Compositions and methods for controlling MAPT

Abstract

This disclosure relates to small interfering RNA (siRNA) molecules that target MAPT and adeno-associated virus (AAV) particles encoding them for treating tauopathy.

Description

[Technical Field]

[0001] Related applications This application claims the interests of U.S. Provisional Application No. 63 / 499,636 filed on 2 May 2023, U.S. Provisional Application No. 63 / 593,735 filed on 27 October 2023, U.S. Provisional Application No. 63 / 615,689 filed on 28 December 2023, and U.S. Provisional Application No. 63 / 564,249 filed on 12 March 2024, the entire contents of each of these, are incorporated herein by reference.

[0002] Sequence List This application has been filed electronically along with the sequence listing. The sequence listing file, named V2071-3011PCT_SL.xml, was created on April 11, 2024, and has a size of 5,686,373 bytes. The electronic information of the sequence listing is incorporated herein by reference in its entirety.

[0003] This disclosure generally relates to compositions, methods, and uses of AAV capsid proteins and their variants for vector delivery of drugs that inhibit variants, variants, or wild-type human microtubule-associated protein tau (MAPT) genes, mRNA, and / or proteins, such as RNA agents. [Background technology]

[0004] Tauopathy, also referred to herein as tau-related disease, is a hybrid group of neurodegenerative diseases characterized by dysfunction and / or aggregation of the microtubule-binding protein tau (MAPT), also referred to herein as tau, encoded by the MAPT gene. Tau is a highly soluble protein normally known to bind to microtubules based on its degree of phosphorylation. In tauopathy, tau is hyperphosphorylated, misfolded, and aggregates as neurofibrillary tangles (NFTs) of paired helical filaments (PHFs), twisted ribbons, or linear filaments. These NFTs can generally contribute to widespread neuronal cell loss and are thought to present with imminent neuronal degeneration resulting in diverse behavioral and cognitive impairments, and can be fatal. Currently, very limited treatment options are available for tauopathy, often only symptomatic relief and supportive care. Thus, there is a medical need for improved compositions and methods for the prevention, treatment, and diagnosis of diseases associated with abnormal tau expression, including tauopathy and related neurodegenerative disorders. [Overview of the project]

[0005] This disclosure provides AAV particles and methods of use thereof, comprising AAV capsid variants encoding agents for targeting MAPT, such as RNA agents, to regulate, for example, inhibit MAPT gene expression and / or MAPT protein production. In some embodiments, the agent for targeting MAPT, such as the MAPT gene, mRNA, or protein (e.g., tau protein), is an RNA agent for targeting MAPT, such as a double-stranded siRNA for targeting MAPT. In some embodiments, the agent for targeting MAPT comprises a regulatory polynucleotide encoding a double-stranded siRNA for targeting MAPT. Methods are provided in subjects requiring the treatment of diseases associated with abnormal MAPT expression, such as tauopathies, including but not limited to Alzheimer's disease (AD), frontotemporal dementia (FTD), and / or Dravet syndrome (DS).

[0006] Accordingly, in one embodiment, the present disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3] (wherein (i) optionally [N1] comprises X1, X2, and X3, at least one of X1, X2, or X3 being G; (ii) [N2] comprises the amino acid sequence of SPH; (iii) [N3] comprises X4, X5, and X6, at least one of X4, X5, or X6 being a basic amino acid, e.g., K or R). In some embodiments, position X4 in [N3] is K. In some embodiments, position X5 in [N3] is K. In some embodiments, [N3] is SKA, or comprises SKA. In some embodiments, [N3] is KSG, or contains it. In some embodiments, [N2]-[N3] are located immediately after position 455, numbered according to SEQ ID NO: 138, 981, or 982. In some embodiments, [N1] is located immediately after position 452, compared to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982. In some embodiments, [N1] replaces positions 453-455 (e.g., G453, S454, and G455), compared 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, numbered 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, numbered according to SEQ ID NO: 138 or 981. In some embodiments, an 8-amino acid insert replaces SG at positions 454-455, numbered according to SEQ ID NO: 138. In some embodiments, a 6-amino acid insert is located immediately after position 455, numbered according to SEQ ID NO: 138, 981, or 982.

[0007] In yet another embodiment, the disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 10) (wherein (i) [N1] comprises positions X1, X2, and X3, where position X2 is S and position X3 is G; (ii) [N2] comprises an SPH amino acid sequence; (iii) [N3] comprises positions X4, X5, and X6, where position X5 is K). In some embodiments, [N1]-[N2]-[N3] is located immediately after position 452 and replaces positions 453-455, numbered according to SEQ ID NO: 138 or 982. In some embodiments, [N1]-[N2]-[N3] are GSGSPHSKA (SEQ ID NO: 60) or include it.

[0008] In another embodiment, the present disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 61) (wherein (i) [N1] comprises 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] comprises an SPH amino acid sequence; (iii) [N3] comprises positions X4, X5, and X6, where position X4 is K). In some embodiments, [N1]-[N2]-[N3] is located immediately after position 452 and replaces positions 453-455, numbered according to SEQ ID NO: 138 or 982. In some embodiments, [N1]-[N2]-[N3] are GHDSPHKSG (SEQ ID NO: 62) or include it.

[0009] In yet another aspect, the Disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting the expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant comprises an amino acid sequence having the following formula:[N1]-[N2]-[N3] (wherein (i)[N1] comprises X1, X2, and X3, at least one of X1, X2, or X3 being G; (ii)[N2] comprises the amino acid sequence of SPH; (iii)[N3] comprises X4, X5, and X6, at least one of X4, X5, or X6 being a basic amino acid, e.g., K or R); [N1]-[N2]-[N3] is located in hypervariable loop IV; and the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203-736 of SEQ ID NO: 138.

[0010] In yet another aspect, the disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting the expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant comprises (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV; and (ii) an amino acid sequence at least 95% identical to the amino acid sequence at positions 203-736 of SEQ ID NO: 138.

[0011] In yet another aspect, the disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting the expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant comprises (i) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV; and (ii) an amino acid sequence at least 95% identical to the amino acid sequence at positions 203-736 of SEQ ID NO: 138.

[0012] In yet another embodiment, the disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) in the hypervariable loop IV. In some embodiments, the hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence of SEQ ID NO: 941 is located immediately after position 455, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises amino acid E at position 451, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises amino acid V at position 453, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941); amino acid E at position 451, numbered according to SEQ ID NO: 981; and amino acid V at position 453, numbered according to SEQ ID NO: 3094 or 981.

[0013] In yet another embodiment, the disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) in the hypervariable loop IV. In some embodiments, the hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence of SEQ ID NO: 941 is located immediately after position 455, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises amino acid E at position 451, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises amino acid R at position 452, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises amino acid V at position 453, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941); amino acid E at position 451, numbered according to SEQ ID NO: 981; amino acid R at position 452, numbered according to SEQ ID NO: 981; and amino acid V at position 453, numbered according to SEQ ID NO: 36 or 981.

[0014] In yet another aspect, the Disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, wherein (a) the encoded sense strand sequence comprises SEQ ID NO: 4906 and the encoded antisense strand sequence comprises SEQ ID NO: 4908; (b) the encoded sense strand sequence comprises SEQ ID NO: 4978 and the encoded antisense strand sequence comprises SEQ ID NO: 4920; or (c) the encoded sense strand sequence comprises SEQ ID NO: 4918 and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

[0015] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, the encoded sense strand sequence comprising SEQ ID NO: 4906, and the encoded antisense strand sequence comprising SEQ ID NO: 4908.

[0016] In yet another aspect, the Disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, wherein (a) the encoded sense strand sequence comprises SEQ ID NO: 4906 and the encoded antisense strand sequence comprises SEQ ID NO: 4908; (b) the encoded sense strand sequence comprises SEQ ID NO: 4978 and the encoded antisense strand sequence comprises SEQ ID NO: 4920; or (c) the encoded sense strand sequence comprises SEQ ID NO: 4918 and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

[0017] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, the encoded sense strand sequence comprising SEQ ID NO: 4906, and the encoded antisense strand sequence comprising SEQ ID NO: 4908.

[0018] In yet another aspect, the Disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, wherein (a) the encoded sense strand sequence comprises SEQ ID NO: 4906 and the encoded antisense strand sequence comprises SEQ ID NO: 4908; (b) the encoded sense strand sequence comprises SEQ ID NO: 4978 and the encoded antisense strand sequence comprises SEQ ID NO: 4920; or (c) the encoded sense strand sequence comprises SEQ ID NO: 4918 and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

[0019] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, the encoded sense strand sequence comprising SEQ ID NO: 4906, and the encoded antisense strand sequence comprising SEQ ID NO: 4908.

[0020] In yet another aspect, the Disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, wherein (a) the encoded sense strand sequence comprises SEQ ID NO: 4906 and the encoded antisense strand sequence comprises SEQ ID NO: 4908; (b) the encoded sense strand sequence comprises SEQ ID NO: 4978 and the encoded antisense strand sequence comprises SEQ ID NO: 4920; or (c) the encoded sense strand sequence comprises SEQ ID NO: 4918 and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

[0021] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises an siRNA comprising a sense strand sequence and an antisense strand sequence, the encoded sense strand sequence comprising SEQ ID NO: 4906, and the encoded antisense strand sequence comprising SEQ ID NO: 4908.

[0022] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0023] In yet another aspect, the disclosure provides AAV particles comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising the nucleotide sequence of SEQ ID NO: 4405.

[0024] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising any one of the nucleotide sequences of SEQ ID NO: 4405, 4408, or 4393.

[0025] In yet another embodiment, the disclosure provides AAV particles comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising the nucleotide sequence of SEQ ID NO: 4405.

[0026] In yet another aspect, the Disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0027] In yet another aspect, the disclosure provides AAV particles comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising the nucleotide sequence of SEQ ID NO: 4405.

[0028] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising any one of the nucleotide sequences of SEQ ID NO: 4405, 4408, or 4393.

[0029] In yet another aspect, the disclosure provides AAV particles comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a nucleic acid encoding a human MAPT-targeting polynucleotide comprising the nucleotide sequence of SEQ ID NO: 4405.

[0030] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a viral genome comprising any one nucleotide sequence of SEQ ID NO: 5173, 5195, 5184, or 3886.

[0031] In yet another embodiment, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0032] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0033] In yet another embodiment, the disclosure provides (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) an AAV particle comprising a viral genome comprising any one nucleotide sequence of SEQ ID NO: 5173, 5195, 5184, or 3886.

[0034] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0035] In yet another embodiment, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0036] In yet another aspect, the disclosure provides (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981; and (ii) an AAV particle comprising a viral genome comprising one of the nucleotide sequences of SEQ ID NOs: 5173, 5195, 5184, or 3886.

