AAV capsid variants and uses thereof

Abstract

The present disclosure relates to compositions and methods for making, using and / or formulating adeno-associated viral capsid protein variants.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 464,034, filed May 4, 2023; U.S. Provisional Application No. 63 / 593,622, filed October 27, 2023; and U.S. Provisional Application No. 63 / 564,320, filed March 12, 2024; the entire contents of each of these applications are incorporated herein by reference.

[0003] sequence list

[0004] This application is submitted electronically together with the sequence list. The sequence list file, named V2071-3015PCT_SL.xml, was created on April 3, 2024, and has a size of 5,493,507 bytes. The information in the electronic format of the sequence list is incorporated herein by reference in its entirety. Technical Field

[0005] This disclosure relates to compositions and methods for preparing, using, and / or formulating adeno-associated virus capsid proteins and their variants. Background Technology

[0006] Delivering genes to the adult central nervous system (CNS) remains a major challenge in gene therapy. Engineered adeno-associated virus (AAV) capsids with improved brain orientation represent an attractive solution to the limitations of CNS delivery.

[0007] AAV-derived vectors are promising tools for clinical gene transfer due to their non-pathogenic properties, low immunogenicity, low integration rates into the host genome, and long-term transgenic expression in non-dividing cells. However, the transduction efficiency of natural AAV variants in certain organs is too low for clinical application, and capsid neutralization by pre-existing neutralizing antibodies may prevent treatment in most patients. For these reasons, considerable effort has been devoted to obtaining capsid variants with enhancing properties. Among the many methods tested to date, directed evolution of the AAV capsid has made significant progress using error-prone PCR, shuffling of various parental serotypes, or insertion of completely randomized short peptides at defined locations, as well as in vitro or in vivo selection of capsid variants generated through capsid sequence randomization.

[0008] Attempts to provide improved properties to AAV capsids (e.g., improved tropism to target cells or tissues when administered systemically) have had limited success. Therefore, there is a need for methods to generate AAV capsids and improved versions of the resulting AAV capsids for delivering payloads of interest to target cells or tissues, such as CNS cells or tissues, or muscle cells or tissues. Summary of the Invention

[0009] This disclosure relates, at least in part, to compositions and methods for generating and using AAV particles comprising an AAV capsid polypeptide (e.g., an AAV capsid variant). In some embodiments, the AAV capsid variant has enhanced tropism toward tissues or cells (e.g., CNS tissues or CNS cells). This tropism can be used to deliver a payload (e.g., the payload described herein) to cells or tissues for the treatment of conditions such as neurological or neurodegenerative diseases, muscle or neuromuscular diseases, or neurooncological diseases.

[0010] Therefore, in one aspect, this disclosure provides an AAV capsid variant comprising: (A) a modification in ring VIII, such as substitution (e.g., a conserved substitution); and / or (B) an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein: (i) optionally [N1] comprises X1, X2, and X3, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises an amino acid sequence containing SPH; and (iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid, such as K or R. In some embodiments, ring VIII comprises positions 587-599 according to SEQ ID NO: 981, 982, 6411, or 6412, or positions 581-593 according to SEQ ID NO: 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 SKA or contains SKA. In some embodiments, [N3] is or contains KSG. In some embodiments, [N2]-[N3] immediately follow position 455 according to SEQ ID NO: 138, 981, or 982. In some embodiments, [N1] immediately follows position 452 relative to the reference sequence numbered according to SEQ ID NO: 138, 981, or 982. In some embodiments, [N1] replaces positions 453-455 (e.g., G453, S454, and G455) relative to the reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant contains H at position 454 and D at position 455 according to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant contains S at position 454 and G at position 455 according to SEQ ID NO: 138 or 981. In some embodiments, an insertion of 8 amino acids replaces SG at positions 454-455 according to SEQ ID NO: 138. In some embodiments, an insertion of 6 amino acids immediately follows position 455 according to SEQ ID NO: 138, 981, or 982.

[0011] On the other hand, this disclosure provides an AAV capsid variant comprising: (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 X1X2X3X4X5X6X7, wherein: (a) position X1 is S, C, F, or V; and (b) position X2 is K, L, R, I, E, Y, V, or S; (c) Position X3 is A, R, L, G, I, Y, S, F, or W; (d) Position X4 is W, Q, R, G, L, V, S, or F; (e) Position X5 is N, Y, R, C, K, or L; (f) Position X6 is Q, G, K, R, T, L, or Y; and (g) Position X7 is Q, L, R, or V; and / or (B) modifications in ring VIII, such as substitutions (e.g., conservative substitutions). In some embodiments, ring VIII includes 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.

[0012] In another aspect, this disclosure provides an AAV capsid variant comprising: (A) [A][B] (SEQ ID NO: 4699), wherein: (i) [A] comprises X1 X2 X3 X4 X5 X6, wherein (A) position X1 is T, M, A, C, I, R, L, D, F, V, Q, N, or H; (b) position X2 is I, P, E, N, D, S, A, T, M, or Q; (c) position X3 is N, E, G, Y, W, M, T, I, K, Q, F, S, V, A, or L; (d) position X4 is G, D, R, or E; (e) position X5 is H, Q, N, or D; (f) position X6 is D or R; and (ii) [B] comprises SPHKSG (SEQ ID NO: 4699). 946); and / or (B) modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring VIII contains 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.

[0013] In another aspect, this 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, wherein position X2 is S and position X3 is G; (ii) [N2] comprises the amino acid sequence SPH; and (iii) [N3] comprises positions X4, X5, and X6, wherein position X5 is K; and / or (B) modifications in ring VIII, such as substitutions (e.g., conservative substitutions). In some embodiments, ring 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, [N1]-[N2]-[N3] immediately follows position 452 and replaces positions 453-455 numbered according to SEQ ID NO: 138 or 982. In some embodiments, [N1]-[N2]-[N3] is or contains GSGSPHA (SEQ ID NO: 4697).

[0014] On the other hand, this 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 positions X1, X2, and X3, wherein position X2 is an amino acid other than S, and position X3 is an amino acid other than G; (ii) [N2] comprises the amino acid sequence SPH; and (iii) [N3] comprises positions X4, X5, and X6, wherein position X4 is K; and / or (B) modifications in ring VIII, such as substitutions (e.g., conservative substitutions). In some embodiments, ring 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, [N1]-[N2]-[N3] immediately follows position 452 and replaces positions 453-455 numbered according to SEQ ID NO: 138 or 982. In some embodiments, [N1]-[N2]-[N3] is or includes GHDSPHKSG (SEQ ID NO: 4698).

[0015] In another aspect, this disclosure provides an AAV capsid variant comprising: (A) formula [A]-[B] (SEQ ID NO: 4696), wherein: (i) [A] comprises GSGSPH (SEQ ID NO: 4695); and (ii) [B] comprises X1, X2, X3, X4, and X5, wherein: (a) position X1 is S, I, F, V, C, Y, W, R, P, L, Q, M, K, or G; (b) position X2 is K, M, R, F, V, C, P, Y, L, W, G, N, S, T, I, or A; (c) position X3 is A, Y, L, R, W, C, T, F, H, I, P, M, K, S, V, G, Q, or N; (d) position X4 is Q, M, F, K, H, R, C, W, P, V, L, G, S, Y, I, A, T, D, N, or E; and (e) position X5 is A, N, Y, R, K, L, I, M, Q, S, C, W, F, T, G, V, or P; optionally wherein the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(e); and / or a modification, such as a substitution (e.g., a conservative substitution), in (B) ring VIII. In some embodiments, ring 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, [A]-[B] are immediately present after position 452 relative to a reference sequence with amino acid sequence numbering according to SEQ ID NO: 138, and wherein [A]-[B] replaces positions 453-457 (e.g., G453, S454, G455, Q456, N457). In some embodiments, the AAV capsid variant exhibits increased tropism for liver cells or tissues relative to the tropism of a reference sequence containing the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV capsid shows preferential transduction in the liver, for example, compared to SEQ ID NO: 138, relative to transduction in the brain and / or dorsal root ganglia (DRG).

[0016] On the other hand, this disclosure provides an AAV capsid variant comprising: (a) three, four, or all of the following amino acids: R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, as specified in SEQ ID NO: 138; and (b) an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein [N1]-[N2]-[N3] is present in a hypervariable ring IV, wherein: (i) [N1] comprises X1, X2, and X3, wherein 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, wherein at least one of X4, X5, or X6 is a basic amino acid, such as K or R; and wherein the AAV capsid variant comprises amino acids of the same type as those specified in SEQ ID NO: 138. The amino acid sequence at position 203-736 of position 138 has at least 95% amino acid sequence identity.

[0017] In another aspect, this disclosure provides an AAV capsid variant comprising three, four, or all of the following amino acids according to SEQ ID NO: 138: amino acid R at position 584, amino acid T at position 586, amino acid L at position 588, amino acid Q at position 589, and / or amino acid L at position 590, wherein the AAV capsid variant comprises an amino acid sequence having at least 95% identity with the amino acid sequence at positions 203-736 of SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein: (i) [N1] comprises X1, X2, and X3, wherein 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, wherein at least one of X4, X5, or X6 is a basic amino acid, such as K or R; wherein [N1]-[N2]-[N3] is present in the hypervariable ring IV.

[0018] In another aspect, this disclosure provides an AAV capsid variant comprising: (a) three, four, or all of the following amino acids: R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, as specified in SEQ ID NO: 138; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in a hypervariable ring IV; wherein the AAV capsid variant comprises an amino acid sequence having at least 95% identity with the amino acid sequence at positions 203-736 of SEQ ID NO: 138. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is immediately following amino acid 453 as specified in SEQ ID NO: 982.

[0019] In another aspect, this disclosure provides an AAV capsid variant comprising: (a) three, four, or all of the following amino acids selected from SEQ ID NO: 138: amino acid R at position 584, amino acid T at position 586, amino acid L at position 588, amino acid Q at position 589, and / or amino acid L at position 590; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in a hypervariable ring IV; wherein the AAV capsid variant comprises an amino acid sequence having at least 95% identity with the amino acid sequence at positions 203-736 of SEQ ID NO: 138. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is immediately following amino acid 455 selected from SEQ ID NO: 981.

[0020] On the other hand, this disclosure provides an AAV capsid variant comprising: (I) (a) an amino acid sequence of any one of the sequences provided in Tables 1, 2A, 2B, 13 to 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 to 19; (c) an amino acid sequence comprising at least one, two, or three but not more than four different amino acids relative to any one of the sequences provided in Tables 1, 2A, 2B, 13 to 19; or (d) an amino acid sequence comprising at least one, two, or three but not more than four modifications, such as substitutions (e.g., conservative substitutions), relative to any one of the sequences provided in Tables 1, 2A, 2B, 13 to 19; and / or (II) (i) SEQ ID (i) an amino acid sequence of SEQ ID NO: 6419; (ii) an amino acid sequence containing 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 containing at least one or two modifications, such as substitutions (e.g., conservative substitutions), but no more than three modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 6419; or (iv) at least three, four, five, six, or seven consecutive amino acids from SEQ ID NO: 6419; optionally wherein the amino acid sequences of (i), (ii), (iii), and / or (iv) are present at positions 590-596 according to the amino acid sequence number of SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the amino acid sequence is present in ring IV. In some embodiments, the amino acid sequence is present in ring VIII. In some embodiments, the amino acid sequence is present in both ring IV and ring VIII. In some embodiments, the amino acid sequence is immediately following positions 448, 452, 453, and 455 relative to the reference sequence numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence is present at positions 590, 592, 594, 595, and / or 596 of the amino acid sequence numbered according to 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 of the amino acid sequence numbered according to SEQ ID NO: 981, 982, 6411, or 6412.

[0021] In another aspect, this disclosure provides an AAV capsid variant comprising: (I) (a) an amino acid sequence of any one of SEQ ID NO: 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 NO: 945-980 or 985-986; (c) an amino acid sequence comprising at least one, two, or three but not more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 945-980 or 985-986; (d) an amino acid sequence comprising at least one, two, or three but not more than four modified, such as substituted (e.g., conservative substitution), amino acid sequences relative to the amino acid sequence of any one of SEQ ID NO: 945-980 or 985-986; and / or (II) (i) an amino acid sequence of SEQ ID NO: 6419; (ii) an amino acid sequence comprising at least one or two but not 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, two, or not more than three different amino acids relative to the amino acid sequence of SEQ ID NO: 6419; The amino acid sequence of SEQ ID NO: 6419 contains at least one or two modifications, such as substitutions (e.g., conservative substitutions), but no more than three modifications, such as substitutions (e.g., conservative substitutions), in the amino acid sequence; or (iv) at least three, four, five, six, or seven consecutive amino acids from SEQ ID NO: 6419; optionally, wherein the amino acid sequences of (i), (ii), (iii), and / or (iv) are present at positions 590-596 of the amino acid sequence number according to SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the amino acid sequence is present in ring IV. In some embodiments, the amino acid sequence is present in ring VIII. In some embodiments, the amino acid sequence is present in both ring IV and ring VIII. In some embodiments, the amino acid sequence is immediately present after positions 448, 452, 453, and 455 relative to the reference sequence of the amino acid sequence number according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence is present at positions 590, 592, 594, 595, and / or 596 according to the amino acid sequence numbering 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 according to the amino acid sequence numbering of SEQ ID NO: 981, 982, 6411, or 6412.

[0022] In another aspect, this disclosure provides an AAV capsid variant comprising: (I) (a) an amino acid sequence of any one of SEQ ID NO: 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 NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909; (c) an amino acid sequence comprising at least one, two or three but not more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909; or (d) an amino acid sequence comprising at least one, two or three but not more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 2. The amino acid sequence of any one of 200, 201, 941, 943, 204, 208, 404 or 903-909 contains at least one, two or three but no more than four modifications, such as substitutions (e.g., conservative substitutions) of the amino acid sequence; and / or (II) (i) the amino acid sequence of SEQ ID NO: 6419; (ii) an amino acid sequence containing 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 containing at least one or two modifications, such as substitutions (e.g., conservative substitutions) but no more than three modifications, such as substitutions (e.g., conservative substitutions) of the amino acid sequence of SEQ ID NO: 6419; or (iv) at least three, four, five, six or seven consecutive amino acids from SEQ ID NO: 6419; optionally wherein the amino acid sequences of (i), (ii), (iii) and / or (iv) are present according to SEQ ID NO: The amino acid sequences numbered 981, 982, 6411, or 6412 are located at positions 590-596. In some embodiments, the amino acid sequences are present in ring IV. In some embodiments, the amino acid sequences are present in ring VIII. In some embodiments, the amino acid sequences are present in both ring IV and ring VIII. In some embodiments, the amino acid sequences are immediately following positions 448, 452, 453, and 455 relative to a reference sequence with amino acid sequence numbers according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequences are present at positions 590, 592, 594, 595, and / or 596 with amino acid sequence numbers according to 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 according to the amino acid sequence number of SEQ ID NO: 981, 982, 6411 or 6412.

[0023] In another aspect, this disclosure provides a polynucleotide encoding the AAV capsid variant described herein. In some embodiments, the polynucleotide comprises (i) a nucleotide sequence containing at least one, two, three, four, five, six, or seven modifications, such as substitutions (e.g., conserved substitutions), but not more than ten modifications, such as substitutions (e.g., conserved substitutions), relative to the nucleotide sequence of SEQ ID NO: 3 or 942; (ii) a nucleotide sequence containing at least one, two, three, four, five, six, or seven, but not more than ten different nucleotides, relative to the nucleotide sequence of SEQ ID NO: 3 or 942; or (iii) a nucleotide sequence of SEQ ID NO: 3 or 942, 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).

[0024] In another aspect, this disclosure provides an AAV capsid variant comprising an amino acid sequence containing 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 contain SPH; (ii) 4 consecutive amino acids contain SPHS (SEQ ID NO: 4700); (iii) 5 consecutive amino acids contain SPHSK (SEQ ID NO: 4701); or (iv) 6 consecutive amino acids contain SPHSKA (SEQ ID NO: 941); wherein the AAV capsid variant comprises: (a) a VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or 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 VP2 protein containing the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-736 of SEQ ID NO: 981. The VP3 protein of 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)-(c). In some embodiments, the amino acid sequence immediately follows position 455 as numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises modifications in ring VIII, such as substitutions (e.g., conserved substitutions). In some embodiments, ring VIII comprises positions 587-599 as numbered according to SEQ ID NO: 981, 982, 6411, or 6412; or positions 581-593 as numbered according to SEQ ID NO: 138 or 6414.

[0025] In another aspect, this disclosure provides an AAV capsid variant comprising one or two, but no more than three, substitutions relative 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 of 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 of 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)-(c). In some embodiments, the amino acid sequence immediately follows position 455 according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant includes modifications in ring VIII, such as substitutions (e.g., conservative substitutions). In some embodiments, ring VIII includes 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.

[0026] In another aspect, this disclosure provides 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); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982; (c) a VP2 protein comprising positions 203-736 of SEQ ID NO: 138 or positions 203-736 of SEQ ID NO: 982. The VP3 protein of 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)-(c). In some embodiments, the amino acid sequence immediately follows position 453 as numbered according to SEQ ID NO: 138 or 982. In some embodiments, the AAV capsid variant comprises modifications in ring VIII, such as substitutions (e.g., conserved substitutions). In some embodiments, ring VIII comprises positions 587-599 as numbered according to SEQ ID NO: 981, 982, 6411, or 6412; or positions 581-593 as numbered according to SEQ ID NO: 138 or 6414.

[0027] In another aspect, this disclosure provides an AAV capsid variant comprising one or two, but no more than three, substitutions relative 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 of 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 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)-(c). In some embodiments, the AAV capsid variant comprises modifications in ring VIII, such as substitutions (e.g., conserved substitutions). In some embodiments, ring VIII includes 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.

[0028] In another aspect, this disclosure provides a peptide comprising: (a) an amino acid sequence of any one of the sequences provided in Tables 1, 2A, 2B, 13 to 19, or 33; and (b) an amino group 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 to 19, or 33. (c) An amino acid sequence relative to any of the sequences provided in Tables 1, 2A, 2B, 13 to 19 or 33 that contains at least one, two or three but no more than four different amino acids; or (d) An amino acid sequence relative to any of the sequences provided in Tables 1, 2A, 2B, 13 to 19 or 33 that contains at least one, two or three but no more than four modified, such as substituted (e.g., conservatively substituted) amino acid sequences.

[0029] In another aspect, this disclosure provides a peptide comprising (a) an amino acid sequence of any one of SEQ ID NO: 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 NO: 945-980 or 985-986; (c) an amino acid sequence comprising at least one, two or three but not more than four different amino acids relative to an amino acid sequence of any one of SEQ ID NO: 945-980 or 985-986; or (d) an amino acid sequence comprising at least one, two or three but not more than four modified, such as substituted (e.g., conservatively substituted) amino acid sequences relative to an amino acid sequence of any one of SEQ ID NO: 945-980 or 985-986.

[0030] In another aspect, this disclosure provides a peptide comprising: (a) an amino acid sequence of any one of SEQ ID NO: 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 NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909; or (c) an amino acid sequence comprising at least one, two or three but not more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909; or (d) an amino acid sequence comprising at least one, two or three but not more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 2. The amino acid sequence of any one of 200, 201, 941, 943, 204, 208, 404 or 903-909 contains at least one, two or three but no more than four modifications, such as substituted (conservatively substituted) amino acid sequences.

[0031] In another aspect, this disclosure provides a peptide comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941); (ii) an amino acid sequence comprising at least one, two, or three, but not 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, such as substitutions (e.g., conservative substitutions), but not more than four modifications, such as 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).

[0032] In another aspect, this disclosure provides a peptide encoded by: (i) the nucleotide sequence of SEQ ID NO: 942, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity); or (ii) a nucleotide sequence containing at least one, two, three, four, five, six or seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942; or (iii) a nucleotide sequence containing at least one, two, three, four, five, six or seven modifications, such as substitutions (e.g., conservative substitutions), but not more than ten modifications, such as substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 942.

[0033] In another aspect, this disclosure provides a peptide wherein the nucleotide sequence encoding the peptide comprises (i) the nucleotide sequence of SEQ ID NO: 942, 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 one, two, three, four, five, six, or seven, but not more than ten, different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942; or (iii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, such as substitutions (e.g., conservative substitutions), but not more than ten modifications, such as substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 942.

[0034] In another aspect, this disclosure provides a peptide comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2); (ii) an amino acid sequence comprising at least one, two, or three but not more than four different amino acids relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2); (iii) an amino acid sequence comprising at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but not more than four modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2); or (iv) at least three, four, or five consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2).

[0035] In another aspect, this 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 containing at least one, two, three, four, five, six, or seven, but not more than ten, different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3; and (iii) a nucleotide sequence containing at least one, two, three, four, five, six, or seven modifications, such as substitutions (e.g., conservative substitutions), but not more than ten modifications, such as substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 3.

[0036] In another aspect, this disclosure provides a peptide wherein the nucleotide sequence encoding the peptide comprises (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 one, two, three, four, five, six, or seven, but not more than ten, different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3; or (iii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, such as substitutions (e.g., conservative substitutions), but not more than ten modifications, such as substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 3.

[0037] In another aspect, this disclosure provides a polynucleotide encoding an AAV capsid variant comprising: (I) (a) an amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 13 to 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 of the sequences provided in Tables 1, 2A, 2B, 13 to 19; (c) an amino acid sequence comprising at least one, two, or three but not more than four different amino acids relative to any of the sequences provided in Tables 1, 2A, 2B, 13 to 19; or (d) an amino acid sequence comprising at least one, two, or three but not more than four modifications, such as substitutions (e.g., conserved substitutions), relative to any of the sequences provided in Tables 1, 2A, 2B, 13 to 19; and / or (II) (i) the amino acid sequence of any of 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 relative to any of the amino acid sequences provided in Table 33; (iii) an amino acid sequence containing at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but no more than four modifications, such as substitutions (e.g., conservative substitutions), relative to any of the amino acid sequences provided in Table 33; or (iv) at least three, four, five, six, seven, eight, nine, ten, or eleven consecutive amino acids from any of the amino acid sequences in Table 33. In some embodiments, the amino acid sequences (a), (b), (c), and / or (d) are immediately following positions 448, 449, 450, 451, 452, 453, 454, or 455 relative to the reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequences of (i), (ii), (iii) and / or (iv) are present at positions 500-511 according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0038] In another aspect, this disclosure provides a polynucleotide encoding an AAV capsid variant, wherein the AAV capsid variant comprises: (I) (a) an amino acid sequence of SPHSKA (SEQ ID NO: 941); (b) an amino acid sequence comprising at least one, two, or three, but not more than four, different amino acids relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941); (c) an amino acid sequence comprising at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but not more than four modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941); or (d) at least three, four, five, six, seven, eight, or nine consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941); and / or (II) (i) the amino acid sequence of any of 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 relative to any of the amino acid sequences provided in Table 33; (iii) an amino acid sequence containing at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but no more than four modifications, such as substitutions (e.g., conservative substitutions), relative to any of the amino acid sequences provided in Table 33; or (iv) at least three, four, five, six, seven, eight, nine, ten, or eleven consecutive amino acids from any of the amino acid sequences in Table 33. In some embodiments, the amino acid sequences (a), (b), (c), and / or (d) are immediately present after position 455 relative to the reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequences of (i), (ii), (iii) and / or (iv) are present at positions 500-511 according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0039] In another aspect, this disclosure provides a polynucleotide encoding an AAV capsid variant, wherein the AAV capsid variant comprises: (I) (a) an amino acid sequence of HDSPHK (SEQ ID NO: 2); (b) an amino acid sequence comprising at least one, two, or three, but not more than four, different amino acids relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2); (c) an amino acid sequence comprising at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but not more than four modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2); or (d) at least three, four, five, or six consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2); and / or (II) (i) an amino acid sequence of any of the sequences provided in Table 33; (ii) an amino acid sequence relative to any of the amino acid sequences provided in Table 33 that contains at least one, two, or three but no more than four different amino acids; (iii) an amino acid sequence relative to any of the amino acid sequences provided in Table 33 that contains at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but no more than four modifications, such as substitutions (e.g., conservative substitutions); or (iv) at least three, four, five, six, seven, eight, nine, ten, or eleven consecutive amino acids from any of the amino acid sequences in Table 33; optionally, wherein the amino acid sequences of (i), (ii), (iii), and / or (iv) are present at positions 500-511 of the amino acid sequence number according to SEQ ID NO: 981 or 982. In some embodiments, the amino acid sequences (a), (b), (c), and / or (d) are immediately following position 453 relative to the reference sequence with amino acid sequence numbering according to SEQ ID NO: 138. In some embodiments, the amino acid sequences (i), (ii), (iii), and / or (iv) are located at positions 500-511 with amino acid sequence numbering according to SEQ ID NO: 981 or 982.

[0040] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPH, wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to any of SEQ ID NO: 5-10, 36-59, 138, 981, 982 or 6409-6413; and / or (ii) a modification in ring VIII, such as substitution (e.g., a conservative substitution). In some embodiments, ring 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 another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138; and / or (ii) a modification in ring VIII, such as substitution (e.g., a conservative substitution). In some embodiments, ring 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.

[0042] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 981 or 6411; and / or (ii) a modification in ring VIII, such as substitution (e.g., a conservative substitution). In some embodiments, ring 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.

[0043] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) one, two, three, four, or all of the following amino acids: excluding H at position 590, excluding S at position 592, excluding Q at position 594, excluding A at position 595, and / or excluding Q at position 596. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461 of SEQ ID NO: 981 or 6411.

[0044] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) an amino acid other than H at position 590, an amino acid other than S at position 592, an amino acid other than Q at position 594, an amino acid other than A at position 595, and an amino acid other than Q at position 596, all according to SEQ ID NO: 981 or 6411. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461 according to SEQ ID NO: 981 or 6411.

[0045] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) one, two, three, four, or all of the following amino acids: R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, or a substitution thereof, such as a conservative substitution. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461 of the sequence numbered according to SEQ ID NO: 981 or 6411.

[0046] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present at amino acids 456-461 as numbered according to SEQ ID NO: 981 or 6411; and (ii) one, two, three, four, or all of the following amino acids as numbered according to SEQ ID NO: 981 or 6411: amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, or a substitution thereof, such as a conservative substitution.

[0047] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, according to SEQ ID NO: 981 or 6411. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461, according to SEQ ID NO: 981 or 6411.

[0048] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present at amino acids 456-461 as numbered according to SEQ ID NO: 981 or 6411; and (ii) amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596 as numbered according to SEQ ID NO: 981 or 6411.

[0049] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) one, two, three, four, or all of the following amino acids: excluding H at position 584, excluding S at position 586, excluding Q at position 588, excluding A at position 589, and / or excluding Q at position 590. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461 of SEQ ID NO: 981 or 6411.

[0050] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) an amino acid other than H at position 584, an amino acid other than S at position 586, an amino acid other than Q at position 588, an amino acid other than A at position 589, and an amino acid other than Q at position 590, all according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461 of SEQ ID NO: 981 or 6411.

[0051] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) one, two, three, four, or all of the following amino acids: R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, or a substitution thereof, such as a conservative substitution. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461 of the sequence numbered according to SEQ ID NO: 981 or 6411.

[0052] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence numbered according to SEQ ID NO: 138, 981, or 6411; and (ii) amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, all according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461, according to SEQ ID NO: 981 or 6411.

[0053] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present at amino acids 456-461 numbered according to SEQ ID NO: 981 or 6411; and (ii) 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.

[0054] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and / or (ii) a modification in ring VIII, such as substitution (e.g., a conservative substitution). In some embodiments, ring 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 present at amino acids 454-459 numbered according to SEQ ID NO: 982 or 6412.

[0055] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) one, two, three, four, or all of the following amino acids: excluding H at position 590, excluding S at position 592, excluding Q at position 594, excluding A at position 595, and / or excluding Q at position 596. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 of the sequence numbered according to SEQ ID NO: 982 or 6412.

[0056] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) an amino acid other than H at position 590, an amino acid other than S at position 592, an amino acid other than Q at position 594, an amino acid other than A at position 595, and an amino acid other than Q at position 596, all according to SEQ ID NO: 982 or 6412. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412.

[0057] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) one, two, three, four, or all of the following amino acids: R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, or a substitution thereof, such as a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at positions 454-459 of the amino acids numbered according to SEQ ID NO: 982 or 6412.

[0058] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412; and (ii) one, two, three, four, or all of the following amino acids: R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, or a substitution thereof, such as a conservative substitution.

[0059] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, according to SEQ ID NO: 982 or 6412. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459, according to SEQ ID NO: 982 or 6412.

[0060] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412; and (ii) amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596 according to SEQ ID NO: 982 or 6412.

