 6071), WTQN (sequence code 6072), KACR (sequence code 6073), RKQN (sequence code 6074), KCSV (sequence code 6075), KARI (array Number 6076), FVQN (Sequence ID 6077), KLPK (Sequence ID 6078), KSEQ (Sequence ID 6079), VAQN (Sequence ID 6080), LYQN (Sequence ID 6081), KVRM (Sequence ID 6082), ALQN (Sequence ID 6083), SCTN (Sequence ID 6084), KNSR (Sequence ID 6085), KRKR (Sequence ID 6086), CTQN (Sequence ID 6087), TCLN (Sequence ID 6088), YARN (Sequence ID 6089), KQRP (Sequence ID 6090), KRVV (Sequence ID 6091), SGQN (Sequence ID 6092),An AAV capsid variant according to any one of Embodiments 300 to 302, comprising YYSN (SEQ ID NO: 6093), LTCN (SEQ ID NO: 6094), CQSN (SEQ ID NO: 6095), KAKG (SEQ ID NO: 6096), KPQN (SEQ ID NO: 6097), PFQN (SEQ ID NO: 6098), KCTS (SEQ ID NO: 6099), VFEN (SEQ ID NO: 6100), or KAKK (SEQ ID NO: 6101).

[0392] 304.[B] is, (i) SKAQA (SEQ ID NO: 6102), SKAQN (SEQ ID NO: 6103), SMYMN (SEQ ID NO: 6104), SKAFY (SEQ ID NO: 6105), SKLKR (SEQ ID NO: 6106), SKRHR (SEQ ID NO: 6107), SKAQK (SEQ ID NO: 6108), SKWRL (SEQ ID NO: 6109), SRCRN (SEQ ID NO: 6110), SFTCN (SEQ ID NO: 6111), SKFFI (SEQ ID NO: 6112), SKAQY (SEQ ID NO: 6113), IVWQN (SEQ ID NO: 6114), SKYFM (SEQ ID NO: 6115), SKARQ (SEQ ID NO: 6116), SCHQN (SEQ ID NO: 6117), FPWQN (SEQ ID NO: 6118), SKIRR (SEQ ID NO: 6119), VYYQN (SEQ ID NO: 6120), SLYWN (SEQ ID NO: 6121), SKPKR (SEQ ID NO: 6122), SKAFS (SEQ ID NO: 6123), SRFWN (SEQ ID NO: 6124), SKAQC (SEQ ID NO: 6125), SRMRN (SEQ ID NO: 6126), SVKKN (SEQ ID NO: 6127), SWAPN (SEQ ID NO: 6128), SLWKN (SEQ ID NO: 6129), SKARW (SEQ ID NO: 6130), SFRPN (SEQ ID NO: 6131), SKKVF (SEQ ID NO: 6132) ), SYAFN (sequence number 6133), SKACS (sequence number 6134), SKRLW (sequence number 6135), SCSRN (sequence number 6136), SRCPN (sequence number 6137), SGACN (sequence number 6138), SKFRQ (sequence number 6139), SFPFN (sequence number 6140), SFFGN (sequence number 6141), SMCQN (sequence number 6142), SKLFW (sequence number 6143), SKTRK (sequence number 6144), SGKRN (sequence number 6145), FYRQN (sequence number 6146), CRVQN (sequence number 6147), YGIQN (distribution) Column number 6148), SKAQR (sequence number 6149), VNCQN (sequence number 6150), SKPFR (sequence number 6151), SLAWN (sequence number 6152), SRKRSY (sequence number 6153), WSYQN (sequence number 6154), RWLQN (sequence number 6155), PSCQN (sequence number 6156), SSWLN (sequence number 6157), SKRRA (sequence number 6158), SKAQT (sequence number 6159), SKGCT (sequence number 6160), VPWQN (sequence number 6161), SKRYT (sequence number 6162), SGCQN (sequence number 6163),SFTPN (sequence code 6164), STTCN (sequence code 6165), SKARM (sequence code 6166), PKRQN (sequence code 6167), SKCFL (sequence code 6168), WVPQN (sequence code 6169), SFWSN (sequence code 6170), SKFKN (sequence code 6171), RIKQN (sequence code 6172), SKAPR (sequence code 6173), SFRYN (sequence code 6174), SKMIC (sequence code 6175), LRWQN (sequence code 6176), LPTQN (sequence code 6177), SKWKS (sequence code 6178), SYMRN (sequence code) Number 6179), SKAAR (SEQ ID NO: 6180), LLCQN (SEQ ID NO: 6181), RCCQN (SEQ ID NO: 6182), LCVQN (SEQ ID NO: 6183), SKLTR (SEQ ID NO: 6184), SKLCT (SEQ ID NO: 6185), SKIRG (SEQ ID NO: 6186), SYLVN (SEQ ID NO: 6187), QGCQN (SEQ ID NO: 6188), MAFQN (SEQ ID NO: 6189), SKACQ (SEQ ID NO: 6190), SKWGL (SEQ ID NO: 6191), SKILR (SEQ ID NO: 6192), SFQIN (SEQ ID NO: 6193), SKACI (SEQ ID NO: 6194), SKALR (sequence number 6195), SKAHA (sequence number 6196), SLCLN (sequence number 6197), SKAFV (sequence number 6198), RPWQN (sequence number 6199), RPRQN (sequence number 6200), SCPQN (sequence number 6201), SKAQF (sequence number 6202), SVRYN (sequence number 6203), SVRCN (sequence number 6204), SKMPC (sequence number 6205), SKKTS (sequence number 6206), SLPYN (sequence number 6207), VYHQN (sequence number 6208), SKAQS (sequence number 6209), SYTRN (sequence number) Number 6210), LVYQN (sequence number 6211), YRYQN (sequence number 6212), SWLKN (sequence number 6213), SKAQM (sequence number 6214), CPAQN (sequence number 6215), SMCTN (sequence number 6216), SPPDN (sequence number 6217), SKRNY (sequence number 6218), RWTQN (sequence number 6219), SKACR (sequence number 6220), PRKQN (sequence number 6221), SKCSV (sequence number 6222), SKARI (sequence number 6223), PFVQN (sequence number 6224), SKLPK (sequence number 6225),SKSEQ (SEQ ID NO: 6226), WVAQN (SEQ ID NO: 6227), SLYQN (SEQ ID NO: 6228), SKVRM (SEQ ID NO: 6229), CALQN (SEQ ID NO: 6230), SSCTN (SEQ ID NO: 6231), SKNSR (SEQ ID NO: 6232), SKRKR (SEQ ID NO: 6233), LCTQN (SEQ ID NO: 6234), STCLN (SEQ ID NO: 6235), SYARN (SEQ ID NO: 6236), SKQRP (SEQ ID NO: 6237), SK RVV (sequence code 6238), KSGQN (sequence code 6239), SYYSN (sequence code 6240), SLTCN (sequence code 6241), SCQSN (sequence code 6242), SKAKG (sequence code 6243), SKPQN (sequence code 6244), FPFQN (sequence code 6245), SKCTS (sequence code 6246), SVFEN (sequence code 6247), SKAKK (sequence code 6248), or GRYQN (sequence code 6249), (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any two, three, or four amino acids therein, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 300 to 303, wherein the amino acid sequence contains one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i), or contains such a sequence.

[0393] 305.[A]-[B] is, (i) GSGSPHSKAQA (SEQ ID NO: 6250), GSGSPHSKAQN (SEQ ID NO: 6251), GSGSPHSMYMN (SEQ ID NO: 6252), GSGSPHSKAFY (SEQ ID NO: 6253), GSGSPHSKLKR (SEQ ID NO: 6254), GSGSPHSKRHR (SEQ ID NO: 6255), GSGSPHSKAQK (SEQ ID NO: 6256), GSGSPHSKWRL (SEQ ID NO: 6257), GSGSPHSRCRN (SEQ ID NO: 6258), GSGSPHSFTCN (SEQ ID NO: 6259), GSGSPHSKFFI (SEQ ID NO: 6260), GSG SPHSKAQY (SEQ ID NO: 6261), GSGSPHIVWQN (SEQ ID NO: 6262), GSGSPHSKYFM (SEQ ID NO: 6263), GSGSPHSKARQ (SEQ ID NO: 6264), GSGSPHSCHQN (SEQ ID NO: 6265), GSGSPHFPWQN (SEQ ID NO: 6266), GSGSPHSKIRR (SEQ ID NO: 6267), GSGSPHVYYQN (SEQ ID NO: 6268), GSGSPHSLYWN (SEQ ID NO: 6269), GSGSPHSKPKR (SEQ ID NO: 6270), GSGSPHSKAFS (SEQ ID NO: 6271), GSGSPHSRF WN (Sequence ID 6272), GSGSPHSKAQC (Sequence ID 6273), GSGSPHSRMRN (Sequence ID 6274), GSGSPHSVKKN (Sequence ID 6275), GSGSPHSWAPN (Sequence ID 6276), GSGSPHSLWKN (Sequence ID 6277), GSGSPHSKARW (Sequence ID 6278), GSGSPHSFRPN (Sequence ID 6279), GSGSPHSKKVF (Sequence ID 6280), GSGSPHSYAFN (Sequence ID 6281), GSGSPHSKACS (Sequence ID 6282), GSGSPHSKRLW (Sequence ID number (Sequence number 6283), GSGSPHSCSRN (Sequence number 6284), GSGSPHSRCPN (Sequence number 6285), GSGSPHSGACN (Sequence number 6286), GSGSPHSKFRQ (Sequence number 6287), GSGSPHSFPFN (Sequence number 6288), GSGSPHSFFGN (Sequence number 6289), GSGSPHSMCQN (Sequence number 6290), GSGSPHSKLFW (Sequence number 6291), GSGSPHSKTRK (Sequence number 6292), GSGSPHSGKRN (Sequence number 6293), GSGSPHFYRQN (Sequence number 6294),GSGSPHCRVQN (SEQ ID NO: 6295), GSGSPHYGIQN (SEQ ID NO: 6296), GSGSPHSKAQR (SEQ ID NO: 6297), GSGSPHVNCQN (SEQ ID NO: 6298), GSGSPHSKPFR (SEQ ID NO: 6299), GSGSPHSLAWN (SEQ ID NO: 6300), GSGSPHSKRSY (SEQ ID NO: 6301), GSGSPHWSYQN (SEQ ID NO: 6302), GSGSPHRWLQN (SEQ ID NO: 6303), GSGSPHPSCQN (SEQ ID NO: 6304), GSGSPHSSWLN (SEQ ID NO: 6305), GSGSP HSKRRA (SEQ ID NO: 6306), GSGSPHSKAQT (SEQ ID NO: 6307), GSGSPHSKGCT (SEQ ID NO: 6308), GSGSPHVPWQN (SEQ ID NO: 6309), GSGSPHSKRYT (SEQ ID NO: 6310), GSGSPHSGCQN (SEQ ID NO: 6311), GSGSPHSFTPN (SEQ ID NO: 6312), GSGSPHSTTCN (SEQ ID NO: 6313), GSGSPHSKARM (SEQ ID NO: 6314), GSGSPHPKRQN (SEQ ID NO: 6315), GSGSPHSKCFL (SEQ ID NO: 6316), GSGSPHWVPQN (SEQ ID NO: 6317), GSGSPHSFWSN (SEQ ID NO: 6318), GSGSPHSKFKN (SEQ ID NO: 6319), GSGSPHRIKQN (SEQ ID NO: 6320), GSGSPHSKAPR (SEQ ID NO: 6321), GSGSPHSFRYN (SEQ ID NO: 6322), GSGSPHSKMIC (SEQ ID NO: 6323), GSGSPHLRWQN (SEQ ID NO: 6324), GSGSPHLPTQN (SEQ ID NO: 6325), GSGSPHSKWKS (SEQ ID NO: 6326), GSGSPHSYMRN (SEQ ID NO: 6327), GSGSPHSKAAR (SEQ ID NO: 6327) 6328), GSGSPHLLCQN (sequence number 6329), GSGSPHRCCQN (sequence number 6330), GSGSPHLCVQN (sequence number 6331), GSGSPHSKLTR (sequence number 6332), GSGSPHSKLCT (sequence number 6333), GSGSPHSKIRG (sequence number 6334), GSGSPHSYLVN (sequence number 6335), GSGSPHQGCQN (sequence number 6336), GSGSPHMAFQN (sequence number 6337), GSGSPHSKACQ (sequence number 6338), GSGSPHSKWGL (sequence number 6339),GSGSPHSKILR (SEQ ID NO: 6340), GSGSPHSFQIN (SEQ ID NO: 6341), GSGSPHSKACI (SEQ ID NO: 6342), GSGSPHSKALR (SEQ ID NO: 6343), GSGSPHSKAHA (SEQ ID NO: 6344), GSGSPHSLCLN (SEQ ID NO: 6345), GSGSPHSKAFV (SEQ ID NO: 6346), GSGSPHRPWQN (SEQ ID NO: 6347), GSGSPHRPRQN (SEQ ID NO: 6348), GSGSPHSCPQN (SEQ ID NO: 6349), GSGSPHSKAQF (SEQ ID NO: 6350), GSGSP HSVRYN (SEQ ID NO: 6351), GSGSPHSVRCN (SEQ ID NO: 6352), GSGSPHSKMPC (SEQ ID NO: 6353), GSGSPHSKKTS (SEQ ID NO: 6354), GSGSPHSLPYN (SEQ ID NO: 6355), GSGSPHVYHQN (SEQ ID NO: 6356), GSGSPHSKAQS (SEQ ID NO: 6357), GSGSPHSYTRN (SEQ ID NO: 6358), GSGSPHLVYQN (SEQ ID NO: 6359), GSGSPHYRYQN (SEQ ID NO: 6360), GSGSPHSWLKN (SEQ ID NO: 6361), GSGSPHSKAQM (SEQ ID NO: 6362), GSGSPHCPAQN (SEQ ID NO: 6363), GSGSPHSMCTN (SEQ ID NO: 6364), GSGSPHSPPDN (SEQ ID NO: 6365), GSGSPHSKRNY (SEQ ID NO: 6366), GSGSPHRWTQN (SEQ ID NO: 6367), GSGSPHSKACR (SEQ ID NO: 6368), GSGSPHPRKQN (SEQ ID NO: 6369), GSGSPHSKCSV (SEQ ID NO: 6370), GSGSPHSKARI (SEQ ID NO: 6371), GSGSPHPFVQN (SEQ ID NO: 6372), GSGSPHSKLPK (SEQ ID NO: 6362) 6373), GSGSPHSKSEQ (sequence number 6374), GSGSPHWVAQN (sequence number 6375), GSGSPHSLYQN (sequence number 6376), GSGSPHSKVRM (sequence number 6377), GSGSPHCALQN (sequence number 6378), GSGSPHSSCTN (sequence number 6379), GSGSPHSKNSR (sequence number 6380), GSGSPHSKRKR (sequence number 6381), GSGSPHLCTQN (sequence number 6382), GSGSPHSTCLN (sequence number 6383), GSGSPHSYARN (sequence number 6384),GSGSPHSKQRP (SEQ ID NO: 6385), GSGSPHSKRVV (SEQ ID NO: 6386), GSGSPHKSGQN (SEQ ID NO: 6387), GSGSPHSYYSN (SEQ ID NO: 6388), GSGSPHSLTCN (SEQ ID NO: 6389), GSGSPHSCQSN (SEQ ID NO: 6390), GSGSPHSKAKG (SEQ ID NO: 6391), GSGSPHSKPQN (SEQ ID NO: 6392), GSGSPHFPFQN (SEQ ID NO: 6393), GSGSPHSKCTS (SEQ ID NO: 6394), GSGSPHSVFEN (SEQ ID NO: 6395), GSGSPHSKAKK (SEQ ID NO: 6396), or GSGSPHGRYQN (SEQ ID NO: 6397), (ii) An amino acid sequence containing any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 300 to 304, wherein the amino acid sequence contains one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i), or contains such a sequence.