[0037] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0038] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0039] In yet another aspect, the disclosure provides (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) an AAV particle comprising a viral genome comprising one of the nucleotide sequences of SEQ ID NOs: 5173, 5195, 5184, or 3886.

[0040] In yet another aspect, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0041] In yet another embodiment, the disclosure provides an AAV particle comprising (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0042] In another aspect, the present disclosure relates to AAV particles comprising AAV capsid variants and nucleic acids encoding polynucleotides (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises (a) an amino acid sequence of any of the sequences provided in Table 1A, 2A, 2B, 21-23, 25, 26, or 30; and (b) at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 from any one of the sequences provided in Table 1A, 2A, 2B, 21-23, 25, 26, or 30. (c) an amino acid sequence containing 14, 15, 16, or 17 consecutive amino acids; (d) an amino acid sequence containing at least 1, 2, or 3, but no more than 4, different amino acids compared to any one of the sequences provided in Table 1A, 2A, 2B, 21-23, 25, 26, or 30; or (e.g., an amino acid sequence containing at least 1, 2, or 3, but no more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), compared to any one of the sequences provided in Table 1A, 2A, 2B, 21-23, 25, 26, or 30. In some embodiments, the amino acid sequence is located in loop IV. In some embodiments, the amino acid sequence is located immediately after positions 448, 452, 453, 455 compared to a reference sequence numbered according to the amino acid sequence of sequence number 138.

[0043] In yet another embodiment, the disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises (a) an amino acid sequence of any of SEQ ID NOs: 945-980 or 985-986; (b) an amino acid sequence comprising at least 3, 4, or 5 consecutive amino acids from any one of SEQ ID NOs: 945-980 or 985-986; (c) an amino acid sequence comprising at least 1, 2, or 3, but no more than 4, different amino acids compared to any one of SEQ ID NOs: 945-980 or 985-986; and (d) an amino acid sequence comprising at least 1, 2, or 3, but no more than 4, modifications, e.g., substitutions (e.g., conservative substitutions) compared to any one of SEQ ID NOs: 945-980 or 985-986. In some embodiments, the amino acid sequence is located in loop IV. In some embodiments, the amino acid sequence is located immediately after positions 448, 452, 453, and 455, compared to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0044] In yet another aspect, the Disclosure relates to an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises (a) any amino acid sequence of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; and (b) at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 from any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909. The present invention provides an AAV particle comprising: (c) an amino acid sequence containing 2 or 13 consecutive amino acids; (d) an amino acid sequence containing at least 1, 2, or 3, but no more than 4, different amino acids compared to any one of the amino acid sequences of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; or (e.g., an amino acid sequence containing at least 1, 2, or 3, but no more than 4, modifications, e.g., substitutions (e.g., conservative substitutions), compared to any one of the amino acid sequences of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909. In some embodiments, the amino acid sequence is located in loop IV. In some embodiments, the amino acid sequence is located immediately after positions 448, 452, 453, and 455 compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0045] In yet another aspect, the disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises an amino acid sequence of SPH, the amino acid sequence being located immediately after position 455, and numbered according to any one of the amino acid sequences of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981, or 982.

[0046] In yet another aspect, the disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), the amino acid sequence being located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0047] In yet another aspect, the disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), the amino acid sequence being located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 981.

[0048] In yet another aspect, the disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), the amino acid sequence being located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0049] In yet another aspect, the disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), the amino acid sequence being located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 982.

[0050] In yet another aspect, the Disclosure relates to an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941), (i) at least 3 consecutive amino acids comprising SPH; (ii) at least 4 consecutive amino acids comprising SPHS (SEQ ID NO: 63); (iii) at least 5 consecutive amino acids comprising SPHSK (SEQ ID NO: 64); or (iv) The AAV particle comprises at least six consecutive amino acids, including SPHSKA (SEQ ID NO: 941); the AAV capsid variant includes (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 VP3 protein containing the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) an 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 some embodiments, the amino acid sequence is located immediately after position 455, numbered according to SEQ ID NO: 138 or 981.

[0051] In yet another aspect, the Disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises one or two, but no more than three, substitutions compared to the amino acid sequence of SPHSKA (SEQ ID NO: 941), and 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) to (c). In some embodiments, the amino acid sequence is located immediately after position 455, numbered according to sequence number 138 or 981.

[0052] In another aspect, the Disclosure relates to an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2), (i) at least 3 consecutive amino acids comprising HDS; (ii) at least 4 consecutive amino acids comprising HDSP (SEQ ID NO: 65); (iii) at least 5 consecutive amino acids comprising HDSPH (SEQ ID NO: 66); and / or (iv) at least 6 consecutive The amino acids include HDSPHK (SEQ ID NO: 2); the AAV capsid variant provides AAV particles comprising: (a) a VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein containing the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982; (c) a VP3 protein containing the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 982; or (d) an amino acid sequence having at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a) to (c). In some embodiments, the amino acid sequence is located immediately after position 453, numbered according to SEQ ID NO: 138 or 982.

[0053] In another embodiment, the Disclosure provides AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises one or two, but no more than three, substitutions compared to the amino acid sequence of HDSPHK (SEQ ID NO: 2), and 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) to (c). In some embodiments, the amino acid sequence is located immediately after position 453, numbered according to sequence number 138 or 982.

[0054] According to some aspects of this disclosure, a short-interference ribonucleic acid (siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) comprises a sense strand sequence and an antisense strand sequence, the antisense sequence being complementary to at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides containing 0, 1, 2, or 3 mismatches of a MAPT sequence, including the nucleotide sequence of SEQ ID NO: 5024 or the nucleotide sequences provided in Table 3A or 19. In some embodiments, the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Table 4A, 5A, 9A, or 9B; the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Table 4A, 5A, 9A, or 9B; and the sense strand sequence and antisense strand sequence comprise a complementary region of at least 15 nucleotides. In some embodiments, the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from any one of the antisense strand sequences provided in Table 4A, 5A, 9A, or 9B; the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from any one of the sense strand sequences provided in Table 4A, 5A, 9A, or 9B, and the sense strand sequence and antisense strand sequence comprise a complementary region of at least 15 nucleotides. In some embodiments, the antisense strand sequence comprises a nucleotide sequence from any one of the antisense strand sequences provided in Table 4A, 5A, 9A, or 9B; the sense strand sequence comprises a nucleotide sequence from any one of the sense strand sequences provided in Table 4A, 5A, 9A, or 9B, and the sense strand sequence and antisense strand sequence comprise a complementary region of at least 15 nucleotides.

[0055] According to some aspects of this disclosure, the encoded polynucleotide for inhibiting the expression of MAPT (e.g., human MAPT) comprises siRNA including a sense strand sequence and an antisense strand sequence. In some embodiments, the antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides of any one of sequence numbers 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; the sense strand sequence comprises sequence numbers 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 50 The sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the following sequences: 74, 4914, 4934, 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144, or 5146; the sense strand sequence and antisense strand sequence each contain a complementary region of at least 15 nucleotides.

[0056] In another embodiment, the disclosure provides a modulo polynucleotide encoding an siRNA for targeting MAPT as described herein. In some embodiments, the modulo polynucleotide further comprises a 5' flanking region, a loop region, and / or a 3' flanking region.

[0057] In another aspect, the disclosure provides AAV particles comprising a promoter functionally ligated to a nucleic acid encoding a regulatory polynucleotide, including an siRNA, for targeting MAPT as described herein.

[0058] In another embodiment, the Disclosure provides a method for producing AAV particles comprising an AAV capsid protein encoding an siRNA for targeting MAPT as described herein, e.g., an AAV capsid variant. In some embodiments, the method comprises providing a host cell comprising a viral genome encoding an siRNA as described herein and incubating the host cell under conditions suitable for encapsulating the viral genome in an AAV capsid protein, e.g., an AAV capsid variant, thereby producing AAV particles.

[0059] In yet another embodiment, the Disclosure provides a method for delivering siRNA to cells to inhibit MAPT. In some embodiments, the method includes administering an effective amount of the siRNA described herein or AAV particles encoding the siRNA.

[0060] In yet another embodiment, the Disclosure provides a method for treating subjects who have or have been diagnosed with a genetic disorder, such as a monogenic disorder or a polygenic disorder. In some embodiments, the method includes administering an effective amount of the siRNA or AAV particles encoding the siRNA described herein.

[0061] In yet another aspect, the Disclosure provides a method for treating a subject having or diagnosed with a neurological disorder, such as a neurodegenerative disorder. The method comprises administering an effective amount of the siRNA or AAV particles encoding the siRNA described herein.

[0062] In yet another aspect, the Disclosure provides a method for treating a subject having or diagnosed with a disorder related to tau expression, for example, abnormal tau expression. The method comprises administering an effective amount of siRNA or an AAV particle containing an AAV capsid variant described herein that encodes the siRNA described herein.

[0063] In yet another aspect, the Disclosure provides a method for treating a subject having or diagnosed with tauopathy. The method comprises administering an effective amount of siRNA or an AAV particle containing an AAV capsid variant described herein that encodes the siRNA described herein.

[0064] In some embodiments, hereditary disorders, neurological disorders (e.g., neurodegenerative disorders), disorders associated with tau expression (e.g., abnormal tau expression), and / or tauopathies include Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome (DS), neurodegenerative diseases, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion diseases, CJD, multiple system atrophy, mild cognitive impairment, entangled dementia, or progressive subcortical gliosis.

[0065] Those skilled in the art will be able to recognize or confirm many equivalents to specific embodiments of the inventions described herein by simply using conventional experiments. Such equivalents are intended to be encompassed by the embodiments listed below.

[0066] Enumerated embodiments

[0067] 1. An AAV particle comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and human microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant is given by the following formula: [N1]-[N2]-[N3](wherein, (i) [N1] optionally includes X1, X2, and X3, where at least one of X1, X2, or X3 is G; (ii)[N2] contains the amino acid sequence of SPH; (iii)[N3] comprises X4, X5, and X6, where at least one of X4, X5, or X6 is a basic amino acid, e.g., K or R. The AAV particle having an amino acid sequence.

[0068] 2. The AAV particle according to Embodiment 1, wherein X4, X5, or both of [N3] are K.

[0069] 3. The AAV particle according to Embodiment 1 or 2, wherein X4, X5, or X6 of [N3] is R.

[0070] 4. (a) Position X4 of [N3] is K, S, A, V, T, G, F, W, V, N, or R; (b) Position X5 of [N3] is S, K, T, F, I, L, Y, H, M, or R; and / or (c) Position X6 of [N3] is G, A, R, M, I, N, T, Y, D, P, V, L, E, W, N, Q, K, or S; The AAV particle according to any one of Embodiments 1 to 3, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (a) to (c), for example, a conservative substitution.