[0061] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) one, two, three, four, or all of the following amino acids: excluding H at position 584, excluding S at position 586, excluding Q at position 588, excluding A at position 589, and / or excluding Q at position 590. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 of SEQ ID NO: 982 or 6412.

[0062] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) an amino acid other than H at position 584, an amino acid other than S at position 586, an amino acid other than Q at position 588, an amino acid other than A at position 589, and an amino acid other than Q at position 590, all according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412.

[0063] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) one, two, three, four, or all of the following amino acids: R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, or a substitution thereof, such as a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 of the amino acid sequence numbered according to SEQ ID NO: 982 or 6412.

[0064] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present at amino acids 454-459 as numbered according to SEQ ID NO: 982 or 6412; and (ii) one, two, three, four, or all of the following amino acids: R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, or a substitution thereof, such as a conservative substitution.

[0065] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138, 982, or 6412; and (ii) amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, all according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412.

[0066] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present at amino acids 454-459 as numbered according to SEQ ID NO: 982 or 6412; and (ii) amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590 as numbered according to SEQ ID NO: 138 or 6414.

[0067] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) one, two, three, or all of the following amino acids: excluding Q at position 594, excluding A at position 597, excluding Q at position 598, and / or excluding T at position 599. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 of the sequence numbered according to SEQ ID NO: 982 or 6412.

[0068] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) an amino acid other than Q at position 594, an amino acid other than A at position 597, an amino acid other than Q at position 598, and an amino acid other than T at position 599, all according to SEQ ID NO: 982 or 6413. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412.

[0069] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) one, two, three, or all of the following: amino acid K at position 594, amino acid S at position 597, amino acid S at position 598, and / or amino acid A at position 599, or a substitution thereof, such as a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 of the sequence numbered according to SEQ ID NO: 982 or 6412.

[0070] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) amino acid K at position 594, amino acid S at position 597, amino acid S at position 598, and amino acid A at position 599, all according to SEQ ID NO: 982 or 6413. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412.

[0071] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) one, two, three, or all of the following amino acids: excluding Q at position 588, excluding A at position 591, excluding Q at position 592, and / or excluding T at position 593. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 of the amino acid sequence numbered according to SEQ ID NO: 982 or 6412.

[0072] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) an amino acid other than Q at position 588, an amino acid other than A at position 591, an amino acid other than Q at position 592, and an amino acid other than T at position 593, all according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 according to SEQ ID NO: 982 or 6412.

[0073] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) one, two, three, or all of the following: amino acid K at position 588, amino acid S at position 591, amino acid S at position 592, and / or amino acid A at position 593, or a substitution thereof, such as a conservative substitution. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459 of the amino acids numbered according to SEQ ID NO: 982 or 6412.

[0074] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 138 or 982; and (ii) amino acid K at position 588, amino acid S at position 591, amino acid S at position 592, and amino acid A at position 593, all according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at positions 454-459 of the amino acids numbered according to SEQ ID NO: 982 or 6412.

[0075] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) an amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence numbered according to SEQ ID NO: 982; and / or (ii) ring VIII comprising 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 present at amino acids 454-459 numbered according to SEQ ID NO: 982 or 6412.

[0076] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present in ring IV relative to the reference sequence of SEQ ID NO: 138; and / or (ii) modifications in ring VIII, such as substitutions (e.g., conservative substitutions). In some embodiments, ring 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, ring IV comprises positions 449-460 numbered according to SEQ ID NO: 138.

[0077] In another aspect, this disclosure provides an AAV capsid variant comprising: (i) the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present in ring IV relative to the reference sequence of SEQ ID NO: 138; and / or (ii) modifications in ring VIII, such as substitutions (e.g., conservative substitutions). In some embodiments, ring 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, ring IV comprises positions 449-460 numbered according to SEQ ID NO: 138.

[0078] In another aspect, this disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6411.

[0079] In another aspect, this disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412.

[0080] In another aspect, this disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6413.

[0081] In another aspect, this disclosure provides an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6414.

[0082] In another aspect, this disclosure provides an AAV capsid variant comprising one, two, three, four, or all of the amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, or a substitution thereof, such as a conservative substitution.

[0083] In another aspect, this disclosure provides an AAV capsid variant comprising amino acid R at position 584, amino acid T at position 586, amino acid L at position 588, amino acid Q at position 589, and amino acid L at position 590, as specified in SEQ ID NO: 138 or 6414.

[0084] In another aspect, this disclosure provides an AAV particle comprising an AAV capsid variant as described herein. In some embodiments, the AAV particle comprises a nucleic acid sequence encoding a payload. In some embodiments, the AAV particle also comprises a viral genome containing a promoter operatively linked to the nucleic acid encoding the payload.

[0085] In another aspect, this disclosure provides a method for preparing AAV particles containing an AAV capsid variant as described herein. The method includes 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 (e.g., the AAV capsid variant described herein), thereby preparing AAV particles.

[0086] In another aspect, this disclosure provides a method for delivering a payload to cells or tissues (e.g., CNS cells, CNS tissues, hepatocytes, or liver tissues). The method includes administering an effective amount of AAV particles comprising an AAV capsid variant as described herein.

[0087] In another aspect, this disclosure provides a method for treating a subject suffering from or diagnosed with a hereditary condition, such as a monogenic or polygenic condition. The method includes administering to the subject an effective amount of AAV particles comprising an AAV capsid variant as described herein.

[0088] In another aspect, this disclosure provides a method for treating a subject suffering from or diagnosed with a neurological condition, such as neurodegenerative disease. The method comprises administering an effective amount of AAV particles containing an AAV capsid variant as described herein.

[0089] In another aspect, this disclosure provides a method for treating a subject suffering from or diagnosed with neuro-oncology. The method includes administering an effective amount of AAV particles comprising an AAV capsid variant as described herein.

[0090] Those skilled in the art will recognize, or can determine, many equivalent forms of the specific embodiments of the invention described herein using only conventional experiments. Such equivalents are intended to be covered by the embodiments listed below.

[0091] List of implementation plans

[0092] 1. An AAV capsid variant comprising: (A) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring 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; and / or (B) Has the following amino acid sequence: [N1]-[N2]-[N3], where: (i) Optionally, [N1] includes X1, X2 and X3, wherein at least one of X1, X2 or X3 is G; (ii) [N2] contains the amino acid sequence of SPH; and (iii) [N3] contains X4, X5 and X6, wherein at least one of X4, X5 or X6 is a basic amino acid, such as K or R.

[0093] 2. The AAV capsid variant as described in embodiment 1, wherein X4, X5, or both of [N3] are K.

[0094] 3. The AAV capsid variant as described in embodiment 1 or 2, wherein X4, X5, or X6 of [N3] is R.

[0095] 4. AAV capsid variant as described in any one of embodiments 1 to 3, wherein: (a) The position X4 of [N3] is: K, S, A, V, T, G, F, W, V, N or R; (b) The position X5 of [N3] is: S, K, T, F, I, L, Y, H, M, or R; and / or (c) The position X6 of [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 comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(c).

[0096] 5. AAV capsid variant as described in any one of embodiments 1 to 4, wherein [N3] comprises 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.

[0097] 6. AAV capsid variant as described in any one of embodiments 1 to 5, wherein [N3] is or includes 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.

[0098] 7. AAV capsid variants as described in any one of embodiments 1 to 6, wherein [N2]-[N3] comprise SPHSK (SEQ ID NO: 4701), SPHKS (SEQ ID NO: 4704), SPHAR (SEQ ID NO: 4705), SPHVK (SEQ ID NO: 4706), SPHAS (SEQ ID NO: 4707), SPHKK (SEQ ID NO: 4708), SPHVR (SEQ ID NO: 4709), SPHRK (SEQ ID NO: 4710), SPHKT (SEQ ID NO: 4711), SPHKF (SEQ ID NO: 4712), SPHKI (SEQ ID NO: 4713), SPHKL (SEQ ID NO: 4714), SPHKY (SEQ ID NO: 4715), SPHTR (SEQ ID NO: 4716), SPHKR (SEQ ID NO: 4717), SPHGA (SEQ ID NO: 4718), SPHKT (SEQ ID NO: 4719), SPHKT (SEQ ID NO: 4710), SPHKT (SEQ ID NO: 4711), SPHKT (SEQ ID NO: 4712), SPHKK (SEQ ID NO: 4713), SPHKL (SEQ ID NO: 4714), SPHKK (SEQ ID NO: 4715), SPHKT (SEQ ID NO: 4716), SPHKT (SEQ ID NO: 4717), SPHKT (SEQ ID NO: 4718), SPHKT (SEQ ID NO: 4719), SPHKT (SEQ ID NO: 4710), SPHKT (SEQ ID NO: 4711), SPHKT (SEQ ID NO: 4712), SPHKT (SEQ ID NO: 4713), SPHKT (SEQ ID NO: 4714), SPHKT (SEQ ID NO: 4715), SPHKT (SEQ ID NO: 4716), SP 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).

[0099] 8. AAV capsid variant as described in any one of embodiments 1 to 7, wherein [N2]-[N3] is or comprises: (i) SPHSKA (SEQ ID NO: 941)、SPHKSG (SEQ ID NO: 946)、SPHARM (SEQ IDNO: 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: 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)、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 contains any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0100] 9. An AAV capsid variant as described in any one of embodiments 1 to 8, comprising an amino acid other than G (e.g., V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C) at position 453 numbered according to any one of SEQ ID NO: 5-10, 36-59, 138, 981, 982, or 6409-6414, an amino acid other than S (V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q) at position 454, and / or an amino acid other than G (e.g., C, L, D, E, Y, H, V, A, N, P, or S) at position 455.

[0101] 10. The AAV capsid variant as described in 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, as specified in SEQ ID NO: 138 or 981.

[0102] 11. The AAV capsid variant as described in 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, as specified in SEQ ID NO: 138 or 982.

[0103] 12. AAV capsid variant as described in any one of embodiments 1 to 11, wherein [N1] comprises X1, X2 and X3, wherein at least one of X1, X2 or X3 is G.

[0104] 13. AAV capsid variant as described in any one of embodiments 1 to 12, wherein: (a) The position X1 of [N1] is: G, V, R, D, E, M, T, I, S, A, N, L, K, H, P, W or C; (b) The position X2 of [N1] is: S, V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q; and / or (c) The position X3 of [N1] is: G, C, L, D, E, Y, H, V, A, N, P or S; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(c).

[0105] 14. AAV capsid variant as described in any one of embodiments 1 to 13, wherein [N1] comprises 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.

[0106] 15. AAV capsid variant as described in any one of embodiments 1 to 14, wherein [N1] is or comprises 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.

[0107] 16. AAV capsid variant as described in any one of embodiments 1 to 15, wherein [N1]-[N2] comprises: (i) SGSPH (SEQ ID NO: 4752), HDSPH (SEQ ID NO: 4703), QDSPH (SEQ ID NO: 4753), RGSPH (SEQ ID NO: 4754), SHSPH (SEQ ID NO: 4755), QSSPH (SEQ ID NO: 4756), DDSPH (SEQ ID NO: 4757), HESPH (SEQ ID NO: 4758), NYSPH (SEQ ID NO: 4759), VGSPH (SEQ ID NO: 4760), SCSPH (SEQ ID NO: 4761), LLSPH (SEQ ID NO: 4762), NGSPH (SEQ ID NO: 4763), PGSPH (SEQ ID NO: 4764), GGSPH (SEQ ID NO: 4762) NO:4765), TGSPH (SEQ ID NO: 4766), SVSPH (SEQ ID NO: 4767), IGSPH (SEQ ID NO:4768), DGSPH (SEQ ID NO: 4769), LGSPH (SEQ ID NO: 4770), AGSPH (SEQ ID NO:4771), EGSPH (SEQ ID NO: 4772), SASPH (SEQ ID NO: 4773), YDSPH (SEQ ID NO:4774), HGSPH (SEQ ID NO: 4775), RDSPH (SEQ ID NO: 4776), NDSPH (SEQ ID NO: 4777), PDSPH (SEQ ID NO: 4778), MGSPH (SEQ ID NO: 4779), QVSPH (SEQ ID NO: 4780), HNSPH (SEQ ID NO: 4781), HPSPH (SEQ ID NO: 4782) or HSSPH (SEQ ID NO:4783); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any two, three, or four amino acids therein, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0108] 17. AAV capsid variant as described in any one of embodiments 1 to 16, wherein [N1]-[N2] is or comprises: (i) GSGSPH (SEQ ID NO: 4695)、GHDSPH (SEQ ID NO: 4784)、GQDSPH (SEQ IDNO: 4785)、VSGSPH (SEQ ID NO: 4786)、CSGSPH (SEQ ID NO: 4787)、GRGSPH (SEQ IDNO: 4788)、CSHSPH (SEQ ID NO: 4789)、GQSSPH (SEQ ID NO: 4790)、GSHSPH (SEQ IDNO: 4791)、GDDSPH (SEQ ID NO: 4792)、GHESPH (SEQ ID NO: 4793)、GNYSPH (SEQ IDNO: 4794)、RVGSPH (SEQ ID NO: 4795)、GSCSPH (SEQ ID NO: 4796)、GLLSPH (SEQ IDNO: 4797)、MSGSPH (SEQ ID NO: 4798)、RNGSPH (SEQ ID NO: 4799)、TSGSPH (SEQ IDNO: 4800)、ISGSPH (SEQ ID NO: 4801)、GPGSPH (SEQ ID NO: 4802)、ESGSPH (SEQ IDNO: 4803)、SSGSPH (SEQ ID NO: 4804)、GNGSPH (SEQ ID NO: 4805)、ASGSPH (SEQ IDNO: 4806)、NSGSPH (SEQ ID NO: 4807)、LSGSPH (SEQ ID NO: 4808)、GGGSPH (SEQ IDNO: 4809)、KSGSPH (SEQ ID NO: 4810)、HSGSPH (SEQ ID NO: 4811)、GTGSPH (SEQ IDNO: 4812)、PSGSPH (SEQ ID NO: 4813)、GSVSPH (SEQ ID NO: 4814)、RSGSPH (SEQ IDNO: 4815)、GIGSPH (SEQ ID NO: 4816)、WSGSPH (SEQ ID NO: 4817)、DSGSPH (SEQ IDNO: 4818)、IDGSPH (SEQ ID NO: 4819)、GLGSPH (SEQ ID NO: 4820)、DAGSPH (SEQ IDNO: 4821)、DGGSPH (SEQ ID NO: 4822)、MEGSPH(SEQ ID NO: 4823), ENGSPH (SEQ ID NO: 4824), GSASPH (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 IDNO: 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 contains any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0109] 18. AAV capsid variant as described in any one of embodiments 1 to 17, wherein [N1]-[N2]-[N3] comprises: (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: 4843) 4844). 4850)、RGSPHAS (SEQ ID NO: 4851)、RGSPHSK (SEQ ID NO: 4852)、SGSPHKF (SEQ ID NO: 4853)、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 (SEQID NO:4877), DGSPHSK (SEQ ID NO: 4878), SGSPHNK (SEQ ID NO: 4879), LGSPHSK (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 (SEQ ID NO: 4894), MGSPHSK (SEQ ID NO: 4895), HDSPHKH (SEQ ID NO: 4896), QVSPHKS (SEQ ID NO: 4897), HNSPHKS (SEQ ID NO: 4898), NGSPHKR (SEQ ID NO: 4899), HDSPHKY (SEQ ID NO: 4900), NDSPHKI (SEQ ID NO: 4901), HDSPHKL (SEQ ID NO: 4902), HPSPHWK (SEQ ID NO: 4903), HDSPHKM (SEQ ID NO: 4904) or HSSPHRS (SEQ ID NO: 4905); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5 or 6 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0110] 19. AAV capsid variant as described in any one of embodiments 1 to 18, wherein [N1]-[N2]-[N3] are or comprise: (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: 4908) 4909). NO: 4915)、CSGSPHKTS (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: 4925) 4926)、GSGSPHKYG (SEQ ID NO:4927)、GSGSPHSKD (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: 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) GSSCSPHRKA (SEQ ID NO: 4950) GSGSPHFLR (SEQ ID NO:4951)、GSGSPHSKW (SEQ ID NO: 4952)、GSGSPHSKS (SEQ ID NO: 4953)、GLLSPHWKA (SEQID 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 (SEQID NO: 4962)、ESGSPHSKA (SEQ ID NO: 4963). 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 IDNO: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 IDNO: 5009), GHDSPHKSW (SEQ ID NO: 5010), GHDSPHKSN (SEQ ID NO: 5011), GMGSPHSKT (SEQ ID NO: 5012), GHDSPHKHG (SEQ ID NO: 5013), GQVSPHKSG (SEQ ID NO: 5014), GDDSPHKSV (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016), GGNSPHKRG (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 contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7 or 8 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0111] 20. AAV capsid variant as described in any one of embodiments 1 to 19, wherein [N3] comprises SK, KA, KS or SG.

[0112] 21. AAV capsid variant as described in any one of embodiments 1 to 20, wherein [N3] is or comprises SKA, KSG or KYG.

[0113] 22. The AAV capsid variant as described in any one of embodiments 1 to 21, wherein [N2]-[N3] comprises SPHSK (SEQ ID NO: 4701), SPHKS (SEQ ID NO: 4704), or SPHKY (SEQ ID NO: 4715).

[0114] 23. The AAV capsid variant as described in any one of embodiments 1 to 22, wherein [N2]-[N3] is or contains SPHSKA (SEQ ID NO: 941).

[0115] 24. The AAV capsid variant as described in any one of embodiments 1 to 22, wherein [N2]-[N3] is or contains SPHKSG (SEQ ID NO: 946).

[0116] 25. The AAV capsid variant as described in any one of embodiments 1 to 22, wherein [N2]-[N3] is or contains SPHKYG (SEQ ID NO: 966).

[0117] 26. AAV capsid variant as described in any one of embodiments 1 to 25, wherein [N1] comprises GS, SG, GH or HD.

[0118] 27. AAV capsid variant as described in any one of embodiments 1 to 26, wherein [N1] is or contains GSG.

[0119] 28. AAV capsid variant as described in any one of embodiments 1 to 26, wherein [N1] is or contains GHD.

[0120] 29. AAV capsid variant as described in any one of embodiments 1 to 23 or 26 to 27, wherein [N1]-[N2]-[N3] comprises SGSPHSK (SEQ ID NO: 4839).

[0121] 30. AAV capsid variant as described in any one of embodiments 1 to 22, 24, 26 or 28, wherein [N1]-[N2]-[N3] comprises HDSPHKS (SEQ ID NO: 4840).

[0122] 31. AAV capsid variant as described in any one of embodiments 1 to 22 or 25 to 27, wherein [N1]-[N2]-[N3] comprises SGSPHKYG (SEQ ID NO: 5027).

[0123] 32. AAV capsid variant as described in any one of embodiments 1 to 8, 10, 12 to 23, 26 to 27 or 29, wherein [N1]-[N2]-[N3] is or contains GGSPHSKA (SEQ ID NO: 4697).

[0124] 33. AAV capsid variant as described in any one of embodiments 1 to 9, 11 to 22, 24, 26, 28 or 30, wherein [N1]-[N2]-[N3] is or contains GHDSPHKSG (SEQ ID NO: 4698).

[0125] 34. AAV capsid variant as described in any one of embodiments 1 to 8, 10, 12 to 22, 25 to 27 or 31, wherein [N1]-[N2]-[N3] is or contains GSGSPHKYG (SEQ ID NO: 4927).

[0126] 35. The AAV capsid variant as described in any one of embodiments 1 to 34, wherein [N1]-[N2]-[N3] replaces positions 453-455 of the amino acid sequence number according to SEQ ID NO: 138.

[0127] 36. The AAV capsid variant as described in any one of embodiments 1 to 35, comprising, relative to the reference sequence numbered according to SEQ 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).

[0128] 37. The AAV capsid variant as described in any one of embodiments 1 to 36, which, relative to the reference sequence numbered according to SEQ ID NO: 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56 or 57, comprises an 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 an amino acid other than N at position 463 (e.g., Y, C, K, T, H, R, D, ... The amino acid at position 464 other than Q (e.g., G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y) and / or the amino acid at position 465 other than Q (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V).

[0129] 38. AAV capsid variant as described in any one of embodiments 1 to 37, comprising: (a) 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, relative to the reference sequence numbered according to SEQ ID NO: 138; or (b) 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, relative to the reference sequence numbered according to SEQ ID NO: 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56 or 57.

[0130] 39. The AAV capsid variant as described in any one of embodiments 1 to 38, further comprising [N4], wherein [N4] comprises X7 X8 X9 X10, and wherein: (a) Position X7 is: Q, W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F; (b) Position X8 is: N, Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, I, M, Q or L; (c) Position X9 is: Q, G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y; and (d) Position X10 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 comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(d).

[0131] 40. The AAV capsid variant as described in embodiment 39, wherein: (a) The position of [N4] X7 is either Q or R; (b) The position of [N4] X8 is N or R; (c) The position X9 of [N4] is either Q or R; and (d) The position X10 of [N4] is Q, L or R.

[0132] 41. AAV capsid variant as described in embodiment 39 or 40, wherein [N4] is or comprises: (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 IDNO: 5040)、LNQQ (SEQ ID NO: 5041)、QRKL (SEQ ID NO: 5042)、LRRQ (SEQ ID NO:5043)、QRLR (SEQ ID NO: 5044)、QRRL (SEQ ID NO: 5045)、RRLQ (SEQ ID NO: 5046)、RLRQ (SEQ ID NO: 5047)、SKRQ (SEQ ID NO: 5048)、QLYR (SEQ ID NO: 5049)、QLTV(SEQ ID NO: 5050)、QNKQ (SEQ ID NO: 5051)、KNQQ (SEQ ID NO: 5052)、QKQQ (SEQ IDNO: 5053)、QTQQ (SEQ ID NO: 5054)、QNHQ (SEQ ID NO: 5055)、QHQQ (SEQ ID NO:5056)、QNQH (SEQ ID NO: 5057)、QHRQ (SEQ ID NO: 5058)、LTQQ (SEQ ID NO: 5059)、QNQW (SEQ ID NO: 5060)、QNTH (SEQ ID NO: 5061)、RRRQ (SEQ ID NO: 5062)、QYQQ(SEQ ID NO: 5063)、QNDQ (SEQ ID NO: 5064)、QNRH (SEQ ID NO: 5065)、RDQQ (SEQ IDNO: 5066)、PNLQ (SEQ ID NO: 5067)、HVRQ (SEQ ID NO: 5068)、PNQH (SEQ ID NO:5069)、HNQQ (SEQ ID NO: 5070)、QSQQ (SEQ ID NO:5071)、QPAK (SEQ ID NO: 5072)、QNLA (SEQ ID NO: 5073)、QNQL (SEQ ID NO: 5074)、QGQQ (SEQ ID NO: 5075)、LNRQ(SEQ ID NO: 5076)、QNPP (SEQ ID NO: 5077)、QNLQ (SEQ ID NO: 5078)、QDQE (SEQ IDNO: 5079)、QDQQ (SEQ ID NO: 5080)、HWQQ (SEQ ID NO: 5081)、PNQQ (SEQ ID NO:5082)、PEQQ (SEQ ID NO: 5083)、QRTM (SEQ ID NO: 5084)、LHQH (SEQ ID NO: 5085)、QHRI (SEQ ID NO: 5086)、QYIH (SEQ ID NO: 5087)、QKFE (SEQ ID NO: 5088)、QFPS(SEQ ID NO: 5089)、QNPL (SEQ ID NO: 5090)、QAIK (SEQ ID NO: 5091)、QNRQ (SEQ IDNO: 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 IDNO: 5105)、QAQQ (SEQ ID NO: 5106)、QTPP (SEQ ID NO: 5107)、QPPA (SEQ ID NO:5108)、QERP (SEQ ID NO: 5109)、QDLQ (SEQ ID NO: 5110)、QAMH (SEQ ID NO: 5111)、QHPS (SEQ ID NO: 5112)、PGLQ (SEQ ID NO: 5113)、QGIR (SEQ ID NO: 5114)、QAPA(SEQ IDNO: 5115)、QIPP (SEQ ID NO: 5116)、QTQL (SEQ ID NO: 5117)、QAPS (SEQ IDNO: 5118)、QNTY (SEQ ID NO: 5119)、QDKQ (SEQ ID NO: 5120)、QNHL (SEQ ID NO:5121)、QIGM (SEQ ID NO: 5122)、LNKQ (SEQ ID NO: 5123)、PNQL (SEQ ID NO: 5124)、QLQQ (SEQ ID NO: 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 IDNO: 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: 5143)、QSKV (SEQ IDNO: 5144)、QLPS (SEQ ID NO: 5145)、IGKQ (SEQ ID NO: 5146)、QAIH (SEQ ID NO:5147)、QHGL (SEQ ID NO: 5148)、QFMC (SEQ ID NO: 5149)、QNQM (SEQ ID NO: 5150)、QHLQ (SEQ ID NO: 5151)、QPAR (SEQ ID NO: 5152)、QSLQ (SEQ ID NO: 5153)、QSQL(SEQ ID NO: 5154)、HSQQ (SEQ ID NO: 5155)、QMPS (SEQ ID NO: 5156)、QGSL (SEQ IDNO: 5157)、QVPA (SEQ ID NO: 5158)、HYQQ (SEQID 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 IDNO: 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: 5175)、RGLQ (SEQ ID NO: 5176)、PSLQ (SEQ ID NO: 5177)、QRDQ (SEQ ID NO: 5178)、QAKG (SEQ ID NO: 5179)、QSAH(SEQ ID NO: 5180)、QSTM (SEQ ID NO: 5181)、QREM (SEQ ID NO: 5182)、QYRA (SEQ IDNO: 5183)、QRQQ (SEQ ID NO: 5184)、QWQQ (SEQ ID NO: 5185)、QRMN (SEQ ID NO:5186)、GDSQ (SEQ ID NO: 5187)、QKIS (SEQ ID NO: 5188)、PSMQ (SEQ ID NO: 5189)、SPRQ (SEQ ID NO: 5190)、MEQQ (SEQ ID NO: 5191)、QYQN (SEQ ID NO: 5192)、QIRQ(SEQ ID NO: 5193)、QSVQ (SEQ ID NO: 5194)、RSQQ (SEQ ID NO: 5195)、QNKL (SEQ IDNO: 5196)、QIQH (SEQ ID NO: 5197)、PRQQ (SEQ ID NO: 5198)、HTQQ (SEQ ID NO:5199)、QRQH (SEQ ID NO: 5200)、RNQE (SEQ ID NO: 5201)、QSKQ (SEQ ID NO: 5202)、QNQP(SEQ ID NO: 5203), QSPQ (SEQ ID NO: 5204), QTRQ (SEQ ID NO: 5205), QNLH(SEQ ID NO: 5206), QNQE (SEQ ID NO: 5207), LNQP (SEQ ID NO: 5208), QNQD (SEQ IDNO: 5209), QNLL (SEQ ID NO: 5210), QLVI (SEQ ID NO: 5211), RTQE (SEQ ID NO:5212), QTHQ (SEQ ID NO: 5213), QDQH (SEQ ID NO: 5214), QSQH (SEQ ID NO: 5215), VRQQ (SEQ ID NO: 5216), AWQQ (SEQ ID NO: 5217), QSVP (SEQ ID NO: 5218), QNIQ(SEQ ID NO: 5219), LDQQ (SEQ ID NO: 5220), PDQQ (SEQ ID NO: 5221), ESQQ (SEQ IDNO: 5222), QRQL (SEQ ID NO: 5223), QIIV (SEQ ID NO: 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 IDNO: 5235), QKQL (SEQ ID NO: 5236), 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); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any two or three of its amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0133] 42. The AAV capsid variant as described in any one of embodiments 39 to 41, wherein [N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 1800-2241; (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0134] 43. The AAV capsid variant as described in any one of embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is or contains GSGSPHSKAQNQQ (SEQ ID NO: 1801).

[0135] 44. The AAV capsid variant as described in any one of embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is or contains GHDSPHKSGQNQQ (SEQ ID NO: 1800).

[0136] 45. AAV capsid variant as described in any one of embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is or contains GSGSPHKYGQNQQT (SEQ ID NO: 910).

[0137] 46. ​​The AAV capsid variant as described in any one of embodiments 1 to 45, wherein, relative to the reference sequence numbered according to any one of SEQ ID NO: 5-10, 36-59, 138, 981, 982 or 6409-6414, it comprises 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).

[0138] 47. The AAV capsid variant as described in any one of embodiments 1 to 46, comprising, relative to the reference sequence numbered according to any one of SEQ ID no: 138, 981 or 982, amino acid T at position 450, amino acid I at position 451 and / or amino acid N at position 452.

[0139] 48. The AAV capsid variant as described in any one of embodiments 1 to 47, further comprising [N0], wherein [N0] comprises XA, XB, and XC, and wherein: (a) Position XA is: T, S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E or G; (b) Position XB is: I, M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L; and (c) Position XC is: N, M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S; and Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(c).