[0394] 306. An AAV capsid according to any one of Embodiments 300 to 305, wherein [A]-[B] does not contain the amino acid sequence of GSGSPHSKAQN (SEQ ID NO: 6251).

[0395] 307. An AAV capsid variant according to any one of embodiments 300 to 306, comprising one, two, or all of the following amino acids numbered for Sequence ID No. 138: an amino acid other than Q at position 458 (e.g., R, C, S, W, L, F, Y, H, I, V, A, or P), an amino acid other than Q at position 459 (e.g., K, I, R, L, or S), and / or an amino acid other than T at position 460 (e.g., R).

[0396] 308. (i) Amino acid R at position 458, (ii) Amino acid W at position 458, (iii) Amino acid Y at position 458, (iv) Amino acid F at position 458, (v) Amino acid S at position 458, (vi) Amino acid C at position 458, (vii) Amino acid I at position 458, (viii) Amino acid L at position 458, (ix) Amino acid P at position 458, (x) Amino acid I at position 459, (xi) Amino acid H at position 458, or (xii) Contains amino acid V at position 458, (i) to (xii) are numbered according to Sequence ID No. 138, and the AAV capsid variant is as described in any one of Embodiments 300 to 307.

[0397] 309. (i) Amino acid R at position 458, and amino acid K at position 459, (ii) Amino acid C at position 458, and amino acid I at position 459, (iii) Amino acid S at position 458 and amino acid R at position 459', (iv) Amino acid L at position 458 and amino acid K at position 459, (v) Amino acid F at position 458, and amino acid K at position 459, (vi) Amino acid C at position 458, and amino acid R at position 459, (vii) Amino acid H at position 458, and amino acid R at position 459, (viii) Amino acid I at position 458, and amino acid L at position 459, (ix) Amino acid V at position 458, and amino acid R at position 459, (x) Amino acid A at position 458, and amino acid K at position 459, (xi) Amino acid I at position 458, and amino acid K at position 459, (xii) Amino acid C at position 458, and amino acid S at position 459, or (xiii) Contains amino acid C at position 458 and amino acid L at position 459, (i) to (xiii) are numbered according to sequence number 138, the AAV capsid variant according to any one of embodiments 300 to 307.

[0398] 310. An AAV capsid variant according to any one of Embodiments 300 to 307, comprising amino acid F at position 458, amino acid K at position 459, and amino acid R at position 460, as numbered for Sequence ID No. 138.

[0399] 311. An AAV capsid variant according to any one of Embodiments 300 to 310, comprising one, two, or all of the amino acids numbered for Sequence ID No. 138, other than T at position 450 (e.g., Y, P, W, R, K, S, or F), other than I at position 451 (e.g., R, S, Y, L, V, H, P, A, or F), and / or other than N at position 452 (e.g., V, W, A, T, F, Y, L, R, H, S, or M).

[0400] 312. An AAV capsid variant according to any one of embodiments 300 to 311, comprising amino acid V at position 452, numbered according to Sequence ID No. 138.

[0401] 313. An AAV capsid variant according to any one of embodiments 300 to 312, comprising amino acid Y at position 450 and amino acid V at position 452, numbered according to Sequence ID No. 138.

[0402] 314. An AAV capsid variant according to any one of embodiments 300 to 312, comprising amino acid R at position 450 and amino acid Y at position 451, numbered according to Sequence ID No. 138.

[0403] 315. (i) Amino acid P at position 450, amino acid R at position 451, and amino acid W at position 452, (ii) Amino acid Y at position 450, amino acid S at position 451, and amino acid A at position 452, (iii) Amino acid Y at position 450, amino acid Y at position 451, and amino acid T at position 452, (iv) Amino acid P at position 450, amino acid R at position 451, and amino acid F at position 452, (v) Amino acid W at position 450, amino acid L at position 451, and amino acid T at position 452, (vi) Amino acid R at position 450, amino acid S at position 451, and amino acid Y at position 452, (vii) Amino acid Y at position 450, amino acid V at position 451, and amino acid F at position 452, (viii) Amino acid K at position 450, amino acid H at position 451, and amino acid L at position 452, (ix) Amino acid P at position 450, amino acid P at position 451, and amino acid L at position 452, (x) Amino acid P at position 450, amino acid A at position 451, and amino acid R at position 452, (xi) Amino acid S at position 450, amino acid R at position 451, and amino acid R at position 452, (xii) Amino acid F at position 450, amino acid F at position 451, and amino acid H at position 452, (xiii) Amino acid R at position 450, amino acid F at position 451, and amino acid S at position 452, (xiv) Amino acid Y at position 450, amino acid S at position 451, and amino acid M at position 452, or (xv) Contains amino acid P at position 450, amino acid F at position 451, and amino acid L at position 452. (i) to (xv) are numbered according to sequence number 138, an AAV capsid variant according to any one of embodiments 300 to 311.

[0404] 316. (i) The amino acid sequence described in any one of sequence numbers 3849-3982, 2984-4010, or 4681-4693, (ii) An amino acid sequence that includes any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids, for example, consecutive amino acids, (iii)(i)Amniotic sequences in which any of the above amino acid sequences have one, two, or three but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, or (iv) An AAV capsid variant according to any one of Embodiments 300 to 315, comprising an amino acid sequence containing one, two, or three but no more than four different amino acids for any one of the amino acid sequences in (i).

[0405] 317. An AAV capsid variant according to any one of embodiments 300 to 316, which does not contain the amino acid sequence of GSGSPHSKAQNQQ (SEQ ID NO: 1801) or GSGSPHSKAQNQQT (SEQ ID NO: 200).

[0406] 318. An AAV capsid variant according to any one of embodiments 300 to 317, wherein [A]-[B] are present in loop IV.

[0407] 319. An AAV capsid variant according to any one of Embodiments 300 to 318, wherein [A] is located immediately after position 452 with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 981.

[0408] 320. An AAV capsid variant according to any one of Embodiments 300 to 319, wherein [A] replaces positions 453 to 455 (e.g., G453, S454, G455) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 981.

[0409] 321. An AAV capsid variant according to any one of Embodiments 300 to 320, wherein [A] is located immediately after position 452, and [A] replaces positions 453 to 455 (e.g., G453, S454, G455) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 981.

[0410] 322. An AAV capsid variant according to any one of embodiments 300 to 321, wherein [B] is located immediately after [A].

[0411] 323. An AAV capsid variant according to any one of Embodiments 300 to 322, wherein [B] replaces the 456th and 457th positions (e.g., Q456, N457) numbered for Sequence ID No. 138.

[0412] 324. An AAV capsid variant according to any one of Embodiments 300 to 323, wherein [A]-[B] replaces positions 453-457 (e.g., G453, S454, G455, Q456, N457) of a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0413] 325. An AAV capsid variant according to any one of Embodiments 300 to 324, wherein [A]-[B] is located immediately after position 452, and [A]-[B] replaces positions 453-457 (e.g., G453, S454, G455, Q456, N457) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0414] 326. An AAV capsid variant according to any one of embodiments 300 to 325, comprising [A] and [B] from the N-terminus to the C-terminus.

[0415] 327. An AAV capsid variant according to any one of the prior embodiments, comprising at least 1, 2, 3, or 4 (e.g., 1-4 to 1-5) charged amino acid residues (e.g., acidic and / or basic amino acid residues) relative to SEQ ID NO: 138, located at the N-terminus of the SPH amino acid sequence (e.g., within 1, 2, 3, 4, 5, or 6 amino acids from the start of the SPH amino acid sequence (e.g., within positions 450-455 as numbered according to SEQ ID NO: 138)), and optionally, the SPH amino acid sequence located at positions 456-458 as numbered according to any one of SEQ ID NOs: 5-10, 36-59, 981, 982, or 6409-6413.

[0416] 328. The AAV capsid variant according to Embodiment 327, wherein the amino acid sequence of the SPH is located at positions 456-458, numbered according to any one of SEQ ID NOs. 5-10, 36-59, 981, 982, or 6409-6413.

[0417] 329. An AAV capsid variant of Embodiment 327 or 328 comprising fewer than 4, 3, or 2 (e.g., 2 or 1) charged amino acid residues (e.g., acidic and / or basic amino acid residues) relative to Sequence ID No. 138.

[0418] 330. An AAV capsid variant according to any one of embodiments 327 to 329, wherein one charged amino acid residue (e.g., an acidic or basic amino acid residue) is optionally included in one of the positions numbered from 450 to 455 relative to sequence number 138.

[0419] 331. An AAV capsid variant according to any one of embodiments 327 to 330, wherein the charged amino acid residue is an acidic amino acid (e.g., D or E).

[0420] 332. An AAV capsid variant according to any one of embodiments 327 to 331, wherein the charged amino acid residue is a negatively charged amino acid (e.g., D or E).

[0421] 333. An AAV capsid variant according to any one of embodiments 327 to 332, wherein the charged amino acid residue is D.

[0422] 334. An AAV capsid variant according to any one of embodiments 327 to 333, wherein the charged amino acid residue is E.

[0423] 335. An AAV capsid variant according to any one of embodiments 327 to 334, wherein the charged amino acid residue is a basic amino acid (e.g., K, R, or H).

[0424] 336. An AAV capsid variant according to any one of embodiments 327 to 335, wherein the charged amino acid residue is a positively charged amino acid (e.g., K, R, or H).

[0425] 337. An AAV capsid variant according to any one of embodiments 327 to 336, wherein the charged amino acid residue is H.

[0426] 338. An AAV capsid variant according to any one of embodiments 327 to 337, wherein the charged amino acid residue is R.

[0427] 339. An AAV capsid variant according to any one of embodiments 327 to 338, wherein the charged amino acid residue is K.

[0428] 340. The AAV capsid variant according to any one of Embodiments 327 to 339, wherein the AAV capsid variant comprises an acidic amino acid (e.g., E or D) and a basic amino acid (e.g., R, K, or H).

[0429] 341. An AAV capsid variant according to any one of embodiments 327 to 340, wherein at least 1, 2, 3, or 4 charged amino acid residues are located within 1, 2, 3, 4, 5, or 6 (e.g., 1 to 6) amino acids from the start of the SPH amino acid sequence.

[0430] 342. An AAV capsid variant according to any one of Embodiments 327 to 341, comprising two charged amino acid residues immediately preceding the amino acid sequence of the SPH (for example, at positions 454 and 455, numbered according to SEQ ID NO: 138 or SEQ ID NO: 982).

[0431] 343. An AAV capsid variant according to any one of embodiments 327 to 342, comprising a charged amino acid residue (e.g., E) within 1, 2, 3, 4, or 5 (e.g., 5) amino acids from the start of the SPH amino acid sequence.

[0432] 344. An AAV capsid variant according to any one of Embodiments 327 to 343, numbered according to any one of Sequence ID No. 138, 981, or 982, comprising a charged amino acid residue (e.g., E) at position 451.

[0433] 345. An AAV capsid variant according to any one of Embodiments 327 to 344, numbered according to any one of Sequence ID No. 138, 981, or 982, comprising E at position 451.

[0434] 346. An AAV capsid variant according to any one of Embodiments 327 to 345, numbered according to any one of Sequence ID No. 138, 981, or 982, comprising a charged amino acid residue (e.g., R or K) at position 452.

[0435] 347. An AAV capsid variant according to any one of embodiments 327 to 346, numbered according to Sequence ID No. 138 or Sequence ID No. 982, comprising R at position 452.

[0436] 348. An AAV capsid variant according to any one of Embodiments 327 to 347, numbered according to Sequence ID No. 138 or Sequence ID No. 982, comprising E at position 451 and R at position 452.

[0437] 349. An AAV capsid variant according to any one of Embodiments 327 to 348, having reduced tropism towards liver cells or tissues compared to the tropism of a reference sequence containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981.

[0438] 350. An AAV capsid variant according to any one of the prior embodiments, comprising at least 1, 2, 3, or 4 (e.g., 1-4 to 1-5) charged amino acid residues (e.g., basic amino acid residues) relative to SEQ ID NO: 138, located at the C-terminus of the SPH amino acid sequence (e.g., within 1, 2, 3, 4, 5, 6, or 7 amino acids from the end of the SPH amino acid sequence (e.g., within positions 459-465, numbered according to any one of SEQ ID NOs: 5-10, 36-59, 981, or 6409-6413)), wherein the SPH amino acid sequence is located at positions 456-458, numbered according to any one of SEQ ID NOs: 36-59, 981, or 982.