[0071] 5.[N3] is an AAV particle according to any one of Embodiments 1 to 4, comprising 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.

[0072] 6.[N3] is SKA, KSG, ARM, VKS, ASR, VKI, KKN, VRM, RKA, KTS, KFG, KIG, KLG, KTT, KTY, KYG, SKD, SKP, TRG, VRG, KRG, GAR, KSA, KSR, SKL, SRA, SKR, SLR, SRG, SSR, FLR, SKW, SKS, WKA, VRR, SKV, SKT, SKG, GKA, TKA, NKA, SKL, SKN, AKA, KTG, KSL, KSE, KSV, KSW, KSN, KHG, KSQ, KSK, KLW, WKG, KMG, KMA, or RSG, or an AAV particle according to any one of Embodiments 1 to 5.

[0073] 7. [N2]-[N3] are SPHSK (sequence number 64), SPHKS (sequence number 67), SPHAR (sequence number 68), SPHVK (sequence number 69), SPHAS (sequence number 70), SPHKK (sequence number 71), SPHVR (sequence number 72), SPHRK (sequence number 73), SPHKT (sequence number 74), SPHKF (sequence number 75), SPHKI (sequence number 76), SPHKL (sequence number 77), SPHKY (sequence number 78), SPHTR (sequence number 79), SPHKR (sequence number) AAV particles according to any one of Embodiments 1 to 6, including (number 80), SPHGA (sequence number 81), SPHSR (sequence number 82), SPHSL (sequence number 83), SPHSS (sequence number 84), SPHFL (sequence number 85), SPHWK (sequence number 86), SPHGK (sequence number 87), SPHTK (sequence number 88), SPHNK (sequence number 89), SPHAK (sequence number 90), SPHKH (sequence number 91), SPHKM (sequence number 92), or SPHRS (sequence number 93).

[0074] 8. [N2]-[N3] are, (i) SPHSKA (sequence number 941), SPHKSG (sequence number 946), SPHARM (sequence number 947), SPHVKS (sequence number 948), SPHASR (sequence number 949), SPHVKI (sequence number 950), SPHKKN (sequence number 954), SPHVRM (sequence number 955), SPHRKA (sequence number 956), SPHKFG (sequence number 957), SPHKIG (sequence number 958), SPHKLG (sequence number 959), SPHKTS (sequence number 963), SPHKTT (sequence number 964), SPHKTY (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: 94), 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), SPHSR G (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: 95), SPHSKG (SEQ ID NO: 96), SPHGKA (SEQ ID NO: 97), SPHNKA (SEQ ID NO: 98), SPHSKN (SEQ ID NO: 99), SPHAKA (SEQ ID NO: 100), SPHSKV (SEQ ID NO: 101), SPHKTG (SEQ ID NO: 102) SPHTKA (sequence number 103), SPHKSL (sequence number 104), SPHKSE (sequence number 105), SPHKSV (sequence number 106), SPHKSW (sequence number 107), SPHKSN (sequence number 108), SPHKHG (sequence number 109), SPHKSQ (sequence number 110), SPHKSK (sequence number 111), SPHKLW (sequence number 112), SPHWKG (sequence number 113), SPHKMG (sequence number 114), SPHKMA (sequence number 115), or SPHRSG (sequence number 976); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of Embodiments 1 to 7, which are or include such particles.

[0075] 9. The AAV particle according to any one of Embodiments 1 to 8, wherein the AAV capsid variant is numbered according to any one of Sequence IDs 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981, or 982, and comprises an amino acid other than G at position 453 (e.g., V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C), an amino acid other than S at position 454 (V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q), and / or G at position 455 (e.g., C, L, D, E, Y, H, V, A, N, P, or S).

[0076] 10. The AAV particle according to any one of Embodiments 1 to 8, wherein the AAV capsid variant is numbered according to Sequence ID No. 138 or 981 and comprises amino acid G at position 453, amino acid S at position 454, and amino acid G at position 455.

[0077] 11. The AAV particle according to any one of Embodiments 1 to 9, wherein the AAV capsid variant is numbered according to Sequence ID No. 138 or 982 and comprises amino acid G at position 453, amino acid H at position 454, and amino acid D at position 455.

[0078] 12.[N1] comprises X1, X2, and X3, where at least one of X1, X2, or X3 is G, as described in any one of Embodiments 1 to 11.

[0079] 13. (a) Position X1 of [N1] is G, V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C; (b) 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) Position X3 of [N1] is G, C, L, D, E, Y, H, V, A, N, P, or S; The AAV particle according to any one of Embodiments 1 to 12, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (a) to (c), for example, a conservative substitution.

[0080] 14.[N1] is an AAV particle according to any one of Embodiments 1 to 13, comprising 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.

[0081] 15.[N1] is GSG, GHD, GQD, VSG, CSG, GRG, CSH, GQS, GSH, RVG, GSC, GLL, GDD, GHE, GNY, MSG, RNG, TSG, ISG, GPG, ESG, SSG, GNG, ASG, NSG, LSG, GGG, KSG, HSG, GTG, PSG, GSV, RSG, GIG, WSG, DSG, IDG, GLG, DAG, DGG, MEG, ENG, GSA, KNG, KEG, AIG, GYD, GHG, GRD, GND, GPD, GMG, GQV, GHN, GHP, or GHS, or an AAV particle according to any one of Embodiments 1 to 14.

[0082] 16. [N1]-[N2] is, (i)SGSPH (sequence number 116), HDSPH (sequence number 66), VGSPH (sequence number 124), QDSPH (sequence number 117), RGSPH (sequence number 118), SHSPH (sequence number 119), QSSPH (sequence number 120), DDSPH (sequence number 121), HESPH (sequence number 122), NYSPH (sequence number 123), SCSPH (sequence number 125), LLSPH (sequence number 126), NGSPH (sequence number 127), PGSPH (sequence number 128), GGSPH (sequence number 129), TGSPH (sequence number 130), SVSPH (sequence number) Number 131), IGSPH (sequence number 132), DGSPH (sequence number 133), LGSPH (sequence number 134), AGSPH (sequence number 135), EGSPH (sequence number 136), SASPH (sequence number 139), YDSPH (sequence number 140), HGSPH (sequence number 141), RDSPH (sequence number 142), NDSPH (sequence number 143), PDSPH (sequence number 144), MGSPH (sequence number 145), QVSPH (sequence number 146), HNSPH (sequence number 147), HPSPH (sequence number 148), or HSSPH (sequence number 149); (ii) Any part of the amino acid sequence in (i), for example, any two, three, or four amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of Embodiments 1 to 15, which are or include such particles.

[0083] 17. [N1]-[N2] is, (i) GSGSPH (SEQ ID NO: 150), GHDSPH (SEQ ID NO: 151), VSGSPH (SEQ ID NO: 153), GQDSPH (SEQ ID NO: 152), CSGSPH (SEQ ID NO: 154), GRGSPH (SEQ ID NO: 155), CSHSPH (SEQ ID NO: 156), GQSSPH (SEQ ID NO: 157), GSHSPH (SEQ ID NO: 158), GDDSPH (SEQ ID NO: 159), GHESPH (SEQ ID NO: 160), GNYSPH (SEQ ID NO: 161), RVGSPH (SEQ ID NO: 162), GSCSPH (SEQ ID NO: 163) ), GLLSPH (sequence number 164), MSGSPH (sequence number 165), RNGSPH (sequence number 166), TSGSPH (sequence number 167), ISGSPH (sequence number 168), GPGSPH (sequence number 169), ESGSPH (sequence number 170), SSGSPH (sequence number 171), GNGSPH (sequence number 172), ASGSPH (sequence number 173), NSGSPH (sequence number 174), LSGSPH (sequence number 175), GGGSPH (sequence number 176), KSGSPH (sequence number 177), HSGSPH (SEQ ID NO: 178), GTGSPH (SEQ ID NO: 179), PSGSPH (SEQ ID NO: 180), GSVSPH (SEQ ID NO: 181), RSGSPH (SEQ ID NO: 182), GIGSPH (SEQ ID NO: 183), WSGSPH (SEQ ID NO: 184), DSGSPH (SEQ ID NO: 185), IDGSPH (SEQ ID NO: 186), GLGSPH (SEQ ID NO: 187), DAGSPH (SEQ ID NO: 188), DGGSPH (SEQ ID NO: 189), MEGSPH (SEQ ID NO: 190), ENGSPH (SEQ ID NO: 191), GS ASPH (sequence number 192), KNGSPH (sequence number 193), KEGSPH (sequence number 194), AIGSPH (sequence number 195), GYDSPH (sequence number 196), GHGSPH (sequence number 197), GRDSPH (sequence number 198), GNDSPH (sequence number 199), GPDSPH (sequence number 989), GMGSPH (sequence number 992), GQVSPH (sequence number 993), GHNSPH (sequence number 994), GHPSPH (sequence number 997), or GHSSPH (sequence number 1008); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of embodiments 1 to 16, which are or include such particles.

[0084] 18. [N1]-[N2]-[N3] is, (i)SGSPHSK (sequence number 1009), HDSPHKS (sequence number 1010), VGSPHSK (sequence number 1037), SGSPHAR (sequence number 1011), SGSPHVK (sequence number 1012), QDSPHKS (sequence number 1013), SGSPHKK (sequence number 1014), SGSPHVR (sequence number 1015), SGSPHAS (sequence number 1016), SGSPHRK (sequence number 1017), SGSPHKT (sequence number 1018), SHSPHKS (sequence number 1019), QSSPHRS (sequence number 1020), RGSPHAS (sequence number SEQ ID NO: 1021), RGSPHSK (SEQ ID NO: 1022), SGSPHKF (SEQ ID NO: 1023), SGSPHKI (SEQ ID NO: 1024), SGSPHKL (SEQ ID NO: 1025), SGSPHKY (SEQ ID NO: 1026), SGSPHTR (SEQ ID NO: 1027), SHSPHKR (SEQ ID NO: 1028), SGSPHGA (SEQ ID NO: 1029), HDSPHKR (SEQ ID NO: 1030), DDSPHKS (SEQ ID NO: 1031), HESPHKS (SEQ ID NO: 1032), NYSPHKI (SEQ ID NO: 1033), SGSPHSR (SEQ ID NO: 1034), SGSPHSL (SEQ ID NO: 1035), SGSPHSS (SEQ ID NO: 1036), SCSPHRK (SEQ ID NO: 1038), SGSPHFL (SEQ ID NO: 1039), LLSPHWK (SEQ ID NO: 1040), NGSPHSK (SEQ ID NO: 1041), PGSPHSK (SEQ ID NO: 1042), GGSPHSK (SEQ ID NO: 1043), TGSPHSK (SEQ ID NO: 1044), SVSPHGK (SEQ ID NO: 1045), SGSPHTK (SEQ ID NO: 1046), IGSPHSK (SEQ ID NO: 1047), DGSPHSK (SEQ ID NO: 1048), SGSPHNK (SEQ ID NO: 1049), LGS PHSK (SEQ ID NO: 1050), AGSPHSK (SEQ ID NO: 1051), EGSPHSK (SEQ ID NO: 1052), SASPHSK (SEQ ID NO: 1053), SGSPHAK (SEQ ID NO: 1054), HDSPHKI (SEQ ID NO: 1055), YDSPHKS (SEQ ID NO: 1056), HDSPHKT (SEQ ID NO: 1057), RGSPHKR (SEQ ID NO: 1058), HGSPHSK (SEQ ID NO: 1059), RDSPHKS (SEQ ID NO: 1060), NDSPHKS (SEQ ID NO: 1061), QDSPHKI (SEQ ID NO: 1062), PDSPHKI (SEQ ID NO: 1063),PDSPHKS (sequence code 1064), MGSPHSK (sequence code 1065), HDSPHKH (sequence code 1066), QVSPHKS (sequence code 1067), HNSPHKS (sequence code 1068), NGSPHKR (sequence code 1069), HDSPHKY (sequence code 1070), NDSPHKI (sequence code 1071), HDSPHKL (sequence code 1072), HPSPHWK (sequence code 1073), HDSPHKM (sequence code 1074), or HSSPHRS (sequence code 1075); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, or 6 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of Embodiments 1 to 17, which are or include such particles.