[0140] 49. The AAV capsid variant of embodiment 48, wherein [NO] is or comprises TIN, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW, ANN, IPE, AD M, IEY, ADY, IET, MEW, CEY, RIN, MEI, LEY, ADW, IEI, DIM, FEQ, MEF, CDQ, LPE, IEN, MES, AEI, VEY, I IN, 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, TER, TSY, ELH, AIN, SVN, TDN, TFH , TVH, TEN, TSS, TID, TCN, NIN, TEH, AEM, AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TI Y, TFS, TES, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, N AD, 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 dipeptide thereof.

[0141] 50. AAV capsid variant as described in embodiment 48 or 49, wherein [N0]-[N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 2242-2886; (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0142] 51. The AAV capsid variant as described in any one of embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains TINGSGSPHSKAQNQQ (SEQ ID NO: 2242).

[0143] 52. The AAV capsid variant as described in any one of embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains TINGHDSPHKSGQNQQ (SEQ ID NO: 2243).

[0144] 53. The AAV capsid variant as described in any one of embodiments 48 to 52, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains TINGSGSPHKYGQNQQT (SEQ ID NO: 5246).

[0145] 54. AAV capsid variant as described in any one of embodiments 1 to 53, wherein [N1]-[N2]-[N3] are present in ring IV.

[0146] 55. AAV capsid variant as described in any one of embodiments 48 to 54, wherein [N0] and [N4] are present in ring IV.

[0147] 56. The AAV capsid variant as described in any one of embodiments 48 to 55, wherein [NO] is immediately present after position 449 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 138.

[0148] 57. The AAV capsid variant as described in any one of embodiments 48 to 56, wherein [NO] is immediately present after position 449 relative to the reference sequence numbered according to the amino acid sequence number of any one of SEQ ID NO: 5-10, 36-59, 981, 982 or 6409-6413.

[0149] 58. AAV capsid variant as described in any one of embodiments 48 to 57, wherein [N0] replaces positions 450, 451 and 452 (e.g., T450, I451 and N452) relative to the reference sequence numbered according to SEQ ID NO: 138.

[0150] 59. AAV capsid variant as described in any one of embodiments 48 to 58, wherein [N0] replaces positions 450-452 (e.g., T450, I451, and N452) relative to the reference sequence numbered according to any one of SEQ ID NO: 5-10, 36-59, 981, 982, or 6409-6413.

[0151] 60. AAV capsid variant as described in any one of embodiments 48 to 59, wherein [N0] corresponds to position 450-452 of any one of SEQ ID NO: 5-10, 36-59, 138, 981, 982 or 6409-6414.

[0152] 61. AAV capsid variant as described in any one of embodiments 48 to 60, wherein [N0] is immediately present after position 449 relative to the reference sequence numbered according to SEQ ID NO: 138, and wherein [N0] replaces positions 450-452 (e.g., T450, I451 and N452).

[0153] 62. AAV capsid variant as described in any one of embodiments 48 to 61, wherein [N0] is immediately present after position 449 relative to the reference sequence numbered according to any one of SEQ ID NO: 5-10, 36-59, 981, 982 or 6409-6413, and wherein [N0] replaces positions 450-452 (e.g., T450, I451 and N452).

[0154] 63. The AAV capsid variant as described in any one of embodiments 1 to 62, wherein [N1] is immediately present after position 452 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO:138.

[0155] 64. The AAV capsid variant as described in any one of embodiments 1 to 63, wherein [N1] is immediately following position 452 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0156] 65. The AAV capsid variant as described in any one of embodiments 1 to 61, wherein [N1] replaces positions 453-455 (e.g., G453, S454, and G455) relative to the reference sequence numbered according to SEQ ID NO:138.

[0157] 66. The AAV capsid variant as described in any one of embodiments 1 to 64, wherein [N1] replaces position 453 (e.g., G453) relative to the reference sequence numbered according to SEQ ID NO:138.

[0158] 67. The AAV capsid variant as described in any one of embodiments 1 to 65, wherein [N1] replaces positions 453-455 (e.g., G453, S454, and G455) relative to the reference sequence numbered according to SEQ ID NO:981.

[0159] 68. AAV capsid variant as described in any one of embodiments 1 to 65 or 67, wherein [N1] is replaced at positions 453-455 relative to the reference sequence numbered according to SEQ ID NO: 982.

[0160] 69. AAV capsid variant as described in any one of embodiments 1-65, 67 or 68, wherein [N1] is immediately present after position 452 relative to the reference sequence numbered according to SEQ ID NO: 138, and wherein [N1] replaces positions 453-455 (e.g., G453, S454 and G455).

[0161] 70. AAV capsid variant as described in any one of embodiments 1 to 64 or 66, wherein [N1] is immediately present after position 452 relative to the reference sequence numbered according to SEQ ID NO: 138, and wherein [N1] replaces position 453 (e.g., G453).

[0162] 71. AAV capsid variant as described in any one of embodiments 1 to 64, 66 or 70, wherein [N1] is immediately present after position 452 relative to the reference sequence numbered according to SEQ ID NO: 981 or 982, and wherein [N1] replaces positions 453-455.

[0163] 72. The AAV capsid variant as described in any one of embodiments 1 to 71, wherein [N1] corresponds to position 453-455 of any one of SEQ ID NO: 5-10, 36-59, 981, 982 or 6409-6413.

[0164] 73. The AAV capsid variant as described in 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 according to SEQ ID NO: 138, 981 or 982.

[0165] 74. The AAV capsid variant as described in any one of embodiments 1 to 73, comprising amino acid H at position 454 and amino acid D at position 455 according to SEQ ID NO: 138 or 982.

[0166] 75. The AAV capsid variant as described in any one of embodiments 1 to 74, comprising a substitution at position 454 (e.g., S454H) and / or a substitution at position 455 (e.g., G455D) according to SEQ ID NO: 138.

[0167] 76. The AAV capsid variant as described in any one of embodiments 1 to 75, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138, amino acid H at position 454 and amino acid D at position 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455.

[0168] 77. The AAV capsid variant as described in any one of embodiments 1 to 76, comprising amino acid H at position 454 and amino acid D at position 455 relative to the reference sequence numbered according to SEQ ID NO:982.

[0169] 78. The AAV capsid variant as described in any one of embodiments 1 to 77, comprising, relative to the reference sequence numbered according to SEQ ID NO: 982, amino acid H at position 454 and amino acid D at position 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455.

[0170] 79. The AAV capsid variant as described in any one of embodiments 1 to 72, comprising amino acid S at position 454 and amino acid G at position 455 relative to the reference sequence numbered according to SEQ ID NO:138.

[0171] 80. The AAV capsid variant as described in any one of embodiments 1 to 72 or 79, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138, amino acid S at position 454 and amino acid G at position 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455.

[0172] 81. The AAV capsid variant as described in any one of embodiments 1 to 72, 79 or 80, comprising amino acid S at position 454 and amino acid G at position 455 relative to the reference sequence numbered according to SEQ ID NO: 981.

[0173] 82. The AAV capsid variant as described in any one of embodiments 1 to 72 or 79 to 81, comprising, relative to the reference sequence numbered according to SEQ ID NO: 981, amino acid S at position 454 and amino acid G at position 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455.

[0174] 83. The AAV capsid variant as described in any one of embodiments 1 to 82, wherein [N2] is immediately following position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO:138.

[0175] 84. AAV capsid variant as described in any one of embodiments 1 to 83, wherein [N2] corresponds to position 456-458 of SEQ ID NO: 981 or 982 (e.g., S456, P457, H458).

[0176] 85. The AAV capsid variant as described in any one of embodiments 1 to 83, wherein [N2] corresponds to position 456-458 (e.g., S456, P457, H458) of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413.

[0177] 86. The AAV capsid variant as described in any one of embodiments 1 to 85, wherein [N2]-[N3] are immediately present after position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO:138.

[0178] 87. The AAV capsid variant as described in any one of embodiments 1 to 86, wherein [N2] is immediately present after position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0179] 88. The AAV capsid variant as described in any one of embodiments 1 to 87, wherein [N2]-[N3] are immediately present after position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0180] 89. AAV capsid variant as described in any one of embodiments 1 to 88, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 981 (e.g., S456, P457, H458, S459, K460, A461).

[0181] 90. AAV capsid variant as described in any one of embodiments 1 to 88, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 982 (e.g., S456, P457, H458, K459, S460, G461).

[0182] 91. AAV capsid variant as described in any one of embodiments 1 to 90, wherein [N2] immediately follows [N1].

[0183] 92. AAV capsid variant as described in any one of embodiments 1 to 64, 66, 70 or 71, wherein [N3] is immediately present after [N2] and replaces positions 454 and 455 (e.g., S454 and G455) according to SEQ ID NO: 138.

[0184] 93. AAV capsid variant as described in any one of embodiments 1 to 64, 66, 70, 71 or 92, wherein [N3] is immediately present after [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455) as numbered according to SEQ ID NO: 138.

[0185] 94. The AAV capsid variant as described in any one of embodiments 39 to 93, wherein [N4] is immediately following position 455 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 138.

[0186] 95. The AAV capsid variant as described in any one of embodiments 39 to 94, wherein [N4] is replaced at positions 456-459 (e.g., Q456, N457, Q458, and Q459) relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0187] 96. AAV capsid variant as described in any one of embodiments 39 to 95, wherein [N4] corresponds to positions 462-465 of SEQ ID NO: 981 or 982 (e.g., Q462, N463, Q464, Q465).

[0188] 97. The AAV capsid variant as described in any one of embodiments 39 to 96, wherein [N2]-[N3]-[N4] replace positions 456-459 (e.g., Q456, N457, Q458, and Q459) relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138.

[0189] 98. The AAV capsid variant as described in any one of embodiments 39 to 97, wherein [N2]-[N3]-[N4] is immediately present after position 455 relative to the reference sequence numbered according to SEQ ID NO: 138, and wherein [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459).

[0190] 99. AAV capsid variant as described in any one of embodiments 39 to 98, wherein [N2]-[N3]-[N4] correspond to positions 456-465 of SEQ ID NO: 981 (e.g., S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0191] 100. AAV capsid variant as described in any one of embodiments 39 to 98, wherein [N2]-[N3]-[N4] correspond to positions 456-465 of SEQ ID NO: 982 (e.g., S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0192] 101. The AAV capsid variant as described in any one of embodiments 39 to 98, wherein [N2]-[N3]-[N4] correspond to positions 456-465 of any one of SEQ ID NO: 5-10, 36-59, 6409-6413.

[0193] 102. The AAV capsid variant as described in any one of embodiments 39 to 101, wherein [N1]-[N2]-[N3]-[N4] substitution positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459) are replaced relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0194] 103. The AAV capsid variant as described in any one of embodiments 39 to 102, wherein [N1]-[N2]-[N3]-[N4] is immediately present after position 452 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, and wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459).

[0195] 104. AAV capsid variant as described in any one of embodiments 39 to 99, 102, and 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, and Q465).

[0196] 105. AAV capsid variant as described in any one of embodiments 39 to 98, 100, 102 or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0197] 106. The AAV capsid variant as described in any one of embodiments 39 to 98, 102 or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413.

[0198] 107. AAV capsid variant as described in any one of embodiments 1 to 99 or 102 to 104, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0199] 108. AAV capsid variant as described in any one of embodiments 1 to 98, 100, 102, 103 or 105, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461).

[0200] 109. The AAV capsid variant as described in any one of embodiments 39 to 98, 102, 103 or 106, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413.

[0201] 110. The AAV capsid variant as described in any one of embodiments 48 to 109, wherein [N0]-[N1]-[N2]-[N3]-[N4] substitution positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459) are replaced relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0202] 111. The AAV capsid variant as described in any one of embodiments 48 to 110, wherein [N0]-[N1]-[N2]-[N3]-[N4] is immediately present after position 449 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458 and Q459).

[0203] 112. AAV capsid variant as described in any one of embodiments 48 to 99, 102 to 104 or 106, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of SEQ ID NO: 981 (e.g., T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0204] 113. AAV capsid variant as described in any one of embodiments 48 to 98, 100, 102, 103, 105 or 108, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of SEQ ID NO: 982 (e.g., T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0205] 114. The AAV capsid variant as described in any one of embodiments 48 to 98, 102, 103, 106 or 109, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413.

[0206] 115. The AAV capsid variant as described in any one of embodiments 39 to 114, wherein [N4] is replaced at positions 462-465 (e.g., Q462, N463, Q464, and Q465) relative to the reference sequence with amino acid sequence number according to SEQ ID NO: 981 or 982.

[0207] 116. The AAV capsid variant as described in any one of embodiments 39 to 115, wherein [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465) relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0208] 117. The AAV capsid variant as described in any one of embodiments 39 to 116, wherein [N2]-[N3]-[N4] is immediately present after position 455 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 981 or 982, and wherein [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465).

[0209] 118. AAV capsid variant as described in any one of embodiments 1 to 117, wherein [N3] immediately follows [N2].

[0210] 119. The AAV capsid variant as described in any one of embodiments 1 to 118, comprising [N2]-[N3] from the N-terminus to the C-terminus.

[0211] 120. The AAV capsid variant as described in any one of embodiments 1 to 119, comprising [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0212] 121. The AAV capsid variant as described in any one of embodiments 48 to 120, comprising [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0213] 122. The AAV capsid variant as described in any one of embodiments 39 to 121, comprising [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0214] 123. The AAV capsid variant as described in any one of embodiments 48 to 122, comprising [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0215] 124. The AAV capsid variant as described in any of the preceding embodiments, comprising an amino acid other than T (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S) at position 460 of the amino acid sequence number according to SEQ ID NO: 138.

[0216] 125. The AAV capsid variant as described in any of the preceding embodiments, comprising amino acids N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S at position 460 according to the amino acid sequence number of SEQ ID NO: 138.

[0217] 126. The AAV capsid variant as described in any of the preceding embodiments, comprising an amino acid other than T (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S) at position 466 of the amino acid sequence number according to any of SEQ ID NO: 5-10, 36-59, 981, 982, or 6409-6413.

[0218] 127. The AAV capsid variant as described in any of the preceding embodiments, comprising the amino acid N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G or S at position 466 according to the amino acid sequence number of any of SEQ ID NO: 5-10, 36-59, 981, 982 or 6409-6413.

[0219] 128. The AAV capsid variant as described in any of the preceding embodiments, comprising an amino acid other than K (e.g., E, N, or T) at position 449 according to the amino acid sequence number of any of SEQ ID NO: 36-59, 138, 981, or 982.

[0220] 129. The AAV capsid variant as described in any of the preceding embodiments, comprising amino acid E, N or T at position 449 of the amino acid sequence number according to any of SEQ ID NO: 5-10, 36-59, 138, 981, 982 or 6409-6414.

[0221] 130. An AAV capsid variant comprising: (A) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring 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; and / or (B) [A][B] (SEQ ID NO: 4694), where: (i) [A] contains the amino acid sequence of GSGSPH (SEQ ID NO: 4695); and (ii) [B] includes X1 X2 X3 X4 X5 X6 X7, where: (a) Position X1 is: S, C, F or V; (b) Position X2 is: K, L, R, I, E, Y, V, or S; (c) Position X3 is: A, R, L, G, I, Y, S, F, or W; (d) Position X4 is: W, Q, R, G, L, V, S, or F; (e) Position X5 is: N, Y, R, C, K, or L; (f) Position X6 is: Q, G, K, R, T, L, or Y; and (g) Position X7 is: Q, L, R or V; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(g).

[0222] 131. The AAV capsid variant as described in embodiment 130, wherein

[0223] (a) Position X1 is S; (b) Position X2 is K or L; (c) Position X3 is: A, R, or L; (d) Position X4 is: Q or R; (e) Position X5 is: N or R; (f) Position X6 is: Q or R; and (g) Position X7 is: Q, L or R.

[0224] 132. AAV capsid variant as described in embodiment 130 or 131, wherein [B] comprises: (i) SLLWNQQ (SEQ ID NO: 5247)、SKAQYYV (SEQ ID NO: 5248)、SKLRRQQ (SEQID NO: 5249)、SIWQNQQ (SEQ ID NO: 5250)、SKAGCGQ (SEQ ID NO: 5251)、SRAQNQQ (SEQID NO: 5252)、SKRLRQQ (SEQ ID NO: 5253)、SLRRNQQ (SEQ ID NO: 5254)、SRGRNQQ (SEQID NO: 5255)、SEIVNQQ (SEQ ID NO: 5256)、SSRRNQQ (SEQ ID NO: 5257)、CLLQNQQ (SEQID NO: 5258)、SKAFRLQ (SEQ ID NO: 5259)、CLAQNQQ (SEQ ID NO: 5260)、FLRQNQQ (SEQID NO: 5261)、SLRFNQQ (SEQ ID NO: 5262)、SYLRNQQ (SEQ ID NO: 5263)、CSLQNQQ (SEQID NO: 5264)、VLWQNQQ (SEQ ID NO: 5265)、SKWLLQQ (SEQ ID NO: 5266)、SLWSNQQ (SEQID NO: 5267)、SKRRLQQ (SEQ ID NO: 5268)、SVYLNQQ (SEQ ID NO: 5269)、SLWLNQQ (SEQID NO: 5270)、SKAQRKL (SEQ ID NO: 5271)、SKALRRQ (SEQ ID NO: 5272)、SKAQRLR (SEQID NO: 5273)、SKAQNQQ (SEQ ID NO: 5274)、SKAQRRL (SEQ ID NO: 5275)、SKARRQQ (SEQID NO: 5276)、SKARRLQ (SEQ ID NO: 5277)、SKSRRQQ (SEQ ID NO: 5278)、SKARLRQ (SEQID NO: 5279)、SKASKRQ (SEQ ID NO: 5280)、VRRQNQQ (SEQ ID NO: 5281)、SKAQLYR (SEQID NO: 5282)、SLFRNQQ (SEQ ID NO: 5283)、SKAQLTV (SEQ ID NO: 5284); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5 or 6 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0225] 133. AAV capsid variant as described in any one of embodiments 130 to 132, wherein [A][B] comprises: (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)、GSGSPHSEIVNQQ (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 (SEQ ID NO: 2072)、GSGSPHSLWSNQQ (SEQ ID (SEQ ID NO: 5293) GSGSPHSKRRLQQ (SEQ ID NO: 2073) GSGSPHSVYLNQQ (SEQ ID NO: 5294) GSGSPHSLWLNQQ (SEQ ID NO: 5295) GSGSPHSKAQRKL (SEQ ID NO: 2074) GSGSPHSKALRRQ (SEQ ID NO: 2075) GSGSPHSKAQRLR (SEQ ID NO: 2076) GSGSPHSKAQNQQ (SEQ ID NO: 1801) GSGSPHSKAQRRL (SEQ ID NO: 2077) GSGSPHSKARRQQ (SEQ ID NO: 2078) GSGSPHSKARRLQ (SEQ ID NO:2079), GGSPHSKSRRQQ (SEQ ID NO: 2080), GGSPHSKARLRQ (SEQ ID NO: 2082), GSGSPHSKASKRQ (SEQ ID NO: 2083), GGSSPSVRRQNQQ (SEQ ID NO: 2084), GGSSPHSKAQLYR (SEQ ID NO: 2085), GGSSPHSLFRNQQ (SEQ ID NO: 5296), GGSSPHSKAQLTV (SEQ ID NO: 2086); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0226] 134. The AAV capsid variant as described in any one of embodiments 130 to 133, which, relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138, further comprises one, both, or all of the following: an amino acid other than T (e.g., S, Y, or G) at position 450, an amino acid other than I (e.g., M or L) at position 451, and / or an amino acid other than N (e.g., S) at position 452.

[0227] 135. The AAV capsid variant as described in any one of embodiments 130 to 134, further comprising, relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, an S at position 450 and an M at position 451.

[0228] 136. The AAV capsid variant as described in any one of embodiments 130 to 134, further comprising, relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, Y at position 450, L at position 451, and S at position 452.

[0229] 137. The AAV capsid variant as described in any one of embodiments 130 to 134, further comprising, relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, G at position 450, L at position 451 and S at position 452.

[0230] 138. AAV capsid variant as described in any one of embodiments 130 to 137, wherein [A][B] is present in ring IV.

[0231] 139. The AAV capsid variant as described in any one of embodiments 130 to 138, wherein [A] is immediately following position 452 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 138.

[0232] 140. The AAV capsid variant as described in any one of embodiments 130 to 139, wherein [A] is replaced at positions 453-455 (e.g., G453, S454, G455) relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0233] 141. The AAV capsid variant as described in any one of embodiments 130 to 140, wherein [A] is immediately present after position 452 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138, and wherein [A] replaces positions 453-455 (e.g., G453, S454, G455).

[0234] 142. AAV capsid variant as described in any one of embodiments 130 to 141, wherein [B] immediately follows [A].

[0235] 143. The AAV capsid variant as described in any one of embodiments 130 to 142, wherein [B] replaces positions 456-459 (e.g., Q456, N457, Q458, Q459) relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0236] 144. The AAV capsid variant as described in any one of embodiments 130 to 143, wherein [A][B] substitution positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, Q459) are relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0237] 145. The AAV capsid variant as described in any one of embodiments 130 to 144, wherein [A][B] is immediately present after position 452 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138, and wherein [A][B] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, Q459).

[0238] 146. The AAV capsid variant as described in any one of embodiments 130 to 145, comprising [A][B] from the N-terminus to the C-terminus.

[0239] 147. An AAV capsid comprising: (A) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring 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; and / or (B) [A][B] (SEQ ID NO: 4699), where: (i) [A] contains X1 X2 X3 X4 X5 X6, where (a) Position X1 is T, M, A, C, I, R, L, D, F, V, Q, N, or H; (b) Position X2 is I, P, E, N, D, S, A, T, M, or Q; (c) Position X3 is N, E, G, Y, W, M, T, I, K, Q, F, S, V, A or L; (d) Position X4 is G, D, R, or E; (e) Position X5 is H, Q, N, or D; (f) Position X6 is D or R; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conserved substitution, of any one of the aforementioned amino acids in (a)-(f); and (ii) [B] Contains SPHKSG (SEQ ID NO: 946).

[0240] 148. The AAV cap as described in embodiment 147, wherein

[0241] (a) Position X1 is: T, M, A or I; (b) Position X2 is: E, I, or D; (c) Position X3 is: N, Q, Y, I, M, or V; (d) Position X4 is G; (e) Position X5 is H; and (f) Position X6 is D.

[0242] 149. AAV capsid variant as described in embodiment 147 or 148, wherein [A] comprises: (i) TINGHD (SEQ ID NO: 5297)、MPEGHD (SEQ ID NO: 5298)、MEGGHD (SEQ IDNO: 5299)、MEYGHD (SEQ ID NO: 5300)、AEWGHD (SEQ ID NO: 5301)、CEWGHD (SEQ IDNO: 5302)、ANNGQD (SEQ ID NO: 5303)、IPEGHD (SEQ ID NO: 5304)、ADMGHD (SEQ IDNO: 5305)、IEYGHD (SEQ ID NO: 5306)、ADYGHD (SEQ ID NO: 5307)、IETGHD (SEQ IDNO: 5308)、MEWGHD (SEQ ID NO: 5309)、CEYGHD (SEQ ID NO: 5310)、RINGHD (SEQ IDNO: 5311)、MEIGHD (SEQ ID NO: 5312)、LEYGHD (SEQ ID NO: 5313)、ADWGHD (SEQ IDNO: 5314)、IEIGHD (SEQ ID NO: 5315)、TIKDND (SEQ ID NO: 5316)、DIMGHD (SEQ IDNO: 5317)、FEQGHD (SEQ ID NO: 5318)、MEFGHD (SEQ ID NO: 5319)、CDQGHD (SEQ IDNO: 5320)、LPEGHD (SEQ ID NO: 5321)、IENGHD (SEQ ID NO: 5322)、MESGHD (SEQ IDNO: 5323)、AEIGHD (SEQ ID NO: 5324)、VEYGHD (SEQ ID NO: 5325)、TSNGDD (SEQ IDNO: 5326)、IEVGHD (SEQ ID NO: 5327)、MEMGHD (SEQ ID NO: 5328)、AEVGHD (SEQ IDNO: 5329)、MDAGHD (SEQ ID NO: 5330)、VEWGHD (SEQ ID NO: 5331)、AEQGHD (SEQ IDNO: 5332)、LEWGHD (SEQ ID NO: 5333)、MELGHD (SEQ ID NO: 5334)、METGHD (SEQ IDNO: 5335)、MEAGHD (SEQ ID NO: 5336)、TINRQR(SEQ ID NO: 5337), IESGHD (SEQ ID NO: 5338), TAKDHD (SEQ ID NO: 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 contains any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0243] 150. AAV capsid variant as described in any one of embodiments 147-149, wherein [A][B] comprises: (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)、IETGHDSPHKS (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: 5374) 5375)、MEFGHDSPHKS (SEQ ID NO: 5376)、CDQGHDSPHKS (SEQ ID NO: 5377)、LPEGHDSPHKS (SEQ ID NO: 5378)、IENGHDSPHKS (SEQ ID NO: 5379)、MESGHDSPHKS (SEQ ID NO: 5380)、AEIGHDSPHKS (SEQ ID NO: 5381)、VEYGHDSPHKS (SEQ ID NO: 5382)、TSNGDDSPHKS (SEQ ID NO: 5383)、IEVGHDSPHKS (SEQ ID NO: 5384)、MEMGHDSPHKS (SEQ ID NO: 5385)、AEVGHDSPHKS (SEQ ID NO: 5386)、MDAGHDSPHKS(SEQ ID NO: 5387), VEWGHDSPHKS (SEQ ID NO: 5388), AEQGHDSPHKS (SEQ ID NO: 5389), LEWGHDSPHKS (SEQ ID NO: 5390), MELGHDSPHKS (SEQ ID NO: 5391), METGHDSPHKS (SEQ ID NO: 5392), MEAGHDSPHKS (SEQ ID NO: 5393), TINRQRSPHKS (SEQ ID NO: 5394), IESGHDSPHKS (SEQ ID NO: 5395), TAKDHDSPHKS (SEQ ID NO: 5396), MEVGHDSPHKS (SEQ ID NO: 5397), CEIGHDSPHKS (SEQ ID NO: 5398), ATNGHDSPHKS (SEQ ID NO: 5399), MDGGHDSPHKS (SEQ ID NO: 5400), QEVGHDSPHKS (SEQ ID NO: 5401), ADQGHDSPHKS (SEQ ID NO: 5402), NNMNGHDSPHKS (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 that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0244] 151. The AAV capsid variant as described in any one of embodiments 147 to 150, which, relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138, further comprises one, two, three, four, or all of the following: an amino acid other than Q (e.g., R or L) at position 456, an amino acid other than N (e.g., H, K, or R) at position 457, an amino acid other than Q (e.g., R or T) at position 458, an amino acid other than Q (H) at position 459, and / or an amino acid other than T (N or S) at position 460.

[0245] 152. The AAV capsid variant as described in any one of embodiments 147 to 151, further comprising R at position 456 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0246] 153. The AAV capsid variant as described in any one of embodiments 147 to 151, which further comprises L at position 456 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0247] 154. The AAV capsid variant as described in any one of embodiments 147 to 153, which, relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, further comprises H at position 457 and R at position 458.

[0248] 155. The AAV capsid variant as described in any one of embodiments 147 to 153, which, relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, further comprises K at position 457 and N at position 460.

[0249] 156. The AAV capsid variant as described in any one of embodiments 147 to 153, which, relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, further comprises T at position 458, H at position 459 and S at position 460.

[0250] 157. The AAV capsid variant as described in any one of embodiments 147 to 151, which, relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, further comprises R at position 456, R at position 457 and R at position 458.

[0251] 158. AAV capsid variant as described in any one of embodiments 147 to 157, wherein [A][B] is present in ring IV.

[0252] 159. The AAV capsid variant as described in any one of embodiments 147 to 158, wherein [A] is immediately following position 449 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 138.

[0253] 160. The AAV capsid variant as described in any one of embodiments 147 to 159, wherein [A] is replaced at positions 450-453 (e.g., T450, I451, N452, G453) relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0254] 161. The AAV capsid variant as described in any one of embodiments 147 to 160, wherein [A] is immediately present after position 449 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138, and wherein [A] replaces positions 450-453 (e.g., T450, I451, N452, G453).

[0255] 162. The AAV capsid variant as described in any one of embodiments 147 to 161, wherein [A][B] substitution positions 450-455 (e.g., T450, I451, N452, G453, S454, G455) are relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0256] 163. The AAV capsid variant as described in any one of embodiments 147 to 162, wherein [A][B] is immediately present after position 449 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, and wherein [A][B] replaces positions 450-455 (e.g., T450, I451, N452, G453, S454, G455).