[0439] 351. The AAV capsid variant according to Embodiment 350, wherein the amino acid sequence of the SPH is located at positions 456-458, numbered according to any one of SEQ ID NOs: 5-10, 36-59, 981, 982, or 6409-6413.

[0440] 352. An AAV capsid variant according to Embodiment 350 or 351, comprising fewer than 4, 3, or 2 (e.g., 2 or 1) charged amino acid residues (e.g., basic amino acid residues) relative to SEQ ID NO: 138.

[0441] 353. An AAV capsid variant according to any one of Embodiments 350 to 352, wherein, with respect to Sequence ID No. 138, optionally, one charged amino acid residue (e.g., a basic amino acid residue) is contained at any one of positions 456 to 460 numbered for Sequence ID No. 138, or at positions 462 to 466 numbered according to any one of Sequence ID Nos. 5 to 10, 36 to 59, 981, 982, or 6409 to 6413.

[0442] 354. An AAV capsid variant according to any one of embodiments 350 to 353, wherein the charged amino acid residue is a basic amino acid (e.g., R or K).

[0443] 355. An AAV capsid variant according to any one of embodiments 350 to 354, wherein the charged amino acid residue is a positively charged amino acid (e.g., R or K).

[0444] 356. An AAV capsid variant according to any one of embodiments 350 to 355, wherein the charged amino acid residue is R.

[0445] 357. An AAV capsid variant according to any one of embodiments 350 to 355, wherein the charged amino acid residue is K.

[0446] 358. An AAV capsid variant according to any one of embodiments 350 to 357, wherein at least 1, 2, 3, or 4 charged amino acid residues are located within 1, 2, 3, 4, 5, 6, or 7 (e.g., 1 to 7) amino acids from the end of the SPH amino acid sequence.

[0447] 359. An AAV capsid variant according to any one of embodiments 350 to 358, comprising a charged amino acid residue (e.g., K or R) immediately following the SPH sequence (e.g., at position 459 as numbered according to SEQ ID NO: 981).

[0448] 360. An AAV capsid variant according to any one of Embodiments 350 to 359, comprising a charged amino acid residue (e.g., K or R) at position 459, as numbered according to Sequence ID No. 138 or Sequence ID No. 982.

[0449] 361. An AAV capsid variant according to any one of embodiments 350 to 360, numbered according to sequence number 981, comprising K at position 459.

[0450] 362. An AAV capsid variant according to any one of embodiments 350 to 360, numbered according to sequence number 981, comprising R at position 459.

[0451] 363. An AAV capsid variant according to any one of Embodiments 350 to 362, comprising one, two, three, four, five, or all of the charged amino acid residues (e.g., R or K) at positions 460, 461, 462, 463, 464, and / or 465, numbered according to Sequence ID No. 138 or 981.

[0452] 364. An AAV capsid variant according to any one of embodiments 300-326 or 350-363, having increased tropism towards liver cells or tissues compared to the tropism of a reference sequence containing the amino acid sequence of SEQ ID NO: 138.

[0453] 365. An AAV capsid variant according to any one of Embodiments 300-326 or 350-364, which is concentrated at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 150, 160, 170, 180, 190, or 200 times in the liver compared to the reference sequence of SEQ ID NO: 138, as measured by an assay such as that described in Example 4.

[0454] 366. An AAV capsid variant according to any one of embodiments 300-326, 364, or 365, having reduced tropism to CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells, or spinal cord tissue, compared to the tropism to a reference sequence containing the amino acid sequence of SEQ ID NO: 138.

[0455] 367. An AAV capsid variant according to any one of embodiments 300-326 or 364-366, exhibiting preferential transduction in the hepatic region compared to transduction in the brain and / or dorsal root ganglia (DRG).

[0456] 368. An AAV capsid variant according to any one of embodiments 300-326 or 364-367, exhibiting preferential transduction in the hepatic region compared to transduction in the heart and / or muscle (e.g., quadriceps femoris).

[0457] 369. AAV capsid variant, (I)(a) Any amino acid sequence from the sequences provided in Tables 1, 2A, 2B, 13-19, (b) an amino acid sequence containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 13-19, or (c) For any one of the sequences provided in Tables 1, 2A, 2B, 13-19, an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, or (d) Amino acid sequences that include at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions) to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 13-19, and / or (II)(i) Amino acid sequence of sequence number 6419, (ii) An amino acid sequence that includes at least one or two but no more than three different amino acids relative to the amino acid sequence of SEQ ID NO: 6419, (iii) an amino acid sequence of the amino acid sequence of SEQ ID NO: 6419 that has at least one or two modifications, e.g., substitutions (e.g., conservative substitutions), but no more than three modifications, e.g., substitutions (e.g., conservative substitutions), or (iv) comprising at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID NO: 6419, The AAV capsid variant wherein, optionally, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 590–596, numbered according to the amino acid sequences of sequence numbers 981, 982, 6411, or 6412.

[0458] 370. AAV capsid variant, (I)(a) Any amino acid sequence from sequence numbers 945-980 or 985-986, (b) an amino acid sequence containing at least 3, 4, or 5 consecutive amino acids from any one of sequence numbers 945-980 or 985-986, or (c) For any one of the amino acid sequences among sequence numbers 945-980 or 985-986, an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (d) an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), to any one of the amino acid sequences of sequence numbers 945-980 or 985-986, and / or (II)(i) Amino acid sequence of sequence number 6419, (ii) An amino acid sequence that includes at least one or two but no more than three different amino acids relative to the amino acid sequence of SEQ ID NO: 6419, (iii) an amino acid sequence of the amino acid sequence of SEQ ID NO: 6419 that has at least one or two modifications, e.g., substitutions (e.g., conservative substitutions), but no more than three modifications, e.g., substitutions (e.g., conservative substitutions), or (iv) comprising at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID NO: 6419, The AAV capsid variant wherein, optionally, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 590–596, numbered according to the amino acid sequences of sequence numbers 981, 982, 6411, or 6412.

[0459] 371. AAV capsid variant, (I)(a) Any amino acid sequence from sequence numbers 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, (b) an amino acid sequence containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of sequence numbers 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, (c) For any one of the amino acid sequences of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, or (d) Amino acid sequences that include at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), to any one of the amino acid sequences of SEQ ID NOs. 2, 200, 201, 941, 943, 204, 208, 404, or 903-909, and / or (II)(i) Amino acid sequence of sequence number 6419, (ii) An amino acid sequence that includes at least one or two but no more than three different amino acids relative to the amino acid sequence of SEQ ID NO: 6419, (iii) an amino acid sequence of the amino acid sequence of SEQ ID NO: 6419 that has at least one or two modifications, e.g., substitutions (e.g., conservative substitutions), but no more than three modifications, e.g., substitutions (e.g., conservative substitutions), or (iv) comprising at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID NO: 6419, The AAV capsid variant wherein, optionally, the amino acid sequences of (i), (ii), (iii), and / or (iv) are located at positions 590–596, numbered according to the amino acid sequences of sequence numbers 981, 982, 6411, or 6412.

[0460] 372. AAV capsid variant, (a) Any amino acid sequence from sequence numbers 3849-4051 or 4681-4693, (b) an amino acid sequence containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of sequence numbers 3849-4051 or 4681-4693, (c) For any one of the amino acid sequences among sequence numbers 3849-4051 or 4681-4693, an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (d) The AAV capsid variant comprising an amino acid sequence having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions) to any one of the amino acid sequences from sequence numbers 3849-4051 or 4681-4693.

[0461] 373. AAV capsid variant, (a) Any amino acid sequence from sequence numbers 4052 to 4092, (b) an amino acid sequence containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of sequence numbers 4052 to 4092, (c) For any one of the amino acid sequences of sequence numbers 4052 to 4092, an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, or (d) The AAV capsid variant comprising an amino acid sequence having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions) to any one of the amino acid sequences among sequence numbers 4052 to 4092.

[0462] 374. AAV capsid variant, (a) Any amino acid sequence from sequence numbers 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097, (b) an amino acid sequence containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of sequence numbers 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097, (c) For any one of the amino acid sequences among SEQ ID NOs. 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097, an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, or (d) The AAV capsid variant comprising an amino acid sequence with at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions) to any one of the amino acid sequences of sequence numbers 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097.

[0463] 375. An AAV capsid variant according to Embodiment 369 or 371, comprising an amino acid sequence containing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0464] 376. An AAV capsid variant according to any one of embodiments 369 to 375, wherein the at least three consecutive amino acids comprise SPH.

[0465] 377. An AAV capsid variant according to any one of embodiments 369 to 371 or 376, wherein the at least four consecutive amino acids include SPHS (SEQ ID NO: 4700).

[0466] 378. An AAV capsid variant according to any one of embodiments 369-371, 376, or 377, wherein the at least five consecutive amino acids include SPHSK (SEQ ID NO: 4701).

[0467] 379. An AAV capsid variant according to any one of embodiments 369-371 or 376-378, wherein the at least six consecutive amino acids include SPHSKA (SEQ ID NO: 941).

[0468] 380. The AAV capsid variant according to embodiments 369-371, wherein the at least three consecutive amino acids comprise HDS.

[0469] 381. An AAV capsid variant according to any one of embodiments 369 to 371 or 380, wherein the at least four consecutive amino acids include HDSP (SEQ ID NO: 4702).

[0470] 382. An AAV capsid variant according to any one of embodiments 369-371, 380, or 381, wherein the at least five consecutive amino acids include HDSPH (SEQ ID NO: 4703).

[0471] 383. An AAV capsid variant according to any one of embodiments 369-371 or 380-382, wherein the at least six consecutive amino acids comprise HDSPHK (SEQ ID NO: 2).

[0472] 384. (i) The three consecutive amino acids include SPH, (ii) The at least four consecutive amino acids include SPHK (SEQ ID NO: 6398), (iii) The at least five consecutive amino acids include SPHKY (SEQ ID NO: 4715), and / or (iv) The AAV capsid variant according to any one of Embodiments 369 to 371, wherein the at least six consecutive amino acids include SPHKYG (SEQ ID NO: 966).

[0473] 385. An AAV capsid variant according to Embodiment 369 or 371, comprising an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), to any one of the amino acid sequences of SEQ ID NOs. 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0474] An AAV capsid variant according to any one of Embodiments 369, 371, or 385, comprising an amino acid sequence with at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), to the amino acid sequence of 386.SPHSKA (SEQ ID NO: 941).

[0475] An AAV capsid variant according to any one of Embodiments 369, 371, or 385, comprising an amino acid sequence with at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), to the amino acid sequence of 387.HDSPHK (SEQ ID NO: 2).

[0476] An AAV capsid variant according to any one of embodiments 369 to 371, 384, or 385, comprising an amino acid sequence with at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), to the amino acid sequence of 388.SPHKYG (SEQ ID NO: 966).

[0477] 389. (i) The amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272) has at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), (ii) The amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589) has at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), (iii) The amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754) has at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), (iv) The amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241) has at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), (v) The amino acid sequence of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100) has at least one, two, or three but no more than four modifications, for example, substitutions (for example, conservative substitutions), or (vi) An AAV capsid variant according to Embodiment 370, comprising an amino acid sequence with at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), to the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062).

[0478] 390. An AAV capsid variant according to Embodiment 369 or 371, comprising an amino acid sequence containing at least one, two, or three, but no more than four, different amino acids for any one of the amino acid sequences of SEQ ID NOs. 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0479] 391. An AAV capsid variant according to any one of Embodiments 369, 371, or 390, comprising an amino acid sequence containing at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0480] An AAV capsid variant according to any one of Embodiments 369, 371, or 390, comprising an amino acid sequence containing at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of 392.HDSPHK (SEQ ID NO: 2).

[0481] 393. An AAV capsid variant according to any one of embodiments 369 to 371, 384, or 390, comprising an amino acid sequence containing at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of SPHKYG (SEQ ID NO: 966).

[0482] 394. (i) An amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids relative to the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589), (ii) An amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids relative to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), (iii) An amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids relative to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), (iv) An amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids relative to the amino acid sequence of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100), (v) An amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids relative to the amino acid sequence of KTVNGHDSPHSKAQNQQT (Sequence ID 4062), (vi) For the amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272), an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (vii) For the amino acid sequence of KTEKVSGSPHSKAQNQQT (sequence number 3274), an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (viii) For the amino acid sequence of KTINGSGSPHKSGQNKTS (SEQ ID NO: 4406), an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (ix) For the amino acid sequence of KTSNASGSPHSKAHNQQT (SEQ ID NO: 3382), an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (x) For the amino acid sequence of KNSIGSGSPHSKAQNQQT (Sequence ID 3421), an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (xi) For the amino acid sequence of KTVNGHDSPHKSGQRPST (sequence number 4478), an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, (xii) For the amino acid sequence of KAENGSGSPHSKAQNQQT (Sequence ID 3487), an amino acid sequence containing at least 1, 2, or 3 but no more than 4 different amino acids, or (xiii) An AAV capsid variant according to Embodiment 369, comprising an amino acid sequence containing at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTINGSGSPHKSGQNQQP (Sequence ID 4081).

[0483] 395. An AAV capsid variant according to any one of Embodiments 1-129, 269, 271, 375-388, or 390-394, comprising any amino acid sequence of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0484] An AAV capsid variant according to any one of embodiments 295-297, 301-305, 313, 314, 318, 319, or 323, comprising the amino acid sequence 396.ERVSGSPHSKA (SEQ ID NO: 6399), and optionally replacing positions 451-455 (e.g., I451, N542, G453, S454, G455) located immediately after position 450 and numbered according to SEQ ID NO: 138.

[0485] An AAV capsid variant according to any one of embodiments 369-371, 375-379, 385, 386, 389-391, or 394-396, comprising the amino acid sequence 397.KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589), and optionally replacing positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) located immediately after position 448 and numbered according to SEQ ID NO: 138.

[0486] An AAV capsid variant according to any one of embodiments 269-371, 375, 380-383, 385, 387, 389, 390, 393, or 394, comprising the amino acid sequence 398.AEIGHDSPHKSG (SEQ ID NO: 6400), and optionally replacing positions 450-455 (e.g., T450, I451, N452, G453, S454, G455) located immediately after position 449 and numbered according to SEQ ID NO: 138.