[0085] 19. [N1]-[N2]-[N3] is, (i) GSGSPHSKA (SEQ ID NO: 60), GHDSPHKSG (SEQ ID NO: 62), VSGSPHSKA (SEQ ID NO: 1083), GSGSPHARM (SEQ ID NO: 1076), GSGSPHVKS (SEQ ID NO: 1077), GQDSPHKSG (SEQ ID NO: 1078), GSGSPHASR (SEQ ID NO: 1079), GSGSPHVKI (SEQ ID NO: 1080), GSGSPHKKN (SEQ ID NO: 1081), GSGSPHVRM (SEQ ID NO: 1082), CSGSPHSKA (SEQ ID NO: 1084), GSGSPHRKA (SEQ ID NO: 1085), CSGSPHKTS ( SEQ ID NO: 1086), CSHSPHKSG (SEQ ID NO: 1087), GQSSPHRSG (SEQ ID NO: 1088), GRGSPHASR (SEQ ID NO: 1089), GRGSPHSKA (SEQ ID NO: 1090), GSGSPHKFG (SEQ ID NO: 1091), GSGSPHKIG (SEQ ID NO: 1092), GSGSPHKLG (SEQ ID NO: 1093), GSGSPHKTS (SEQ ID NO: 1094), GSGSPHKTT (SEQ ID NO: 1095), GSGSPHKTY (SEQ ID NO: 1096), GSGSPHKYG (SEQ ID NO: 1097), GSGSPHSKD (SEQ ID NO: 1098), GSGSPHSKP (SEQ ID NO: 1099), GSGSPHTRG (SEQ ID NO: 1100), GSGSPHVRG (SEQ ID NO: 1101), GSHSPHKRG (SEQ ID NO: 1102), GSHSPHKSG (SEQ ID NO: 1103), VSGSPHASR (SEQ ID NO: 1104), VSGSPHGAR (SEQ ID NO: 1105), VSGSPHKFG (SEQ ID NO: 1106), GHDSPHKRG (SEQ ID NO: 1107), GDDSPHKSG (SEQ ID NO: 1108), GHESPHKSA (SEQ ID NO: 1109), GHDSPHKSA (SEQ ID NO: 1110), GNYSPHKIG ( SEQ ID NOs: 1111), GHDSPHKSR (SEQ ID NOs: 1112), GSGSPHSKL (SEQ ID NOs: 1113), GSGSPHSRA (SEQ ID NOs: 1114), GSGSPHSKR (SEQ ID NOs: 1115), GSGSPHSLR (SEQ ID NOs: 1116), GSGSPHSRG (SEQ ID NOs: 1117), GSGSPHSSR (SEQ ID NOs: 1118), RVGSPHSKA (SEQ ID NOs: 1119), GSCSPHRKA (SEQ ID NOs: 1120), GSGSPHFLR (SEQ ID NOs: 1121), GSGSPHSKW (SEQ ID NOs: 1122), GSGSPHSKS (SEQ ID NOs: 1123),GLLSPHWKA (SEQ ID NO: 1124), GSGSPHVRR (SEQ ID NO: 1125), GSGSPHSKV (SEQ ID NO: 1126), MSGSPHSKA (SEQ ID NO: 1127), RNGSPHSKA (SEQ ID NO: 1128), TSGSPHSKA (SEQ ID NO: 1129), ISGSPHSKA (SEQ ID NO: 1130), GPGSPHSKA (SEQ ID NO: 1131), GSGSPHSKT (SEQ ID NO: 1132), ESGSPHSKA (SEQ ID NO: 1133), SSGSPHSKA (SEQ ID NO: 1134), GNGSPHSKA (SEQ ID NO: 1135), ASGSPHSKA ( SEQ ID NO: 1136), NSGSPHSKA (SEQ ID NO: 1137), LSGSPHSKA (SEQ ID NO: 1138), GGGSPHSKA (SEQ ID NO: 1139), KSGSPHSKA (SEQ ID NO: 1140), GGGSPHSKS (SEQ ID NO: 1141), GSGSPHSKG (SEQ ID NO: 1142), HSGSPHSKA (SEQ ID NO: 1143), GTGSPHSKA (SEQ ID NO: 1144), PSGSPHSKA (SEQ ID NO: 1145), GSVSPHGKA (SEQ ID NO: 1146), RSGSPHSKA (SEQ ID NO: 1147), GSGSPHTKA (SEQ ID NO: 1148), GIGSPHSKA (SEQ ID NO: 1149), WSGSPHSKA (SEQ ID NO: 1150), DSGSPHSKA (SEQ ID NO: 1151), IDGSPHSKA (SEQ ID NO: 1152), GSGSPHNKA (SEQ ID NO: 1153), GLGSPHSKS (SEQ ID NO: 1154), DAGSPHSKA (SEQ ID NO: 1155), DGGSPHSKA (SEQ ID NO: 1156), MEGSPHSKA (SEQ ID NO: 1157), ENGSPHSKA (SEQ ID NO: 1158), GSASPHSKA (SEQ ID NO: 1159), GNGSPHSKS (SEQ ID NO: 1160), KNGSPHSKA ( SEQ ID NO: 1161), KEGSPHSKA (SEQ ID NO: 1162), AIGSPHSKA (SEQ ID NO: 1163), GSGSPHSKN (SEQ ID NO: 1164), GSGSPHAKA (SEQ ID NO: 1165), GHDSPHKIG (SEQ ID NO: 1166), GYDSPHKSG (SEQ ID NO: 1167), GHESPHKSG (SEQ ID NO: 1168), GHDSPHKTG (SEQ ID NO: 1169), GRGSPHKRG (SEQ ID NO: 1170), GQDSPHKSG (SEQ ID NO: 1078), GHDSPHKSL (SEQ ID NO: 1171), GHGSPHSKA (SEQ ID NO: 1172),GHDSPHKSE (SEQ ID NO: 1173), VSGSPHSKA (SEQ ID NO: 1083), GRDSPHKSG (SEQ ID NO: 1174), GNDSPHKSV (SEQ ID NO: 1175), GQDSPHKIG (SEQ ID NO: 1176), GHDSPHKSV (SEQ ID NO: 1177), GPDSPHKIG (SEQ ID NO: 1178), GPDSPHKSG (SEQ ID NO: 1179), GHDSPHKSW (SEQ ID NO: 1180), GHDSPHKSN (SEQ ID NO: 1181), GMGSPHSKT (SEQ ID NO: 1182), GHDSPHKHG (SEQ ID NO: 1183), GQVSPHKSG (SEQ ID NO: 1173) Number 1184), GDDSPHKSV (sequence number 1185), GHNSPHKSG (sequence number 1186), GNGSPHKRG (sequence number 1187), GHDSPHKYG (sequence number 1188), GHDSPHKSQ (sequence number 1189), GNDSPHKIG (sequence number 1190), GHDSPHKSK (sequence number 1191), GHDSPHKLW (sequence number 1192), GHPSPHWKG (sequence number 1193), GHDSPHKMG (sequence number 1194), GHDSPHKMA (sequence number 1195), or GHSSPHRSG (sequence number 1196); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, or 8 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of Embodiments 1 to 18, which are or include such particles.

[0086] 20.[N3] is an AAV particle according to any one of Embodiments 1 to 19, comprising SK, KA, KS, or SG.

[0087] 21.[N3] is SKA, KSG, or KYG, or an AAV particle according to any one of Embodiments 1 to 20, comprising the same.

[0088] 22.[N2]-[N3] are AAV particles according to any one of Embodiments 1 to 21, comprising SPHSK (SEQ ID NO: 64), SPHKS (SEQ ID NO: 67), or SPHKY (SEQ ID NO: 78).

[0089] 23.[N2]-[N3] is SPHSKA (SEQ ID NO: 941), or an AAV particle according to any one of Embodiments 1 to 22, comprising the same.

[0090] 24.[N2]-[N3] is SPHKSG (SEQ ID NO: 946), or an AAV particle according to any one of Embodiments 1 to 22, comprising the same.

[0091] 25.[N2]-[N3] is SPHKYG (SEQ ID NO: 966), or an AAV particle according to any one of Embodiments 1 to 22, comprising the same.

[0092] 26.[N1] is an AAV particle according to any one of Embodiments 1 to 25, comprising GS, SG, GH, or HD.

[0093] 27.[N1] is a GSG, or an AAV particle according to any one of Embodiments 1 to 26, comprising the same.

[0094] 28.[N1] is a GHD, or an AAV particle according to any one of Embodiments 1 to 26, comprising the same.

[0095] 29.[N1]-[N2]-[N3] are AAV particles according to any one of Embodiments 1-23 or 26-27, including SGSPHSK (SEQ ID NO: 1009).

[0096] 30. [N1]-[N2]-[N3] is an AAV particle according to any one of Embodiments 1 to 22, 24, 26, or 28, including HDSPHKS (SEQ ID NO: 1010).

[0097] 31. [N1]-[N2]-[N3] is an AAV particle according to any one of Embodiments 1 to 22 or 25 to 27, including SGSPHKYG (SEQ ID NO: 1197).

[0098] 32. [N1]-[N2]-[N3] is GSGSPHSKA (SEQ ID NO: 60) or an AAV particle according to any one of Embodiments 1 to 8, 10, 12 to 23, 26 to 27, or 29, including the same.