[0257] 164. The AAV capsid variant as described in any one of embodiments 147 to 163, wherein [B] is immediately following [A] relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, and positions 454 and 455 (e.g., S454 and G455) are substituted.

[0258] 165. The AAV capsid variant as described in any one of embodiments 147 to 164, wherein [B] is immediately following position 455 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 982.

[0259] 166. AAV capsid variant as described in any one of embodiments 147 to 165, wherein [B] immediately follows [A].

[0260] 167. The AAV capsid variant as described in any one of embodiments 147 to 166, comprising [A][B] from the N-terminus to the C-terminus.

[0261] 168. An AAV capsid variant comprising: (A) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring 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; and / or (B) Having the following amino acid sequence: [N1]-[N2]-[N3] (SEQ ID NO: 6407), wherein: (i) [N1] contains positions X1, X2 and X3, where position X2 is S and position X3 is G; (ii) [N2] contains the amino acid sequence SPH; and (iii) [N3] contains positions X4, X5 and X6, where position X5 is K.

[0262] 169. AAV capsid variant as described in embodiment 168, wherein: (i) X4 of [N3] is S, T, N, or A; and (ii) X5 of [N3] is A, V, T, S, G, R, L or N; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (i) or (ii).

[0263] 170. AAV capsid variant as described in embodiment 168 or 169, wherein X4 is S and / or X5 is A.

[0264] 171. AAV capsid variant as described in any one of embodiments 168 to 170, wherein [N3] comprises SK, TK, NK, AK, KA, KV, KT, KS, KG, KR, KL or KN.

[0265] 172. AAV capsid variant as described in any one of embodiments 168 to 171, wherein [N3] is or includes SKA, SKV, SKT, SKS, SKG, SKR, TKA, NKA, SKL, SKN or AKA.

[0266] 173. AAV capsid variant as described in any one of embodiments 168 to 172, wherein [N3] is or contains SKA.

[0267] 174. The AAV capsid variant as described in any one of embodiments 168 to 173, wherein [N2]-[N3] comprises SPHSK (SEQ ID NO: 4701), SPHTK (SEQ ID NO: 4725), SPHNK (SEQ ID NO: 4726) or SPHAK (SEQ ID NO: 4727).

[0268] 175. AAV capsid variant as described in any one of embodiments 168 to 174, wherein [N2]-[N3] is or comprises: (i) SPHSKA (SEQ ID NO: 941), SPHSKV (SEQ ID NO: 4737), SPHSKT (SEQ ID NO: 4731), SPHSKS (SEQ ID NO: 962), SPHSKG (SEQ ID NO: 4732), SPHSKR (SEQ ID NO: 978), SPHTKA (SEQ ID NO: 4739), SPHNKA (SEQ ID NO: 4734), SPHSKL (SEQ ID NO: 960), SPHSKN (SEQ ID NO: 4735) or SPHAKA (SEQ ID NO: 4736); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0269] 176. AAV capsid variant as described in any one of embodiments 168 to 175, wherein [N2]-[N3] is or contains SPHSKA (SEQ ID NO: 941).

[0270] 177. An AAV capsid variant as described in any one of embodiments 168 to 176, comprising an amino acid other than G (e.g., M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D) at position 453 according to SEQ ID NO: 138 or 981.

[0271] 178. The AAV capsid variant as described in any one of embodiments 168 to 177, comprising amino acid G at position 453 according to SEQ ID NO: 138 or 981.

[0272] 179. The AAV capsid variant as described in 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; optionally wherein the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids.

[0273] 180. AAV capsid variant as described in any one of embodiments 168 to 179, wherein [N1] comprises SG, GS, MS, TS, IS, ES, SS, AS, NS, VS, LS, KS, HS, PS, RS, WS, or DS.

[0274] 181. The AAV capsid variant as described in any one of embodiments 168 to 180, wherein [N1] is or comprises: GSG, MSG, TSG, ISG, ESG, SSG, ASG, NSG, VSG, LSG, KSG, HSG, PSG, RSG, WSG, or DSG.

[0275] 182. AAV capsid variant as described in any one of embodiments 168 to 181, wherein [N1] is or contains GSG.

[0276] 183. AAV capsid variant as described in any one of embodiments 168 to 182, wherein [N1]-[N2] comprises SGSPH (SEQ ID NO: 4752).

[0277] 184. AAV capsid variant as described in any one of embodiments 168 to 183, wherein [N1]-[N2] is or comprises: (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 that contains any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0278] 185. AAV capsid variant as described in any one of embodiments 168 to 184, wherein [N1]-[N2]-[N3] are or comprise: (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), GGSSPHSKA (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), GGSSPHSKR (SEQ ID NO: 4945), HSGSPHSKA (SEQ ID NO: 4973), PSGSPHSKA (SEQ ID NO: 4975), RGSSPHSKA (SEQ ID NO: 4977), GGSSPHTKA (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 contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8 or 9 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0279] 186. AAV capsid variant as described in any one of embodiments 168 to 185, wherein [N1]-[N2]-[N3] is or contains GGSPHSKA (SEQ ID NO: 4697).

[0280] 187. AAV capsid variants as described in any of embodiments 168 to 186, which are relative to those according to SEQ ID Reference sequence number NO:138 includes an amino acid other than Q at position 456 (e.g., R, P, H, L, K, I, G, S, M, or E), an 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), an amino acid other than Q at position 458 (e.g., R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, or D), 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).

[0281] 188. AAV capsid variants as described in any of embodiments 168 to 187, which are relative to those according to SEQ ID Reference sequence number NO:981 includes an amino acid other than Q at position 462 (e.g., R, P, H, L, K, I, G, S, M, or E), an 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), an amino acid other than Q at position 464 (e.g., R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, or D), 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).

[0282] 189. The AAV capsid variant as described in any one of embodiments 168 to 188, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138, 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.

[0283] 190. The AAV capsid variant as described in 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, according to SEQ ID NO:981.

[0284] 191. The AAV capsid variant as described in any one of embodiments 168 to 190, further comprising [N4], wherein [N4] comprises X7, X8, X9, X10, and X11, wherein: (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; and (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q; Optionally, the AAV capsid variant may contain an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(e).

[0285] 192. The AAV capsid variant as described in embodiment 191, wherein [N4] is or comprises: (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 IDNO: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: 5458)、QNQQY (SEQ ID NO:5459)、QKLNT (SEQ ID NO: 5460)、QNVQT (SEQ ID NO: 5461)、QAQQT (SEQ ID NO:5462)、QNLQA (SEQ ID NO: 5463)、QTPPT (SEQ ID NO: 5464)、QYQHA (SEQ ID NO:5465)、QGQQA (SEQ ID NO: 5466)、QPPAT (SEQ ID NO: 5467)、QERPT (SEQ ID NO:5468)、QDLQT (SEQ ID NO:5468) NO: 5469), QAMHT (SEQ ID NO: 5470), LNNQQT (SEQ ID NO: 5471), QHPST (SEQ ID NO: 5472), PGLQT (SEQ ID NO: 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: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 IDNO: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: 5520)、QVPAT (SEQ ID NO: 5521)、QDKQT (SEQ ID NO:5522)、HYQQT (SEQ ID NO: 5523)、QVPST (SEQ ID NO: 5524)、RGEQT (SEQ ID NO:5525)、PGQQT (SEQ ID NO: 5526)、QSLQI (SEQ ID NO: 5527)、LEQQT (SEQ ID NO:5528)、QNQST (SEQ ID NO: 5529)、QKVIT (SEQ ID NO: 5530)、QNNDQ (SEQ ID NO:5531)、QSVHT (SEQ ID NO: 5532)、QPLGT (SEQ ID NO: 5533)、HNQET (SEQ ID NO:5534)、QNLQI (SEQ ID NO: 5535)、QIQQT (SEQ ID NO: 5536)、QVRNT (SEQ IDNO:5537), PSNQT (SEQ ID NO: 5538), QVGHT (SEQ ID NO: 5539), QRDIT (SEQ ID NO:5540), QMPNT (SEQ ID NO: 5541), RGLQT ​​(SEQ ID NO: 5542), QKQQT (SEQ ID NO:5543), PSLQT (SEQ ID NO: 5544), QRDQT (SEQ ID NO: 5545), QAKGT (SEQ ID NO: 5546), QSAHT (SEQ ID NO: 5547), QSTMT (SEQ ID NO: 5548), QREMT (SEQ ID NO: 5549), QYRAT (SEQ ID NO: 5550), QWQQT (SEQ ID NO: 5551), QRMNT (SEQ ID NO:5552), GDSQT (SEQ ID NO: 5553), QKIST (SEQ ID NO: 5554), PSMQT (SEQ ID NO: 5555), SPRQT (SEQ ID NO: 5556), MEQQT (SEQ ID NO: 5557), QYQNT (SEQ ID NO: 5558), QHQQT (SEQ ID NO: 5559), INQQT (SEQ ID NO: 5560), PNQQH (SEQ ID NO:5561), ENRQT (SEQ ID NO:5562), QTQQA (SEQ ID NO:5563) or QNQAT (SEQ ID NO:5564); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any two, three, or four amino acids therein, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0286] 193. AAV capsid variant as described in embodiment 191 or 192, wherein [N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 200 or 2887-3076; (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0287] 194. AAV capsid variant as described in any one of embodiments 191 to 193, wherein [N1]-[N2]-[N3]-[N4] is or contains GGSGSPHSKAQNQQT (SEQ ID NO: 200).

[0288] 195. AAV capsid variant as described in any one of embodiments 191 to 193, wherein [N1]-[N2]-[N3]-[N4] is or contains VSGSPHASKAQNQQT (SEQ ID NO: 903).

[0289] 196. The AAV capsid variant as described in any one of embodiments 168 to 195, comprising, relative to the reference sequence numbered according to SEQ 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).

[0290] 197. The AAV capsid variant as described in any one of embodiments 168 to 196, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138 or 981, 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.

[0291] 198. AAV capsid variant as described in any one of embodiments 168 to 197, further comprising [N0], wherein [N0] comprises XA X B X C and X D ,in: (a) X A It is K, T, E, or N; (b) X B It is T, S, E, A, N, V, Q, or G; (c) X C It is I, F, E, V, L, D, S, C, T, A, N, H, R, G, or W; and (d) X D It is N, I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(d).

[0292] 199. AAV capsid variant as described in embodiment 198, wherein [N0] is or comprises: (i) KTII (SEQ ID NO: 5565)、KTFP (SEQ ID NO: 5566)、KTEK (SEQ ID NO:5567)、KTVN (SEQ ID NO: 5568)、KTFN (SEQ ID NO: 5569)、KTIN (SEQ ID NO: 5570)、TTIN (SEQ ID NO: 5571)、KSIN (SEQ ID NO: 5572)、KTER (SEQ ID NO: 5573)、KELH(SEQ ID NO: 5574)、KAIN (SEQ ID NO: 5575)、KTDN (SEQ ID NO: 5576)、KTFH (SEQ IDNO: 5577)、KTSN (SEQ ID NO: 5578)、ETIN (SEQ ID NO: 5579)、NTIN (SEQ ID NO: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 IDNO: 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 (SEQ ID NO: 5598)、NTIY (SEQ ID NO: 5599)、KTFS(SEQ ID NO: 5600)、KTES (SEQ ID NO: 5601)、KTTN (SEQ ID NO: 5602)、KTED (SEQ IDNO: 5603)、KTNN (SEQ ID NO: 5604)、KEVH (SEQ ID NO: 5605)、KTIS (SEQ ID NO:5606)、KTVR (SEQ ID NO: 5607)、KTDR (SEQ ID NO:5608)、ETIK (SEQ ID NO: 5609)、KNHI (SEQ ID NO: 5610)、KESD (SEQ ID NO: 5611)、KTIK (SEQ ID NO: 5612)、KTDL(SEQ ID NO: 5613)、KTV ID NO: 5614)、KTVI (SEQ ID NO: 5615)、KAEH (SEQ IDNO: 5616)、KNCL (SEQ ID NO: 5617)、KTVK (SEQ ID NO: 5618)、KNAD (SEQ ID NO: 5619)、KNAD (SEQ ID NO: 5619)、K IDNO: 5620)、KNCV (SEQ ID NO: 5621)、KNAL (SEQ ID NO: 5622)、KVIN (SEQ ID NO: 5623)、KTEF (SEQ ID NO: 5624)、KTRE (SEQ ID NO: 5625)、KTRE (SEQ ID NO: 5625)、SEQ ID NO: 5625) 5626)、KSEK (SEQ ID NO: 5627)、KNVN (SEQ ID NO: 5628)、KGGE (SEQ IDNO: 5629)、KEFV (SEQ ID NO: 5630)、KSDK (SEQ ID NO: 5631) (SEQ ID NO: 5631) 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)、KSDI (SEQ ID NO: 5637) (SEQ ID NO: 5637) 5638)、KNSL(SEQ ID NO: 5639)、KEVV (SEQ ID NO: 5640)、KTEP (SEQ ID NO: 5641)、KSEL (SEQ IDNO: 5642)、KTWQ (SEQ ID NO: 5643)、KTWQ (SEQ ID NO: 5643) (SEQ ID NO: 5643) 5644)、KAVN (SEQ ID NO:5645)、KGVL (SEQ ID NO: 5646)、KTEG (SEQ ID NO: 5647)、KTRD (SEQ ID NO: 5648)、KTGN (SEQ ID NO: 5649)、KTGN (SEQ ID NO: 5649) (SEQ ID NO: 5649) 5650)、FABRIC (SEQ ID NO: 5651)、KIT(SEQ IDNO: 5652), KTVH (SEQ ID NO: 5653), KETA (SEQ ID NO: 5654), KNNL (SEQ ID NO: 5655), EAIN (SEQ ID NO: 5656), KSLN (SEQ ID NO: 5657), KTIP (SEQ ID NO: 5658) or KTIH (SEQ ID NO: 5659); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any two or three of its amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0293] 200. AAV capsid variant as described in embodiment 198 or 199, wherein [N0]-[N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 3239-3526 or 3591-3605; (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0294] 201. The AAV capsid variant as described in any one of embodiments 198 to 200, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTINGSGSPHSKAQNQQT (SEQ ID NO: 5660).

[0295] 202. The AAV capsid variant as described in any one of embodiments 198 to 200, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589).

[0296] 203. An AAV capsid variant comprising: (A) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring 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; and / or (B) Having the following amino acid sequence: [N1]-[N2]-[N3] (SEQ ID NO: 6408), wherein: (i) [N1] contains positions X1, X2 and X3, where position X2 is an amino acid other than S and position X3 is an amino acid other than G; (ii) [N2] contains the amino acid sequence SPH; and (iii) [N3] contains positions X4, X5 and X6, where position X4 is K.

[0297] 204. The AAV capsid variant as described in embodiment 203, wherein: (i) X5 of [N3] is S, I, T, R, H, Y, L, or M; and (ii) X6 of [N3] is G, A, L, E, V, R, W, N, Q or K; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (i) or (ii).

[0298] 205. AAV capsid variant as described in embodiment 203 or 204, wherein X5 is S and / or X6 is G.

[0299] 206. The AAV capsid variant as described in any one of embodiments 203 to 205, wherein [N3] comprises 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.

[0300] 207. The AAV capsid variant as described in any one of embodiments 203 to 206, wherein [N3] is or comprises KSG, KIG, KTG, KRG, KSA, KSL, KSE, KSV, KSR, KSW, KSN, KHG, KYG, KSQ, KIV, KSK, KLW, KMG, or KMA.

[0301] 208. AAV capsid variant as described in any one of embodiments 203 to 207, wherein [N3] is or contains KSG.

[0302] 209. AAV capsid variants as described in any one of embodiments 203 to 208, wherein [N2]-[N3] comprise 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).

[0303] 210. AAV capsid variant as described in any one of embodiments 203 to 209, wherein [N2]-[N3] is or comprises: (i) SPHKSG (SEQ ID NO: 946), SPHKIG (SEQ ID NO: 958), SPHKTG (SEQ ID NO: 4738), SPHKRG (SEQ ID NO: 974), NPHKSG (SEQ ID NO: 5662), SPHKSA (SEQ ID NO: 977), SPHKSL (SEQ ID NO: 4740), SPHKSE (SEQ ID NO: 4741), SPHKSV (SEQ ID NO: 4742), SPHKSR (SEQ ID NO: 951), SPHKSW (SEQ ID NO: 4743), SPHKSN (SEQ ID NO: 4744), SPHKHG (SEQ ID NO: 4745), SPHKYG (SEQ ID NO: 966), SPHKSQ (SEQ ID NO:4746), SPHKIV (SEQ ID NO: 5663), SPHKSK (SEQ ID NO: 4747), SPHKLW (SEQ ID (SEQ ID NO: 4748), SPHKMG (SEQ ID NO: 4750) or SPHKMA (SEQ ID NO: 4751); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0304] 211. AAV capsid variant as described in any one of embodiments 203 to 210, wherein [N2]-[N3] is or contains SPHKSG (SEQ ID NO: 946).

[0305] 212. The AAV capsid variant as described in any one of embodiments 203 to 211, comprising an amino acid other than G (e.g., A, K, W, R, L, I, M, N, T, E, Q, Y, H, F, or V) at position 453 according to SEQ ID NO: 138 or 981.

[0306] 213. The AAV capsid variant as described in any one of embodiments 203 to 212, comprising amino acid G at position 453 according to SEQ ID NO: 138 or 981.

[0307] 214. AAV capsid variant as described in any one of embodiments 203 to 214, wherein: (i) The position X1 of [N1] is G, A, K, W, R, L, I, M, N, T, E, Q, Y, H, F or V; (ii) The position of [N1] X2 is H, Y, R, Q, N, P or D; (iii) The position X3 of [N1] is D, E, G, V or N; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (i), (ii), or (iii).

[0308] 215. AAV capsid variant as described in any one of embodiments 203 to 214, wherein position X2 of [N1] is H, and position X3 of [N1] is D.

[0309] 216. AAV capsid variant as described in any one of embodiments 203 to 215, wherein position X1 of [N1] is G, position X2 of [N1] is H, and position X3 of [N1] is D.

[0310] 217. AAV capsid variant as described in any one of embodiments 203 to 216, wherein [N1] comprises 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.

[0311] 218. AAV capsid variant as described in any one of embodiments 203 to 217, wherein [N1] is or includes 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.

[0312] 219. AAV capsid variant as described in any one of embodiments 203 to 218, wherein [N1] is or contains GHD.

[0313] 220. AAV capsid variant as described in any one of embodiments 203 to 219, wherein [N1]-[N2] comprises HDSPH (SEQ ID NO: 4703).

[0314] 221. AAV capsid variant as described in any one of embodiments 203 to 220, wherein [N1]-[N2] is or comprises: (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 (SEQ ID NO: 4835), IHDSPH (SEQ ID NO: 5670), MHDSPH (SEQ ID NO: 5671), GDDSPH (SEQ ID NO: 4792), GHNSPH (SEQ ID NO: 4836), NHDSPH (SEQ ID NO: 5672), THDSPH (SEQ ID NO: 5673), GNGSPH (SEQ ID NO: 4805), EHDSPH (SEQ ID NO: 5674), QHDSPH (SEQ ID NO: 5675), YHDSPH (SEQ ID NO: 5676), HHDSPH (SEQ ID NO: 5677), FHDSPH (SEQ ID NO: 5678) or VHDSPH (SEQ ID NO: 5679); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0315] 222. The AAV capsid variant as described in any one of embodiments 203 to 221, wherein [N1]-[N2]-[N3] are or comprise: (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) AHDSPHKSG (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), RHDSPHKSG (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), GGNSPHKRG (SEQ ID NO: 5017), EHDSPHKSG (SEQ ID NO: 5691), GHDSPHKYG (SEQ ID NO: 5018), GHDSPHKSQ (SEQ ID NO: 5019), QHDSPHKSG (SEQ ID NO: 5692), RHDSPHKIV (SEQ ID NO: 5693), YHDSPHKSG (SEQ ID NO: 5694), GNDSPHKIG (SEQ ID NO: 5020), HHDSPHKSG (SEQ ID NO: 5695), GHDSPHKSK (SEQ ID NO: 5021), FHDSPHKSG (SEQ ID NO: 5696), GHDSPHKLW (SEQ ID NO:5022), VHDSPHKSG (SEQ ID NO: 5697), GHDSPHKMG (SEQ ID NO: 5024), GHDSPHKMA (SEQ ID NO: 5025) or GDDSPHKSG (SEQ ID NO: 4938); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8 or 9 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0316] 223. The AAV capsid variant as described in any one of embodiments 203 to 222, wherein [N1]-[N2]-[N3] is or contains GHDSPHKSG (SEQ ID NO: 4698).

[0317] 224. The AAV capsid variant as described in any one of embodiments 203 to 223, which, relative to the reference sequence numbered according to SEQ ID NO: 138, comprises 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).

[0318] 225. The AAV capsid variant as described in any one of embodiments 203 to 224, comprising, relative to the reference sequence numbered according to SEQ 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).

[0319] 226. The AAV capsid variant as described in any one of embodiments 203 to 225, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138, 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.

[0320] 227. The AAV capsid variant as described in any one of embodiments 203 to 226, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138, 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.

[0321] 228. The AAV capsid variant as described in any one of embodiments 203 to 227, further comprising [N4], wherein [N4] comprises X7, X8, X9, X10, and X11, wherein: (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; and (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q; Optionally, the AAV capsid variant may contain an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(e).

[0322] 229. The AAV capsid variant as described in embodiment 228, wherein [N4] is or comprises: (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 IDNO: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: 5729)、QDQHT (SEQ ID NO:5730)、QSQHT (SEQ ID NO: 5731)、RNQQI (SEQ ID NO: 5732)、VRQQT (SEQ ID NO:5733)、QNQHS (SEQ ID NO: 5734)、AWQQT (SEQ ID NO: 5735)、QSVPT (SEQ ID NO:5736)、QNIQP (SEQ ID NO: 5737)、QNHLN (SEQ ID NO: 5738)、LDQQT (SEQ ID NO:5739)、PDQQS (SEQ ID NO: 5740)、ESQQT (SEQ ID NO: 5741)、QNKQT (SEQ ID NO:5742)、QRQLT (SEQ ID NO: 5743)、QIIVT (SEQ ID NO: 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:5758)、QTQPT (SEQ ID NO: 5759)、INQQT (SEQ ID NO: 5560)、QKQLT (SEQ IDNO: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 contains any part of the amino acid sequence in (i), such as any two, three, or four amino acids therein, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0323] 230. AAV capsid variant as described in embodiment 228 or 229, wherein [N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 201 or 3160-3237; (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0324] 231. The AAV capsid variant as described in any one of embodiments 228 to 230, wherein [N1]-[N2]-[N3]-[N4] is or contains GHDSPHKSGQNQQT (SEQ ID NO: 201).

[0325] 232. The AAV capsid variant as described in any one of embodiments 203 to 231, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138 or 982, an amino acid other than K (e.g., T) at position 449, an amino acid other than T (e.g., A, S, I, V, N, E, Y, C, G, W, or Q) at position 450, an amino acid other than I (e.g., E, V, S, T, N, D, C, G, Q, L, P, A) at position 451, and / or an amino acid other than N (e.g., S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R).

[0326] 233. The AAV capsid variant as described in any one of embodiments 203 to 232, comprising, relative to the reference sequence numbered according to SEQ ID NO: 138 or 982, 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.

[0327] 234. The AAV capsid variant as described in any one of embodiments 203 to 233, further comprising [N0], wherein [N0] comprises X A X B X C and X D ,in: (a) X A Is it K or T; (b) X B It is T, A, S, I, V, N, E, Y, C, G, W, or Q; (c) X C It is I, E, V, S, T, N, D, C, G, Q, L, P, A; and (d) X D It 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, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(d).

[0328] 235. AAV capsid variant as described in embodiment 234, wherein [N0] is or comprises: (i) KAIN (SEQ ID NO: 5575)、KTIN (SEQ ID NO: 5570)、KTES (SEQ ID NO:5601)、TTIN (SEQ ID NO: 5571)、KSIN (SEQ ID NO: 5572)、KTVN (SEQ ID NO: 5568)、KSIY (SEQ ID NO: 5775)、KTSN (SEQ ID NO: 5578)、KTTN (SEQ ID NO: 5602)、KIIN(SEQ ID NO: 5776)、KTIS (SEQ ID NO: 5606)、KAII (SEQ ID NO: 5777)、KTIK (SEQ IDNO: 5612)、KTEF (SEQ ID NO: 5624)、KTIT (SEQ ID NO: 5620)、KTNN (SEQ ID NO: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 IDNO: 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 (SEQ ID NO: 5565)、KIVN (SEQ ID NO: 5785)、KTEK(SEQ ID NO: 5567)、KTEN (SEQ ID NO: 5581)、KIGN (SEQ ID NO: 5786)、KEVM (SEQ IDNO: 5787)、KYQV (SEQ ID NO: 5788)、KTEA (SEQ ID NO: 5597)、KATN (SEQ ID NO:5586)、KTEH (SEQ ID NO: 5584)、KTVE (SEQ ID NO:5789)、KAID (SEQ ID NO: 5790)、KTIM (SEQ ID NO: 5791)、KEVG (SEQ ID NO: 5792)、KSEM (SEQ ID NO: 5793)、KAQQ(SEQ ID NO: 5794)、KAQQ(SEQ ID NO: 5794)、K IDC NO: 5795)、KASN (SEQ ID NO: 5796)、KTET (SEQ IDNO: 5594)、KTIG (SEQ ID NO: 5797)、KTDP (SEQ ID NO: 5798)、KELV (SEQ ID NO: 5799)、KELM (SEQ ID NO: 5799) (SEQ ID NO: 5801)、KTPN (SEQ ID NO: 5802)、KTDI (SEQ ID NO: 5803)、KTDQ (SEQ ID NO: 5805)、KGIN(SEQ ID NO: 5806)、KGIN(SEQ ID NO: 5806) 5807)、KSEK (SEQ ID NO: 5627)、KWSA (SEQ IDNO: 5808)、KELA (SEQ ID NO: 5809)、KQTQ (SEQ ID NO: 5810)、KGAD (SEQ ID NO: 5811)、KGAD (SEQ ID NO: 5811)、KVGE (SEQ ID NO: 5808) (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) 5819)、KNEL (SEQ ID NO: 5820)、KAAE (SEQ IDNO: 5821)、KGQN (SEQ ID NO: 5822)、KNEF (SEQ ID NO: 5823)、KTSI (SEQ ID NO:5824)、KTSI (SEQ ID NO: 5824)、SEQ IDNO: 5616)、KCDQ (SEQ ID NO: 5825)、KEIL (SEQ ID NO: 5826)、KTER (SEQ ID NO: 5573)、KNAI (SEQ ID NO: 5650)、KTDK (SEQ ID NO: 5588)、K IDTPD(SEQ ID NO: 5573)NO: 5827), KTIH (SEQ ID NO: 5659) or KTEI (SEQ ID NO: 5591); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any two or three of its amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0329] 236. AAV capsid variant as described in embodiment 234 or 235, wherein [N0]-[N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 3606-3836; (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0330] 237. The AAV capsid variant as described in any one of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTINGHDSPHKSGQNQQT (SEQ ID NO: 5828).

[0331] 238. The AAV capsid variant as described in any one of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754).

[0332] 239. AAV capsid variant as described in any one of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241).

[0333] 240. AAV capsid variant as described in any one of embodiments 168 to 239, wherein [N1]-[N2]-[N3] are present in ring IV.

[0334] 241. AAV capsid variant as described in any one of embodiments 198 to 202 or 234 to 240, wherein [N0] and [N4] are present in ring IV.

[0335] 242. The AAV capsid variant as described in any one of embodiments 198 to 202 or 234 to 241, wherein [NO] is immediately present after position 448 relative to the reference sequence with amino acid sequence number according to SEQ ID NO: 138, 981 or 982.

[0336] 243. AAV capsid variants as described in any one of embodiments 198 to 202 or 234 to 242, wherein [N0] replaces positions 449-452 (e.g., K449, T450, I451, and N452) relative to the reference sequence numbered according to SEQ ID NO: 138, 981, or 982.

[0337] 244. AAV capsid variants as described in any one of embodiments 198 to 202 or 234 to 243, wherein [N0] is immediately present after position 448 relative to the reference sequence numbered according to SEQ ID NO: 138, 981 or 982, and wherein [N0] replaces positions 449-452 (e.g., K449, T450, I451 and N452).

[0338] 245. AAV capsid variants as described in any one of embodiments 198 to 202 or 234 to 244, wherein [N0] corresponds to position 449-452 of any one of SEQ ID NO: 138, 981 or 982 (e.g., K449, T450, I451 and N452).