[0487] An AAV capsid variant according to any one of Embodiments 369-371, 375, 380-383, 385, 387, 389, 390, 393, 394, or 398, comprising the amino acid sequence 399.KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), and optionally replacing positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) located immediately after position 448 and numbered according to SEQ ID NO: 138.

[0488] An AAV capsid variant according to any one of Embodiments 369-371, 375-379, 390, 391, or 395, comprising the amino acid sequence 400.EKMSGSPHSKA (SEQ ID NO: 6401), and optionally replacing positions 451-455 (e.g., I451, N452, G453, S454, G455) located immediately after position 450 and numbered according to SEQ ID NO: 138.

[0489] An AAV capsid variant according to any one of Embodiments 369-371, 375-379, 390, 391, or 395, comprising the amino acid sequence 401.KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), and optionally replacing positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) located immediately after position 448 and numbered according to SEQ ID NO: 138.

[0490] An AAV capsid variant according to any one of Embodiments 369-371, 375-379, 390, 391, or 395, comprising the amino acid sequence 402.HDSPHSKAQNL (SEQ ID NO: 6402), and optionally replacing positions 456-458 (e.g., Q456, N457, Q458) located immediately after position 453 and numbered according to SEQ ID NO: 138.

[0491] An AAV capsid variant according to any one of embodiments 369-371, 375-379, 390, 391, or 395, comprising the amino acid sequence 403.KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100), and optionally replacing positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) located immediately after position 448 and numbered according to SEQ ID NO: 138.

[0492] An AAV capsid variant according to any one of Embodiments 369-371, 375-379, 390, 391, or 395, comprising the amino acid sequence 404.VNGHDSPHSKA (SEQ ID NO: 6403), and optionally replacing positions 451-455 (e.g., I451, N452, G453, S454, G455) located immediately after position 450 and numbered according to SEQ ID NO: 138.

[0493] 405. (i) The amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062), which optionally includes the amino acid sequence that is located immediately after position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) numbered according to SEQ ID NO: 138, or (ii) The AAV capsid variant according to any one of Embodiments 369-371, 375-379, 390, 391, or 395, wherein the AAV capsid variant comprises the amino acid sequence of ENVSGSPHSKA (SEQ ID NO: 60), and optionally, the amino acid sequence is located immediately after position 450 and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455) numbered according to SEQ ID NO: 138, or corresponds to positions 451-461 of SEQ ID NO: 5, or is located at positions 451-461 numbered according to SEQ ID NO: 5 or 981.

[0494] 406. The nucleotide sequence of SEQ ID NO: 942, the nucleotide sequence of SEQ ID NO: 942, a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, or an amino acid sequence encoded by a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 but 10 or fewer different nucleotides, relative to the nucleotide sequence of SEQ ID NO: 942, An AAV capsid variant listed in any one of the following states: 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, or 395.

[0495] 407. Embodiments 1-9, 11, 12 include an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 3, a nucleotide sequence of SEQ ID NO: 3 with at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, or a nucleotide sequence of SEQ ID NO: 3 with at least 1, 2, 3, 4, 5, 6, or 7 but 10 or fewer different nucleotides. AAV capsid variants listed in any one of the following categories: ~22, 24, 26, 28, 30, 33, 35~42, 44, 46~50, 52, 54~77, 83~88, 90~97, 100~103, 105, 110, 111, 113~129, 203~248, 251, 252, 254~257, 260, 261, 264~280, 283~287, 289~299, 327~363, 369, 369, 371, 380~383, 385, 386, 390, 392, or 395.

[0496] 408. The nucleotide sequence encoding the capsid variant includes the nucleotide sequence of SEQ ID NO: 942, a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, or a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 but 10 or fewer different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942. An AAV capsid variant according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, or 406.

[0497] 409. Embodiments 1-9, 11, in which the nucleotide sequence encoding the capsid variant includes the nucleotide sequence of SEQ ID NO: 3, a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, or a nucleotide sequence containing at least 1, 2, 3, 4, 5, 6, or 7 but 10 or fewer different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3 AAV capsid variants listed in any one of the following: 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, or 407.

[0498] 410. An AAV capsid variant according to any one of embodiments 369 to 409, wherein the amino acid sequence is present in loop IV.

[0499] 411. An AAV capsid variant according to any one of Embodiments 369 to 410, wherein the amino acid sequence is located immediately after position 448, 449, 450, 451, 452, 453, 454, or 455 with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0500] 412. An AAV capsid variant according to any one of Embodiments 369 to 411, wherein the amino acid sequence replaces amino acids 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, and / or 460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and / or T460) numbered according to the amino acid sequence of Sequence ID No. 138.

[0501] 413. An AAV capsid variant according to any one of embodiments 369 to 412, wherein the amino acid sequence is located immediately after position 455 with respect to a reference sequence numbered according to the amino acid sequence of sequence number 138.

[0502] 414. An AAV capsid variant according to any one of embodiments 369 to 413, wherein the amino acid sequence is located immediately after position 453 with respect to a reference sequence numbered according to the amino acid sequence of sequence number 138.

[0503] 415.SPHSKA (SEQ ID NO: 941) contains the amino acid sequence, and the amino acid sequence is located immediately after position 455 relative to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, in embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112 AAV capsid variants listed in any one of the following categories: 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, or 410-413.

[0504] 416.SPHSKA (SEQ ID NO: 941) contains the amino acid sequence, and the amino acid sequence is located immediately after position 455 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981, in embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 1 AAV capsid variants listed in any one of the following categories: 15-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, or 415.

[0505] 417. (i) an amino acid other than I at position 451, an amino acid other than N at position 452, and an amino acid other than G at position 453, numbered according to any one of sequence numbers 36, 138, or 981, (ii) The AAV capsid variant according to Embodiment 415 or 416, further comprising an amino acid other than I at position 451 and / or G at position 453, as numbered according to Sequence ID No. 5, 138, or 981.

[0506] 418. (i) E at position 451, R at position 452, and V at position 453, numbered according to any one of sequence numbers 36, 138, or 981, or (ii) An AAV capsid variant according to any one of embodiments 415 to 417, further comprising an E at position 451 and / or a V at position 453, numbered to sequence number 138, 981, or 5.

[0507] 419. (i) Substitutions I451E, N452R, and G453V, numbered according to any one of sequence numbers 36, 138, or 981, (ii) An AAV capsid variant according to any one of Embodiments 415 to 418, comprising substitution I451E or G453V, numbered according to Sequence ID No. 138, 981, or 5.

[0508] 420. (A)(i) E at position 451, R at position 452, and V at position 453, numbered according to one of sequence numbers 36, 138, or 981, and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to any one of SEQ ID NOs: 36, 138, or 981, or (B)(i) E at position 451 and V at position 453, numbered for sequence number 5 or 138, and (ii) An AAV capsid variant according to any one of embodiments 415 to 419, comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located at positions 456 to 461, immediately following position 455, as numbered according to SEQ ID NO: 5 or 138.

[0509] 421. An AAV capsid variant according to Embodiment 415 or 416, further comprising an amino acid other than I at position 451, an amino acid other than N at position 452, and / or an amino acid other than G at position 453, as numbered according to Sequence ID No. 39 or 138.

[0510] 422. An AAV capsid variant according to any one of Embodiments 415, 416, or 421, further comprising E at position 451, K at position 452, and / or M at position 453, as numbered according to Sequence ID No. 138 or 39.

[0511] 423. An AAV capsid variant according to any one of Embodiments 415, 416, 421, or 422, further comprising substitutions I451E, N452K, and G453M, numbered according to Sequence ID No. 39 or 138.

[0512] 424. (i) Numbered according to sequence number 39 or 138, with E at position 451, K at position 452, and M at position 453, and (ii) An AAV capsid variant according to any one of Embodiments 415, 416, or 421-423, comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, as numbered according to SEQ ID NO: 39 or 138.

[0513] 425. An AAV capsid variant according to Embodiment 415 or 416, further comprising an amino acid other than S at position 454, an amino acid other than G at position 455, and / or an amino acid other than Q at position 458, numbered according to Sequence ID No. 138.

[0514] 426. An AAV capsid variant according to any one of Embodiments 415, 416, or 425, further comprising H at position 454, D at position 455, and / or L at position 458, numbered according to Sequence ID No. 138.

[0515] 427. An AAV capsid variant according to any one of Embodiments 415, 416, 425, or 426, further comprising substitutions S454H, G455D, and Q458L, numbered according to Sequence ID No. 138.

[0516] 428. (i) H at position 454, D at position 455, and / or L at position 458, as numbered according to Sequence ID No. 138, (ii) An AAV capsid variant according to any one of Embodiments 415, 416, or 425-427, comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, as numbered according to SEQ ID NO: 138.

[0517] 429. An AAV capsid variant according to Embodiment 415 or 416, further comprising an amino acid other than I at position 451, an amino acid other than S at position 454, and / or an amino acid other than G at position 455, as numbered according to Sequence ID No. 52 or 138.

[0518] 430. An AAV capsid variant according to any one of Embodiments 415, 416, or 429, further comprising V at position 451, H at position 454, and / or D at position 455, numbered according to Sequence ID No. 52 or 138.

[0519] 431. An AAV capsid variant according to any one of embodiments 415, 416, 429, or 430, further comprising substitutions I451V, S454H, and / or G455D, numbered according to Sequence ID No. 52 or 138.

[0520] 432. (i) V at position 451, H at position 454, and / or D at position 455, numbered according to sequence number 52 or 138, and (ii) An AAV capsid variant according to any one of Embodiments 415, 416, or 429-431, comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, as numbered according to SEQ ID NO: 52 or 138.

[0521] 433.HDSPHK (SEQ ID NO: 2) contains the amino acid sequence, and the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138, in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 11 AAV capsid variants listed in any one of the following categories: 0, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, or 414.

[0522] 434.HDSPHK (SEQ ID NO: 2) contains the amino acid sequence, and the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 982, in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, AAV capsid variants listed in any one of the following: 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, or 433.

[0523] 435. The amino acid sequence of SPHKSG (SEQ ID NO: 946) is included, and the amino acid sequence is located immediately after position 455, numbered relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982, in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 10 AAV capsid variants listed in any one of the following: 5, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433, or 434.

[0524] 436. (i) The amino acid sequence of HDSPHSKA (sequence number 4486) located immediately after position 453, and (ii) Including deletions of amino acids SG at positions 454 and 455, (i) and (ii) are AAV capsid variants according to any one of embodiments 369 to 435, numbered according to Sequence ID No. 138.

[0525] An AAV capsid variant according to any one of embodiments 369 to 436, further comprising the amino acid sequence of SPHSKA (sequence number 941), located immediately after position 455, and numbered relative to sequence number 138, with amino acid HD at positions 437, 454 and 455.

[0526] 438. An AAV capsid variant according to any one of embodiments 433 to 435, further comprising an amino acid other than T at position 450, an amino acid other than I at position 451, and an amino acid other than N at position 452, numbered according to Sequence ID No. 138 or 982.

[0527] 439. An AAV capsid variant according to any one of embodiments 433-435 or 438, further comprising A at position 450, E at position 451, and I at position 452, as numbered according to Sequence ID No. 138 or 982.

[0528] 440. An AAV capsid variant according to any one of embodiments 433-435, 438, or 439, further comprising substitutions T450A, I451E, and N452I, numbered according to Sequence ID No. 138 or 982.

[0529] 441. (i) Numbered according to sequence number 138 or 982, with A at position 450, E at position 451, and I at position 452, and (ii) An AAV capsid variant according to any one of Embodiments 433, 434, or 438-440, comprising the amino acid sequence of HDSPHK (Sequence ID 2) located immediately after position 453, as numbered according to SEQ ID NO: 138 or 982.

[0530] An AAV capsid variant according to any one of Embodiments 1-22, 25-27, 31, 34-42, 45-50, 53-63, 69, 79, 83-86, 91-98, 102, 103, 110, 111, 118-129, 369-371, 384, 385, 390, 393, 395, 410-413, comprising the amino acid sequence of 442.SPHKYG (SEQ ID NO: 966), wherein the amino acid sequence is located immediately after position 455 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0531] 443. AAV capsid variant, (i) The amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 982, and / or (ii) The AAV capsid variant comprising the said modification, e.g., a substitution (e.g., a conservative substitution), which optionally includes the said modification, such that the loop VIII includes positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414.

[0532] 444. AAV capsid variant, (i) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 981, and / or (ii) The AAV capsid variant comprising the said modification, e.g., a substitution (e.g., a conservative substitution), which optionally includes the said modification, such that the loop VIII includes positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414.

[0533] 445. AAV capsid variant, (A) The amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 37, and is optionally selected. (i) One, two, or all of the amino acids other than T at position 450, an amino acid other than I at position 541, and / or an amino acid other than N at position 452, numbered according to Sequence ID No. 138 or 37, (ii) One, two, or all of the following, numbered according to Sequence ID No. 138 or 37, with A at position 450, E at position 451, and / or I at position 452, and / or (B) The AAV capsid variant comprising the said modifications, e.g., substitutions (e.g., conservative substitutions) in loop VIII, which optionally include the said modifications, such that loop VIII includes positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414.

[0534] 446. AAV capsid variant, (i) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to any one of the amino acid sequences of SEQ ID NOs: 36, 38-55, 57, or 59, and / or (ii) The AAV capsid variant comprising the said modification, e.g., a substitution (e.g., a conservative substitution), which optionally includes the said modification, such that the loop VIII includes positions 587-599 numbered according to sequence numbers 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414.

[0535] 447. (i) Modifications in loops I, II, V, VI, and / or VIII, e.g., insertions, substitutions (e.g., conservative substitutions), and / or deletions, and / or (ii) An AAV capsid variant according to any one of the prior embodiments, further comprising a substitution at the K449 position, numbered according to Sequence ID No. 138, e.g., a K449R substitution.

[0536] 448. An AAV capsid variant according to any one of the prior embodiments, comprising an amino acid sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but 30, 20, or 10 or fewer modifications, e.g., substitutions (e.g., conservative substitutions), to the amino acid sequence of SEQ ID NO: 138.