[0099] 33. [N1]-[N2]-[N3] is GHDSPHKSG (SEQ ID NO: 62) or an AAV particle according to any one of Embodiments 1 to 9, 11 to 22, 24, 26, 28, or 30, including the same.

[0100] 34. [N1]-[N2]-[N3] is GSGSPHKYG (SEQ ID NO: 1097) or an AAV particle according to any one of Embodiments 1 to 8, 10, 12 to 22, 25 to 27, or 31, including the same.

[0101] 35. [N1]-[N2]-[N3] is an AAV particle according to any one of Embodiments 1 to 34, numbered according to the amino acid sequence of SEQ ID NO: 138, and replaced at positions 453 to 455.

[0102] 36. The AAV particle according to any one of Embodiments 1 to 35, wherein the AAV capsid variant comprises, compared to the reference sequence numbered according to Sequence ID No. 138, an amino acid other than Q at position 456 (e.g., W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F), an amino acid other than N at position 457 (e.g., Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, I, M, Q, or L), an amino acid other than Q at position 458 (e.g., G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y), and / or an amino acid other than Q at position 459 (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V).

[0103] 37. The AAV capsid variant, compared to the reference sequence numbered according to SEQ ID NOs. 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57, has 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, V, S, AAV particles according to any one of Embodiments 1 to 36, comprising P, G, W, E, F, A, I, M, Q, or L, an amino acid other than Q at position 464 (e.g., G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y), and / or an amino acid other than Q at position 465 (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V).

[0104] 38. The AAV capsid variant is (a) Compared to the reference sequence numbered according to Sequence ID No. 138, amino acid Q at position 456, amino acid N at position 457, amino acid Q at position 458, and / or amino acid Q at position 459; or (b) Compared to the reference sequence numbered according to SEQ ID NOs: 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57, 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 AAV particles according to any one of embodiments 1 to 37, including the AAV particles described.

[0105] 39. The AAV capsid variant further comprises [N4], where [N4] comprises X7, X8, X9, X10. (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; (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; The AAV particle according to any one of Embodiments 1 to 38, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (a) to (d), for example, a conservative substitution.

[0106] 40. (a) Position X7 of [N4] is either Q or R; (b) Position X8 of [N4] is either N or R; (c) Position X9 of [N4] is either Q or R; (d) Position X10 of [N4] is Q, L, or R. AAV particles as described in Embodiment 39.

[0107] 41. [N4] is, (i) QNQQ (sequence number 1198), WNQQ (sequence number 1199), QYYV (sequence number 1200), RRQQ (sequence number 1201), GCGQ (sequence number 1202), LRQQ (sequence number 1203), RNQQ (sequence number 1204), VNQQ (sequence number 1205), FRLQ (sequence number 1206), FNQQ (sequence number 1207), LLQQ (sequence number 1208), SNQQ (sequence number 1209), RLQQ (sequence number 1210), LNQQ (sequence number 1211), QRKL (sequence number 1212), LRRQ (sequence number 1213), QRLR( QNQQ (SEQ ID NO: 1214), QRL (SEQ ID NO: 1215), RRLQ (SEQ ID NO: 1216), RLRQ (SEQ ID NO: 1217), SKRQ (SEQ ID NO: 1218), QLYR (SEQ ID NO: 1219), QLTV (SEQ ID NO: 1220), QNKQ (SEQ ID NO: 1221), KNQQ (SEQ ID NO: 1222), QKQQ (SEQ ID NO: 1223), QTQQ (SEQ ID NO: 1224), QNHQ (SEQ ID NO: 1225), QHQQ (SEQ ID NO: 1226), QNQH (SEQ ID NO: 1227), QHRQ (SEQ ID NO: 1228), LTQQ (SEQ ID NO: 1229), QNQW (SEQ ID NO: 1230) QNTH (sequence number 1231), RRRQ (sequence number 1232), QYQQ (sequence number 1233), QNDQ (sequence number 1234), QNRH (sequence number 1235), RDQQ (sequence number 1236), PNLQ (sequence number 1237), HVRQ (sequence number 1238), PNQH (sequence number 1239), HNQQ (sequence number 1240), QSQQ (sequence number 1241), QPAK (sequence number 1242), QNLA (sequence number 1243), QNQL (sequence number 1244), QGQQ (sequence number 1245), LNRQ (sequence number 1246), QNPP (distribution) Column number 1247), QNLQ (sequence number 1248), QDQE (sequence number 1249), QDQQ (sequence number 1250), HWQQ (sequence number 1251), PNQQ (sequence number 1252), PEQQ (sequence number 1253), QRTM (sequence number 1254), LHQH (sequence number 1255), QHRI (sequence number 1256), QYIH (sequence number 1257), QKFE (sequence number 1258), QFPS (sequence number 1259), QNPL (sequence number 1260), QAIK (sequence number 1261), QNRQ (sequence number 1263), QYQH (sequence number 1264),QNPQ (sequence number 1265), QHQL (sequence number 1266), QSPP (sequence number 1267), QAKL (sequence number 1268), KSQQ (sequence number 1269), QDRP (sequence number 1270), QNLG (sequence number 1271), QAFH (sequence number 1272), QNAQ (sequence number 1273), HNQL (sequence number 1274), QKLN (sequence number 1275), QNVQ (sequence number 1276), QAQQ (sequence number 1277), QTPP (sequence number 1278), QPPA (sequence number 1279), QERP (sequence number 1280), QDLQ (sequence number) QAMH (sequence number 1282), QHPS (sequence number 1283), PGLQ (sequence number 1284), QGIR (sequence number 1285), QAPA (sequence number 1286), QIPP (sequence number 1287), QTQL (sequence number 1288), QAPS (sequence number 1289), QNTY (sequence number 1290), QDKQ (sequence number 1291), QNHL (sequence number 1292), QIGM (sequence number 1293), LNKQ (sequence number 1294), PNQL (sequence number 1295), QLQQ (sequence number 1296), QRMS (sequence number 1297), QGIL (SEQ ID NO: 1298), QDRQ (SEQ ID NO: 1299), RDWQ (SEQ ID NO: 1300), QERS (SEQ ID NO: 1301), QNYQ (SEQ ID NO: 1302), QRTC (SEQ ID NO: 1303), QIGH (SEQ ID NO: 1304), QGAI (SEQ ID NO: 1305), QVPP (SEQ ID NO: 1306), QVQQ (SEQ ID NO: 1307), LMRQ (SEQ ID NO: 1308), QYSV (SEQ ID NO: 1309), QAIT (SEQ ID NO: 1310), QKTL (SEQ ID NO: 1311), QLHH (SEQ ID NO: 1312), QNII (SEQ ID NO: 1313), QGHH (SEQ ID NO: 1308), QGIL (SEQ ID NO: 1308), QDRQ09), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 1308), QDRQ (SEQ ID NO: 130 Number 1314), QSKV (sequence number 1315), QLPS (sequence number 1316), IGKQ (sequence number 1317), QAIH (sequence number 1318), QHGL (sequence number 1319), QFMC (sequence number 1320), QNQM (sequence number 1321), QHLQ (sequence number 1322), QPAR (sequence number 1323), QSLQ (sequence number 1324), QSQL (sequence number 1325), HSQQ (sequence number 1326), QMPS (sequence number 1327), QGSL (sequence number 1328), QVPA (sequence number 1329), HYQQ (sequence number 1330),QVPS (SEQ ID NO: 1331), RGEQ (SEQ ID NO: 1332), PGQQ (SEQ ID NO: 1333), LEQQ (SEQ ID NO: 1334), QNQS (SEQ ID NO: 1335), QKVI (SEQ ID NO: 1336), QNND (SEQ ID NO: 1337), QSVH (SEQ ID NO: 1338), QPLG (SEQ ID NO: 1339), HNQE (SEQ ID NO: 1340), QIQQ (SEQ ID NO: 1341), QVRN (SEQ ID NO: 1342), PSNQ (SEQ ID NO: 1343), QVGH (SEQ ID NO: 1344), QRDI (SEQ ID NO: 1345), QMPN (SEQ ID NO: 1346), RGLQ (SEQ ID NO: 1346) Number 1347), PSLQ (SEQ ID NO: 1348), QRDQ (SEQ ID NO: 1349), QAKG (SEQ ID NO: 1350), QSAH (SEQ ID NO: 1351), QSTM (SEQ ID NO: 1352), QREM (SEQ ID NO: 1353), QYRA (SEQ ID NO: 1354), QRQQ (SEQ ID NO: 1355), QWQQ (SEQ ID NO: 1356), QRMN (SEQ ID NO: 1357), GDSQ (SEQ ID NO: 1358), QKIS (SEQ ID NO: 1359), PSMQ (SEQ ID NO: 1360), SPRQ (SEQ ID NO: 1361), MEQQ (SEQ ID NO: 1362), QYQN (SEQ ID NO: 1363), QIRQ (SEQ ID NO: 1364), QSVQ (SEQ ID NO: 1365), RSQQ (SEQ ID NO: 1366), QNKL (SEQ ID NO: 1367), QIQH (SEQ ID NO: 1368), PRQQ (SEQ ID NO: 1369), HTQQ (SEQ ID NO: 1370), QRQH (SEQ ID NO: 1371), RNQE (SEQ ID NO: 1372), QSKQ (SEQ ID NO: 1373), QNQP (SEQ ID NO: 1374), QSPQ (SEQ ID NO: 1375), QTRQ (SEQ ID NO: 1376), QNLH (SEQ ID NO: 1377), QNQE (SEQ ID NO: 1378), LNQP (SEQ ID NO: 1379), QNQD (SEQ ID NO: 1379) Number 1380), QNLL (Sequence ID 1381), QLVI (Sequence ID 1382), RTQE (Sequence ID 1383), QTHQ (Sequence ID 1384), QDQH (Sequence ID 1385), QSQH (Sequence ID 1386), VRQQ (Sequence ID 1387), AWQQ (Sequence ID 1388), QSVP (Sequence ID 1389), QNIQ (Sequence ID 1390), LDQQ (Sequence ID 1391), PDQQ (Sequence ID 1392), ESQQ (Sequence ID 1393), QRQL (Sequence ID 1394), QIIV (Sequence ID 1395), QKQS (Sequence ID 1396),QSHQ (sequence number 1397), QFVV (sequence number 1398), QSQP (sequence number 1399), QNEQ (sequence number 1400), INQQ (sequence number 1401), RNRQ (sequence number 1402), RDQK (sequence number 1403), QWKR (sequence number 1404), ENRQ (sequence number 1405), QTQP (sequence number 1406), QKQL (sequence number 1407), RNQL (sequence number 1408), ISIQ (sequence number 1409), QTVC (sequence number 1410), QQIM (sequence number 1411), LNHQ (sequence number 1412), QNQA (sequence number 1413), QMIH (sequence number 1414), RNHQ (sequence number 1415), or QKMN (sequence number 1416); (ii) Any part of the amino acid sequence in (i), for example, any two or three amino acids, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 39 or 40, which are or include the same.