[0339] 246. The AAV capsid variant as described in any one of embodiments 168 to 245, wherein [N1] is immediately present after position 452 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, 981 or 982.

[0340] 247. AAV capsid variant as described in any one of embodiments 168 to 246, wherein [N1] replaces positions 453-455 (e.g., G453, S454, and G455) relative to the reference sequence numbered according to SEQ ID NO: 138, 981, or 982.

[0341] 248. AAV capsid variant as described in any one of embodiments 168 to 246, wherein [N1] replaces position 453 (e.g., G453) relative to the reference sequence numbered according to SEQ ID NO: 138, 981 or 982.

[0342] 249. AAV capsid variants as described in any one of embodiments 168 to 177, 179 to 181, 183 to 185, 187 to 193, 195 to 200, 202 or 240 to 246, wherein: (i) Replace position 453 (e.g., G453) with position X1 of [N1]; (ii) Position X2 of [N1] corresponds to position 454 (e.g., S454); and (iii) Position X3 of [N1] corresponds to position 455 (e.g., G455). (i), (ii) and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981.

[0343] 250. AAV capsid variants as described in any one of embodiments 168 to 176, 178 to 201, or 240 to 246, wherein: (i) The position X1 of [N1] corresponds to position 453 (e.g., G453); (ii) Position X2 of [N1] corresponds to position 454 (e.g., S454); and (iii) The position X3 of [N1] corresponds to position 455 (e.g., G455); (i), (ii) and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981.

[0344] 251. AAV capsid variant as described in any one of embodiments 203 to 248, wherein: (i) The position X1 of [N1] corresponds to position 453 (e.g., G453); (ii) Replace position 454 (e.g., S454) with position X2 of [N1]; and (iii) Replace position 455 with position X3 of [N1] (e.g., G455). (i), (ii) and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0345] 252. The AAV capsid variant as described in any one of embodiments 203 to 248 or 251, wherein [N1] corresponds to positions 453-455 of SEQ ID NO: 982 (e.g., G453, H454, D455).

[0346] 253. AAV capsid variant as described in any one of embodiments 168 to 176, 178 to 201, 240 to 247 or 250, wherein [N1] corresponds to position 453-455 of SEQ ID NO: 138 or 981 (e.g., G453, S454, G455).

[0347] 254. The AAV capsid variant as described in any one of embodiments 168 to 253, wherein [N2] is immediately present after position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, 981 or 982.

[0348] 255. AAV capsid variant as described in any one of embodiments 168 to 254, wherein [N2] corresponds to positions 456-458 of SEQ ID NO: 981 or 982 (e.g., S456, P457, and H458).

[0349] 256. AAV capsid variant as described in any one of embodiments 168 to 254, wherein [N2] corresponds to position 456-458 (e.g., S456, P457, and H458) of any one of SEQ ID NO: 5-10, 36-59, or 6409-6413.

[0350] 257. AAV capsid variant as described in any one of embodiments 168 to 256, wherein [N2] immediately follows [N1].

[0351] 258. AAV capsid variants as described in any one of embodiments 168 to 202, 240 to 247, 249 to 257, wherein [N3] corresponds to positions 459-460 of SEQ ID NO: 981 (e.g., S459, K460, A461).

[0352] 259. AAV capsid variants as described in any one of embodiments 168 to 202, 240 to 247, 249 to 257, wherein [N3] corresponds to positions 459-460 (e.g., S459, K460, A461) of SEQ ID NO: 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57 or 59.

[0353] 260. The AAV capsid variant as described in any one of embodiments 168 to 259, wherein [N2]-[N3] are immediately present after position 455 relative to the reference sequence numbered according to the amino acid sequence number of any one of SEQ ID NO: 138, 981 or 982.

[0354] 261. The AAV capsid variant as described in any one of embodiments 168 to 259, wherein [N2]-[N3] are immediately present after position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 981.

[0355] 262. AAV capsid variant as described in any one of embodiments 168 to 261, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 981 (e.g., S456, P457, H458, S459, K460, A461).

[0356] 263. AAV capsid variant as described in any one of embodiments 168 to 262, wherein [N2]-[N3] correspond to positions 456-461 (e.g., S456, P457, H458, S459, K460, A461) of any of SEQ ID NO: 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57 or 59.

[0357] 264. AAV capsid variants as described in any one of embodiments 203 to 257 or 259 to 261, wherein [N3] corresponds to positions 459-460 of SEQ ID NO: 982 (e.g., K459, S460, G461).

[0358] 265. AAV capsid variant as described in any one of embodiments 203 to 257 or 259 to 261, wherein [N3] corresponds to positions 459-460 of SEQ ID NO: 37 (e.g., K459, S460, G461).

[0359] 266. The AAV capsid variant as described in any one of embodiments 203 to 265, wherein [N2]-[N3] are immediately present after position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 982.

[0360] 267. AAV capsid variant as described in any one of embodiments 203 to 246, 248, 252, 255, 257, 260, 263 to 266, wherein [N3] replaces positions 454 and 455 (e.g., S454 and G455) according to SEQ ID NO: 138.

[0361] 268. AAV capsid variant as described in any one of embodiments 203 to 246, 248, 252, 255, 257, 260, 263 to 267, wherein [N3] immediately follows [N2] and replaces positions 454 and 455 (e.g., S454 and G455) according to SEQ ID NO: 138.

[0362] 269. AAV capsid variant as described in any one of embodiments 203 to 246, 248, 252, 255, 257, 260, 263 to 268, wherein [N3] is immediately present after [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455) numbered according to SEQ ID NO: 138.

[0363] 270. AAV capsid variant as described in any one of embodiments 203 to 257, 260, 264 to 269, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 982 (e.g., S456, P457, H458, K459, S460, G461).

[0364] 271. AAV capsid variant as described in any one of embodiments 203 to 257, 260, 264 to 270, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 37 (e.g., S456, P457, H458, K459, S460, G461).

[0365] 272. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 271, wherein [N4] is immediately present after position 455 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 138.

[0366] 273. The AAV capsid variant as described in any one of embodiments 191 to 202, wherein, relative to the reference sequence according to the amino acid sequence numbering of SEQ ID NO: 138 or 228 to 272, [N4] is replaced at positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460).

[0367] 274. AAV capsid variants as described in any one of embodiments 191 to 202 or 228 to 273, wherein [N4] corresponds to positions 462-466 ​​of SEQ ID NO: 981 or 982 (e.g., Q462, N463, Q464, Q465, and T466).

[0368] 275. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 273, wherein [N4] corresponds to position 462-466 ​​of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413.

[0369] 276. AAV capsid variants as described in any one of embodiments 191 to 202 or 228 to 274, wherein [N4] corresponds to positions 456-460 of SEQ ID NO: 138 (e.g., Q456, N457, Q458, Q459, and T460).

[0370] 277. The AAV capsid variant as described in any one of embodiments 191 to 202, wherein [N2]-[N3]-[N4] substitution positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) are relative to the reference sequence according to the amino acid sequence numbering according to SEQ ID NO: 138 or 228 to 276.

[0371] 278. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 277, wherein [N2]-[N3]-[N4] is immediately present after position 455 relative to the reference sequence numbered according to SEQ ID NO: 138, and wherein [N2]-[N3]-[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460).

[0372] 279. The AAV capsid variant as described in any one of embodiments 191 to 202, wherein [N1]-[N2]-[N3]-[N4] substitution positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460) are used relative to the reference sequence according to the amino acid sequence numbering according to SEQ ID NO: 138 or 228 to 278.

[0373] 280. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 279, wherein [N1]-[N2]-[N3]-[N4] is immediately present after position 452 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138, and wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459 and T460).

[0374] 281. AAV capsid variants as described in any one of embodiments 191 to 202, 240 to 247, 249, 250, 253 to 263, 266 or 272 to 280, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-466 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465 and T466).

[0375] 282. AAV capsid variants as described in any of embodiments 168 to 202, 240 to 247, 249, 250, 253 to 263, 266 or 272 to 280, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0376] 283. AAV capsid variants as described in any of embodiments 228 to 257, 260, 261, 264 to 282, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-466 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466).

[0377] 284. AAV capsid variants as described in any of embodiments 203 to 257, 260, 261, 264 to 283, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461).

[0378] 285. AAV capsid variant as described in any one of embodiments 228 to 257, 260, 261, 264 to 282, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-466 of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413.

[0379] 286. The AAV capsid variant as described in any one of embodiments 198 to 202, wherein [N0]-[N1]-[N2]-[N3]-[N4] substitution positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459 and T460) are replaced relative to the reference sequence according to the amino acid sequence numbering according to SEQ ID NO: 138 or 234 to 286.

[0380] 287. The AAV capsid variant as described in any one of embodiments 198 to 202 or 234 to 286, wherein [N0]-[N1]-[N2]-[N3]-[N4] is immediately present after position 448 relative to the reference sequence numbered according to SEQ ID NO: 138, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459 and T460).

[0381] 288. AAV capsid variants as described in any one of embodiments 198 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286 or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of SEQ ID NO: 981 (e.g., K449, T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466).

[0382] 289. AAV capsid variants as described in any of embodiments 234 to 257, 260, 261, 264 to 284, 286 or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of SEQ ID NO: 982 (e.g., K449, T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466).

[0383] 290. AAV capsid variant as described in any one of embodiments 234 to 257, 260, 261, 264 to 284, 286 or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413.

[0384] 291. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 290, wherein [N4] is immediately present after position 461 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 981 or 982.

[0385] 292. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 291, wherein [N4] is replaced at positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0386] 293. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 292, wherein [N2]-[N3]-[N4] substitution positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) are relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 981 or 982.

[0387] 294. The AAV capsid variant as described in any one of embodiments 191 to 202 or 228 to 293, wherein [N2]-[N3]-[N4] is immediately present after position 455 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 981 or 982, and wherein [N2]-[N3]-[N4] replaces positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466).

[0388] 295. The AAV capsid variant as described in any one of embodiments 168 to 294, comprising [N2]-[N3] from the N-terminus to the C-terminus.

[0389] 296. The AAV capsid variant as described in any one of embodiments 168 to 295, comprising [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0390] 297. The AAV capsid variant as described in any one of embodiments 168 to 296, comprising [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0391] 298. The AAV capsid variant as described in any one of embodiments 168 to 297, comprising [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0392] 299. The AAV capsid variant as described in any one of embodiments 168 to 298, comprising [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0393] 300. An AAV capsid variant comprising: (A) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring 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; and / or (B) Equation [A]-[B] (SEQ ID NO: 4696), where: (i) [A] includes GSGSPH (SEQ ID NO: 4695); and (ii) [B] includes X1, X2, X3, X4, and X5, where: (a) Position X1 is S, I, F, V, C, Y, W, R, P, L, Q, M, K or G; (b) Position X2 is K, M, R, F, V, C, P, Y, L, W, G, N, S, T, I, or A; (c) Position X3 is A, Y, L, R, W, C, T, F, H, I, P, M, K, S, V, G, Q or N; (d) Position X4 is Q, M, F, K, H, R, C, W, P, V, L, G, S, Y, I, A, T, D, N, or E; and (e) Position X5 is A, N, Y, R, K, L, I, M, Q, S, C, W, F, T, G, V or P; Optionally, the AAV capsid variant may contain an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(e).

[0394] 301. A variant of the AAV capsid as described in embodiment 300, wherein: (a) Position X1 is S, L, R, V or P; (b) Position X2 is K, C, F, L, P, R, S, or V; (c) Position X3 is A, C, F, I, K, L, M, P, R, T, W, or Y; (d) Position X4 is Q, R, S, T, C, F, K, L, P, or Y; and (e) Position X5 is N, R, S, T, K, M, Q, or Y; Optionally, the AAV capsid variant may contain an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (a)-(e).

[0395] 302. The AAV capsid variant as described in embodiment 300 or 301, wherein [B] comprises SKA, SMY, SKL, SKR, SKW, SRC, SFT, SKF, IVW, SKY, SCH, FPW, SKI, VYY, 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, SLC, 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, GRY, 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, PFR, 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, ALR, AHA, CLN, AFV, AQF, RCN, MPC, KTS, PYN, AQS, TRN, LKN, AQM, CTN, PDN, RNY, ACR, 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, PWQ, KIR, YYQ, LYW, KPK, RFW, RMR, VKK, WAP, LWK, FRP, KKV, YAF, KAC, KRL, CSR, RCP, GAC, KFR, FFG, MCQ, KLF, KTR, GKR, YRQ,RVQ、GIQ、NCQ、KPF、LAW、KRS、SYQ、WLQ、KRR、KGC、KRY、GCQ、FTP、TTC、KRQ、KCF、VPQ、FWS、KFKKKKK FRY, KMI, RWQ, PTQ, KWK, YMR, KAA, LCQ, CCQ, CVQ, KLT, KLC, YLV, AFQ, KWG, KIL, FQI, KAL, LLC Q, CPQ, VRY, VRC, KMP, KKT, LPY, YHQ, YTR, VYQ, RYQ, WLK, PAQ, MCT, PPD, WTQ, RKQ, KCS, FVQ, KLPV, K AQ、LYQ、KVR、ALQ、SCT、KNS、KRK、CTQ、TCL、YAR、KQR、KRV、SGQ、YYS、LTC、CQS、KAK、KPQ、KKVCT

[0396] 303. The AAV capsid variant according to any one of embodiments 300-302, wherein [B] comprises SKAQ (SEQ ID NO: 5829), SMYM (SEQ ID NO: 5830), SKAF (SEQ ID NO: 5831), SKLK (SEQ ID NO: 5832), SKRH (SEQ ID NO: 5833), SKWR (SEQ ID NO: 5834), SRCR (SEQ ID NO: 5835), SFTC (SEQ ID NO: 5836), SKFF (SEQ ID NO: 5837), IVWQ (SEQ ID NO: 5838), SKYF (SEQ ID NO: 5839), SKAR (SEQ ID NO: 5840), SCHQ (SEQ ID NO: 5841), FPWQ (SEQ ID NO: 5842), SKIR (SEQ ID NO: 5843), VYYQ (SEQ ID NO: 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: 5861), 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 NO: 5878)、SKGC (SEQ ID NO: 5879)、VPWQ (SEQ ID NO: 5880)、SKRY (SEQ IDNO: 5881)、SGCQ (SEQ ID NO: 5882)、SFTP (SEQ ID NO: 5883)、STTC (SEQ ID NO:5884)、PKRQ (SEQ ID NO: 5885)、SKCF (SEQ ID NO: 5886)、WVPQ (SEQ ID NO: 5887)、SFWS (SEQ ID NO: 5888)、SKFK (SEQ ID NO: 5889)、RIKQ (SEQ ID NO: 5890)、SKAP(SEQ ID NO: 5891)、SFRY (SEQ ID NO: 5892)、SKMI (SEQ ID NO: 5893)、LRWQ (SEQ IDNO: 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 IDNO: 5907)、SKIL (SEQ ID NO: 5908)、SFQI (SEQ ID NO: 5909)、SKAL (SEQ ID NO:5910)、SKAH (SEQ ID NO: 5911)、SLCL (SEQ ID NO: 5912)、RPWQ (SEQ ID NO: 5913)、RPRQ (SEQ ID NO:5914)、SCPQ (SEQ ID NO: 5915)、SVRY (SEQ ID NO: 5916)、SVRC(SEQ ID NO: 5917)、SKMP (SEQ ID NO: 5918)、SKKT (SEQ ID NO: 5919)、SLPY (SEQ IDNO: 5920)、VYHQ (SEQ ID NO: 5921)、SYTR (SEQ ID NO: 5922)、LVYQ (SEQ ID NO:5923)、YRYQ (SEQ ID NO: 5924)、SWLK (SEQ ID NO: 5925)、CPAQ (SEQ ID NO: 5926)、SMCT (SEQ ID NO: 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 IDNO: 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: 5944)、SYAR (SEQ ID NO: 5945)、SKQR (SEQ IDNO: 5946)、SKRV (SEQ ID NO: 5947)、KSGQ (SEQ ID NO: 5948)、SYYS (SEQ ID NO:5949)、SLTC (SEQ ID NO: 5950)、SCQS (SEQ ID NO: 5951)、SKAK (SEQ ID NO: 5952)、SKPQ (SEQ ID NO: 5953)、FPFQ (SEQ ID NO: 5954)、SKCT (SEQ ID NO: 5955)、SVFE(SEQ ID NO: 5956)、GRYQ (SEQ ID NO: 5957)、KAQA (SEQ IDNO: 5958)、KAQN (SEQ IDNO: 5959)、MYMN (SEQ ID NO: 5960)、KAFY (SEQ ID NO: 5961)、KLKR (SEQ ID NO:5962)、KRHR (SEQ ID NO: 5963)、KAQK (SEQ ID NO: 5964)、KWRL (SEQ ID NO: 5965)、RCRN (SEQ ID NO: 5966)、FTCN (SEQ ID NO: 5967)、KFFI (SEQ ID NO: 5968)、KAQY(SEQ ID NO: 5969)、VWQN (SEQ ID NO: 5970)、KYFM (SEQ ID NO: 5971)、KARQ (SEQ IDNO: 5972)、CHQN (SEQ ID NO: 5973)、PWQN (SEQ ID NO: 5974)、KIRR (SEQ ID NO:5975)、YYQN (SEQ ID NO: 5976)、LYWN (SEQ ID NO: 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 IDNO: 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 (SEQ ID NO: 5994)、KFRQ(SEQ ID NO: 5995)、FPFN (SEQ ID NO: 5996)、FFGN (SEQ ID NO: 5997)、MCQN (SEQ IDNO: 5998)、KLFW (SEQ ID NO: 5999)、KTRK (SEQ ID NO: 6000)、GKRN (SEQ ID NO:6001)、YRQN (SEQ IDNO: 6002)、RVQN (SEQ ID NO: 6003)、GIQN (SEQ ID NO: 6004)、KAQR (SEQ ID NO: 6005)、NCQN (SEQ ID NO: 6006)、KPFR (SEQ ID NO: 6007)、LAWN(SEQ ID NO: 6008)、KRSY (SEQ ID NO: 6009)、SYQN (SEQ ID NO: 6010)、WLQN (SEQ IDNO: 6011)、SCQN (SEQ ID NO: 6012)、SWLN (SEQ ID NO: 6013)、KRRA (SEQ ID NO:6014)、KAQT (SEQ ID NO: 6015)、KGCT (SEQ ID NO: 6016)、KRYT (SEQ ID NO: 6017)、GCQN (SEQ ID NO: 6018)、FTPN (SEQ ID NO: 6019)、TTCN (SEQ ID NO: 6020)、KARM(SEQ ID NO: 6021)、KRQN (SEQ ID NO: 6022)、KCFL (SEQ ID NO: 6023)、VPQN (SEQ IDNO: 6024)、FWSN (SEQ ID NO: 6025)、KFKN (SEQ ID NO: 6026)、IKQN (SEQ ID NO:6027)、KAPR (SEQ ID NO: 6028)、FRYN (SEQ ID NO: 6029)、KMIC (SEQ ID NO: 6030)、RWQN (SEQ ID NO: 6031)、PTQN (SEQ ID NO: 6032)、KWKS (SEQ ID NO: 6033)、YMRN(SEQ ID NO: 6034)、KAAR (SEQ ID NO: 6035)、LCQN (SEQ ID NO: 6036)、CCQN (SEQ IDNO: 6037)、CVQN (SEQ ID NO: 6038)、KLTR (SEQ ID NO: 6039)、KLCT (SEQ ID NO:6040)、KIRG (SEQ ID NO: 6041)、YLVN (SEQ ID NO: 6042)、AFQN (SEQ ID NO: 6043)、KACQ (SEQ ID NO: 6044)、KWGL (SEQ ID NO: 6045)、KILR (SEQID NO: 6046)、FQIN(SEQ ID NO: 6047)、KACI (SEQ ID NO: 6048)、KALR (SEQ ID NO: 6049)、KAHA (SEQ IDNO: 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(SEQ ID NO: 6060)、YHQN (SEQ ID NO: 6061)、KAQS (SEQ ID NO: 6062)、YTRN (SEQ IDNO: 6063)、VYQN (SEQ ID NO: 6064)、RYQN (SEQ ID NO: 6065)、WLKN (SEQ ID NO:6066)、KAQM (SEQ ID NO: 6067)、PAQN (SEQ ID NO: 6068)、MCTN (SEQ ID NO: 6069)、PPDN (SEQ ID NO: 6070)、KRNY (SEQ ID NO: 6071)、WTQN (SEQ ID NO: 6072)、KACR(SEQ ID NO: 6073)、RKQN (SEQ ID NO: 6074)、KCSV (SEQ ID NO: 6075)、KARI (SEQ IDNO: 6076)、FVQN (SEQ ID NO: 6077)、KLPK (SEQ ID NO: 6078)、KSEQ (SEQ ID NO:6079)、VAQN (SEQ ID NO: 6080)、LYQN (SEQ ID NO: 6081)、KVRM (SEQ ID NO: 6082)、ALQN (SEQ ID NO: 6083)、SCTN (SEQ ID NO: 6084)、KNSR (SEQ ID NO: 6085)、KRKR(SEQ ID NO: 6086)、CTQN (SEQ ID NO: 6087)、TCLN (SEQ ID NO: 6088)、YARN (SEQ IDNO: 6089)、KQRP (SEQID NO: 6090), KRVV (SEQ ID NO: 6091), SGQN (SEQ ID NO: 6092), 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).

[0397] 304. AAV capsid variant as described in any one of embodiments 300-303, wherein [B] is or comprises: (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 (SEQ ID NO: 6133)、SKACS (SEQ ID NO:6134)、SKRLW (SEQ ID NO: 6135)、SCSRN (SEQ ID NO: 6136)、SRCPN (SEQ ID NO:6137)、SGACN (SEQ ID NO: 6138)、SKFRQ (SEQ ID NO: 6139)、SFPFN (SEQ ID NO:6140)、SFFGN (SEQ ID NO: 6141)、SMCQN (SEQ ID NO: 6142)、SKLFW (SEQ IDNO:6143)、SKTRK (SEQ ID NO: 6144)、SGKRN (SEQ ID NO: 6145)、FYRQN (SEQ ID NO:6146)、CRVQN (SEQ ID NO: 6147)、YGIQN (SEQ ID NO: 6148)、SKAQR (SEQ ID NO:6149)、VNCQN (SEQ ID NO: 6150)、SKPFR (SEQ ID NO: 6151)、SLAWN (SEQ ID NO:6152)、SKRSY (SEQ ID NO: 6153)、WSYQN (SEQ ID NO: 6154)、RWLQN (SEQ ID NO:6155)、PSCQN (SEQ ID NO: 6156)、SSWLN (SEQ ID NO: 6157)、SKRRA (SEQ ID NO:6158)、SKAQT (SEQ ID NO: 6159)、SKGCT (SEQ ID NO: 6160)、VPWQN (SEQ ID NO:6161)、SKRYT (SEQ ID NO: 6162)、SGCQN (SEQ ID NO: 6163)、SFTPN (SEQ ID NO:6164)、STTCN (SEQ ID NO: 6165)、SKARM (SEQ ID NO: 6166)、PKRQN (SEQ ID NO:6167)、SKCFL (SEQ ID NO: 6168)、WVPQN (SEQ ID NO: 6169)、SFWSN (SEQ ID NO:6170)、SKFKN (SEQ ID NO: 6171)、RIKQN (SEQ ID NO: 6172)、SKAPR (SEQ ID NO:6173)、SFRYN (SEQ ID NO: 6174)、SKMIC (SEQ ID NO: 6175)、LRWQN (SEQ ID NO:6176)、LPTQN (SEQ ID NO: 6177)、SKWKS (SEQ ID NO: 6178)、SYMRN (SEQ ID NO: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 IDNO: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 (SEQ ID NO: 6195)、SKAHA (SEQ ID NO: 6196)、SLCLN (SEQ ID NO:6197)、SKAFV (SEQ ID NO: 6198)、RPWQN (SEQ ID NO: 6199)、RPRQN (SEQ ID NO:6200)、SCPQN (SEQ ID NO: 6201)、SKAQF (SEQ ID NO: 6202)、SVRYN (SEQ ID NO:6203)、SVRCN (SEQ ID NO: 6204)、SKMPC (SEQ ID NO: 6205)、SKKTS (SEQ ID NO:6206)、SLPYN (SEQ ID NO: 6207)、VYHQN (SEQ ID NO: 6208)、SKAQS (SEQ ID NO:6209)、SYTRN (SEQ ID NO: 6210)、LVYQN (SEQ ID NO: 6211)、YRYQN (SEQ ID NO:6212)、SWLKN (SEQ ID NO: 6213)、SKAQM (SEQ ID NO: 6214)、CPAQN (SEQ ID NO:6215)、SMCTN (SEQ ID NO: 6216)、SPPDN (SEQ ID NO: 6217)、SKRNY (SEQ ID NO:6218)、RWTQN (SEQ ID NO: 6219)、SKACR (SEQ ID NO: 6220)、PRKQN (SEQ ID NO:6221)、SKCSV (SEQ ID NO: 6222)、SKARI (SEQ ID NO: 6223)、PFVQN (SEQ ID NO:6224)、SKLPK (SEQ ID NO: 6225)、SKSEQ (SEQ ID NO: 6226)、WVAQN (SEQ IDNO: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), SKRVV (SEQ ID NO: 6238), KSGQN (SEQ ID NO: 6239), SYYSN (SEQ ID NO: 6240), SLTCN (SEQ ID NO: 6241), SCQSN (SEQ ID NO:6242), SKAKG (SEQ ID NO: 6243), SKPQN (SEQ ID NO: 6244), FPFQN (SEQ ID NO: 6245), SKCTS (SEQ ID NO: 6246), SVFEN (SEQ ID NO: 6247), SKAKK (SEQ ID NO: 6248) or GRYQN (SEQ ID NO: 6249); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any two, three, or four amino acids therein, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0398] 305. AAV capsid variant as described in any one of embodiments 300 to 304, wherein [A]-[B] is or comprises: (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)、GSGSPHSKAQY (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)、GSGSPHSRFWN (SEQ ID NO: 6272)、GSGSPHSKAQC (SEQ ID NO: 6273)、GSGSPHSRMRN (SEQID NO: 6274)、GSGSPHSVKKN (SEQ ID NO: 6275)、GSGSPHSWAPN (SEQ ID NO: 6276)、GSGSPHSLWKN (SEQ ID NO: 6277)、GSGSPHSKARW (SEQ ID NO: 6278)、GSGSPHSFRPN (SEQID NO: 6279)、GSGSPHSKKVF (SEQ ID NO: 6280)、GSGSPHSYAFN (SEQ ID NO: 6281)、GSGSPHSKACS (SEQ ID NO: 6282)、GSGSPHSKRLW(SEQ ID NO: 6283)、GSGSPHSCSRN (SEQID NO: 6284)、GSGSPHSRCPN (SEQ ID NO: 6285)、GSGSPHSGACN (SEQ ID NO: 6286)、GSGSPHSKFRQ (SEQ ID NO: 6287)、GSGSPHSFPFN (SEQ ID NO: 6288)、GSGSPHSFFGN (SEQID NO: 6289)、GSGSPHSMCQN (SEQ ID NO: 6290)、GSGSPHSKLFW (SEQ ID NO: 6291)、GSGSPHSKTRK (SEQ ID NO: 6292)、GSGSPHSGKRN (SEQ ID NO: 6293)、GSGSPHFYRQN (SEQID NO: 6294)、GSGSPHCRVQN (SEQ ID NO: 6295)、GSGSPHYGIQN (SEQ ID NO: 6296)、GSGSPHSKAQR (SEQ ID NO: 6297)、GSGSPHVNCQN (SEQ ID NO: 6298)、GSGSPHSKPFR (SEQID NO: 6299)、GSGSPHSLAWN (SEQ ID NO: 6300)、GSGSPHSKRSY (SEQ ID NO: 6301)、GSGSPHWSYQN (SEQ ID NO: 6302)、GSGSPHRWLQN (SEQ ID NO: 6303)、GSGSPHPSCQN (SEQID NO: 6304)、GSGSPHSSWLN (SEQ ID NO: 6305)、GSGSPHSKRRA (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). 6332). 6337)、GSGSPHSKACQ (SEQ ID NO: 6338)、GSGSPHSKWGL (SEQID NO: 6339)、GSGSPHSKILR (SEQ ID NO: 6340)、GSGSPHSFQIN (SEQ ID NO: 6341)、GSGSPHSKACI (SEQ ID NO: 6342)、GSGSPHSKALR (SEQ ID NO: 6343)、GSGSPHSKAHA (SEQID NO: 6344)、GSGSPHSLCLN (SEQ ID NO: 6345)、GSGSPHSKAFV (SEQ ID NO: 6346)、GSGSPHRPWQN (SEQ ID NO: 6347)、GSGSPHRPRQN (SEQ ID NO: 6348)、GSGSPHSCPQN (SEQID NO: 6349)、GSGSPHSKAQF(SEQ ID NO: 6350)、GSGSPHSVRYN (SEQ ID NO: 6351)、GSGSPHSVRCN (SEQ ID NO: 6352)、GSGSPHSKMPC (SEQ ID NO: 6353)、GSGSPHSKKTS (SEQID NO: 6354)、GSGSPHSLPYN (SEQ ID NO: 6355)、GSGSPHVYHQN (SEQ ID NO: 6356)、GSGSPHSKAQS (SEQ ID NO: 6357)、GSGSPHSYTRN (SEQ ID NO: 6358)、GSGSPHLVYQN (SEQID NO: 6359)、GSGSPHYRYQN (SEQ ID NO: 6360)、GSGSPHSWLKN (SEQ ID NO: 6361)、GSGSPHSKAQM (SEQ ID NO: 6362)、GSGSPHCPAQN (SEQ ID NO: 6363)、GSGSPHSMCTN (SEQID NO: 6364)、GSGSPHSPPDN (SEQ ID NO: 6365)、GSGSPHSKRNY (SEQ ID NO: 6366)、GSGSPHRWTQN (SEQ ID NO: 6367)、GSGSPHSKACR (SEQ ID NO: 6368)、GSGSPHPRKQN (SEQID NO: 6369)、GSGSPHSKCSV (SEQ ID NO: 6370)、GSGSPHSKARI (SEQ ID NO: 6371)、GSGSPHPFVQN (SEQ ID NO: 6372)、GSGSPHSKLPK (SEQ ID NO: 6373)、GSGSPHSKSEQ (SEQID NO: 6374)、GSGSPHWVAQN (SEQ ID NO: 6375)、GSGSPHSLYQN (SEQ ID NO: 6376)、GSGSPHSKVRM (SEQ ID NO: 6377)、GSGSPHCALQN (SEQ ID NO: 6378)、GSGSPHSSCTN (SEQID NO: 6379)、GSGSPHSKNSR (SEQ ID NO: 6380)、GSGSPHSKRKR (SEQ ID NO: 6381)、GSGSPHLCTQN (SEQ ID NO: 6382)、GSGSPHSTCLN (SEQ ID NO:6383), GGSPHSYARN (SEQ ID NO: 6384), GSGSPHSKQRP (SEQ ID NO: 6385), GGSSPHSKRVV (SEQ ID NO: 6386), GGSSPHKSGQN (SEQ ID NO: 6387), GSGSPHSYYSN (SEQ ID NO: 6388), GGSSPHSLTCN (SEQ ID NO: 6389), GGSPHSCQSN (SEQ ID NO: 6390), GGSSPHSKAKG (SEQ ID NO: 6391), GGSSPHSKPQN (SEQ ID NO: 6392), GGSPHSFPFQN (SEQ ID NO: 6393), GGSPHSKCTS (SEQ ID NO: 6394), GGSSPHSVFEN (SEQ ID NO: 6395), GGSSPHSKAKK (SEQ ID NO: 6396) or GGSSPHGRYQN (SEQ ID NO: 6397); (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0399] 306. The AAV capsid as described in any one of embodiments 300 to 305, wherein [A]-[B] do not contain the amino acid sequence of GGSPHSKAQN (SEQ ID NO: 6251).