[0537] 449. An AAV capsid variant according to any one of the prior embodiments, comprising an amino acid sequence containing at least one, two, or three but no more than 30, 20, or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 138.

[0538] 450. An AAV capsid variant according to any one of the prior 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 therewith.

[0539] 451. An AAV capsid variant according to any one of the prior embodiments, comprising the amino acid sequence of SEQ ID NO: 138.

[0540] 452. An AAV capsid variant according to any one of the prior embodiments, comprising an amino acid sequence encoded by the nucleotide sequence of Sequence 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 therewith.

[0541] 453. An AAV capsid variant according to any one of the prior embodiments, wherein the nucleotide sequence encoding the capsid variant includes 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 therewith.

[0542] 454. An AAV capsid variant according to any one of the prior embodiments, comprising VP1 protein, VP2 protein, VP3 protein, or a combination thereof.

[0543] 455. An AAV capsid variant according to any one of Embodiments 1 to 454, comprising the amino acid sequence corresponding to positions 138 to 742 of Sequence ID No. 981 or 982, for example, VP2, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0544] 456. An AAV capsid variant according to any one of Embodiments 1 to 455, comprising the amino acid sequence corresponding to positions 203 to 742 of Sequence ID No. 981 or 982, for example, VP3, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0545] 457. An AAV capsid variant according to any one of Embodiments 1 to 456, comprising the amino acid sequence corresponding to VP2, for example, at positions 138 to 736 of Sequence ID No. 138, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0546] 458. An AAV capsid variant according to any one of Embodiments 1 to 457, comprising the amino acid sequence corresponding to positions 203 to 736 of Sequence ID No. 138, for example, VP3, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0547] 459. Containing an amino acid sequence that includes at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941), (i) The three consecutive amino acids include SPH, (ii) The at least four consecutive amino acids include SPHS (SEQ ID NO: 4700), (iii) The at least five consecutive amino acids include SPHSK (SEQ ID NO: 4701), or (iv) The above-mentioned six consecutive amino acids include SPHSKA (SEQ ID NO: 941), The AAV capsid variant has at least 90% (for example, at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a) to (c) above. An AAV capsid variant comprising a mino acid sequence, as described in any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, or 446-458.

[0548] 460. Containing an amino acid sequence that includes at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941), (i) The three consecutive amino acids include SPH, (ii) The at least four consecutive amino acids include SPHS (SEQ ID NO: 4700), (iii) The at least five consecutive amino acids include SPHSK (SEQ ID NO: 4701), or (iv) The above-mentioned six consecutive amino acids include SPHSKA (SEQ ID NO: 941), The AAV capsid variant contains 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: 981, in embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168- AAV capsid variants listed in any one of the following: 202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, or 446-459.

[0549] 461. The amino acid sequence of SPHSKA (SEQ ID NO: 941) contains one or two but no more than three substitutions, and the AAV capsid variant is (a) VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981 (b) VP2 protein containing the amino acid sequence at positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981 (c) VP3 protein containing the amino acid sequence at positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981, or (d) Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, which include an amino acid sequence having at least 90% (for example, at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a)-(c). AAV capsid variants listed in any one of the following categories: 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, or 446-460.

[0550] 462. SPHSKA (SEQ ID NO: 941) has an amino acid sequence that includes one or two but no more than three substitutions, and the AAV capsid variant contains 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: 138 or SEQ ID NO: 981, Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, AAV capsid variants listed in any one of the following categories: 102-104, 107, 110-112, 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, or 446-461.

[0551] 463. An AAV capsid variant according to any one of embodiments 459 to 462, wherein the amino acid sequence is located immediately after position 455, as numbered according to SEQ ID NO: 138 or 981.

[0552] 464.HDSPHK (SEQ ID NO: 2) contains an amino acid sequence that includes at least 3, 4, 5, or 6 consecutive amino acids, (i) The three consecutive amino acids include HDS, (ii) The at least four consecutive amino acids include HDSP (SEQ ID NO: 4702), (iii) The at least five consecutive amino acids include HDSPH (SEQ ID NO: 4703), or (iv) The above-mentioned six consecutive amino acids include HDSPHK (SEQ ID NO: 2), Embodiments in which the AAV capsid variant includes (a) a VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982, (b) a VP2 protein containing the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982, (c) a VP3 protein containing the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 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). 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283 AAV capsid variants listed in any one of the following: ~287, 289~299, 327~363, 369, 369, 371, 380~383, 385, 386, 390, 392, 395, 407, 409~412, 414, 433~435, 438~441, 443, 445, or 447~458.

[0553] 465.HDSPHK (SEQ ID NO: 2) contains an amino acid sequence that includes at least 3, 4, 5, or 6 consecutive amino acids, (i) The three consecutive amino acids include HDS, (ii) The at least four consecutive amino acids include HDSP (SEQ ID NO: 4702), (iii) The at least five consecutive amino acids include HDSPH (SEQ ID NO: 4703), or (iv) The above-mentioned six consecutive amino acids include HDSPHK (SEQ ID NO: 2), Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 20 in which the AAV capsid variant contains 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. AAV capsid variants listed in any one of the following: 3-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, or 464.

[0554] The AAV capsid variant contains one or two but no more than three substitutions relative to the amino acid sequence of 466.HDSPHK (SEQ ID NO: 2), (a) VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982, (b) VP2 protein containing the amino acid sequence at positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982 (c) VP3 protein containing the amino acid sequence at positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 982, or (d) Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, each containing 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)-(c). AAV capsid variants listed in any one of the following: 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464, or 465.

[0555] Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-10, wherein the AAV capsid variant contains one or two but no more than three substitutions relative to the amino acid sequence of 467.HDSPHK (SEQ ID NO: 2), and the AAV capsid variant contains 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. AAV capsid variants listed in any one of the following: 3, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, or 464-466.

[0556] 468. An AAV capsid variant according to any one of embodiments 464 to 468, wherein the amino acid sequence is located immediately after position 453, as numbered according to SEQ ID NO: 138 or 982.

[0557] 469. An AAV capsid variant according to any one of Embodiments 1 to 468, comprising one amino acid sequence of either SEQ ID NO: 981 or 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 therewith.

[0558] 470. An AAV capsid variant according to any one of Embodiments 1 to 469, comprising an amino acid sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but 30, 20, or 10 or fewer modifications, e.g., substitutions (e.g., conservative substitutions), to the amino acid sequence of SEQ ID NO: 981 or 982.

[0559] 471. An AAV capsid variant according to any one of Embodiments 1 to 470, comprising an amino acid sequence containing at least one, two, or three but no more than 30, 20, or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 981 or 982.

[0560] 472. Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168- , AAV capsid variants listed in any one of the following: 202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, 446-463, or 469-471.

[0561] 473. Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 1, 2 AAV capsid variants listed in any one of the following categories: 15-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, 446-463, or 469-472.

[0562] 474. Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, AAV capsid variants listed in any one of the following: 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, 446-463, or 469-473.

[0563] 475. Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 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 therewith, AAV capsid variants listed in any one of the following categories: 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, or 464-471.

[0564] 476. Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, which include an amino acid sequence with respect to the amino acid sequence of SEQ ID NO: 982, having at least 1, 2, or 3 modifications, e.g., substitutions (e.g., conservative substitutions), but with 30, 20, or 10 or fewer modifications, e.g., substitutions (e.g., conservative substitutions). AAV capsid variants listed in any one of the following: 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464-471, or 475.

[0565] 477. Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 25, which include an amino acid sequence with respect to the amino acid sequence of SEQ ID NO: 982, containing at least 1, 2, or 3 but no more than 30, 20, or 10 different amino acids. AAV capsid variants listed in any one of the following: 1, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464-471, 475, or 476.

[0566] 478. An AAV capsid variant according to any one of Embodiments 1 to 477, comprising an amino acid sequence encoded by the nucleotide sequence of Sequence ID No. 983 or 984, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith.

[0567] 479. An AAV capsid variant according to any one of the prior embodiments 1 to 478, wherein the nucleotide sequence encoding the capsid variant includes the nucleotide sequence of SEQ ID NO: 983 or 984, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith.

[0568] 480. The nucleotide sequence encoding the capsid variant includes the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith, in prior embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112. AAV capsid variants listed in any one of the following: 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, 446-463, 469-474, 478, or 479.

[0569] 481. The nucleotide sequence encoding the capsid variant includes 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 therewith, in the prior embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110. AAV capsid variants listed in any one of the following: 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464-471, or 475-479.

[0570] 482. An AAV capsid variant according to any one of the prior embodiments, wherein the nucleotide sequence encoding the capsid variant is codon-optimized.

[0571] 483. Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 36 An AAV capsid variant comprising any one of the amino acid sequences listed in 9-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, 446-463, 469-474, 478-480, or 482, and further comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 981.

[0572] 484. An AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981, further comprising modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), wherein loop VIII optionally comprises positions 587-599 numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593 numbered according to SEQ ID NO: 138 or 6414.

[0573] 485. The AAV capsid variant according to Embodiment 483 or 484, wherein the nucleotide sequence encoding the AAV capsid variant includes the nucleotide sequence of Sequence ID No. 983, or a nucleotide sequence that is at least 90%, 95%, or 99% identical thereto.

[0574] 486. Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369 An AAV capsid variant comprising the amino acid sequence described in any one of 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464-471, 475-479, 481, or 482, and further comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 982.

[0575] 487. An AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982, further comprising modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), wherein loop VIII optionally comprises positions 587-599 numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593 numbered according to SEQ ID NO: 138 or 6414.

[0576] 488. The AAV capsid variant according to Embodiment 486 or 487, wherein the nucleotide sequence encoding the AAV capsid variant includes the nucleotide sequence of Sequence ID No. 984, or a nucleotide sequence that is at least 90%, 95%, or 99% identical thereto.

[0577] 489. An AAV capsid variant comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 983 or 984, or a nucleotide sequence that is at least 95% identical thereto, further comprising modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), wherein loop VIII comprises positions 587-599 numbered according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593 numbered according to SEQ ID NO: 138 or 6414.

[0578] 490. An AAV capsid variant comprising any one amino acid sequence from SEQ ID NOs. 5-10, 36-59, or 6409-6413, further optionally comprising a modification in loop VIII, e.g., a substitution (e.g., a conservative substitution), and optionally, loop VIII comprising positions 587-599 numbered according to SEQ ID NOs. 981, 982, 6411, or 6412, or positions 581-593 numbered according to SEQ ID NOs. 138 or 6414.

[0579] 491. An AAV capsid variant comprising an amino acid sequence encoded by any one nucleotide sequence of sequence number 4 or 12-35, or a nucleotide sequence that is at least 95% identical thereto, wherein the AAV capsid variant further optionally comprises modifications in loop VIII, e.g., substitutions (e.g., conservative substitutions), wherein loop VIII comprises positions 587-599 numbered according to sequence number 981, 982, 6411, or 6412, or positions 581-593 numbered according to sequence number 138 or 6414.

[0580] 492. The AAV capsid variant according to 490 or 491, wherein the nucleotide sequence encoding the AAV capsid variant includes one of the nucleotide sequences from Sequence ID No. 4 or 12-35, or a nucleotide sequence that is at least 95% identical thereto.

[0581] 493. An AAV capsid variant according to any one of Embodiments 1-299, 369-371, or 375-492, having increased tropism to CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells, or spinal cord tissue, compared to the tropism to a reference sequence containing the amino acid sequence of SEQ ID NO: 138.

[0582] 494. An AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, or 375-493, wherein a brain region, e.g., a midbrain region (e.g., hippocampus or thalamus), or brainstem is transduced, and optionally, when measured by an assay, e.g., an immunohistochemical assay or a qPCR assay, such as as described in Example 2, the level of transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65 times greater than the reference sequence of SEQ ID NO: 138.

[0583] 495. An AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, or 375-494, wherein a brain region, e.g., a midbrain region (e.g., hippocampus or thalamus), or brainstem is transduced, and optionally, when measured by an assay, e.g., an immunohistochemical assay or a qPCR assay, such as as described in Example 2, the level of transduction is at least 30, 35, 40, 45, 50, 55, 60, or 65 times greater than the reference sequence of SEQ ID NO: 138.

[0584] 496. An AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, or 375-495, which, for example, is enriched at least about 3, 4, 5, 6, 7, 8, 9, or 10 times in the brain compared to the reference sequence of SEQ ID NO: 138, as measured by an assay such as that described in Example 1.

[0585] 497. An AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, or 375-496, which, for example, is concentrated at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 times in the brain compared to the reference sequence of SEQ ID NO: 138, as measured by an assay such as that described in Example 1.

[0586] 498. For example, an AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, or 375-497, which is enriched in at least two-three species, e.g., non-human primates and rodents (e.g., mice), compared to the reference sequence of Sequence ID No. 138.

[0587] 499. An AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, or 375-498, which, when measured by assays such as those described in Example 1 or 5, is concentrated at least 2-3 times, for example, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 190, 200, 205, or 210 times in the brains of non-human primates and rodents (e.g., mice), compared to the reference sequence of SEQ ID NO: 138.

[0588] 500. An AAV capsid variant according to Embodiment 498 or 499, wherein at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callitris jacchus, and / or mice (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 uninbred mice).

[0589] 501. An AAV capsid variant according to any one of Embodiments 130-146, 369, 410-414, 447-454, 457, 458, 482, or 493, which is concentrated at least about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 times in the brain compared to the reference sequence of SEQ ID NO: 981, as measured by an assay such as the one described in Example 3.

[0590] 502. (i) For example, when measured by an assay such as that described in Example 3, the sample is concentrated at least approximately 2, 2.5, 3, 3.5, 4, 4.5, 5, or 5.5 times in the brain compared to the reference sequence of SEQ ID NO: 982. (ii) For example, when measured by an assay such as that described in Example 8, at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of cells in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, cerebellar cortex, cerebellum, dentate nucleus, and / or lateral geniculate nucleus (LGN)) can be transduced. (iii) Transduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% of neurons (e.g., NeuN+ neurons) within a brain region (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), (iv) An AAV capsid variant according to any one of Embodiments 147-167, 369, 410-414, 447-454, 457, 458, 482, or 493, which can transduce at least 70%, 75%, 80%, 85%, 90%, or 95% of astrocytes (e.g., Sox9+ astrocytes) in a brain region (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex) as measured by an assay such as that described in Example 8.