[0108] 42. [N1]-[N2]-[N3]-[N4] is, (i) Any amino acid sequence from sequence numbers 1800 to 2241; (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) an AAV particle according to any one of Embodiments 39 to 41, which is or includes the same.

[0109] 43. The [N1]-[N2]-[N3]-[N4] is GSGSPHSKAQNQQ (SEQ ID NO: 1801), or an AAV particle according to any one of Embodiments 37 to 42, which is or includes the same.

[0110] 44. The [N1]-[N2]-[N3]-[N4] is GHDSPHKSGQNQQ (SEQ ID NO: 1800), or an AAV particle according to any one of Embodiments 37 to 42, which is or includes the same.

[0111] 45. The [N1]-[N2]-[N3]-[N4] is GSGSPHKYGQNQQT (SEQ ID NO: 910), or an AAV particle according to any one of Embodiments 37 to 42, which is or includes the same.

[0112] 46. The AAV capsid variant includes an amino acid other than T (e.g., S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G) at position 450, an amino acid other than I (e.g., M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L) at position 451, and / or an amino acid other than N (e.g., M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S) at position 452, as compared with a reference sequence numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36 to 59, 138, 981, or 982. The AAV particle is according to any one of Embodiments 1 to 45.

[0113] 47. The AAV capsid variant (i) amino acid T at position 450, amino acid I at position 451, and / or amino acid N at position 452, as compared with a reference sequence numbered according to any one of SEQ ID NOs: 138, 981, or 982; (ii) Amino acid T at position 450, amino acid E at position 451, and / or amino acid R at position 452, numbered according to Sequence ID No. 36; or (iii) Amino acid T at position 450, amino acid E at position 451, and / or amino acid N at position 452, numbered according to Sequence ID No. 3904. AAV particles according to any one of embodiments 1 to 46, including the AAV particles described.

[0114] 48. The AAV capsid variant further comprises [N0], where [N0] comprises XA, XB and XC. (a) Position XA is T, S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G; (b) Position XB is I, M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L; (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; The AAV particle according to any one of Embodiments 1 to 47, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (a) to (c), for example, a conservative substitution.

[0115] 49.[N0] TIN, 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, T II, TFP, TEK, EIN, TVN, TFN, SIN, TER, TSY, ELH, AIN, SVN, TDN, TFH, TVH, TEN, TSS, TID, TCN, NIN, TE H, 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, NAD, TIT, NCV, TIR, NAL, VIN, TIQ, TEF, The AAV particle of embodiment 48 is or comprises 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.

[0116] 50.[N0]-[N1]-[N2]-[N3]-[N4] is, (i) Any one amino acid sequence from sequence numbers 2242 to 2886; (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 48 or 49, which are or include the same.

[0117] 51. AAV particles according to any one of Embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is TINGSGSPHSKAQNQQ (Sequence ID 2242), or includes it.

[0118] 52.[N0]-[N1]-[N2]-[N3]-[N4] is TINGHDSPHKSGQNQQ (SEQ ID NO: 2243), or an AAV particle according to any one of embodiments 48 to 50, comprising the same.

[0119] 53. AAV particles according to any one of Embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is TINGSGSPHKYGQNQQT (Sequence ID 5246), or includes it.

[0120] 54.[N1]-[N2]-[N3] are AAV particles according to any one of Embodiments 1 to 53, which are present in loop IV of the AAV capsid variant.

[0121] 55. [N0] and [N4] are AAV particles according to any one of embodiments 48 to 54, which are present in loop IV of the AAV capsid variant.

[0122] 56.[N0] is an AAV particle according to any one of embodiments 48 to 55, where N0 is located immediately after position 449 compared to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0123] 57.[N0] is an AAV particle according to any one of embodiments 48 to 55, located immediately after position 449 compared to a reference sequence numbered according to any one of the amino acid sequences of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982.

[0124] 58.[N0] is an AAV particle according to any one of embodiments 48 to 57, which replaces positions 450, 451, and 452 (e.g., T450, I451, and N452) with respect to the reference sequence numbered according to sequence number 138.

[0125] 59.[N0] is an AAV particle according to any one of embodiments 48 to 58, which replaces positions 450 to 452 (e.g., T450, I451, and N452) with respect to a reference sequence numbered according to any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, 36 to 59, 981, or 982.

[0126] 60.[N0] is an AAV particle according to any one of embodiments 48 to 59, corresponding to position 450 to 452 of any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, 36 to 59, 138, 981, or 982.

[0127] 61. An AAV particle according to any one of embodiments 48 to 60, wherein [N0] is located immediately after position 449, and [N0] replaces positions 450 to 452 (e.g., T450, I451, and N452) compared to the reference sequence numbered according to sequence number 138.

[0128] 62. An AAV particle according to any one of embodiments 48 to 61, wherein [N0] is located immediately after position 449 and replaces positions 450 to 452 (e.g., T450, I451, and N452) with respect to a reference sequence numbered according to any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, 36 to 59, 981, or 982.

[0129] 63.[N1] is an AAV particle according to any one of Embodiments 1 to 62, where it is located immediately after position 452 compared to the reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0130] 64.[N1] is an AAV particle according to any one of Embodiments 1 to 63, where it is located immediately after position 452 compared to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 981 or 982.

[0131] 65.[N1] is an AAV particle according to any one of Embodiments 1 to 64, which replaces positions 453-455 (e.g., G453, S454, and G455) with respect to the reference sequence numbered according to Sequence ID No. 138.

[0132] 66.[N1] is an AAV particle according to any one of Embodiments 1 to 65, which replaces position 453 (e.g., G453) with respect to the reference sequence numbered according to Sequence ID No. 138.

[0133] 67.[N1] is an AAV particle according to any one of Embodiments 1 to 66, which replaces positions 453-455 (e.g., G453, S454, and G455) with respect to the reference sequence numbered according to Sequence ID No. 981.

[0134] 68.[N1] is an AAV particle according to any one of Embodiments 1 to 66 or 67, which replaces positions 453 to 455 compared to the reference sequence numbered according to Sequence ID No. 982.

[0135] 69. An AAV particle according to any one of Embodiments 1 to 68, wherein [N1] is located immediately after position 452, and [N1] replaces positions 453-455 (e.g., G453, S454, and G455) compared to the reference sequence numbered according to Sequence ID 138.

[0136] 70. An AAV particle according to any one of embodiments 1 to 64 or 66, wherein [N1] is located immediately after position 452 and [N1] replaces position 453 (e.g., G453) compared to the reference sequence numbered according to sequence number 138.

[0137] 71. An AAV particle according to any one of embodiments 1 to 64, 66, or 70, wherein [N1] is located immediately after position 452 and replaces positions 453 to 455 compared to a reference sequence numbered according to sequence number 981 or 982.

[0138] 72.[N1] is an AAV particle according to any one of Embodiments 1 to 71, corresponding to position 453 to 455 of any one of Sequence IDs 3904, 3905, 3906, 4, 5, 6, 7, 8, 36 to 59, 981, or 982.

[0139] 73. The AAV particle according to any one of Embodiments 1 to 72, wherein the AAV capsid variant comprises an amino acid other than S at position 454 and / or an amino acid other than G at position 455, numbered according to Sequence ID No. 138, 981, or 982.

[0140] 74. The AAV particle according to any one of Embodiments 1 to 73, wherein the AAV capsid variant is numbered according to Sequence ID No. 138 and comprises amino acid H at position 454 and amino acid D at position 455.

[0141] 75. The AAV particle according to any one of Embodiments 1 to 74, wherein the AAV capsid variant is numbered according to Sequence ID No. 138 or 982, and includes substitution at position 454 (e.g., S454H) and / or substitution at position 455 (e.g., G455D).

[0142] 76. The AAV particle according to any one of Embodiments 1 to 75, wherein the AAV capsid variant further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately after position 455, compared to a reference sequence numbered according to SEQ ID NO: 138, which comprises amino acid H at position 454 and amino acid D at position 455.

[0143] 77. The AAV particle according to any one of Embodiments 1 to 71, wherein the AAV capsid variant comprises amino acid H at position 454 and amino acid D at position 455, compared to the reference sequence numbered according to Sequence ID No. 982.

[0144] 78. The AAV particle according to any one of Embodiments 1 to 77, wherein the AAV capsid variant further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately after position 455, compared to a reference sequence numbered according to SEQ ID NO: 982, which comprises amino acid H at position 454 and amino acid D at position 455.

[0145] 79. The AAV particle according to any one of Embodiments 1 to 71, wherein the AAV capsid variant comprises amino acid S at position 454 and amino acid G at position 455, compared to the reference sequence numbered according to Sequence ID No. 138.

[0146] 80. The AAV particle according to any one of Embodiments 1 to 71 or 79, wherein the AAV capsid variant further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately after position 455, compared to a reference sequence numbered according to SEQ ID NO: 138, which comprises amino acid S at position 454 and amino acid G at position 455.

[0147] 81. The AAV particle according to any one of Embodiments 1 to 71, 79, or 80, wherein the AAV capsid variant comprises amino acid S at position 454 and amino acid G at position 455, compared to a reference sequence numbered according to Sequence ID No. 981.

[0148] 82. The AAV particle according to any one of embodiments 1 to 71 or 79 to 81, wherein the AAV capsid variant further comprises the amino acid sequence SPHSKA (sequence number 941) immediately after position 455, compared to a reference sequence numbered according to sequence number 981, which comprises amino acid S at position 454 and amino acid G at position 455.

[0149] 83.[N2] is an AAV particle according to any one of Embodiments 1 to 82, where it is located immediately after position 455 compared to the reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0150] 84.[N2] is an AAV particle according to any one of Embodiments 1 to 82, corresponding to positions 456-458 (e.g., S456, P457, H458) of Sequence ID No. 981 or 982.

[0151] 85.[N2] is an AAV particle according to any one of Embodiments 1 to 84, corresponding to position 456-458 (e.g., S456, P457, H458) of any one of Sequence IDs 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59.

[0152] 86.[N2]-[N3] is an AAV particle according to any one of Embodiments 1 to 85, located immediately after position 455 compared to the reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0153] 87.[N2] is an AAV particle according to any one of Embodiments 1 to 86, where it is located immediately after position 455 compared to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 981 or 982.

[0154] 88.[N2]-[N3] is an AAV particle according to any one of Embodiments 1 to 87, located immediately after position 455 compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982.

[0155] 89.[N2]-[N3] are AAV particles according to any one of Embodiments 1-88, corresponding to positions 456-461 of Sequence ID No. 981 (e.g., S456, P457, H458, S459, K460, A461).