[0400] 307. The AAV capsid variant as described in any one of embodiments 300 to 306, comprising one, both, or all of the following: an amino acid other than Q (e.g., R, C, S, W, L, F, Y, H, I, V, A, or P) at position 458 relative to the SEQ ID NO: 138 number; an amino acid other than Q (e.g., K, I, R, L, or S) at position 459; and / or an amino acid other than T (e.g., R) at position 460.

[0401] 308. A variant of the AAV capsid as described in any one of embodiments 300 to 307, comprising: (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) The amino acid H at position 458; or (xii) Amino acid V at position 458; (i)-(xii) are numbered according to SEQ ID NO: 138.

[0402] 309. A variant of the AAV capsid as described in any one of embodiments 300 to 307, comprising: (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) Amino acid C at position 458 and amino acid L at position 459; (i)-(xiii) are numbered according to SEQ ID NO: 138.

[0403] 310. The AAV capsid variant as described in 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, relative to the number SEQ ID NO: 138.

[0404] 311. The AAV capsid variant as described in any one of embodiments 300 to 310, comprising one, both, or all of the following amino acids relative to the SEQ ID NO: 138 number: position 450 (other than T, e.g., Y, P, W, R, K, S, or F), position 451 (other than I, e.g., R, S, Y, L, V, H, P, A, or F), and / or position 452 (other than N, e.g., V, W, A, T, F, Y, L, R, H, S, or M).

[0405] 312. The AAV capsid variant as described in any one of embodiments 300 to 311, comprising amino acid V at position 452 according to SEQ ID NO:138.

[0406] 313. The AAV capsid variant as described in any one of embodiments 300 to 312, comprising amino acid Y at position 450 and amino acid V at position 452 according to SEQ ID NO:138.

[0407] 314. The AAV capsid variant as described in any one of embodiments 300 to 312, comprising amino acid R at position 450 and amino acid Y at position 451 according to SEQ ID NO:138.

[0408] 315. A variant of the AAV capsid as described in any one of embodiments 300 to 311, comprising: (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) Amino acid P at position 450, amino acid F at position 451, and amino acid L at position 452; (i)-(xv) are numbered according to SEQ ID NO: 138.

[0409] 316. A variant of the AAV capsid as described in any one of embodiments 300 to 315, comprising: (i) The amino acid sequence of any one of SEQ ID NO: 3849-3982, 2984-4010, 4681-4693; (ii) An amino acid sequence that contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 amino acids, such as consecutive amino acids; (iii) Contains one, two, or three, but no more than four, modifications relative to any of the amino acid sequences in (i), such as substitutions (e.g., conserved substitutions), insertions, or deletions of amino acid sequences; or (iv) An amino acid sequence that contains one, two, or three, but no more than four different amino acids, relative to any of the amino acid sequences in (i).

[0410] 317. The AAV capsid variant as described in 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).

[0411] 318. AAV capsid variant as described in any one of embodiments 300 to 317, wherein [A][B] is present in ring IV.

[0412] 319. The AAV capsid variant as described in any one of embodiments 300 to 318, wherein [A] is immediately following position 452 relative to the reference sequence with the amino acid sequence number according to SEQ ID NO: 138 or 981.

[0413] 320. The AAV capsid variant as described in any one of embodiments 300 to 319, wherein [A] is replaced at positions 453-455 (e.g., G453, S454, G455) relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138 or 981.

[0414] 321. The AAV capsid variant as described in any one of embodiments 300 to 320, wherein [A] is immediately present after position 452 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138 or 981, and wherein [A] replaces positions 453-455 (e.g., G453, S454, G455).

[0415] 322. AAV capsid variant as described in any one of embodiments 300 to 321, wherein [B] immediately follows [A].

[0416] 323. AAV capsid variant as described in any one of embodiments 300 to 322, wherein [B] replaces positions 456 and 457 (e.g., Q456, N457) relative to the SEQ ID NO: 138 number.

[0417] 324. The AAV capsid variant as described in any one of embodiments 300 to 323, wherein [A][B] substitution positions 453-457 (e.g., G453, S454, G455, Q456, N457) are relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138.

[0418] 325. The AAV capsid variant as described in any one of embodiments 300 to 324, wherein [A][B] is immediately present after position 452 relative to the reference sequence according to the amino acid sequence number of SEQ ID NO: 138, and wherein [A][B] replaces positions 453-457 (e.g., G453, S454, G455, Q456, N457).

[0419] 326. The AAV capsid variant as described in any one of embodiments 300 to 325, comprising [A][B] from the N-terminus to the C-terminus.

[0420] 327. The AAV capsid variant as described in any of the preceding embodiments, comprising, relative to SEQ ID NO: 138, at least one, two, three, or four (e.g., 1-4 to 1-5) charged amino acid residues (e.g., acidic and / or basic amino acid residues) present at the N-terminus of the amino acid sequence of SPH (e.g., within 1, 2, 3, 4, 5, or 6 amino acids starting from the amino acid sequence of SPH (e.g., within positions 450-455 according to SEQ ID NO: 138)), optionally wherein the amino acid sequence of SPH is present at positions 456-458 according to any one of SEQ ID NO: 5-10, 36-59, 981, 982, or 6409-6413.

[0421] 328. The AAV capsid variant as described in embodiment 327, wherein the amino acid sequence of SPH is present at positions 456-458 as numbered according to any of SEQ ID NO: 5-10, 36-59, 981, 982 or 6409-6413.

[0422] 329. The AAV capsid variant as described in embodiment 327 or 328, which, relative to SEQ ID NO: 138, contains fewer than four, fewer than three, fewer than two (e.g., two or one) charged amino acid residues (e.g., acidic and / or basic amino acid residues).

[0423] 330. The AAV capsid variant as described in any one of embodiments 327 to 329, comprising, relative to SEQ ID NO: 138, a charged amino acid residue (e.g., an acidic or basic amino acid residue), optionally located at any one of positions 450-455 relative to SEQ ID NO: 138.

[0424] 331. The AAV capsid variant as described in any one of embodiments 327 to 330, wherein the charged amino acid residue is an acidic amino acid (e.g., D or E).

[0425] 332. The AAV capsid variant as described in any one of embodiments 327 to 331, wherein the charged amino acid residue is a negatively charged amino acid (e.g., D or E).

[0426] 333. The AAV capsid variant as described in any one of embodiments 327 to 332, wherein the charged amino acid residue is D.

[0427] 334. The AAV capsid variant as described in any one of embodiments 327 to 333, wherein the charged amino acid residue is E.

[0428] 335. The AAV capsid variant as described in any one of embodiments 327 to 334, wherein the charged amino acid residue is a basic amino acid (e.g., K, R, or H).

[0429] 336. The AAV capsid variant as described in 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).

[0430] 337. The AAV capsid variant as described in any one of embodiments 327 to 336, wherein the charged amino acid residue is H.

[0431] 338. The AAV capsid variant as described in any one of embodiments 327 to 337, wherein the charged amino acid residue is R.

[0432] 339. The AAV capsid variant as described in any one of embodiments 327 to 338, wherein the charged amino acid residue is K.

[0433] 340. An AAV capsid variant as described in 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).

[0434] 341. The AAV capsid variant as described in any one of embodiments 327 to 340, wherein at least one, two, three or four charged amino acid residues are present in one, two, three, four, five or six (e.g., one to six) amino acids starting from the SPH amino acid sequence.

[0435] 342. The AAV capsid variant as described in any one of embodiments 327 to 341, comprising two charged amino acid residues immediately preceding the amino acid sequence of SPH (e.g., at positions 454 and 455 according to SEQ ID NO: 138 or SEQ ID NO: 982).

[0436] 343. The AAV capsid variant as described in any one of embodiments 327 to 342, comprising charged amino acid residues (e.g., E) within 1, 2, 3, 4, or 5 (e.g., 5) amino acids starting from the SPH amino acid sequence.

[0437] 344. The AAV capsid variant as described in any one of embodiments 327 to 343, comprising a charged amino acid residue (e.g., E) at position 451 numbered according to any one of SEQ ID NO: 138, 981 or 982.

[0438] 345. AAV capsid variant as described in any one of embodiments 327 to 344, comprising E at position 451 numbered according to any one of SEQ ID NO: 138, 981 or 982.

[0439] 346. The AAV capsid variant as described in any one of embodiments 327 to 345, comprising a charged amino acid residue (e.g., R or K) at position 452 numbered according to any one of SEQ ID NO: 138, 981 or 982.

[0440] 347. The AAV capsid variant as described in any one of embodiments 327 to 346, comprising R at position 452 according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0441] 348. AAV capsid variant as described in any one of embodiments 327 to 347, comprising E at position 451 and R at position 452 according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0442] 349. The AAV capsid variant as described in any one of embodiments 327 to 348, having a reduced tropism for liver cells or tissues relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981.

[0443] 350. The AAV capsid variant as described in any of the preceding embodiments, comprising, relative to SEQ ID NO: 138, at least one, two, three, or four (e.g., 1-4 to 1-5) charged amino acid residues (e.g., basic amino acid residues) present at the C-terminus of the amino acid sequence of SPH (e.g., within 1, 2, 3, 4, 5, 6, or 7 amino acids from the end of the amino acid sequence of SPH (e.g., within positions 459-465 numbered according to any of SEQ ID NO: 5-10, 36-59, 981, or 6409-6413)), optionally wherein the amino acid sequence of SPH is present at positions 456-458 numbered according to any of SEQ ID NO: 36-59, 981, or 982.

[0444] 351. The AAV capsid variant as described in embodiment 350, wherein the amino acid sequence of SPH is present at positions 456-458 as numbered according to any of SEQ ID NO: 5-10, 36-59, 981, 982 or 6409-6413.

[0445] 352. The AAV capsid variant as described in embodiment 350 or 351, which, relative to SEQ ID NO: 138, contains fewer than four, fewer than three, fewer than two (e.g., two or one) charged amino acid residues (e.g., basic amino acid residues).

[0446] 353. The AAV capsid variant as described in any one of embodiments 350 to 352, comprising, relative to SEQ ID NO: 138, a charged amino acid residue (e.g., a basic amino acid residue), optionally located at any of positions 456-460 relative to SEQ ID NO: 138 or at positions 462-466 ​​numbered according to any of SEQ ID NO: 5-10, 36-59, 981, 982 or 6409-6413.

[0447] 354. The AAV capsid variant as described in any one of embodiments 350 to 353, wherein the charged amino acid residue is a basic amino acid (e.g., R or K).

[0448] 355. The AAV capsid variant as described in any one of embodiments 350 to 354, wherein the charged amino acid residue is a positively charged amino acid (e.g., R or K).

[0449] 356. The AAV capsid variant as described in any one of embodiments 350 to 355, wherein the charged amino acid residue is R.

[0450] 357. The AAV capsid variant as described in any one of embodiments 350 to 355, wherein the charged amino acid residue is K.

[0451] 358. The AAV capsid variant as described in any one of embodiments 350 to 357, wherein at least one, two, three, or four charged amino acid residues are present in one, two, three, four, five, six, or seven (e.g., one to seven) amino acids ending in the SPH amino acid sequence.

[0452] 359. An AAV capsid variant as described in 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 according to SEQ ID NO: 981).

[0453] 360. An AAV capsid variant as described in any one of embodiments 350 to 359, comprising a charged amino acid residue (e.g., K or R) at position 459 according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0454] 361. The AAV capsid variant as described in any one of embodiments 350 to 360, comprising K at position 459 according to SEQ ID NO:981.

[0455] 362. The AAV capsid variant as described in any one of embodiments 350 to 360, comprising R at position 459 according to SEQ ID NO:981.

[0456] 363. The AAV capsid variant as described in any one of embodiments 350 to 362, comprising charged amino acid residues (e.g., R or K) at one, two, three, four, five, or all of positions 460, 461, 462, 463, 464, and / or 465 as numbered according to SEQ ID NO: 138 or 981.

[0457] 364. The AAV capsid variant as described in any one of embodiments 300 to 326 or 350 to 363, having increased tropism for liver cells or tissues relative to a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.

[0458] 365. The AAV capsid variant as described in any one of embodiments 300 to 326 or 350 to 364, when measured by an assay as described in Example 4, is enriched in the liver by at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 150, 160, 170, 180, 190, or 200 times compared to the reference sequence of SEQ ID NO: 138.

[0459] 366. The AAV capsid variant as described in any one of embodiments 300 to 326, 364 or 365, having a reduced tropism relative to a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 for CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells or spinal cord tissue.

[0460] 367. The AAV capsid variant as described in any one of embodiments 300 to 326 or 364 to 366, exhibits preferential transduction in the liver region relative to transduction in the brain and / or dorsal root ganglia (DRG).

[0461] 368. The AAV capsid variant as described in any one of embodiments 300 to 326 or 364 to 367, exhibits preferential transduction in the liver region relative to transduction in the heart and / or muscles (e.g., quadriceps).

[0462] 369. An AAV capsid variant comprising: (I) (a) The amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 13 to 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 of the sequences provided in Tables 1, 2A, 2B, 13 to 19; or (c) An amino acid sequence containing at least one, two, or three, but no more than four distinct amino acids relative to any of the sequences provided in Tables 1, 2A, 2B, 13 through 19; or (d) The amino acid sequence relative to any of the sequences provided in Tables 1, 2A, 2B, 13 to 19 contains at least one, two, or three but no more than four modifications, such as substituted (e.g., conserved substitution) amino acid sequences; and / or (II) (i) The amino acid sequence of SEQ ID NO: 6419; (ii) The amino acid sequence relative to SEQ ID NO: 6419 contains at least one or two but no more than three different amino acids; (iii) The amino acid sequence relative to SEQ ID NO: 6419 contains at least one or two modifications, such as substitutions (e.g., conservative substitutions), but no more than three modifications, such as substitutions (e.g., conservative substitutions), in the amino acid sequence; or (iv) At least 3, 4, 5, 6 or 7 consecutive amino acids from SEQ ID NO: 6419; Optionally, the amino acid sequences of (i), (ii), (iii) and / or (iv) are located at positions 590-596 according to the amino acid sequence numbering of SEQ ID NO: 981, 982, 6411 or 6412.

[0463] 370. An AAV capsid variant comprising: (I) (a) The amino acid sequence of any one of SEQ ID NO: 945-980 or 985-986; (b) An amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from any of SEQ ID NO: 945-980 or 985-986; or (c) The amino acid sequence relative to any of SEQ ID NO: 945-980 or 985-986 contains at least one, two or three but no more than four different amino acids; (d) The amino acid sequence relative to any of SEQ ID NO: 945-980 or 985-986 contains at least one, two, or three but no more than four modifications, such as substituted (e.g., conserved substitution) amino acid sequences; and / or (II) (i) The amino acid sequence of SEQ ID NO: 6419; (ii) The amino acid sequence relative to SEQ ID NO: 6419 contains at least one or two but no more than three different amino acids; (iii) The amino acid sequence relative to SEQ ID NO: 6419 contains at least one or two modifications, such as substitutions (e.g., conservative substitutions), but no more than three modifications, such as substitutions (e.g., conservative substitutions), in the amino acid sequence; or (iv) At least 3, 4, 5, 6 or 7 consecutive amino acids from SEQ ID NO: 6419; Optionally, the amino acid sequences of (i), (ii), (iii) and / or (iv) are located at positions 590-596 according to the amino acid sequence numbering of SEQ ID NO: 981, 982, 6411 or 6412.

[0464] 371. An AAV capsid variant comprising: (I) (a) The amino acid sequence of any one of SEQ ID NO: 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 NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909; (c) An amino acid sequence relative to any of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909 that contains at least one, two or three but no more than four distinct amino acids; or (d) The amino acid sequence relative to any of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909 contains at least one, two or three but no more than four modifications, such as substituted (e.g., conserved substitution) amino acid sequences; and / or (II) (i) The amino acid sequence of SEQ ID NO: 6419; (ii) The amino acid sequence relative to SEQ ID NO: 6419 contains at least one or two but no more than three different amino acids; (iii) The amino acid sequence relative to SEQ ID NO: 6419 contains at least one or two modifications, such as substitutions (e.g., conservative substitutions), but no more than three modifications, such as substitutions (e.g., conservative substitutions), in the amino acid sequence; or (iv) At least 3, 4, 5, 6 or 7 consecutive amino acids from SEQ ID NO: 6419; Optionally, the amino acid sequences of (i), (ii), (iii) and / or (iv) are located at positions 590-596 according to the amino acid sequence numbering of SEQ ID NO: 981, 982, 6411 or 6412.

[0465] 372. An AAV capsid variant comprising: (a) The amino acid sequence of any one of SEQ ID NO: 3849-4051 or 4681-4693; (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 of SEQ ID NO: 3849-4051 or 4681-4693; (c) An amino acid sequence relative to any of SEQ ID NO: 3849-4051 or 4681-4693 that contains at least one, two, or three but no more than four distinct amino acids; or (d) The amino acid sequence relative to any of SEQ ID NO: 3849-4051 or 4681-4693 contains at least one, two or three but no more than four modified, such as substituted (e.g., conservative substitution) amino acid sequences.

[0466] 373. An AAV capsid variant comprising: (a) The amino acid sequence of any one of SEQ ID NO: 4052-4092; (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 of SEQ ID NO: 4052-4092; (c) An amino acid sequence relative to any of SEQ ID NO: 4052-4092 that contains at least one, two, or three but no more than four distinct amino acids; or (d) The amino acid sequence relative to any of SEQ ID NO: 4052-4092 contains at least one, two, or three but no more than four modified, such as substituted (e.g., conservatively substituted) amino acid sequences.

[0467] 374. An AAV capsid variant comprising: (a) The amino acid sequence of any one of SEQ ID NO: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090 or 4095-4097; (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 SEQ ID NO: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090 or 4095-4097; (c) An amino acid sequence containing at least one, two, or three but no more than four distinct amino acids relative to any of SEQ ID NO: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097; or (d) The amino acid sequence relative to any of SEQ ID NO: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090 or 4095-4097 contains at least one, two or three but no more than four modified, such as substituted (e.g., conservative substitution) amino acid sequences.

[0468] 375. The AAV capsid variant as described in 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 NO: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0469] 376. The AAV capsid variant as described in any one of embodiments 369 to 375, wherein the at least three consecutive amino acids comprise SPH.

[0470] 377. The AAV capsid variant as described in any one of embodiments 369 to 371 or 376, wherein the at least four consecutive amino acids comprise SPHS (SEQ ID NO: 4700).

[0471] 378. The AAV capsid variant as described in any one of embodiments 369 to 371, 376 or 377, wherein the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 4701).

[0472] 379. The AAV capsid variant as described in any one of embodiments 369 to 371 or 376 to 378, wherein the at least 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941).

[0473] 380. The AAV capsid variant as described in embodiments 369 to 371, wherein the at least three consecutive amino acids comprise HDS.

[0474] 381. The AAV capsid variant as described in any one of embodiments 369 to 371 or 380, wherein the at least four consecutive amino acids comprise HDSP (SEQ ID NO: 4702).

[0475] 382. The AAV capsid variant as described in any one of embodiments 369 to 371, 380 or 381, wherein the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 4703).

[0476] 383. The AAV capsid variant as described in any one of embodiments 369 to 371 or 380 to 382, ​​wherein the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2).

[0477] 384. AAV capsid variant as described in any one of embodiments 369 to 371, wherein: (i) The at least three consecutive amino acids contain SPH; (ii) The at least four consecutive amino acids comprise SPHK (SEQ ID NO: 6398); (iii) The at least five consecutive amino acids comprise SPHKY (SEQ ID NO: 4715); and / or (iv) The at least 6 consecutive amino acids comprise SPHKYG (SEQ ID NO: 966).

[0478] 385. The AAV capsid variant as described in embodiment 369 or 371, comprising an amino acid sequence comprising at least one, two, or three but no more than four modifications, such as substitutions (e.g., conservative substitutions), relative to any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0479] 386. The AAV capsid variant as described in any one of embodiments 369, 371 or 385, comprising an amino acid sequence containing at least one, two or three but no more than four modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0480] 387. The AAV capsid variant as described in any one of embodiments 369, 371 or 385, comprising at least one, two or three but no more than four modifications, such as substitutions (e.g., conservative substitutions), of the amino acid sequence relative to HDSPHK (SEQ ID NO: 2).

[0481] 388. The AAV capsid variant as described in any one of embodiments 369-371, 384 or 385, comprising an amino acid sequence containing at least one, two or three but no more than four modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SPHKYG (SEQ ID NO: 966).

[0482] 389. A variant of the AAV capsid as described in embodiment 370, comprising: (i) The amino acid sequence relative to KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272) contains at least one, two, or three but no more than four modifications, such as substituted (e.g., conservative substitution) amino acid sequences; (ii) The amino acid sequence relative to KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589) contains at least one, two, or three but no more than four modifications, such as substituted (e.g., conserved substitution) amino acid sequences; (iii) The amino acid sequence relative to KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754) contains at least one, two, or three but no more than four modifications, such as substituted (e.g., conserved substitution) amino acid sequences; (iv) The amino acid sequence relative to KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241) contains at least one, two, or three but no more than four modifications, such as substituted (e.g., conserved substitution) amino acid sequences. (v) The amino acid sequence relative to KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100) contains at least one, two, or three but no more than four modifications, such as substituted (e.g., conserved substitution) amino acid sequences; or (vi) The amino acid sequence relative to KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062) contains at least one, two, or three but no more than four modifications, such as substitutions (e.g., conservative substitutions) of the amino acid sequence.

[0483] 390. The AAV capsid variant as described in embodiment 369 or 371, comprising an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to any of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0484] 391. The AAV capsid variant as described in any one of embodiments 369, 371 or 390, comprising 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).

[0485] 392. The AAV capsid variant as described in any one of embodiments 369, 371 or 390, comprising 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 HDSPHK (SEQ ID NO: 2).

[0486] 393. The AAV capsid variant as described in any one of embodiments 369, 371, 384 or 390, comprising 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 SPHKYG (SEQ ID NO: 966).

[0487] 394. The AAV capsid variant as described in embodiment 369, comprising: (i) The amino acid sequence relative to KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589) contains at least one, two, or three but no more than four different amino acids; (ii) The amino acid sequence relative to KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754) contains at least one, two, or three but no more than four different amino acids; (iii) The amino acid sequence relative to KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241) contains at least one, two, or three but no more than four different amino acids; (iv) The amino acid sequence relative to KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100) contains at least one, two, or three but no more than four different amino acids. (v) The amino acid sequence relative to KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062) contains at least one, two, or three but no more than four different amino acid sequences; (vi) The amino acid sequence relative to KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272) contains at least one, two, or three but no more than four different amino acid sequences; (vii) The amino acid sequence relative to KTEKVSGSPHSKAQNQQT (SEQ ID NO: 3274) contains at least one, two, or three but no more than four different amino acid sequences; (viii) The amino acid sequence relative to KTINGSGSPHKSGQNKTS (SEQ ID NO: 4406) contains at least one, two, or three but no more than four different amino acid sequences; (ix) The amino acid sequence relative to KTSNASGSPHSKAHNQQT (SEQ ID NO: 3382) contains at least one, two, or three but no more than four different amino acid sequences; (x) The amino acid sequence relative to KNSIGSGSPHSKAQNQQT (SEQ ID NO: 3421) contains at least one, two, or three but no more than four different amino acid sequences; (xi) The amino acid sequence relative to KTVNGHDSPHKSGQRPST (SEQ ID NO: 4478) contains at least one, two, or three but no more than four different amino acid sequences; (xii) An amino acid sequence relative to KAENGSGSPHSKAQNQQT (SEQ ID NO: 3487) containing at least one, two, or three but no more than four distinct amino acids; or (xiii) The amino acid sequence relative to KTINGSGSPHKSGQNQQP (SEQ ID NO: 4081) contains at least one, two, or three but no more than four different amino acid sequences.

[0488] 395. The AAV capsid variant as described in any one of embodiments 1 to 129, 269, 271, 375 to 388 or 390 to 394, comprising the amino acid sequence of any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909.

[0489] 396. AAV capsid variant as described in any one of embodiments 295 to 297, 301 to 305, 313, 314, 318, 319 or 323, comprising the amino acid sequence of ERVGSPHSKA (SEQ ID NO: 6399), wherein optionally said amino acid sequence is immediately present after position 450 and replaces positions 451-455 (e.g., I451, N542, G453, S454, G455) numbered according to SEQ ID NO: 138.

[0490] 397. An AAV capsid variant as described in any one of embodiments 369 to 371, 375 to 379, 385, 386, 389, 391, or 394 to 396, comprising the amino acid sequence KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589), wherein optionally said amino acid sequence is immediately present after position 448 and replaces positions 449-460 numbered according to SEQ ID NO: 138 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460).

[0491] 398. AAV capsid variant as described in any one of embodiments 269 to 371, 375, 380 to 383, 385, 387, 389, 390, 393 or 394, comprising the amino acid sequence AEIGHDSPHKSG (SEQ ID NO: 6400), wherein optionally said amino acid sequence is immediately present after position 449 and replaces positions 450-455 (e.g., T450, I451, N452, G453, S454, G455) numbered according to SEQ ID NO: 138.

[0492] 399. An AAV capsid variant as described in any one of embodiments 369 to 371, 375, 380 to 383, 385, 387, 389, 390, 393, 394 or 398, comprising the amino acid sequence KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), optionally wherein said amino acid sequence is immediately present after position 448 and replaces positions 449-460 numbered according to SEQ ID NO: 138 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460).