[0591] 503. An AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, or 375-500, which delivers an increased level of payload to a brain region, and optionally, the level of the payload is increased by at least 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 times compared to the reference sequence of SEQ ID NO: 138, when measured by an assay, e.g., qRT-PCR or qPCR assay (e.g., described in Example 2 or 8).

[0592] 504. An AAV capsid variant according to any one of Embodiments 1-129, 168-299, 369-371, 375-500, or 503, which delivers an increased level of viral genome to a brain region, and optionally, the level of viral genome is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50-fold compared to the reference sequence of SEQ ID NO: 138, when measured by an assay, e.g., qRT-PCR or qPCR assay (e.g., described in Example 2 or 8).

[0593] 505. Embodiment 504 or the AAV capsid variant according to 504, wherein the brain region is a midbrain region (e.g., hippocampus or thalamus), frontal cortex, temporal cortex, motor cortex, cerebral cortex, cerebellum, cerebellar...

Claims

1. It is an AAV capsid variant, (a) Three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to Sequence ID No. 138, (b) an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein [N1]-[N2]-[N3] is located in the hypervariable loop IV, (i) [N1] includes X1, X2, and X3, and at least one of X1, X2, or X3 is G, (ii) [N2] contains the amino acid sequence of SPH, (iii) [N3] comprises an amino acid sequence comprising X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid, for example, K or R, The AAV capsid variant comprising an amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203 to 736 of SEQ ID NO:

138.

2. An AAV capsid variant comprising three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to Sequence ID No. 138, wherein the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to the amino acid sequence from positions 203 to 736 of Sequence ID No.

138.

3. The following formula: contains an amino acid sequence having [N1]-[N2]-[N3], where, (i) [N1] includes X1, X2, and X3, and at least one of X1, X2, or X3 is G, (ii) [N2] contains the amino acid sequence of SPH, (iii)[N3] comprises X4, X5, and X6, where at least one of X4, X5, or X6 is a basic amino acid, e.g., K or R. The AAV capsid variant according to claim 2, wherein [N1]-[N2]-[N3] are present in the ultra-variable loop IV.

4. [N3] is SKA, KSG, ARM, VKS, ASR, VKI, KKN, VRM, RKA, KTS, KFG, KIG, KLG, KTT, KTY, K YG, SKD, SKP, TRG, VRG, KRG, GAR, KSA, KSR, SKL, SRA, SKR, SLR, SRG, SSR, FLR, SKW, An AAV capsid variant according to claim 1 or 3, comprising SKS, WKA, VRR, SKV, SKT, SKG, GKA, TKA, NKA, SKL, SKN, AKA, KTG, KSL, KSE, KSV, KSW, KSN, KHG, KSQ, KSK, KLW, WKG, KMG, KMA, or RSG.

5. [N2]-[N3] are SPHSKA (sequence number 941), SPHKSG (sequence number 946), SPHARM (sequence number 947), SPHVKS (sequence number 948), SPHASR (sequence number 949), SPHVKI (sequence number 950), SPHKKN (sequence number 954), SPHVRM (sequence number 955), SPHRKA (sequence number 956), SPHKFG (sequence number 957), SPHKIG (sequence number 958), SPHKLG (sequence number 959), SPHKTS (sequence number 963), SPHKTT (sequence number 964), SPHKTY (sequence number 965), SPHKYG (SEQ ID NO: 966), SPHSKD (SEQ ID NO: 967), SPHSKP (SEQ ID NO: 968), SPHTRG (SEQ ID NO: 972), SPHVRG (SEQ ID NO: 973), SPHKRG (SEQ ID NO: 974), SPHGAR (SEQ ID NO: 975), SPHKSA (SEQ ID NO: 977), SPHKSR (SEQ ID NO: 951), SPHSKL (SEQ ID NO: 960), SPHSRA (SEQ ID NO: 969), SPHSKR (SEQ ID NO: 978), SPHSLR (SEQ ID NO: 952), SPHSRG (SEQ ID NO: 961), SPHSSR (SEQ ID NO: 970), S PHFLR (SEQ ID NO: 979), SPHSKW (SEQ ID NO: 953), SPHSKS (SEQ ID NO: 962), SPHWKA (SEQ ID NO: 971), SPHVRR (SEQ ID NO: 980), SPHSKT (SEQ ID NO: 4731), SPHSKG (SEQ ID NO: 4732), SPHGKA (SEQ ID NO: 4733), SPHNKA (SEQ ID NO: 4734), SPHSKN (SEQ ID NO: 4735), SPHAKA (SEQ ID NO: 4736), SPHSKV (SEQ ID NO: 4737), SPHKTG (SEQ ID NO: 4738), SPHTKA (SEQ ID NO: 4739), SPHKSL (SEQ ID NO: 474 0), an AAV capsid variant according to any one of claims 1, 3, or 4, comprising SPHKSE (SEQ ID NO: 4741), SPHKSV (SEQ ID NO: 4742), SPHKSW (SEQ ID NO: 4743), SPHKSN (SEQ ID NO: 4744), SPHKHG (SEQ ID NO: 4745), SPHKSQ (SEQ ID NO: 4746), SPHKSK (SEQ ID NO: 4747), SPHKLW (SEQ ID NO: 4748), SPHWKG (SEQ ID NO: 4749), SPHKMG (SEQ ID NO: 4750), SPHKMA (SEQ ID NO: 4751), or SPHRSG (SEQ ID NO: 976).

6. An AAV capsid variant according to any one of claims 1 or 3 to 5, wherein [N1] includes GSG, GHD, VSG, GQD, CSG, GRG, CSH, GQS, GSH, RVG, GSC, GLL, GDD, GHE, GNY, MSG, RNG, TSG, ISG, GPG, ESG, SSG, GNG, ASG, NSG, LSG, GGG, KSG, HSG, GTG, PSG, GSV, RSG, GIG, WSG, DSG, IDG, GLG, DAG, DGG, MEG, ENG, GSA, KNG, KEG, AIG, GYD, GHG, GRD, GND, GPD, GMG, GQV, GHN, GHP, or GHS.

7. [N1] - [N2] - [N3] (i) GSGSPHSKA (SEQ ID NO: 4697), GHDSPHKSG (SEQ ID NO: 4698), VSGSPHSKA (SEQ ID NO: 4913), GSGSPHARM (SEQ ID NO: 4906), GSGSPHVKS (SEQ ID NO: 4907), GQDSPHKSG (SEQ ID NO: 4908), GSGSPHASR (SEQ ID NO: 4909), GSGSPHVKI (SEQ ID NO: 4910), GSGSPHKKN (SEQ ID NO: 4911), GSGSPHVRM (SEQ ID NO: 4912), CSGSPHSKA (SEQ ID NO: 4914), GSGSPHRKA (SEQ ID NO: 4915), CS GSPHKTS (SEQ ID NO: 4916), CSHSPHKSG (SEQ ID NO: 4917), GQSSPHRSG (SEQ ID NO: 4918), GRGSPHASR (SEQ ID NO: 4919), GRGSPHSKA (SEQ ID NO: 4920), GSGSPHKFG (SEQ ID NO: 4921), GSGSPHKIG (SEQ ID NO: 4922), GSGSPHKLG (SEQ ID NO: 4923), GSGSPHKTS (SEQ ID NO: 4924), GSGSPHKTT (SEQ ID NO: 4925), GSGSPHKTY (SEQ ID NO: 4926), GSGSPHKYG (SEQ ID NO: 4927), GSGSPHSK D (SEQ ID NO: 4928), GSGSPHSKP (SEQ ID NO: 4929), GSGSPHTRG (SEQ ID NO: 4930), GSGSPHVRG (SEQ ID NO: 4931), GSHSPHKRG (SEQ ID NO: 4932), GSHSPHKSG (SEQ ID NO: 4933), VSGSPHASR (SEQ ID NO: 4934), VSGSPHGAR (SEQ ID NO: 4935), VSGSPHKFG (SEQ ID NO: 4936), GHDSPHKRG (SEQ ID NO: 4937), GDDSPHKSG (SEQ ID NO: 4938), GHESPHKSA (SEQ ID NO: 4939), GHDSPHKSA (SEQ ID NO: 4938) 4940), GNYSPHKIG (SEQ ID NO: 4941), GHDSPHKSR (SEQ ID NO: 4942), GSGSPHSKL (SEQ ID NO: 4943), GSGSPHRA (SEQ ID NO: 4944), GSGSPHSKR (SEQ ID NO: 4945), GSGSPHLR (SEQ ID NO: 4946), GSGSPHRG (SEQ ID NO: 4947), GSGSPHSR (SEQ ID NO: 4948), RVGSPHSKA (SEQ ID NO: 4949), GSCSPHRKA (SEQ ID NO: 4950), GSGSPHFLR (SEQ ID NO: 4951), GSGSPHSKW (SEQ ID NO: 4952),GSGSPHSKS (SEQ ID NO: 4953), GLLSPHWKA (SEQ ID NO: 4954), GSGSPHVRR (SEQ ID NO: 4955), GSGSPHSKV (SEQ ID NO: 4956), MSGSPHSKA (SEQ ID NO: 4957), RNGSPHSKA (SEQ ID NO: 4958), TSGSPHSKA (SEQ ID NO: 4959), ISGSPHSKA (SEQ ID NO: 4960), GPGSPHSKA (SEQ ID NO: 4961), GSGSPHSKT (SEQ ID NO: 4962), ESGSPHSKA (SEQ ID NO: 4963), SSGSPHSKA (SEQ ID NO: 4964), GNGSPHSKA ( SEQ ID NO: 4965), ASGSPHSKA (SEQ ID NO: 4966), NSGSPHSKA (SEQ ID NO: 4967), LSGSPHSKA (SEQ ID NO: 4968), GGGSPHSKA (SEQ ID NO: 4969), KSGSPHSKA (SEQ ID NO: 4970), GGGSPHSKS (SEQ ID NO: 4971), GSGSPHSKG (SEQ ID NO: 4972), HSGSPHSKA (SEQ ID NO: 4973), GTGSPHSKA (SEQ ID NO: 4974), PSGSSPHSKA (SEQ ID NO: 4975), GSVSPHGKA (SEQ ID NO: 4976), RSGSPHSKA (SEQ ID NO: 4977), GSGSPHTKA (SEQ ID NO: 4978), GIGSPHSKA (SEQ ID NO: 4979), WSGSPHSKA (SEQ ID NO: 4980), DSGSPHSKA (SEQ ID NO: 4981), IDGSPHSKA (SEQ ID NO: 4982), GSGSPHNKKA (SEQ ID NO: 4983), GLGSPHSKS (SEQ ID NO: 4984), DAGSPHSKA (SEQ ID NO: 4985), DGGSPHSKA (SEQ ID NO: 4986), MEGSPHSKA (SEQ ID NO: 4987), ENGSPHSKA (SEQ ID NO: 4988), GSASPHSKA (SEQ ID NO: 4989), GNGSPHSKS ( SEQ ID NO: 4990), KNGSPHSKA (SEQ ID NO: 4991), KEGSPHSKA (SEQ ID NO: 4992), AIGSPHSKA (SEQ ID NO: 4993), GSGSPHSKN (SEQ ID NO: 4994), GSGSPHAKA (SEQ ID NO: 4995), GHDSPHKIG (SEQ ID NO: 4996), GYDSPHKSG (SEQ ID NO: 4997), GHESPHKSG (SEQ ID NO: 4998), GHDSPHKTG (SEQ ID NO: 4999), GRGSPHKRG (SEQ ID NO: 5000), GQDSPHKSG (SEQ ID NO: 4908), GHDSPHKSL (SEQ ID NO: 5001),GHGSPHSKA (SEQ ID NO: 5002), GHDSPHKSE (SEQ ID NO: 5003), VSGSPHSKA (SEQ ID NO: 4913), GRDSPHKSG (SEQ ID NO: 5004), GNDSPHKSV (SEQ ID NO: 5005), GQDSPHKIG (SEQ ID NO: 5006), GHDSPHKSV (SEQ ID NO: 5007), GPDSPHKIG (SEQ ID NO: 5008), GPDSPHKSG (SEQ ID NO: 5009), GHDSPHKSW (SEQ ID NO: 5010), GHDSPHKSN (SEQ ID NO: 5011), GMGSPHSKT (SEQ ID NO: 5012), GHDSPHKHG (SEQ ID NO: 5013), GQVS PHKSG (SEQ ID NO: 5014), GDDSPHKSV (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016), GNGSPHKRG (SEQ ID NO: 5017), GHDSPHKYG (SEQ ID NO: 5018), GHDSPHKSQ (SEQ ID NO: 5019), GNDSPHKIG (SEQ ID NO: 5020), GHDSPHKSK (SEQ ID NO: 5021), GHDSPHKLW (SEQ ID NO: 5022), GHPSPHWKG (SEQ ID NO: 5023), GHDSPHKMG (SEQ ID NO: 5024), GHDSPHKMA (SEQ ID NO: 5025), or GHSSPHRSG (SEQ ID NO: 5026), or (ii) An AAV capsid variant according to any one of claims 1 or 3 to 6, comprising GSGSPHSKA (SEQ ID NO: 4697), GHDSPHKSG (SEQ ID NO: 4698), or VSGSPHSKA (SEQ ID NO: 4913).