[0156] 90.[N2]-[N3] are AAV particles according to any one of Embodiments 1-88, corresponding to positions 456-461 of Sequence ID No. 982 (e.g., S456, P457, H458, K459, S460, G461).

[0157] 91.[N2] is an AAV particle according to any one of Embodiments 1 to 88, which is located immediately after [N1].

[0158] 92.[N3] is located immediately after [N2] and replaces positions 454 and 455 (e.g., S454 and G455) numbered according to Sequence ID No. 138, an AAV particle according to any one of Embodiments 1 to 64, 66, 70, or 71.

[0159] 93.[N3] is an AAV particle according to any one of embodiments 1 to 64, 66, 70, 71, or 92, which is located immediately after [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455) numbered according to sequence number 138.

[0160] 94.[N4] is an AAV particle according to any one of embodiments 39 to 93, where it is located immediately after position 455 compared to the reference sequence numbered according to the amino acid sequence of sequence number 138.

[0161] 95.[N4] is replaced at positions 456-459 (e.g., Q456, N457, Q458, and Q459) compared to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 39-94.

[0162] 96.[N4] is an AAV particle according to any one of embodiments 39 to 95, corresponding to positions 462 to 465 (e.g., Q462, N463, Q464, Q465) of sequence number 981 or 982.

[0163] 97.[N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 39-96.

[0164] 98. An AAV particle according to any one of embodiments 39 to 97, wherein [N2]-[N3]-[N4] is located immediately after position 455, and [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459) compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0165] 99.[N2]-[N3]-[N4] are AAV particles according to any one of embodiments 39-98, corresponding to positions 456-465 of sequence number 981 (e.g., S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0166] 100.[N2]-[N3]-[N4] corresponds to positions 456-465 of Sequence ID No. 982 (e.g., S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465), and is an AAV particle according to any one of Embodiments 39-99.

[0167] 101.[N2]-[N3]-[N4] corresponds to any one of the AAV particles according to any one of the embodiments 39-100, with position 456-465 of any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59.

[0168] 102.[N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 39-101.

[0169] 103. An AAV particle according to any one of Embodiments 39 to 102, wherein [N1]-[N2]-[N3]-[N4] is located immediately after position 452, and [N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459) compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0170] 104.[N1]-[N2]-[N3]-[N4] are AAV particles according to any one of embodiments 39-99, 102, or 103, corresponding to positions 453-465 of sequence number 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0171] 105.[N1]-[N2]-[N3]-[N4] are AAV particles according to any one of Embodiments 39-98 or 100-103, corresponding to positions 453-465 of Sequence ID No. 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0172] 106.[N2]-[N3]-[N4] corresponds to position 453-465 of any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59, as described in any one of embodiments 39-98 or 101-103.

[0173] 107.[N1]-[N2]-[N3] are AAV particles according to any one of Embodiments 1-98 or 102-104, corresponding to positions 453-461 of Sequence ID No. 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0174] 108.[N1]-[N2]-[N3] corresponds to positions 453-461 of Sequence ID No. 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461), and is an AAV particle according to any one of Embodiments 1-98, 100, 102, 103, or 105.

[0175] 109.[N1]-[N2]-[N3] corresponds to position 453-461 of any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59, as described in any one of embodiments 40-98, 101-103, or 106.

[0176] 110.[N0]-[N1]-[N2]-[N3]-[N4] are replaced at positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459) compared to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 39-109.

[0177] 111. An AAV particle according to any one of Embodiments 39 to 110, wherein [N0]-[N1]-[N2]-[N3]-[N4] is located immediately after position 449, and [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459) compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0178] 112.[N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of Sequence ID No. 981 (e.g., T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465), as described in any one of Embodiments 39-99, 102-104, 110, or 111.

[0179] 113.[N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 of Sequence ID No. 982 (e.g., T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465), as described in any one of Embodiments 39-98, 100-103, or 105-111.

[0180] 114.[N0]-[N1]-[N2]-[N3]-[N4] corresponds to any one of the AAV particles in any one of the embodiments 48-98, 101-103, 106, or 109, with position 450-465 of any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59.

[0181] 115.[N4] is replaced at positions 462-465 (e.g., Q462, N463, Q464, and Q465) compared to a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982, as described in any one of embodiments 39-113, an AAV particle.

[0182] 116.[N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982, as described in any one of Embodiments 39-115.

[0183] 117. An AAV particle according to any one of embodiments 39 to 116, wherein [N2]-[N3]-[N4] is located immediately after position 455, and [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465) compared to a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982.

[0184] 118.[N3] is an AAV particle according to any one of Embodiments 1 to 117, located immediately after [N2].

[0185] 119. The AAV particle according to any one of Embodiments 1 to 118, wherein the AAV capsid variant comprises [N2]-[N3] from the N-terminus to the C-terminus.

[0186] 120. The AAV particle according to any one of Embodiments 1 to 119, wherein the AAV capsid variant comprises [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0187] 121. The AAV particle according to any one of Embodiments 28 to 120, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0188] 122. The AAV particle according to any one of Embodiments 25 to 121, wherein the AAV capsid variant comprises [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0189] 123. The AAV particle according to any one of Embodiments 25 to 122, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0190] 124. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant comprises an amino acid other than T at position 460 (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S) numbered according to the amino acid sequence of Sequence ID No. 138.

[0191] 125. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is numbered according to the amino acid sequence of Sequence ID No. 138, and comprises amino acids N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S at position 460.

[0192] 126. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is numbered according to any one of the amino acid sequences of SEQ ID NOs. 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982, and contains an amino acid other than T at position 466 (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S).

[0193] 127. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is numbered according to one of the amino acid sequences of SEQ ID NOs. 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982, and comprises amino acids N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S at position 466.

[0194] 128. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is numbered according to any one of the amino acid sequences of SEQ ID NOs. 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981, or 982, and contains an amino acid other than K (e.g., E, N, or T) at position 449.

[0195] 129. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is numbered according to one of the amino acid sequences of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981, or 982, and contains amino E, N, or T at position 449.

[0196] 116. AAV particles comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and human microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant is given by the following formula: [N1]-[N2]-[N3](SEQ ID NO: 10)(wherein, (i)[N1] includes positions X1, X2, and X3, where position X2 is S and position X3 is G; (ii)[N2] contains the SPH amino acid sequence; (iii)[N3] includes positions X4, X5, and X6, where position X5 is K. The AAV particle having an amino acid sequence.

[0197] 131. (i) X4 in [N3] is S, T, N, or A; (ii) X5 in [N3] is A, V, T, S, G, R, L, or N; The AAV particle according to Embodiment 130, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (i) or (ii), for example, a conservative substitution.

[0198] 132. AAV particles according to Embodiment 130 or 131, wherein X4 is S and / or X5 is A.

[0199] 133.[N3] is an AAV particle according to any one of Embodiments 130 to 132, comprising SK, TK, NK, AK, KA, KV, KT, KS, KG, KR, KL, or KN.

[0200] 134.[N3] is SKA, SKV, SKT, SKS, SKG, SKR, TKA, NKA, SKL, SKN, or AKA, or an AAV particle according to any one of Embodiments 130 to 133.

[0201] 135.[N3] is an SKA, or an AAV particle according to any one of embodiments 130 to 134, comprising the same.

[0202] 136.[N2]-[N3] is an AAV particle according to any one of Embodiments 130 to 135, comprising SPHSK (SEQ ID NO: 64), SPHTK (SEQ ID NO: 88), SPHNK (SEQ ID NO: 89), or SPHAK (SEQ ID NO: 90).

[0203] 137. [N2]-[N3] is, (i) SPHSKA (sequence number 941), SPHSKV (sequence number 101), SPHSKT (sequence number 95), SPHSKS (sequence number 962), SPHSKG (sequence number 96), SPHSKR (sequence number 978), SPHTKA (sequence number 103), SPHNKA (sequence number 98), SPHSKL (sequence number 960), SPHSKN (sequence number 99), or SPHAKA (sequence number 100); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of embodiments 130 to 136, which are or include such particles.

[0204] 138.[N2]-[N3] is SPHSKA (SEQ ID NO: 941), or an AAV particle according to any one of embodiments 130-137, comprising the same.

[0205] 139. AAV particles according to any one of embodiments 130 to 138, comprising an amino acid other than G at position 453 (e.g., M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D) numbered according to Sequence ID No. 138 or 981.

[0206] 140. An AAV particle according to any one of embodiments 130 to 139, comprising amino acid G at position 453, numbered according to Sequence ID No. 138 or 981.

[0207] 141. X1 of [N1] is selected from G, M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D; optionally the AAV capsid variant includes an amino acid modification of any of the aforementioned amino acids, e.g., a conservative substitution, as described in any one of Embodiments 130 to 140.

[0208] 142.[N1] is an AAV particle according to any one of Embodiments 130 to 141, comprising SG, GS, MS, TS, IS, ES, SS, AS, NS, VS, LS, KS, HS, PS, RS, WS, or DS.

[0209] 143.[N1] is GSG, MSG, TSG, ISG, ESG, SSG, ASG, NSG, VSG, LSG, KSG, HSG, PSG, RSG, WSG, or DSG, or AAV particles according to any one of Embodiments 130 to 142.

[0210] 144.[N1] is a GSG, or an AAV particle according to any one of embodiments 130 to 143, comprising the same.

[0211] 145.[N1]-[N2] is an AAV particle according to any one of embodiments 130 to 144, comprising SGSPH (SEQ ID NO: 116).

[0212] 146. [N1]-[N2] is, (i) GSGSPH (sequence number 150), VSGSPH (sequence number 153), MSGSPH (sequence number 165), TSGSPH (sequence number 167), ISGSPH (sequence number 168), ESGSPH (sequence number 170), SSGSPH (sequence number 171), ASGSPH (sequence number 173), NSGSPH (sequence number 174), LSGSPH (sequence number 175), KSGSPH (sequence number 177), HSGSPH (sequence number 178), PSGSPH (sequence number 180), RSGSPH (sequence number 182), WSGSPH (sequence number 184), DSGSPH (sequence number 185); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of embodiments 130 to 145, which are or include such particles.