[0493] 400. AAV capsid variant as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, comprising the amino acid sequence EKMSGSPHSKA (SEQ ID NO: 6401), optionally wherein said amino acid sequence is immediately present after position 450 and replaces positions 451-455 numbered according to SEQ ID NO: 138 (e.g., I451, N452, G453, S454, G455).

[0494] 401. An AAV capsid variant as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, comprising the amino acid sequence KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), optionally wherein said amino acid sequence is immediately present after position 448 and replaces positions 449-460 numbered according to SEQ ID NO: 138 (e.g. K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460).

[0495] 402. The AAV capsid variant as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, comprising the amino acid sequence HDSPHSKAQNL (SEQ ID NO: 6402), wherein optionally said amino acid sequence is immediately present after position 453 and replaces positions 456-458 (e.g., Q456, N457, Q458) numbered according to SEQ ID NO: 138.

[0496] 403. An AAV capsid variant as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, comprising the amino acid sequence KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100), optionally wherein said amino acid sequence is immediately present after position 448 and replaces positions 449-460 numbered according to SEQ ID NO: 138 (e.g. K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460).

[0497] 404. The AAV capsid variant as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, comprising the amino acid sequence VNGHDSPHSKA (SEQ ID NO: 6403), optionally wherein said amino acid sequence is immediately present after position 450 and replaces positions 451-455 numbered according to SEQ ID NO: 138 (e.g., I451, N452, G453, S454, G455).

[0498] 405. An AAV capsid variant as described in any one of embodiments 369 to 371, 375 to 379, 390, 391, or 395, comprising: (i) the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062), optionally wherein the amino acid sequence immediately following position 448 replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) according to SEQ ID NO: 138; or (ii) The AAV capsid variant comprises the amino acid sequence of ENVSSPHSKA (SEQ ID NO: 60), wherein optionally the amino acid sequence is immediately present after position 450 and replaces positions 451-455 numbered according to SEQ ID NO: 138 (e.g., I451, N452, G453, S454, G455); corresponding to positions 451-461 of SEQ ID NO: 5; or present at positions 451 to 461 numbered according to SEQ ID NO: 5 or 981.

[0499] 406. A variant of the AAV capsid as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, or 395, comprising an amino acid sequence encoded by: the nucleotide sequence of SEQ ID NO: 942; relative to SEQ ID NO: The nucleotide sequence of 942 contains at least one, two, three, four, five, six, or seven modifications, such as substitutions, but not more than ten modifications, such as substituted nucleotide sequences; or a nucleotide sequence containing at least one, two, three, four, five, six, or seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942.

[0500] 407. AAV capsid variant as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, or 395, comprising an amino acid sequence encoded by: the nucleotide sequence of SEQ ID NO: 3; relative to SEQ ID NO: The nucleotide sequence of SEQ ID NO: 3 contains at least one, two, three, four, five, six or seven modifications, such as substitutions but not more than ten modifications, such as substituted nucleotide sequences; or a nucleotide sequence containing at least one, two, three, four, five, six or seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3.

[0501] 408. AAV capsid variant as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, or 406, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 942; relative to SEQ ID NO: The nucleotide sequence of 942 contains at least one, two, three, four, five, six, or seven modifications, such as substitutions, but not more than ten modifications, such as substituted nucleotide sequences; or, relative to SEQ ID NO: 942, the nucleotide sequence contains at least one, two, three, four, five, six, or seven but not more than ten different nucleotide sequences.

[0502] 409. AAV capsid variant as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, or 407, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 3; relative to SEQ ID NO: The nucleotide sequence of SEQ ID NO: 3 contains at least one, two, three, four, five, six or seven modifications, such as substitutions but not more than ten modifications, such as substituted nucleotide sequences; or a nucleotide sequence containing at least one, two, three, four, five, six or seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3.

[0503] 410. The AAV capsid variant as described in any one of embodiments 369 to 409, wherein the amino acid sequence is present in ring IV.

[0504] 411. The AAV capsid variant as described in any one of embodiments 369 to 410, wherein the amino acid sequence is immediately following position 448, 449, 450, 451, 452, 453, 454 or 455 relative to a reference sequence with an amino acid sequence number according to SEQ ID NO: 138.

[0505] 412. The AAV capsid variant as described in 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) according to the amino acid sequence number of SEQ ID NO: 138.

[0506] 413. The AAV capsid variant as described in any one of embodiments 369 to 412, wherein the amino acid sequence is immediately following position 455 relative to the reference sequence numbered according to SEQ ID NO: 138.

[0507] 414. The AAV capsid variant as described in any one of embodiments 369 to 413, wherein the amino acid sequence is immediately following position 453 relative to the reference sequence numbered according to SEQ ID NO: 138.

[0508] 415. AAV capsid variants as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, or 410 to 413, comprising the amino acid sequence SPHSKA (SEQ ID NO: 941), wherein, relative to according to SEQ ID NO: The reference sequence for amino acid sequence number 138, which is immediately following position 455.

[0509] 416. AAV capsid variants as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413 or 415, comprising the amino acid sequence SPHSKA (SEQ ID NO: 941), wherein, relative to according to SEQ ID NO: The reference sequence for the amino acid sequence number 981, which is immediately following position 455.

[0510] 417. The AAV capsid variant as described in embodiment 415 or 416, further comprising: (i) The amino acid other than I at position 451, the amino acid other than N at position 452, and the amino acid other than G at position 453, according to any of SEQ ID NO: 36, 138, or 981; or (ii) The amino acid other than I at position 451 and / or the amino acid other than G at position 453 according to SEQ ID NO: 5, 138 or 981.

[0511] 418. AAV capsid variant as described in any one of embodiments 415 to 417, further comprising: (i) E at position 451, R at position 452, and V at position 453 according to any of the numbers in SEQ ID NO: 36, 138, or 981; or (ii) E at position 451 and / or V at position 453 according to SEQ ID NO: 138, 981 or 5.

[0512] 419. The AAV capsid variant as described in any one of embodiments 415 to 418, further comprising: (i) Substitutions of I451E, N452R, and G453V according to any of SEQ ID NO: 36, 138, or 981; or (ii) Substitute I451E or G453V according to SEQ ID NO: 138, 981 or 5.

[0513] 420. A variant of the AAV capsid as described in any one of embodiments 415 to 419, comprising: (A) (i) E at position 451, R at position 452, and V at position 453 according to any of the numbers in SEQ ID NO: 36, 138, or 981; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 as numbered according to any one of SEQ ID NO: 36, 138 or 981; or (B) (i) E at position 451 and V at position 453 according to SEQ ID NO: 5 or 138; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is immediately following position 455 of SEQ ID NO: 5 or 138 and is present at positions 456-461.

[0514] 421. The AAV capsid variant as described in 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 specified in SEQ ID NO: 39 or 138.

[0515] 422. The AAV capsid variant as described in 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 SEQ ID NO: 138 or 39.

[0516] 423. The AAV capsid variant as described in any one of embodiments 415, 416, 421 or 422, further comprising the substituted I451E, N452K and G453M according to SEQ ID NO: 39 or 138.

[0517] 424. AAV capsid variant as described in any one of embodiments 415, 416, or 421 to 423, comprising: (i) E at position 451, K at position 452, and M at position 453 according to SEQ ID NO: 39 or 138; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 as numbered according to SEQ ID NO: 39 or 138.

[0518] 425. The AAV capsid variant as described in 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 according to SEQ ID NO: 138.

[0519] 426. The AAV capsid variant as described in any one of embodiments 415, 416 or 425, further comprising H at position 454, D at position 455 and / or L at position 458 according to SEQ ID NO: 138.

[0520] 427. The AAV capsid variant as described in any one of embodiments 415, 416, 425 or 426, further comprising the substitutes S454H, G455D and Q458L according to SEQ ID NO: 138.

[0521] 428. AAV capsid variant as described in any one of embodiments 415, 416, or 425 to 427, comprising: (i) H at position 454, D at position 455, and / or L at position 458 according to SEQ ID NO: 138; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is immediately following position 455 of SEQ ID NO: 138.

[0522] 429. The AAV capsid variant as described in 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 specified in SEQ ID NO: 52 or 138.

[0523] 430. The AAV capsid variant as described in any one of embodiments 415, 416 or 429, further comprising V at position 451, H at position 454 and / or D at position 455 according to SEQ ID NO: 52 or 138.

[0524] 431. The AAV capsid variant as described in any one of embodiments 415, 416, 429 or 430, further comprising the substituted I451V, S454H and / or G455D according to SEQ ID NO: 52 or 138.

[0525] 432. AAV capsid variant as described in any one of embodiments 415, 416, or 429 to 431, comprising: (i) V at position 451, H at position 454, and / or D at position 455 according to SEQ ID NO: 52 or 138; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is immediately following position 455 as numbered according to SEQ ID NO: 52 or 138.

[0526] 433. AAV capsid variants as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412 or 414, comprising HDSPHK (SEQ ID NO: 2) the amino acid sequence, wherein the amino acid sequence immediately follows position 453 of the amino acid sequence number according to SEQ ID NO: 138.

[0527] 434. AAV capsid variants as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, or 433, comprising HDSPHK (SEQ ID NO). The amino acid sequence of NO:2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence number according to SEQ ID NO: 982.

[0528] 435. AAV capsid variant as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 or 434, comprising SPHKSG (SEQ ID NO: The amino acid sequence of 946), wherein the amino acid sequence is immediately following position 455 of the reference sequence number relative to the amino acid sequence number according to SEQ ID NO: 982.

[0529] 436. A variant of the AAV capsid as described in any one of embodiments 369 to 435, comprising: (i) The amino acid sequence of HDSPHSKA (SEQ ID NO: 4486), which is immediately following position 453; and (ii) Deletion of amino acid SG at positions 454 and 455; (i) and (ii) are numbered according to SEQ ID NO: 138.

[0530] 437. The AAV capsid variant as described in any one of embodiments 369 to 436, comprising amino acids HD at positions 454 and 455, and further comprising the amino acid sequence SPHSKA (SEQ ID NO: 941), immediately following position 455 relative to the number SEQ ID NO: 138.

[0531] 438. The AAV capsid variant as described in 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, as specified in SEQ ID NO: 138 or 982.

[0532] 439. The AAV capsid variant as described in any one of embodiments 433 to 435 or 438, further comprising A at position 450, E at position 451, and I at position 452, as numbered according to SEQ ID NO: 138 or 982.

[0533] 440. The AAV capsid variant as described in any one of embodiments 433 to 435, 438 or 439, further comprising the substituted T450A, I451E and N452I according to SEQ ID NO: 138 or 982.

[0534] 441. A variant of the AAV capsid as described in any one of embodiments 433, 434, or 438 to 440, comprising: (i) According to SEQ ID NO: 138 or 982, position 450 is A, position 451 is E, and position 452 is I; and (ii) The amino acid sequence of HDSPHK (SEQ ID NO: 2), which is immediately following position 453 according to SEQ ID NO: 138 or 982.

[0535] 442. The AAV capsid variant as described in any one of embodiments 1 to 22, 25 to 27, 31, 34 to 42, 45 to 50, 53 to 63, 69, 79, 83 to 86, 91 to 98, 102, 103, 110, 111, 118 to 129, 369 to 371, 384, 385, 390, 393, 395, 410 to 413, comprising the amino acid sequence SPHKYG (SEQ ID NO: 966), wherein the amino acid sequence is immediately following position 455 relative to the reference sequence numbered according to the amino acid sequence number of SEQ ID NO: 138.

[0536] 443. An AAV capsid variant comprising: (i) The amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence number according to SEQ ID NO: 982; and / or (ii) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring VIII includes 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.

[0537] 444. An AAV capsid variant comprising: (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence number according to SEQ ID NO: 981; and / or (ii) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring VIII includes 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.

[0538] 445. An AAV capsid variant comprising: (A) The amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence immediately follows position 453 of the amino acid sequence number according to SEQ ID NO: 37, and optionally further comprises: (i) One, both or all of the amino acid other than T at position 450, the amino acid other than I at position 541 and / or the amino acid other than N at position 452, according to SEQ ID NO: 138 or 37. (ii) One, both, or all of the following: position A at position 450, position E at position 451, and / or position I at position 452, according to SEQ ID NO: 138 or 37; and / or (B) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring 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.

[0539] 446. An AAV capsid variant comprising: (i) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence immediately follows position 455 of the amino acid sequence number according to any one of SEQ ID NO: 36, 38-55, 57 or 59; and / or (ii) Modifications in ring VIII, such as substitutions (e.g., conservative substitutions), optionally wherein ring VIII includes 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.

[0540] 447. The AAV capsid variant as described in any of the foregoing embodiments, further comprising: (i) Modifications in rings I, II, V, VI and / or VIII, such as insertions, substitutions (e.g., conservative substitutions) and / or deletions; and / or (ii) Substitution at position K449 according to SEQ ID NO: 138, for example, K449R substitution.

[0541] 448. The AAV capsid variant as described in any of the preceding embodiments, comprising an amino acid sequence containing at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but not exceeding 30, 20, or 10 modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO:138.

[0542] 449. The AAV capsid variant as described in any of the preceding embodiments, comprising an amino acid sequence comprising at least one, two, or three, but not more than 30, 20, or 10 different amino acids relative to the amino acid sequence of SEQ ID NO:138.

[0543] 450. The AAV capsid variant as described in any of the preceding embodiments, comprising the amino acid sequence of SEQ ID NO: 138, or an amino acid sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0544] 451. The AAV capsid variant as described in any of the preceding embodiments, comprising the amino acid sequence of SEQ ID NO: 138.

[0545] 452. The AAV capsid variant as described in any of the preceding embodiments, comprising an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 137, or a sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0546] 453. The AAV capsid variant as described in any of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 137, or a sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0547] 454. The AAV capsid variant as described in any of the foregoing embodiments, comprising VP1 protein, VP2 protein, VP3 protein, or a combination thereof.

[0548] 455. The AAV capsid variant as described in any one of embodiments 1 to 454, comprising an amino acid sequence corresponding to positions 138-742 of SEQ ID NO: 981 or 982, such as VP2, or a sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0549] 456. The AAV capsid variant as described in any one of embodiments 1 to 455, comprising an amino acid sequence corresponding to positions 203-742 of SEQ ID NO: 981 or 982, such as VP3, or a sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0550] 457. The AAV capsid variant as described in any one of embodiments 1 to 456, comprising an amino acid sequence corresponding to positions 138-736 of SEQ ID NO:138, such as VP2, or a sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0551] 458. The AAV capsid variant as described in any one of embodiments 1 to 457, comprising an amino acid sequence corresponding to positions 203-736 of SEQ ID NO:138, such as VP3, or a sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0552] 459. AAV capsid variants as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 458, comprising a derivative of SPHSKA (SEQ ID NO: The amino acid sequence of 941) is a sequence of at least 3, 4, 5 or 6 consecutive amino acids, wherein: (i) The at least three consecutive amino acids contain SPH; (ii) The at least four consecutive amino acids comprise SPHS (SEQ ID NO: 4700); (iii) The at least five consecutive amino acids comprise SPHSK (SEQ ID NO: 4701); or (iv) The at least six consecutive amino acids comprise SPHSKA (SEQ ID NO: 941); The AAV capsid variants described therein comprise: (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 of 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 of 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)-(c).

[0553] 460. AAV capsid variants as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 459, comprising a derivative of SPHSKA (SEQ ID NO: The amino acid sequence of 941) is a sequence of at least 3, 4, 5 or 6 consecutive amino acids, wherein: (i) The at least three consecutive amino acids contain SPH; (ii) The at least four consecutive amino acids comprise SPHS (SEQ ID NO: 4700); (iii) The at least five consecutive amino acids comprise SPHSK (SEQ ID NO: 4701); or (iv) The at least six consecutive amino acids comprise SPHSKA (SEQ ID NO: 941); The AAV capsid variant therein comprises an amino acid sequence that has at least 90% (e.g., at least about 95%, 96%, 97%, 98%, or 99%) identity with the amino acid sequence of SEQ ID NO: 981.

[0554] 461. The AAV capsid variant as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 460, which, relative to SPHSKA (SEQ ID NO: The amino acid sequence of 941) contains one or two, but no more than three, substitutions, wherein the AAV capsid variant comprises: (a) The VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981; (b) The 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) A 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) An amino acid sequence that has 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).

[0555] 462. The AAV capsid variant as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 461, which, relative to SPHSKA (SEQ ID NO: The amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981 contains one or two, but no more than three, substitutions, wherein the AAV capsid variant contains an amino acid sequence that has at least 90% (e.g., at least about 95%, 96%, 97%, 98% or 99%) identity with the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981.

[0556] 463. The AAV capsid variant as described in any one of embodiments 459 to 462, wherein the amino acid sequence is immediately following position 455 as numbered according to SEQ ID NO: 138 or 981.

[0557] 464. As per implementation plans 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 2 AAV capsid variants according to any one of 83 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, or 447 to 458, comprising an amino acid sequence containing at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein: (i) The at least three consecutive amino acids comprise HDS; (ii) The at least four consecutive amino acids comprise HDSP (SEQ ID NO: 4702); (iii) The at least five consecutive amino acids comprise HDSPH (SEQ ID NO: 4703); or (iv) The at least six consecutive amino acids comprise HDSPHK (SEQ ID NO: 2); The AAV capsid variants comprise: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 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 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)-(c).

[0558] 465. As per implementation plans 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 AAV capsid variants according to any one of 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, or 464, comprising an amino acid sequence containing at least 3, 4, 5, or 6 consecutive amino acids from HDSPHK (SEQ ID NO: 2), wherein: (i) The at least three consecutive amino acids comprise HDS; (ii) The at least four consecutive amino acids comprise HDSP (SEQ ID NO: 4702); (iii) The at least five consecutive amino acids comprise HDSPH (SEQ ID NO: 4703); or (iv) The at least six consecutive amino acids comprise HDSPHK (SEQ ID NO: 2); The AAV capsid variant therein comprises an amino acid sequence that has at least 90% (e.g., at least about 95%, 96%, 97%, 98%, or 99%) identity with the amino acid sequence of SEQ ID NO: 982.

[0559] 466. As per implementation plans 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 AAV capsid variants according to any one of 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464, or 465, comprising one or two, but no more than three, substitutions relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the AAV capsid variant comprises: (a) The VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) The 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) A 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) An amino acid sequence that has 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).

[0560] 467. As per implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 AAV capsid variants according to any one of 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, or 464 to 466, comprising one or two but no more than three substitutions relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the AAV capsid variant comprises an amino acid sequence having at least 90% (e.g., at least about 95%, 96%, 97%, 98%, or 99%) identity with the amino acid sequence of SEQ ID NO: 982.

[0561] 468. The AAV capsid variant as described in any one of embodiments 464 to 468, wherein the amino acid sequence immediately follows position 453 as numbered according to SEQ ID NO: 138 or 982.

[0562] 469. The AAV capsid variant as described in any one of embodiments 1 to 468, comprising the amino acid sequence of any one of 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 with it.

[0563] 470. The AAV capsid variant as described in any one of embodiments 1 to 469, comprising an amino acid sequence relative to SEQ ID NO: 981 or 982 containing at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but not exceeding 30, 20, or 10 modifications, such as substitutions (e.g., conservative substitutions), of the amino acid sequence.

[0564] 471. The AAV capsid variant as described in any one of embodiments 1 to 470, comprising an amino acid sequence comprising at least one, two, or three, but not more than 30, 20, or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 981 or 982.

[0565] 472. AAV capsid variant as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, or 469 to 471, comprising SEQ ID NO: The amino acid sequence of 981, or an amino acid sequence that has at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0566] 473. AAV capsid variant as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, or 469 to 472, comprising a variant relative to SEQ ID NO: The amino acid sequence of 981 contains at least one, two, or three modifications, such as substitutions (e.g., conservative substitutions), but no more than 30, 20, or 10 modifications, such as substitutions (e.g., conservative substitutions), in the amino acid sequence.

[0567] 474. AAV capsid variants as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, or 469 to 473, comprising, relative to SEQ ID NO: The amino acid sequence of 981 contains at least one, two, or three, but no more than 30, 20, or 10 different amino acids.

[0568] 475. As per implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 2 The AAV capsid variants described in any one of 83 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, or 464 to 471, 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 with it.

[0569] 476. As per implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 2 AAV capsid variants of any one of 87, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 471 or 475, comprising an amino acid sequence containing at least one, two or three modifications, such as substitutions (e.g., conservative substitutions), but not exceeding 30, 20 or 10 modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 982.

[0570] 477. As per implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287 The AAV capsid variants described in any one of SEQ ID NO: 982, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 471, 475, or 476, 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: 982.

[0571] 478. The AAV capsid variant as described in any one of embodiments 1 to 477, comprising an amino acid sequence encoded by a 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 with it.

[0572] 479. The AAV capsid variant as described in any one of embodiments 1 to 478 above, wherein the nucleotide sequence encoding the capsid variant comprises 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 with it.

[0573] 480. As described in the aforementioned implementation schemes 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 29 AAV capsid variants as described in any one of 1 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, 469 to 474, 478, or 479, wherein the nucleotide sequence encoding the capsid variant comprises 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 with it.

[0574] 481. As described in the aforementioned implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 2 AAV capsid variants as described in any one of 99, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 471, or 475 to 479, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence having at least 80% (e.g., at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with it.

[0575] 482. The AAV capsid variant as described in any of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant is codon-optimized.

[0576] 483. An AAV capsid variant comprising, as described in embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 28 The amino acid sequence of any one of 1, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, 469 to 474, 478 to 480 or 482, and further comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 981.

[0577] 484. An AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981, further comprising modifications, such as substitutions (e.g., conservative substitutions), in ring VIII, optionally wherein ring 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] 485. The AAV capsid variant as described in embodiment 483 or 484, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence having at least 90%, 95%, or 99% identity with it.

[0579] 486. An AAV capsid variant comprising embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to The amino acid sequence of any one of 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 471, 475 to 479, 481 or 482, and further comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 982.

[0580] 487. An AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982, further comprising modifications, such as substitutions (e.g., conservative substitutions), in ring VIII, optionally wherein ring 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.

[0581] 488. The AAV capsid variant as described in embodiment 486 or 487, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence having at least 90%, 95%, or 99% identity with it.

[0582] 489. An AAV capsid variant comprising an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 983 or 984, or a nucleotide sequence having at least 95% identity with it; further comprising a modification in ring VIII, such as a substitution (e.g., a conserved substitution), optionally ring VIII comprising 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.

[0583] 490. An AAV capsid variant comprising the amino acid sequence of any one of SEQ ID NO: 5-10, 36-59 or 6409-6413, optionally further comprising a modification in ring VIII, such as substitution (e.g., a conservative substitution), optionally wherein ring 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.

[0584] 491. An AAV capsid variant comprising an amino acid sequence encoded by a nucleotide sequence of any one of SEQ ID NO: 4 or 12-35, or a nucleotide sequence having at least 95% identity with it, optionally further comprising a modification in ring VIII, such as a substitution (e.g., a conserved substitution), optionally wherein ring 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.

[0585] 492. The AAV capsid variant as described in embodiment 490 or 491, wherein the nucleotide sequence encoding the AAV capsid variant comprises a nucleotide sequence of any one of SEQ ID NO: 4 or 12-35, or a nucleotide sequence having at least 95% identity with it.

[0586] 493. The AAV capsid variant as described in any one of embodiments 1 to 299, 369 to 371 or 375 to 492, having increased tropism relative to a reference sequence comprising the amino acid sequence of SEQ ID NO: 138 for CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells or spinal cord tissue.

[0587] 494. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 493, which transduces brain regions, such as midbrain regions (e.g., hippocampus or thalamus) or brainstem, optionally wherein, for example when measured by assays as described in Example 2, such as immunohistochemical assays or qPCR assays, the transduction level 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.

[0588] 495. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 494, whose transduction brain region, such as a midbrain region (e.g., hippocampus or thalamus) or brainstem, optionally wherein, for example when measured by assays as described in Example 2, such as immunohistochemical assays or qPCR assays, the transduction level is at least 30, 35, 40, 45, 50, 55, 60, or 65 times greater than that of the reference sequence of SEQ ID NO: 138.

[0589] 496. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 495, for example, when measured by a assay as described in Example 1, is enriched in the brain by at least about 3, 4, 5, 6, 7, 8, 9 or 10 times compared to the reference sequence of SEQ ID NO: 138.

[0590] 497. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 496, for example, when measured by a assay as described in Example 1, is enriched in the brain by at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85 times compared to the reference sequence of SEQ ID NO: 138.

[0591] 498. AAV capsid variants as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 497, for example, enriched in the brains of at least two to three species, such as non-human primates and rodents (e.g., mice), compared to the reference sequence of SEQ ID NO: 138.

[0592] 499. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, or 375 to 498, for example, when measured by a determination as described in Example 1 or Example 5, is similar to SEQ ID NO: Compared to the reference sequence of 138, it is enriched by at least 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 at least two to three species, such as non-human primates and rodents (e.g., mice).

[0593] 500. AAV capsid variants as described in embodiments 498 or 499, wherein the at least two or three species are cynomolgus monkeys, green monkeys, common marmosets and / or mice (e.g., BALB / c mice, C57Bl / 6 mice and / or CD-1 outcross mice).

[0594] 501. The AAV capsid variant as described in any one of embodiments 130 to 146, 369, 410 to 414, 447 to 454, 457, 458, 482, or 493, for example, when measured by the assay described in Example 3, is enriched in the brain by at least about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 times compared to the reference sequence of SEQ ID NO: 981.

[0595] 502. AAV capsid variants as described in any one of embodiments 147 to 167, 369, 410 to 414, 447 to 454, 457, 458, 482, or 493, wherein: (i) For example, when measured by a assay as described in Example 3, it is enriched in the brain by at least about 2, 2.5, 3, 3.5, 4, 4.5, 5, or 5.5 times compared to the reference sequence of SEQ ID NO: 982; (ii) For example, when measured by the assay described in Example 8, it is able to transduce at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85% of the 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, dentate nucleus and / or lateral geniculate nucleus (LGN)); (iii) At least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% of neurons (e.g., NeuN+ neurons) in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex) capable of transducing; and / or (iv) For example, when measured by a assay as described in Example 8, it is able to transduce at least 70%, 75%, 80%, 85%, 90%, or 95% of astrocytes (e.g., Sox9+ astrocytes) in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex).

[0596] 503. AAV capsid variants as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, or 375 to 500, which deliver an increased level of payload to a brain region, optionally wherein, for example, when measured by assay, such as qRT-PCR or qPCR assay (e.g., as described in Example 2 or Example 8), the level of said payload is increased by at least 10-fold, 12-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, or 70-fold compared to the reference sequence of SEQ ID NO: 138.

[0597] 504. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503, which delivers an increased level of viral genome to a brain region, optionally wherein, for example, when measured by assay, such as qRT-PCR or qPCR assay (e.g., as described in Example 2 or Example 8), the level of the viral genome is increased by at least 5-fold, 10-fold, 15-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold or 50-fold compared to the reference sequence of SEQ ID NO: 138.

[0598] 505. The AAV capsid variant as described in embodiment 504, wherein the brain region is a midbrain region (e.g., hippocampus or thalamus), frontal cortex, temporal cortex, motor cortex, cerebral cortex, cerebellum, cerebellar cortex, caudate nucleus, putamen, dentate nucleus, substantia nigra, entorhinal cortex, lateral geniculate nucleus (LGN), or brainstem.

[0599] 506. AAV capsid variants as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500, or 503 to 505, wherein: (i) For example, when measured by means of the determination described in Example 1 or Example 8, the spinal cord is enriched by at least about 4, 5, 10, 15, 20, 25, 30 or 35 times compared with the reference sequence of SEQ ID NO: 138, optionally wherein the region of the spinal cord is the thoracic spinal cord region, the cervical spinal cord region, the C5 ventral horn region, the lumbar spinal cord region or the L5 ventral horn region; (ii) For example, when measured by a determination as described in Example 8, at least 90% or 95% of neurons, such as motor neurons (e.g., ChAT+ neurons) in the spinal cord (e.g., cervical, thoracic, or lumbar spinal cord), are able to transduce; and / or (iii) For example, when measured by the assay described in Example 8, it is able to transduce at least 90%, 95%, or 98% of the astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., cervical, thoracic, or lumbar spinal cord).

[0600] 507. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 506, exhibits preferential transduction in brain regions relative to transduction in the dorsal root ganglion (DRG).

[0601] 508. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 507, exhibits preferential transduction in brain regions relative to transduction in the liver.

[0602] 509. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 508, exhibits preferential transduction in brain regions relative to transduction in the heart.

[0603] 510. The AAV capsid variant as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 509, exhibits preferential transduction in brain regions relative to transduction in the dorsal root ganglion (DRG) and the heart.