8. (i) [N0], where [N0] is TIN, TEN, TER, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW, ANN, IPE, ADM, I EY, ADY, IET, MEW, CEY, RIN, MEI, LEY, ADW, IEI, DIM, FEQ, MEF, CDQ, LPE, IEN, MES, AEI, VEY, IIN, TSN, IEV, MEM, AEV, MDA, VEW, AEQ, LEW, MEL, MET, MEA, IES, MEV, CEI, ATN, MDG, QEV, ADQ, NMN, IEM , ISN, TGN, QQQ, HDW, IEG, TII, TFP, TEK, EIN, TVN, TFN, SIN, TSY, ELH, AIN, SVN, TDN, TFH, TVH, TSS , TID, TCN, NIN, TEH, AEM, AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TIY, TFS, TES, TT N, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, NAD, TIT, NCV, T IR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV, SDI, NSI, NSL, [N0] and / or including EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, or NNL; (ii) [N4] where [N4] is QNQQ (sequence number 5028), WNQQ (sequence number 5029), QYYV (sequence number 5030), RRQQ (sequence number 5031), GCGQ (sequence number 5032), LRQQ (sequence number 5033), RNQQ (sequence number 5034), VNQQ (sequence number 5035), FRLQ (sequence number 5036), FNQQ (sequence number 5037), LLQQ (sequence number 5038), SNQQ (sequence number 5039), RLQQ (sequence number 5040), LNQQ (sequence number 5041), QRKL (sequence number 5042), LRRQ (Sequence ID 5043), QRLR (Sequence ID 5044), QRRL (Sequence ID 5045), RRLQ (Sequence ID 5046), RLRQ (Sequence ID 5047), SKRQ (Sequence ID 5048), QLYR (Sequence ID 5049), QLTV (Sequence ID 5050), QNKQ (Sequence ID 5051), KNQQ (Sequence ID 5052), QKQQ (Sequence ID 5053), QTQQ (Sequence ID 5054), QNHQ (Sequence ID 5055), QHQQ (Sequence ID 5056), QNQH (Sequence ID 5057), QHRQ (Sequence ID 5058), LTQQ (Sequence ID 5059 ), QNQW (Sequence ID 5060), QNTH (Sequence ID 5061), RRRQ (Sequence ID 5062), QYQQ (Sequence ID 5063), QNDQ (Sequence ID 5064), QNRH (Sequence ID 5065), RDQQ (Sequence ID 5066), PNLQ (Sequence ID 5067), HVRQ (Sequence ID 5068), PNQH (Sequence ID 5069), HNQQ (Sequence ID 5070), QSQQ (Sequence ID 5071), QPAK (Sequence ID 5072), QNLA (Sequence ID 5073), QNQL (Sequence ID 5074), QGQQ (Sequence ID 5075), LNRQ (Sequence ID Column number 5076), QNPP (sequence number 5077), QNLQ (sequence number 5078), QDQE (sequence number 5079), QDQQ (sequence number 5080), HWQQ (sequence number 5081), PNQQ (sequence number 5082), PEQQ (sequence number 5083), QRTM (sequence number 5084), LHQH (sequence number 5085), QHRI (sequence number 5086), QYIH (sequence number 5087), QKFE (sequence number 5088), QFPS (sequence number 5089), QNPL (sequence number 5090), QAIK (sequence number 5091), QNRQ (sequence number 5092),QYQH (SEQ ID NO: 5093), QNPQ (SEQ ID NO: 5094), QHQL (SEQ ID NO: 5095), QSPP (SEQ ID NO: 5096), QAKL (SEQ ID NO: 5097), KSQQ (SEQ ID NO: 5098), QDRP (SEQ ID NO: 5099), QNLG (SEQ ID NO: 5100), QAFH (SEQ ID NO: 5101), QNAQ (SEQ ID NO: 5102), HNQL (SEQ ID NO: 5103), QKLN (SEQ ID NO: 5104), QNVQ (SEQ ID NO: 5105), QAQQ (SEQ ID NO: 5106), QTPP (SEQ ID NO: 5107), QPPA (SEQ ID NO: 5108), QERP (SEQ ID NO: 5108) Number 5109), QDLQ (Sequence ID 5110), QAMH (Sequence ID 5111), QHPS (Sequence ID 5112), PGLQ (Sequence ID 5113), QGIR (Sequence ID 5114), QAPA (Sequence ID 5115), QIPP (Sequence ID 5116), QTQL (Sequence ID 5117), QAPS (Sequence ID 5118), QNTY (Sequence ID 5119), QDKQ (Sequence ID 5120), QNHL (Sequence ID 5121), QIGM (Sequence ID 5122), LNKQ (Sequence ID 5123), PNQL (Sequence ID 5124), QLQQ (Sequence ID 5125), QRMS (SEQ ID NO: 5126), QGIL (SEQ ID NO: 5127), QDRQ (SEQ ID NO: 5128), RDWQ (SEQ ID NO: 5129), QERS (SEQ ID NO: 5130), QNYQ (SEQ ID NO: 5131), QRTC (SEQ ID NO: 5132), QIGH (SEQ ID NO: 5133), QGAI (SEQ ID NO: 5134), QVPP (SEQ ID NO: 5135), QVQQ (SEQ ID NO: 5136), LMRQ (SEQ ID NO: 5137), QYSV (SEQ ID NO: 5138), QAIT (SEQ ID NO: 5139), QKTL (SEQ ID NO: 5140), QLHH (SEQ ID NO: 5141), QNII (SEQ ID NO: 5138) Number 5142), QGHH (Sequence ID 5143), QSKV (Sequence ID 5144), QLPS (Sequence ID 5145), IGKQ (Sequence ID 5146), QAIH (Sequence ID 5147), QHGL (Sequence ID 5148), QFMC (Sequence ID 5149), QNQM (Sequence ID 5150), QHLQ (Sequence ID 5151), QPAR (Sequence ID 5152), QSLQ (Sequence ID 5153), QSQL (Sequence ID 5154), HSQQ (Sequence ID 5155), QMPS (Sequence ID 5156), QGSL (Sequence ID 5157), QVPA (Sequence ID 5158),HYQQ (SEQ ID NO: 5159), QVPS (SEQ ID NO: 5160), RGEQ (SEQ ID NO: 5161), PGQQ (SEQ ID NO: 5162), LEQQ (SEQ ID NO: 5163), QNQS (SEQ ID NO: 5164), QKVI (SEQ ID NO: 5165), QNND (SEQ ID NO: 5166), QSVH (SEQ ID NO: 5167), QPLG (SEQ ID NO: 5168), HNQE (SEQ ID NO: 5169), QIQQ (SEQ ID NO: 5170), QVRN (SEQ ID NO: 5171), PSNQ (SEQ ID NO: 5172), QVGH (SEQ ID NO: 5173), QRDI (SEQ ID NO: 5174), QMPN (SEQ ID NO: 5174) Number 5175), RGLQ (Sequence ID 5176), PSLQ (Sequence ID 5177), QRDQ (Sequence ID 5178), QAKG (Sequence ID 5179), QSAH (Sequence ID 5180), QSTM (Sequence ID 5181), QREM (Sequence ID 5182), QYRA (Sequence ID 5183), QRQQ (Sequence ID 5184), QWQQ (Sequence ID 5185), QRMN (Sequence ID 5186), GDSQ (Sequence ID 5187), QKIS (Sequence ID 5188), PSMQ (Sequence ID 5189), SPRQ (Sequence ID 5190), MEQQ (Sequence ID 5191), QYQN (Sequence ID 5192), QIRQ (Sequence ID 5193), QSVQ (Sequence ID 5194), RSQQ (Sequence ID 5195), QNKL (Sequence ID 5196), QIQH (Sequence ID 5197), PRQQ (Sequence ID 5198), HTQQ (Sequence ID 5199), QRQH (Sequence ID 5200), RNQE (Sequence ID 5201), QSKQ (Sequence ID 5202), QNQP (Sequence ID 5203), QSPQ (Sequence ID 5204), QTRQ (Sequence ID 5205), QNLH (Sequence ID 5206), QNQE (Sequence ID 5207), LNQP (Sequence ID Number 5208), QNQD (Sequence ID 5209), QNLL (Sequence ID 5210), QLVI (Sequence ID 5211), RTQE (Sequence ID 5212), QTHQ (Sequence ID 5213), QDQH (Sequence ID 5214), QSQH (Sequence ID 5215), VRQQ (Sequence ID 5216), AWQQ (Sequence ID 5217), QSVP (Sequence ID 5218), QNIQ (Sequence ID 5219), LDQQ (Sequence ID 5220), PDQQ (Sequence ID 5221), ESQQ (Sequence ID 5222), QRQL (Sequence ID 5223), QIIV (Sequence ID 5224),QKQS (SEQ ID NO: 5225), QSHQ (SEQ ID NO: 5226), QFVV (SEQ ID NO: 5227), QSQP (SEQ ID NO: 5228), QNEQ (SEQ ID NO: 5229), INQQ (SEQ ID NO: 5230), RNRQ (SEQ ID NO: 5231), RDQK (SEQ ID NO: 5232), QWKR (SEQ ID NO: 5233), ENRQ (SEQ ID NO: 5234), QTQP (SEQ ID NO: 5235), QKQL (SEQ ID NO: 5236), AAV particles according to any one of claims 1 or 3 to 7, further comprising the above [N4], including RNQL (SEQ ID NO: 5237), ISIQ (SEQ ID NO: 5238), QTVC (SEQ ID NO: 5239), QQIM (SEQ ID NO: 5240), LNHQ (SEQ ID NO: 5241), QNQA (SEQ ID NO: 5242), QMIH (SEQ ID NO: 5243), RNHQ (SEQ ID NO: 5244), or QKMN (SEQ ID NO: 5245).

9. [N0]-[N1]-[N2]-[N3]-[N4] (i) Any one of the amino acid sequences from SEQ ID NOs. 2242 to 2886, or (ii) The AAV capsid variant according to claim 8, comprising TENVSGSPHHSKAQNQQ (SEQ ID NO: 2283), TERVSGSPHHSKAQNQQ (SEQ ID NO: 2272), TINGSGSPHSKAQNQQ (SEQ ID NO: 2242), or TINGHDSPHKSGQNQQ (SEQ ID NO: 2243).

10. (i) [N0] is located at amino acids 450-452, numbered according to sequence numbers 981, 982, or 138, (ii) [N1] is located at amino acids 453-455, numbered according to sequence numbers 981, 982, or 138. (iii)[N2] is located at amino acids 456-458, numbered according to sequence number 981 or 982. (iv)[N3] is located at amino acids 459-461, numbered according to sequence number 981 or 982. (v) [N4] is located at amino acids 462-465, numbered according to sequence number 981 or 982, and / or (vi)[N0]-[N1]-[N2]-[N3]-[N4] is present at amino acids 450-465, numbered according to Sequence ID No. 981 or 982, the AAV capsid variant according to claim 8 or 9.

11. It is an AAV capsid variant, (a) Three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to Sequence ID No. 138, (b) The amino acid sequence of HDSPHK (SEQ ID NO: 2) in the hypervariable loop IV, The AAV capsid variant comprising an amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203 to 736 of SEQ ID NO:

138.

12. The AAV capsid variant according to claim 11, wherein the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located immediately after amino acid 453, numbered according to SEQ ID NO:

982.

13. It is an AAV capsid variant, (a) Three, four, or all of the amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to Sequence ID No. 138, (b) The amino acid sequence of SPHSKA (SEQ ID NO: 941) in the hypervariable loop IV, The AAV capsid variant comprising an amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203 to 736 of SEQ ID NO:

138.

14. The AAV capsid variant according to claim 13, wherein the amino acid sequence of SPHSKA (sequence number 941) is located immediately after amino acid 455, numbered according to sequence number 981.

15. The AAV capsid variant according to claim 13 or 14, further comprising amino acid E at position 451, numbered according to Sequence ID No.

981.

16. An AAV capsid variant according to any one of claims 13 to 15, comprising amino acid V at position 453, numbered according to Sequence ID No.

981.

17. An AAV capsid variant according to any one of claims 13 to 16, comprising amino acid R at position 452, numbered according to Sequence ID No.

981.

18. (i) amino acids R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to sequence numbers 981, 982, 6411, or 6412, or (ii) The AAV capsid variant according to any one of claims 1 to 17, comprising amino acids R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to Sequence ID No. 138 or 6414.

19. (i) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 203-742 of sequence number 6412, (ii) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6412, and / or (iii) The AAV capsid variant according to any one of claims 1 to 12 or 18, comprising an amino acid sequence that is at least 95% or at least 98% identical to the amino acid sequence of Sequence ID No. 6412.

20. (i) The amino acid sequence of amino acids 203-742 of sequence number 6412, (ii) The amino acid sequence of amino acids 138-742 of SEQ ID NO: 6412, and / or (iii) An AAV capsid variant according to any one of claims 1 to 12, 18, or 19, comprising the amino acid sequence of Sequence ID No. 6412.

21. (i) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 6411 (ii) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6411, and / or (iii) The AAV capsid variant according to any one of claims 1 to 10 or 13 to 18, comprising an amino acid sequence that is at least 95% or at least 98% identical to the amino acid sequence of Sequence ID No. 6411.

22. (i) The amino acid sequence of amino acids 203-742 of sequence number 6411, (ii) The amino acid sequence of amino acids 138-742 of SEQ ID NO: 6411, and / or (iii) An AAV capsid variant according to any one of claims 1 to 10, 13, 14, 18, or 21, comprising the amino acid sequence of Sequence ID No. 6411.

23. The AAV capsid variant according to any one of claims 1 or 3 to 22, wherein the hypervariable loop IV comprises amino acids 449 to 460, numbered according to Sequence ID No.

138.

24. The AAV capsid variant is (i) Compared to the tropism of a reference sequence containing the amino acid sequence of Sequence ID No. 138, it exhibits increased tropism towards CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells, or spinal cord tissue. (ii) A brain region (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or lateral geniculate nucleus (LGN)) is transduced and, optionally, measured by an assay such as that described in Example 2, for example, an immunohistochemical assay or a qPCR assay, the level of transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65 times greater than the reference sequence of Sequence ID No.

138. (iii) For example, when measured by an assay such as that described in Example 1, the sample is concentrated at least 3, 4, 5, 6, 7, 8, 9, or 10 times in the brain compared to the reference sequence of SEQ ID NO:

138. (iv) When measured by assays such as those described in Example 1 or 5, the brains of at least two to three species, for example, non-human primates and / or rodents (e.g., Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mice (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 non-inbred mice) can be transduced, (v) Deliver an increased level of payload to a brain region, and optionally, the level of the payload, when measured by an assay, e.g., qRT-PCR or qPCR assay (e.g., as described in Example 2 or 8), is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 times compared to the reference sequence of SEQ ID NO: 138, and optionally, the brain region is the putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or lateral geniculate nucleus (LGN), (vi) Deliver an increased level of viral genome to a brain region, and optionally, if the level of the viral genome is measured by an assay, e.g., qRT-PCR or qPCR assay (e.g., as described in Example 2 or 8), it is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 times compared to the reference sequence of SEQ ID NO: 138, and optionally, the putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or lateral geniculate nucleus (LGN), (vii) For example, when measured by an assay as described in Example 1 or 8, the sequence is concentrated at least approximately 5, 10, 15, 20, 25, 30, or 35 times in the spinal cord compared to the reference sequence of Sequence ID No. 138, and optionally the region of the spinal cord is the thoracic, cervical, or lumbar region. (viiii) Compared to transduction in the dorsal root ganglia (DRG) and / or liver, preferential transduction is observed in brain regions. (xi) Neuronal and non-neuronal cells, such as glial cells (e.g., astrocytes), can be transduced. (ix) For example, when measured by an assay such as that described in Example 8, at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of cells in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, cerebellar cortex, cerebellum, dentate nucleus, and / or lateral geniculate nucleus (LGN)) can be transduced. (x) At least 10%, 15%, 20%, 25%, 30%, 40%, 50%, 55%, 60%, or 65% of neurons (e.g., NeuN+ neurons) within a brain region (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex) can be transduced. (xi) For example, when measured by an assay such as that described in Example 8, at least 70%, 75%, 80%, 85%, 90%, or 95% of astrocytes (e.g., Sox9+ astrocytes) in a brain region (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex) can be transduced. (xi) For example, when measured by an assay such as that described in Example 8, at least 90% or 95% of neurons in the spinal cord (e.g., cervical, thoracic, or lumbar), such as motor neurons (e.g., ChAT+ neurons), can be transduced, and / or (xiiii) The AAV capsid variant according to any one of claims 1 to 23, which can transduce at least 90%, 95%, or 98% of astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., cervical, thoracic, or lumbar spinal cord) as measured by an assay such as that described in Example 8.

25. A polynucleotide encoding the AAV capsid variant described in any one of claims 1 to 24.

26. (i) A nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides relative to the nucleotide sequence of sequence number 6415 or 6416, and / or (ii) A nucleotide comprising the nucleotide sequence of sequence number 6415 or 6416, or a nucleotide that is at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical thereto, The polynucleotide according to claim 25, wherein the polynucleotide optionally includes a codon-optimized nucleotide sequence.

27. It is a peptide, (a) Amino acid sequence of SEQ ID NO: 6419, (b) an amino acid sequence comprising at least three or four consecutive amino acids of SEQ ID NO: 6419, or (c) The peptide comprising an amino acid sequence comprising one or two or fewer different amino acids relative to the amino acid sequence of SEQ ID NO: 6419.

28. AAV particles comprising an AAV capsid variant according to any one of claims 1 to 24, an AAV capsid variant encoded by a polynucleotide according to claim 25 or 26, or an AAV capsid variant comprising the peptide according to claim 27.

29. AAV particle according to claim 28, comprising a nucleotide sequence encoding a payload, wherein the encoded payload optionally 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, prim-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA), or a combination thereof.

30. (i) The therapeutic protein or a functional variant thereof, for example, a recombinant protein, is associated with (e.g., abnormally expressed) neuropathy or neurodegenerative disorders, muscle disorders or neuromuscular disorders, or neurotumor disorders, and optionally, the therapeutic protein or a functional variant thereof is selected from apolipoprotein E (APOE) (e.g., ApoE2, ApoE3, and / or ApoE4), human motor neuron survival (SMN) 1 or SMN2, aromatic L-amino acid decarboxylase (AADC), aspartoacylase (ASPA), tripeptidyl peptidase I (CLN2), beta-galactosidase (GLB1), N-sulfoglucosamine sulfohydrolase (SGSH), N-acetyl-alpha-glucosaminidase (NAGLU), isulonate 2-sulfatase (IDS), intracellular cholesterol transporter (NPC1), gigaxonin (GAN), or a combination thereof. (ii) The antibody or antibody-binding fragment is (a) CNS-related targets, e.g., neuropathy or neurodegenerative disorders, e.g., antigens related to β-amyloid, APOE, tau, SOD1, TDP-43, huntingtin (HTT), and / or synuclein, (b) Muscle or neuromuscular-related targets, for example, antigens associated with muscle or neuromuscular disorders, or (c) Binding to neurotumor-related targets, e.g., antigens associated with neurotumor disorders, e.g., HER2, or EGFR (e.g., EGFRvIII), (iii) The enzyme comprises meganuclease, zinc finger nuclease, TALEN, recombinase, integrase, base editor, Cas9, or a fragment thereof. (iv) The components of the gene editing system include one or more components of the CRISPR-Cas system, and optionally, the one or more components of the CRISPR-Cas system include Cas9, for example, a Cas9 ortholog or Cpf1, and a single guide RNA (sgRNA). (a) The sgRNA is located upstream (5') of the cas9 enzyme, and / or (b) The sgRNA is located downstream (3') of the cas9 enzyme, and / or (v) The AAV particle according to claim 29, wherein the RNAi agent (e.g., dsRNA, siRNA, shRNA, pre-miRNA, prim-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA) modulates, for example, inhibits the expression of CNS-related genes, mRNA, and / or proteins, and optionally the CNS-related gene is selected from SOD1, MAPT, APOE, HTT, TDP-43, APP, BACE, SNCA, ATXN1, ATXN3, ATXN7, SCN1A-SCN5A, SCN8A-SCN11A, or a combination thereof.

31. The viral genome comprises a promoter operably linked to a nucleic acid sequence encoding the payload, and optionally the promoter is a human elongation factor 1α-subunit (EF1α), a cytomegalovirus (CMV) early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β-glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG-binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (C AAV particles according to any one of claims 28 to 30, selected from aMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk), and excitatory amino acid transporter 2 (EAAT2), glial fiber 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 fragments thereof, e.g., cleaved forms or functional variants thereof.

32. The aforementioned viral genome, (i) Poly-A signal sequence, (ii) an inverted terminal repeat (ITR) sequence, wherein the ITR sequence is optionally located at the 5' position relative to the coded payload and / or the ITR sequence is located at the 3' position relative to the coded payload, (iii) Enhancer, Kozak sequence, intron region, and / or exon region, (iv) A nucleotide sequence encoding a miR binding site, for example, a miR binding site that modulates, for example, reduces the expression of the antibody molecule encoded by the viral genome in cells or tissues in which the corresponding miRNA is expressed, and optionally, the encoded miR binding site modulates, for example, reduces the expression of the antibody molecule encoded in cells or tissues of the DRG, liver, heart, hematopoietic system, or a combination thereof, and / or (v) AAV particle according to claim 31, a nucleotide sequence encoding a Rep protein, for example, a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein, and optionally further comprises the nucleotide sequence wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene.

33. The aforementioned viral genome, (i) at least one to five copies of the coded miR binding site, for example, at least one, two, three, four, or five copies, (ii) at least three copies of the coded miR junction site, optionally, (a) All three copies contain the same miR binding site, or at least one, two, three, or all of the copies contain different miR binding sites, and / or (b) The three copies of the encoded miR binding site are contiguous (e.g., not separated by a spacer) or separated by a spacer, and optionally the spacer comprises the nucleotide sequence of GATAGTTA, or the at least three copies of the nucleotide sequence of GATAGTTA having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but four or fewer modifications, e.g., substitutions (e.g., conservative substitutions), or (iii) at least four copies of the coded miR junction site, optionally, (a) All four copies contain the same miR binding site, or at least one, two, three, or all of the copies contain different miR binding sites, and / or (b) The AAV particle according to claim 31 or 32, wherein the four copies of the encoded miR binding site are contiguous (e.g., not separated by spacers) or separated by spacers, and optionally the spacers comprise the at least four copies, each comprising a nucleotide sequence of GATAGTTA or a nucleotide sequence of GATAGTTA having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but four or fewer modifications, e.g., substitutions (e.g., conservative substitutions).

34. The coded miR binding site includes the miR122 binding site, the miR183 binding site, the miR-1 binding site, the miR-142-3p, or any combination thereof, optionally. (i) The encoded miR122 binding site is a nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical thereto, or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions. (ii) The coded miR183 binding site is a nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical thereto, or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions. (iii) The coded miR-1 binding site is a nucleotide sequence of SEQ ID NO: 4679, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical thereto, or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, and / or (iv) The AAV particle according to claim 32 or 33, wherein the (iv) coded miR-142-3p binding site comprises the nucleotide sequence of SEQ ID NO: 4675, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical thereto, or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions.

35. The aforementioned viral genome, (i) It is single-stranded, (ii) Complementary to itself, and / or (ii ) An AAV particle according to any one of claims 32 to 34, further comprising a nucleic acid encoding an AAV capsid variant according to any one of claims 1 to 24.

36. An isolated, for example, recombinant, AAV capsid variant, polynucleotide, peptide, or AAV particle according to any one of the prior claims.

37. A vector comprising a polynucleotide encoding an AAV capsid variant according to any one of claims 1 to 24 or 36, a polynucleotide according to any one of claims 25, 26, or 36, or a polynucleotide encoding a peptide according to claim 27 or 36.

38. A cell, for example, a host cell, comprising an AAV capsid variant according to any one of claims 1 to 24 or 36, a polynucleotide according to any one of claims 25, 26 or 36, a peptide according to claim 49 or 60, an AAV particle according to any one of claims 28 to 36, or a vector according to claim 37, optionally, (i) The cells are mammalian cells or insect cells, (ii) The cells are cells of the brain region or spinal cord region, optionally selected to be cells of the putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, lateral geniculate nucleus (LGN), thoracic spinal cord, cervical spinal cord, and / or lumbar spinal cord, and / or (iii) The cell wherein the cell is a neuron or an astrocyte.

39. A method for producing AAV particles, (i) To provide a host cell containing a viral genome, (ii) Incubating the host cells under conditions suitable for encapsulating the viral genome in an AAV capsid variant according to any one of claims 1 to 24 or 36, or an AAV capsid variant encoded by a polynucleotide according to any one of claims 25, 26 or 36, The method for producing the AAV particles thereby.

40. A pharmaceutical composition comprising AAV particles according to any one of claims 28 to 36, AAV particles comprising an AAV capsid variant according to any one of claims 1 to 24 or 36, AAV particles comprising a peptide according to claim 27 or 36, and a pharmaceutically acceptable excipient.

41. A method for delivering a payload to cells or tissues (e.g., CNS cells or CNS tissue), comprising administering an effective amount of the pharmaceutical composition according to claim 40, AAV particles according to any one of claims 28 to 36, AAV particles comprising an AAV capsid variant according to any one of claims 1 to 24 or 36, or AAV particles comprising a peptide according to claim 27 or 36.

42. The aforementioned cells, (i) Cells from brain or spinal cord regions, optionally selected, including cells from the putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, lateral geniculate nucleus (LGN), thoracic spinal cord, cervical spinal cord, and / or lumbar spinal cord. (ii) a neuron, motor neuron, or astrocyte, and / or (iii) The method according to claim 41, wherein the subject is within the scope and optionally has, has been diagnosed with, or is at risk of having, a neurological disorder, such as a neurodegenerative disorder, a neurotumor disorder, a muscular disorder, or a neuromuscular disorder.

43. A method for treating a subject having or diagnosed with a neurological disorder, such as a neurodegenerative disorder, a neurotumor disorder, a muscular disorder, or a neuromuscular disorder, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 40, AAV particles according to any one of claims 28 to 36, AAV particles containing an AAV capsid variant according to any one of claims 1 to 24 or 36, or AAV particles containing a peptide according to claim 27 or 36.

44. The method according to claim 42 or 43, wherein the nerve disorder, neurodegenerative disorder, muscle disorder, neuromuscular disorder, or neurotumor 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 nervous system disorder (ADLD), Canavan disease, cerebral tendon xanthomatous leukodystrophy (CTX), metachromatic leukodystrophy (MLD), Pelizaeus-Merzbacher disease, or Refsum disease), or cancer (e.g., HER2 / neu-positive cancer or glioblastoma).

45. The method according to claim 43 or 44, wherein the treatment comprises preventing the progression of the disease or disorder in the subject, and optionally the subject is a human.

46. The AAV particles or the pharmaceutical composition are applied to the target. (i) Intravenously, via intracisional injection (ICM), into the brain, into the spinal cavity, into the ventricles, via intraparenchymal administration, or into the muscle, (ii) For example, via focused ultrasound (FUS) (FUS-MB) with intravenous administration of microbubbles, or via MRI-guided FUS with intravenous administration, (iii) The method according to any one of claims 41 to 45, administered intravenously.

47. A pharmaceutical composition according to claim 40, an AAV particle according to any one of claims 28 to 36, an AAV particle comprising an AAV capsid variant according to any one of claims 1 to 24 or 36, or an AAV particle comprising a peptide according to claim 27 or 36, for use in a method of delivering a payload to cells or tissues.

48. A pharmaceutical composition according to claim 40, for use in a method for treating neuropathy, neurodegenerative disorders, muscle disorders, neuromuscular disorders, or neurotumor disorders; AAV particles according to any one of claims 28 to 36; AAV particles comprising an AAV capsid variant according to any one of claims 1 to 24 or 36; or AAV particles comprising a peptide according to claim 27 or 36.

49. A pharmaceutical composition according to claim 40, AAV particles according to any one of claims 28 to 36, AAV particles comprising an AAV capsid variant according to any one of claims 1 to 24 or 36, or AAV particles comprising a peptide according to claim 27 or 36, for use in the manufacture of a pharmaceutical.

50. Use of the pharmaceutical composition according to claim 40, the AAV particles according to any one of claims 28 to 36, the AAV particles comprising the AAV capsid variant according to any one of claims 1 to 24 or 36, or the AAV particles comprising the peptide according to claim 27 or 36, in the manufacture of a pharmaceutical for treating a neuropathy, neurodegenerative disorder, muscle disorder, neuromuscular disorder, or neurotumor disorder.

51. Use in the manufacture of a pharmaceutical product of the pharmaceutical composition according to claim 40, AAV particles according to any one of claims 28 to 36, AAV particles containing an AAV capsid variant according to any one of claims 1 to 24 or 36, or AAV particles containing a peptide according to claim 27 or 36.

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