[0604] 511. The AAV capsid variant as described in any of the preceding embodiments, which is capable of transducing neuronal cells, such as NeuN+ neurons, ChAT+ neurons, or dopaminergic neurons (e.g., dopaminergic neurons in the substantia nigra), such as tyrosine hydroxylase (TH)+ neurons.

[0605] 512. The AAV capsid variant as described in any of the preceding embodiments, which is capable of transducing NeuN+ cells (e.g., NeuN+ neurons), ChAT+ cells (e.g., ChAT+ neurons) and / or TH+ cells (e.g., TH+ neurons, such as dopaminergic neurons).

[0606] 513. The AAV capsid variant as described in any of the preceding embodiments, which is capable of transducing non-neuronal cells, such as glial cells (e.g., oligodendrocytes or astrocytes).

[0607] 514. The AAV capsid variant as described in embodiment 513, wherein the non-neur...

Claims

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

138.

2. An AAV capsid variant comprising three, four, or all of the following amino acids: amino acid R at position 584, amino acid T at position 586, amino acid L at position 588, amino acid Q at position 589, and / or amino acid L at position 590, as specified in SEQ ID NO: 138, wherein the AAV capsid variant comprises an amino acid sequence having at least 95% identity with the amino acid sequence at positions 203-736 of SEQ ID NO:

138.

3. The AAV capsid variant of claim 2, comprising an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein: (i) [N1] contains X1, X2 and X3, wherein at least one of X1, X2 or X3 is G; (ii) [N2] contains the amino acid sequence of SPH; and (iii) [N3] contains X4, X5 and X6, wherein at least one of X4, X5 or X6 is a basic amino acid, such as K or R; [N1]-[N2]-[N3] exists in the high-variable ring IV.

4. The AAV capsid variant as claimed in claim 1 or 3, wherein [N3] comprises 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.

5. The AAV capsid variant according to any one of claims 1, 3 or 4, wherein [N2]-[N3] comprises 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), SPHKL G (SEQ ID NO: 959), SPHKTS (SEQ ID NO: 963), SPHKTT (SEQ ID NO: 964), SPHKT Y (SEQ ID NO: 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), 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).

6. The AAV capsid variant as claimed in any one of claims 1 to 5, wherein [N1] comprises 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. The AAV capsid variant as claimed in any one of claims 1 to 6, wherein [N1]-[N2]-[N3] comprises: (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: 4907) 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)、CSGSPHKTS (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: 4925) 4926)、GSGSPHKYG (SEQ ID NO:4927)、GSGSPHSKD (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: 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) GSSCSPHRKA (SEQ ID NO: 4950) GSGSPHFLR (SEQ ID NO:4951)、GSGSPHSKW (SEQ ID NO: 4952)、GSGSPHSKS (SEQ ID NO: 4953)、GLLSPHWKA (SEQID 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 (SEQID NO: 4962)、ESGSPHSKA (SEQ ID NO: 4963). 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 IDNO: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 IDNO: 5009), GHDSPHKSW (SEQ ID NO: 5010), GHDSPHKSN (SEQ ID NO: 5011), GMGSPHSKT (SEQ ID NO: 5012), GHDSPHKHG (SEQ ID NO: 5013), GQVSPHKSG (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) GSGSPHSKA (SEQ ID NO: 4697), GHDSPHKSG (SEQ ID NO: 4698) or VSGSPHSKA (SEQ ID NO: 4913).

8. The AAV particles as claimed in any one of claims 1 to 7, further comprising: (i) [N0], where [N0] contains TIN, TEN, TER, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW, ANN, IPE, ADM, IEY, 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, T VH, TSS, TID, TCN, NIN, TEH, AEM, 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, NA D. TIT, NCV, TIR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TD V, SDI, NSI, NSL, EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, or NNL; and / or (ii) [N4], where [N4] contains 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 IDNO: 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 NO: 5044), QRRL (SEQ ID NO: 5045), RRLQ (SEQ IDNO: 5046), RLRQ (SEQ ID NO: 5047), SKRQ (SEQ ID NO: 5048), QLYR (SEQ ID NO:5049), QLTV (SEQ ID NO: 5050), QNKQ (SEQ ID NO: 5051), KNQQ (SEQ ID NO: 5052), QKQQ (SEQ ID NO: 5053), QTQQ (SEQ ID NO: 5054), QNHQ (SEQ ID NO: 5055), QHQQ(SEQ ID NO: 5056), QNQH (SEQ ID NO: 5057), QHRQ (SEQ ID NO: 5058), LTQQ (SEQ IDNO: 5059), QNQW (SEQ ID NO: 5060), QNTH (SEQ ID NO: 5061), RRRQ (SEQ ID NO:5062), QYQQ (SEQ ID NO: 5063), QNDQ (SEQ ID NO: 5064), QNRH (SEQ ID NO: 5065), RDQQ (SEQ ID NO: 5066), PNLQ (SEQ ID NO: 5067), HVRQ (SEQ ID NO: 5068), PNQH(SEQ ID NO: 5069), HNQQ (SEQ ID NO:5070)、QSQQ (SEQ ID NO: 5071)、QPAK (SEQ IDNO: 5072)、QNLA (SEQ ID NO: 5073)、QNQL (SEQ ID NO: 5074)、QGQQ (SEQ ID NO:5075)、LNRQ (SEQ ID NO: 5076)、QNPP (SEQ ID NO: 5077)、QNLQ (SEQ ID NO: 5078)、QDQE (SEQ ID NO: 5079)、QDQQ (SEQ ID NO: 5080)、HWQQ (SEQ ID NO: 5081)、PNQQ(SEQ ID NO: 5082)、PEQQ (SEQ ID NO: 5083)、QRTM (SEQ ID NO: 5084)、LHQH (SEQ IDNO: 5085)、QHRI (SEQ ID NO: 5086)、QYIH (SEQ ID NO: 5087)、QKFE (SEQ ID NO:5088)、QFPS (SEQ ID NO: 5089)、QNPL (SEQ ID NO: 5090)、QAIK (SEQ ID NO: 5091)、QNRQ (SEQ ID NO: 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 IDNO: 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: 5109)、QDLQ (SEQ ID NO: 5110)、QAMH (SEQ IDNO: 5111)、QHPS (SEQ ID NO: 5112)、PGLQ (SEQ ID NO: 5113)、QGIR (SEQ IDNO:5114)、QAPA (SEQ ID NO: 5115)、QIPP (SEQ ID NO: 5116)、QTQL (SEQ ID NO: 5117)、QAPS (SEQ ID NO: 5118)、QNTY (SEQ ID NO: 5119)、QDKQ (SEQ ID NO: 5120)、QNHL(SEQ ID NO: 5121)、QIGM (SEQ ID NO: 5122)、LNKQ (SEQ ID NO: 5123)、PNQL (SEQ IDNO: 5124)、QLQQ (SEQ ID NO: 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 IDNO: 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: 5143)、QSKV (SEQ ID NO: 5144)、QLPS (SEQ ID NO: 5145)、IGKQ (SEQ ID NO: 5146)、QAIH(SEQ ID NO: 5147)、QHGL (SEQ ID NO: 5148)、QFMC (SEQ ID NO: 5149)、QNQM (SEQ IDNO: 5150)、QHLQ (SEQ ID NO: 5151)、QPAR (SEQ ID NO: 5152)、QSLQ (SEQ ID NO:5153)、QSQL (SEQ ID NO: 5154)、HSQQ (SEQ ID NO: 5155)、QMPS (SEQ ID NO: 5156)、QGSL (SEQ ID NO: 5157)、QVPA (SEQID NO: 5158)、HYQQ (SEQ ID NO: 5159)、QVPS(SEQ ID NO: 5160)、RGEQ (SEQ ID NO: 5161)、PGQQ (SEQ ID NO: 5162)、LEQQ (SEQ IDNO: 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: 5175)、RGLQ (SEQ IDNO: 5176)、PSLQ (SEQ ID NO: 5177)、QRDQ (SEQ ID NO: 5178)、QAKG (SEQ ID NO:5179)、QSAH (SEQ ID NO: 5180)、QSTM (SEQ ID NO: 5181)、QREM (SEQ ID NO: 5182)、QYRA (SEQ ID NO: 5183)、QRQQ (SEQ ID NO: 5184)、QWQQ (SEQ ID NO: 5185)、QRMN(SEQ ID NO: 5186)、GDSQ (SEQ ID NO: 5187)、QKIS (SEQ ID NO: 5188)、PSMQ (SEQ IDNO: 5189)、SPRQ (SEQ ID NO: 5190)、MEQQ (SEQ ID NO: 5191)、QYQN (SEQ ID NO:5192)、QIRQ (SEQ ID NO: 5193)、QSVQ (SEQ ID NO: 5194)、RSQQ (SEQ ID NO: 5195)、QNKL (SEQ ID NO: 5196)、QIQH (SEQ ID NO: 5197)、PRQQ (SEQ ID NO: 5198)、HTQQ(SEQ ID NO: 5199)、QRQH (SEQ ID NO: 5200)、RNQE (SEQ ID NO: 5201)、QSKQ(SEQ ID NO: 5202), QNQP (SEQ ID NO: 5203), QSPQ (SEQ ID NO: 5204), QTRQ (SEQ ID NO: 5205), QNLH (SEQ ID NO: 5206), QNQE (SEQ ID NO: 5207), LNQP (SEQ ID NO: 5208), QNQD (SEQ ID NO: 5209), QNLL (SEQ ID NO: 5210), QLVI (SEQ ID NO: 5211), RTQE (SEQ ID NO: 5212), QTHQ (SEQ ID NO: 5213), QDQH (SEQ ID NO: 5214), QSQH (SEQ ID NO: 5215), VRQQ (SEQ ID NO: 5216), AWQQ (SEQ ID NO: 5217), QSVP (SEQ ID NO: 5218), QNIQ (SEQ ID NO: 5219), LDQQ (SEQ ID NO: 5220), PDQQ (SEQ ID NO: 5221), ESQQ (SEQ ID NO: 5222), QRQL (SEQ ID NO: 5223), QIIV (SEQ ID NO: 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), 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. The AAV capsid variant of claim 8, wherein [N0]-[N1]-[N2]-[N3]-[N4] comprises: (i) The amino acid sequence of any one of SEQ ID NO: 2242-2886; or (ii) TENVSGSPHSKAQNQQ (SEQ ID NO: 2283), TERVSGSPHSKAQNQQ (SEQ ID NO: 2272), TINGSGSPHSKAQNQQ (SEQ ID NO: 2242) or TINGHDSPHKSGQNQQ (SEQ ID NO: 2243).

10. The AAV capsid variant as claimed in claim 8 or 9, wherein: (i) [NO] is present at amino acids 450-452 according to SEQ ID NO: 981, 982 or 138; (ii) [N1] is present at amino acids 453-455 according to SEQ ID NO: 981, 982 or 138; (iii) [N2] is present at amino acids 456-458 according to SEQ ID NO: 981 or 982; (iv) [N3] is present at amino acid 459-461 according to SEQ ID NO: 981 or 982; (v) [N4] is present at amino acids 462-465 according to SEQ ID NO: 981 or 982; and / or (vi) [N0]-[N1]-[N2]-[N3]-[N4] are present at amino acids 450-465 according to SEQ ID NO: 981 or 982.

11. An AAV capsid variant comprising: (a) Three, four, or all of the following amino acids according to SEQ ID NO: 138: amino acid R at position 584, amino acid T at position 586, amino acid L at position 588, amino acid Q at position 589, and / or amino acid L at position 590; and (b) The amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable IV; The AAV capsid variant therein comprises an amino acid sequence that has at least 95% identity with the amino acid sequence at positions 203-736 of SEQ ID NO:

138.

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

982.

13. An AAV capsid variant comprising: (a) Three, four, or all of the following amino acids according to SEQ ID NO: 138: amino acid R at position 584, amino acid T at position 586, amino acid L at position 588, amino acid Q at position 589, and / or amino acid L at position 590; and (b) The amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable IV; The AAV capsid variant therein comprises an amino acid sequence that has at least 95% identity with the amino acid sequence at positions 203-736 of SEQ ID NO:

138.

14. The AAV capsid variant of claim 13, wherein the amino acid sequence of SPHSKA (SEQ ID NO: 941) is immediately following amino acid 455, which is numbered according to SEQ ID NO:

981.

15. The AAV capsid variant of claim 13 or 14, wherein the AAV capsid variant further comprises amino acid E at position 451 according to SEQ ID NO:

981.

16. The AAV capsid variant of any one of claims 13 to 15, comprising amino acid V at position 453 according to SEQ ID NO:

981.

17. The AAV capsid variant of any one of claims 13 to 16, comprising amino acid R at position 452 according to SEQ ID NO:

981.

18. The AAV capsid variant as claimed in any one of claims 1 to 17, comprising: (i) Amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596 according to SEQ ID NO: 981, 982, 6411, or 6412; or (ii) Amino acid R at position 584, amino acid T at position 586, amino acid L at position 588, amino acid Q at position 589 and amino acid L at position 590 according to SEQ ID NO: 138 or 6414.

19. The AAV capsid variant as claimed in any one of claims 1 to 12 or 18, comprising: (i) An amino acid sequence that is at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 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) An amino acid sequence that has at least 95% or at least 98% identity with the amino acid sequence of SEQ ID NO: 6412.

20. The AAV capsid variant as claimed in any one of claims 1 to 12, 18, or 19, comprising: Include: (i) The amino acid sequence of amino acids 203-742 of SEQ ID NO: 6412; (ii) The amino acid sequence of amino acids 138-742 of SEQ ID NO: 6412; and / or (iii) The amino acid sequence of SEQ ID NO: 6412.

21. The AAV capsid variant as claimed in any one of claims 1 to 10 or 13 to 18, comprising: Include: (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) An amino acid sequence that is at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 6411.

22. The AAV capsid variant as claimed in any one of claims 1 to 10, 13, 14, 18 or 21, comprising: Include: (i) The amino acid sequence of amino acids 203-742 of SEQ ID NO: 6411; (ii) The amino acid sequence of amino acids 138-742 of SEQ ID NO: 6411; and / or (iii) The amino acid sequence of SEQ ID NO: 6411.

23. The AAV capsid variant of any one of claims 1 or 3 to 22, wherein the hypervariable IV comprises amino acids 449-460 according to SEQ ID NO:

138.

24. The AAV capsid variant as claimed in any one of claims 1 to 23, wherein the AAV capsid variant (i) An increased tropism relative to a reference sequence containing the amino acid sequence of SEQ ID NO: 138 for CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells or spinal cord tissue; (ii) Transduction brain regions (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)), optionally wherein, when measured by assays such as those described in Example 2, such as immunohistochemistry or qPCR, the transduction level 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; (iii) For example, when measured by the assay described in Example 1, it is enriched in the brain by at least about 3, 4, 5, 6, 7, 8, 9 or 10 times compared with the reference sequence of SEQ ID NO: 138; (iv) When measured by the assays described in Example 1 or Example 5, it is able to transduce the brains of at least two to three species, such as non-human primates and / or rodents (e.g., cynomolgus monkeys, green monkeys, common marmosets and / or mice (e.g., BALB / c mice, C57Bl / 6 mice and / or CD-1 outcrossed mice)). (v) Delivering an increased level of payload to a brain region, optionally wherein, for example, when measured by assays such as qRT-PCR or qPCR (as described in Example 2 or Example 8), the level of the payload 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, wherein 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) Delivering an increased level of viral genome to a brain region, optionally wherein, for example, when measured by assays such as qRT-PCR or qPCR (as described in Example 2 or Example 8), the level of the viral genome 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, optionally wherein 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); (vii) For example, when measured by means of the determination described in Example 1 or Example 8, the spinal cord is enriched by at least about 5, 10, 15, 20, 25, 30 or 35 times compared with the reference sequence of SEQ ID NO: 138, optionally wherein the region of the spinal cord is the thoracic spinal cord region, the cervical spinal cord region or the lumbar spinal cord region. (viii) Preferred transduction in brain regions was shown relative to transduction in the dorsal root ganglion (DRG) and / or liver; (xi) Capable of transducing neuronal and non-neuronal cells, such as glial cells (e.g., astrocytes); (ix) For example, when measured by the assay described in Example 8, it is able to transduce at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85% of the 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, dentate nucleus and / or lateral geniculate nucleus (LGN)); (x) At least 10%, 15%, 20%, 25%, 30%, 40%, 50%, 55%, 60% or 65% of neurons (e.g., NeuN+ neurons) in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex or temporal cortex). (xi) For example, when measured by the assay described in Example 8, it is able to transduce at least 70%, 75%, 80%, 85%, 90% or 95% of astrocytes (e.g., Sox9+ astrocytes) in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex or temporal cortex). (xii) For example, when measured by a determination as described in Example 8, at least 90% or 95% of neurons, such as motor neurons (e.g., ChAT+ neurons) in the spinal cord (e.g., cervical, thoracic, or lumbar spinal cord), are able to transduce; and / or (xiii) For example, when measured by the assay described in Example 8, it is able to transduce at least 90%, 95%, or 98% of the astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., cervical, thoracic, or lumbar spinal cord).

25. A polynucleotide encoding an AAV capsid variant as claimed in any one of claims 1 to 24.

26. The polynucleotide of claim 25, comprising: (i) A nucleotide sequence relative to SEQ ID NO: 6415 or 6416 containing at least one, two, three, four, five, six, or seven but not more than ten distinct nucleotides; and / or (ii) The nucleotide sequence of SEQ ID NO: 6415 or 6416, or a nucleotide having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% identity with it; Optionally, the polynucleotide comprises a codon-optimized nucleotide sequence.

27. A peptide comprising: (a) The 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) An amino acid sequence containing no more than one or two different amino acids relative to the amino acid sequence of SEQ ID NO: 6419.

28. An AAV particle comprising an AAV capsid variant as claimed in any one of claims 1 to 24, an AAV capsid variant encoded by a polynucleotide as claimed in claim 25 or 26, or an AAV capsid variant comprising a peptide as claimed in claim 27.

29. The AAV particle of claim 28, comprising a nucleotide sequence encoding a payload, optionally wherein the encoded payload comprises a therapeutic protein or a functional variant thereof; an antibody or antibody fragment; an enzyme; a component of a gene editing system; an RNAi agent (e.g., dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA); or a combination thereof.

30. The AAV particles as claimed in claim 29, wherein: (i) The therapeutic protein or a functional variant thereof, such as a recombinant protein, is associated with neurological or neurodegenerative diseases, muscle or neuromuscular diseases, or neurooncological diseases (e.g., aberrantly expressed therein), optionally wherein 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 protein (SMN) 1 or SMN2; aromatic L-amino acid decarboxylase (AADC); aspartate acylase (ASPA); tripeptidyl peptidase I (CLN2); β-galactosidase (GLB1); N-sulfoglucosamine thiohydrolase (SGSH); N-acetyl-α-aminoglucosidase (NAGLU); iduronic acid 2-sulfatase (IDS); intracellular cholesterol transporter (NPC1); giant axon (GAN); or combinations thereof; (ii) An antibody or antibody-binding fragment that binds to the following: (a) CNS-related targets, such as antigens associated with neurology or neurodegenerative diseases, such as β-amyloid, APOE, tau, SOD1, TDP-43, huntingtin (HTT) and / or synuclein; (b) Muscle or neuromuscular targets, such as antigens associated with muscle or neuromuscular disorders; or (c) Neuro-oncology-related targets, such as antigens associated with neuro-oncology conditions, such as HER2 or EGFR (e.g., EGFRvIII); (iii) The enzyme comprises a large nuclease, a zinc finger nuclease, TALEN, a recombinase, an integrase, a base editor, Cas9, or a fragment thereof; (iv) The components of the gene editing system comprise one or more components of a CRISPR-Cas system, optionally wherein the one or more components of the CRISPR-Cas system comprise Cas9, such as a Cas9 ortholog or Cpf1, and a single guide RNA (sgRNA), wherein: (a) The sgRNA is located upstream (5') of the Cas9 enzyme; and / or (b) The sgRNA is located downstream of the Cas9 enzyme (3'); and / or (v) The RNAi agent (e.g., dsRNA, siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, or snoRNA) regulates, for example, the expression of CNS-related genes, mRNA, and / or proteins, optionally wherein the CNS-related genes are selected from SOD1, MAPT, APOE, HTT, TDP-43, APP, BACE, SNCA, ATXN1, ATXN3, ATXN7, SCN1A-SCN5A, SCN8A-SCN11A, or combinations thereof.

31. The AAV particle of any one of claims 28 to 30, comprising a viral genome, said viral genome comprising a promoter operatively linked to a nucleic acid sequence encoding said payload, optionally said promoter being selected from human elongation factor 1α subunit (EF1α), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β-glucuronidase (GUSB) or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synaptic protein (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabolite receptor 2. (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin small gene nβ2, proenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), cardiovascular promoters (e.g., αMHC, cTnT and CMV-MLC2k), liver promoters (e.g., hAAT, TBG), skeletal muscle promoters (e.g., myodermal dermin, MCK, C512) or fragments, such as truncated forms, or functional variants thereof.

32. The AAV particle of claim 31, wherein the viral genome further comprises: (i) polyA signal sequence; (ii) An inverted terminal repeat (ITR) sequence, wherein the ITR sequence is located at 5' relative to the encoded payload, and / or the ITR sequence is located at 3' relative to the encoded payload; (iii) Enhancers, Kozak sequences, intron regions and / or exon regions; (iv) Encoding a miR binding site, for example, regulated in cells or tissues expressing the corresponding miRNA, such as reducing the expression of the miR binding site of an antibody molecule encoded by the viral genome, optionally wherein the encoded miR binding site is regulated, for example, reducing the expression of antibody molecules encoded in cells or tissues of the DRG, liver, heart, hematopoietic lineage, or combinations thereof; and / or (v) Encoding a Rep protein, such as a non-structural protein nucleotide sequence, wherein the Rep protein comprises Rep78, Rep68, Rep52 and / or Rep40 proteins, optionally wherein the Rep78, Rep68, Rep52 and / or Rep40 proteins are encoded by at least one Rep gene.

33. The AAV particle of claim 31 or 32, wherein the viral genome comprises: (i) At least 1 to 5 copies of the encoded miR binding site, for example, at least 1, 2, 3, 4 or 5 copies; (ii) at least three copies of the encoded miR binding site, optionally of which: (a) All three copies contain the same miR binding site, or at least one, two, three, or all copies contain different miR binding sites; and / or (b) The three copies of the encoded miR binding site are consecutive (e.g., not separated by spacers) or separated by spacers, optionally wherein the spacer contains a nucleotide sequence of GATAGTTA, or a nucleotide sequence of GATAGTTA with at least one, two, or three modifications, such as substitutions (e.g., conserved substitutions), but no more than four modifications, such as substitutions (e.g., conserved substitutions); or (iii) At least four copies of the encoded miR binding site, optionally of which (a) All four copies contain the same miR binding site, or at least one, two, three, or all copies contain different miR binding sites; and / or (b) The four copies of the encoded miR binding site are either consecutive (e.g., not separated by spacers) or separated by spacers, wherein the spacers optionally contain a nucleotide sequence of GATAGTTA or a nucleotide sequence of GATAGTTA with at least one, two, or three modifications, such as substitutions (e.g., conserved substitutions), but no more than four modifications, such as substitutions (e.g., conserved substitutions), relative to the nucleotide sequence of GATAGTTA.

34. The AAV particle of claim 32 or 33, wherein the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-1 binding site, a miR-142-3p or a combination thereof, optionally wherein: (i) The miR122 binding site encoded contains the nucleotide sequence of SEQ ID NO: 4673, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% identity with it; or has at least one, two, three, four, five, six or seven modifications, such as substitutions, but not more than ten modifications, such as substituted nucleotide sequences relative to SEQ ID NO: 4673; (ii) The miR183 binding site encoded contains the nucleotide sequence of SEQ ID NO: 4676, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% identity with it; or has at least one, two, three, four, five, six or seven modifications, such as substitutions, but not more than ten modifications, such as substituted nucleotide sequences relative to SEQ ID NO: 4676; (iii) The encoded miR-1 binding site comprises the nucleotide sequence of SEQ ID NO: 4679, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identity with it; or a nucleotide sequence having at least one, two, three, four, five, six, or seven modifications, such as substitutions, but not more than ten modifications, such as substituted nucleotide sequences, relative to SEQ ID NO: 4679; and / or (iv) The miR-142-3p binding site encoded contains the nucleotide sequence of SEQ ID NO: 4675, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% identity with it; or a nucleotide sequence having at least one, two, three, four, five, six or seven modifications, such as substitutions, but not more than ten modifications, such as substituted nucleotide sequences relative to SEQ ID NO: 4675.

35. The AAV particle according to any one of claims 32 to 34, wherein the viral genome: (i) is a single chain; (ii) They are complementary to each other; and / or (iii) It also contains a nucleic acid encoding an AAV capsid variant as described in any one of claims 1 to 24.

36. The AAV capsid variant, polynucleotide, peptide, or AAV particle as described in any of the preceding claims, which is isolated, for example, recombinant.

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

38. A cell, such as a host cell, comprising an AAV capsid variant as claimed in any one of claims 1 to 24 or 36, a polynucleotide as claimed in any one of claims 25, 26 or 36, a peptide as claimed in any one of claims 49 or 60, an AAV particle as claimed in any one of claims 28 to 36, or a carrier as claimed in claim 37, optionally wherein: (i) The cell is a mammalian cell or an insect cell; (ii) The cells are cells of brain regions or spinal cord regions, optionally 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 cells are neurons or astrocytes.

39. A method for manufacturing AAV particles, comprising: (i) Providing a host cell containing the viral genome; and (ii) Incubating the host cells under conditions suitable for encapsulating the viral genome in an AAV capsid variant as claimed in any one of claims 1 to 24 or 36 or a polynucleotide-encoded AAV capsid variant as claimed in any one of claims 25, 26 or 36; Thus, the AAV particles are manufactured.

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

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

42. The method of claim 41, wherein the cell is: (i) Cells of brain regions or spinal cord regions, optionally 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. (ii) Neurons, motor neurons, or astrocytes; and / or (iii) Among the subjects, optionally the subject already has a neurological condition, has been diagnosed with a neurological condition, or is at risk of developing a neurological condition, such as neurodegenerative disease, neuro-oncology, myopathy, or neuromuscular disease.

43. A method of treating a subject suffering from or diagnosed with a neurological condition, said neurological condition being, for example, neurodegenerative disease, neuro-oncology, myopathy, or neuromuscular disease, said method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 40, AAV particles of any one of claims 28 to 36, AAV particles comprising an AAV capsid variant of any one of claims 1 to 24 or 36, or AAV particles comprising a peptide of claim 27 or 36.

44. The method of claim 42 or 43, wherein the neurological condition, neurodegenerative condition, myopathy, neuromuscular condition, or neurooncological condition is Huntington's disease, amyotrophic lateral sclerosis (ALS), Gaucher disease, Lewy body dementia, Parkinson's disease, spinal muscular atrophy, Alzheimer's disease, leukodystrophy (e.g., Alexander disease, autosomal dominant leukodystrophy with autonomic dysfunction (ADLD), Canavan disease, cerebral tendon xanthomas (CTX), metachromatic leukodystrophy (MLD), Peyre's disease, or Reversom disease) or cancer (e.g., HER2 / neu-positive cancer or glioblastoma).

45. The method of claim 43 or 44, wherein the treatment comprises preventing the progression of a disease or condition in the subject, optionally wherein the subject is a person.

46. ​​The method of any one of claims 41 to 45, wherein the AAV particles or pharmaceutical composition are administered to the subject via: (i) Intravenous, intracerebral (ICM) injection, intracerebral, intrathecal, intravenous, intraparenchymal or intramuscular administration; (ii) FUS guided by focused ultrasound (FUS), such as FUS-MB combined with intravenous administration of microbubbles or FUS-MB combined with intravenous administration; or (iii) Intravenous.

47. The pharmaceutical composition of claim 40, the AAV particles of any one of claims 28 to 36, the AAV particles comprising a variant of the AAV capsid of any one of claims 1 to 24 or 36, or the AAV particles comprising the peptide of claim 27 or 36, in a method for delivering a payload to cells or tissues.

48. The pharmaceutical composition of claim 40, the AAV particles of any one of claims 28 to 36, the AAV particles comprising a variant of the AAV capsid of any one of claims 1 to 24 or 36, or the AAV particles comprising the peptide of claim 27 or 36, in a method of treating neurological conditions, neurodegenerative conditions, myopathy, neuromuscular conditions, or neurooncology.

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

50. Use of the pharmaceutical composition of claim 40, the AAV particles of any one of claims 28 to 36, the AAV particles comprising a variant of the AAV capsid of any one of claims 1 to 24 or 36, or the AAV particles comprising the peptide of claim 27 or 36 in the manufacture of a medicament for treating neurological disorders, neurodegenerative disorders, myopathy, neuromuscular disorders, or neurooncology.

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

Images