[0213] 147. [N1]-[N2]-[N3] is, (i) GSGSPHSKA (SEQ ID NO: 60), VSGSPHSKA (SEQ ID NO: 1083), GSGSPHSKV (SEQ ID NO: 1126), MSGSPHSKA (SEQ ID NO: 1127), TSGSPHSKA (SEQ ID NO: 1129), ISGSPHSKA (SEQ ID NO: 1130), GSGSPHSKT (SEQ ID NO: 1132), ESGSPHSKA (SEQ ID NO: 1133), SSGSPHSKA (SEQ ID NO: 1134), GSGSPHSKS (SEQ ID NO: 1123), ASGSPHSKA (SEQ ID NO: 1136), NSGSPHSKA (SEQ ID NO: 1137), LSGSPHSKA (SEQ ID NO: 1138), K SGSPHSKA (sequence number 1140), GSGSPHSKG (sequence number 1142), GSGSPHSKR (sequence number 1115), HSGSPHSKA (sequence number 1143), PSGSPHSKA (sequence number 1145), RSGSPHSKA (sequence number 1147), GSGSPHTKA (sequence number 1148), WSGSPHSKA (sequence number 1150), DSGSPHSKA (sequence number 1151), GSGSPHNKA (sequence number 1153), GSGSPHSKL (sequence number 1113), GSGSPHSKN (sequence number 1164), or GSGSPHAKA (sequence number 1165); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of embodiments 130 to 146, which are or include such particles.

[0214] 148. AAV particles according to any one of Embodiments 130 to 147, wherein [N1]-[N2]-[N3] are GSGSPHSKA (SEQ ID NO: 60) or VSGSPHSKA (SEQ ID NO: 1083), or include the same.

[0215] 149. The AAV capsid variant, compared to the reference sequence numbered according to Sequence ID No. 138, has 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), and an amino acid other than Q at position 458 (e.g., R, L, A, AAV particles according to any one of Embodiments 130 to 148, comprising 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).

[0216] 150. The AAV capsid variant, compared to the reference sequence numbered according to Sequence ID No. 981, has 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), and an amino acid other than Q at position 464 (e.g., R, L, A, AAV particles according to any one of Embodiments 130 to 149, comprising 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).

[0217] 151. The AAV particle according to any one of Embodiments 130 to 150, wherein the AAV capsid variant comprises 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, compared to a reference sequence numbered according to Sequence ID No. 138.

[0218] 152. The AAV particle according to any one of Embodiments 130 to 151, wherein the AAV capsid variant comprises amino acid Q at position 462, amino acid N at position 463, amino acid Q at position 464, amino acid Q at position 465, and / or amino acid T at position 466, numbered according to Sequence ID No. 981.

[0219] 153. The AAV capsid variant further comprises [N4], which comprises X7, X8, X9, X10, and X11. (a) X7 is Q, R, P, H, L, K, I, G, S, M, or E; (b) X8 is N, D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M; (c)X9 is Q, R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, D; (d) X10 is Q, H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G; (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q; The AAV particle according to any one of Embodiments 130 to 152, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (a) to (e), for example, a conservative substitution.

[0220] 154.[N4] is, (i) QNQQT (SEQ ID NO: 1417), QNRHT (SEQ ID NO: 1418), RDQQT (SEQ ID NO: 1419), PNLQT (SEQ ID NO: 1420), HVRQT (SEQ ID NO: 1421), PNQHT (SEQ ID NO: 1422), QSQQT (SEQ ID NO: 1423), QNQQI (SEQ ID NO: 1424), QPAKT (SEQ ID NO: 1425), QTQQN (SEQ ID NO: 1426), QNLAT (SEQ ID NO: 1427), QNQLT (SEQ ID NO: 1428), QGQQT (SEQ ID NO: 1429), LNRQS (SEQ ID NO: 1430), HNQQT (SEQ ID NO: 1431), QNPPT (SEQ ID NO: 1432), QNLQT (SEQ ID NO: 1433), QYQQT (SEQ ID NO: 1434), QDQET (SEQ ID NO: 1435), QNHQT (SEQ ID NO: 1436), QDQQT (SEQ ID NO: 1437), HWQQT (SEQ ID NO: 1438), PNQQT (SEQ ID NO: 1439), QNQLI (SEQ ID NO: 1440), PEQQT (SEQ ID NO: 1441), QRTMT (SEQ ID NO: 1442), QNQQH (SEQ ID NO: 1443), LHQHT (SEQ ID NO: 1444), QHRIT (SEQ ID NO: 1445), QYIHT (SEQ ID NO: 1446), QKFET (SEQ ID NO: 1447) QFPST (sequence number 1448), HNQQR (sequence number 1449), QAIKT (sequence number 1450), QNRQT (sequence number 1451), QYQHT (sequence number 1452), QNPQS (sequence number 1453), QHQLT (sequence number 1454), QSPPT (sequence number 1455), QAKLT (sequence number 1456), KSQQT (sequence number 1457), QDRPT (sequence number 1458), QSQQL (sequence number 1459), QAFHT (sequence number 1460), QKQQD (sequence number 1461), QNAQT (sequence number 1462), HNQLT (distribution) Column number 1463), QNQQY (sequence number 1464), QKLNT (sequence number 1465), QNVQT (sequence number 1466), QAQQT (sequence number 1467), QNLQA (sequence number 1468), QTPPT (sequence number 1469), QYQHA (sequence number 1470), QGQQA (sequence number 1471), QPPAT (sequence number 1472), QERPT (sequence number 1473), QDLQT (sequence number 1474), QAMHT (sequence number 1475), LNQQT (sequence number 1476), QHPST (sequence number 1477), PGLQT (sequence number 1478),QGIRT (SEQ ID NO: 1479), QAPAT (SEQ ID NO: 1480), QSQQI (SEQ ID NO: 1481), QIPPT (SEQ ID NO: 1482), QTQLT (SEQ ID NO: 1483), QAPST (SEQ ID NO: 1484), QNTYA (SEQ ID NO: 1485), QNQHI (SEQ ID NO: 1486), QNHLT (SEQ ID NO: 1487), QIGMT (SEQ ID NO: 1488), LNKQT (SEQ ID NO: 1489), QLQQT (SEQ ID NO: 1490), QRMST (SEQ ID NO: 1491), QGILT (SEQ ID NO: 1492), QDRQT (SEQ ID NO: 1493), RDWQT (SEQ ID NO: 1493) (Sequence number 1494), QNTHD (Sequence number 1495), PNLQI (Sequence number 1496), QERST (Sequence number 1497), QNYQT (Sequence number 1498), QRTCT (Sequence number 1499), QIGHT (Sequence number 1500), QGAIT (Sequence number 1501), QVPPT (Sequence number 1502), QVQQI (Sequence number 1503), LMRQT (Sequence number 1504), QYSVT (Sequence number 1505), QAITT (Sequence number 1506), QKTLT (Sequence number 1507), QNQWT (Sequence number 1508), QLHHT (Sequence number 1509), QNIII (sequence number 1510), QGHHT (sequence number 1511), QSKVT (sequence number 1512), QLPST (sequence number 1513), IGKQT (sequence number 1514), QAIHT (sequence number 1515), QHGLT (sequence number 1516), QFMCT (sequence number 1517), QHLQT (sequence number 1518), QNHQN (sequence number 1519), QPART (sequence number 1520), QSLQT (sequence number 1521), QSQLT (sequence number 1522), QDRQS (sequence number 1523), QMPST (sequence number 1524), QGSLT (array (Sequence number 1525), QVPAT (Sequence number 1526), ​​QDKQT (Sequence number 1527), HYQQT (Sequence number 1528), QVPST (Sequence number 1529), RGEQT (Sequence number 1530), PGQQT (Sequence number 1531), QSLQI (Sequence number 1532), LEQQT (Sequence number 1533), QNQST (Sequence number 1534), QKVIT (Sequence number 1535), QNNDQ (Sequence number 1536), QSVHT (Sequence number 1537), QPLGT (Sequence number 1538), HNQET (Sequence number 1539), QNLQI (Sequence number 1540),QIQQT (sequence number 1541), QVRNT (sequence number 1542), PSNQT (sequence number 1543), QVGHT (sequence number 1544), QRDIT (sequence number 1545), QMPNT (sequence number 1546), RGLQT ​​(sequence number 1547), QKQQT (sequence number 1548), PSLQT (sequence number 1549), QRDQT (sequence number 1550), QAKGT (sequence number 1551), QSAHT (sequence number 1552), QSTMT (sequence number 1553), QREMT (sequence number 1554), QYRAT (sequence number QWQQT (sequence number 1556), QRMNT (sequence number 1557), GDSQT (sequence number 1558), QKIST (sequence number 1559), PSMQT (sequence number 1560), SPRQT (sequence number 1561), MEQQT (sequence number 1562), QYQNT (sequence number 1563), QHQQT (sequence number 1564), INQQT (sequence number 1565), PNQQH (sequence number 1566), ENRQT (sequence number 1567), QTQQA (sequence number 1568), or QNQAT (sequence number 1569); (ii) Any part of the amino acid sequence in (i), for example, any two, three, or four amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 153, which are or include the same.

[0221] 155.[N1]-[N2]-[N3]-[N4] is, (i) The amino acid sequence of either SEQ ID NO: 200 or 2887-3076; (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 153 or 154, which are or include the same.

[0222] 156. AAV particles according to any one of embodiments 153 to 155, wherein [N1]-[N2]-[N3]-[N4] is GSGSPHSKAQNQQT (Sequence ID 200), or includes it.

[0223] 157.[N1]-[N2]-[N3]-[N4] is VSGSPHSKAQNQQT (SEQ ID NO: 903), or an AAV particle according to any one of embodiments 153 to 155, comprising the same.

[0224] 158. The AAV particle according to any one of Embodiments 130 to 157, wherein the AAV capsid variant comprises, compared to the reference sequence numbered according to Sequence ID No. 138, an amino acid other than K at position 449 (e.g., T, E, or N), 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).

[0225] 159. The AAV capsid variant is (i) Compared to a reference sequence numbered according to sequence number 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; (ii) Compared to the reference sequence numbered according to Sequence ID No. 3904, amino acid K at position 449, amino acid T at position 450, amino acid E at position 451, and / or amino acid N at position 452; or (iii) Compared to the reference sequence numbered according to Sequence ID No. 36, amino acid K is at position 449, amino acid T is at position 450, amino acid E is at position 451, and / or amino acid R is at position 452. AAV particles according to any one of embodiments 130 to 157, including the AAV particles described.

[0226] 160. The AAV capsid variant further comprises [N0], where [N0] is X A , X B , X C , and X D (In the formula, (a)X A is K, T, E, or N; (b)X b is T, S, E, A, N, V, Q, or G; (c)X C is I, F, E, V, L, D, S, C, T, A, N, H, R, G, or W; (d)X D is N, I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G; The AAV particle according to any one of Embodiments 130 to 159, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (a) to (d), for example, a conservative substitution.

[0227] 161.[N0] is, (i) KTIN (sequence number 1575), KTEN (sequence number 1586), KTER (sequence number 1578), KTII (sequence number 1570), KTFP (sequence number 1571), KTEK (sequence number 1572), KTVN (sequence number 1573), KTFN (sequence number 1574), TTIN (sequence number 1576), KSIN (sequence number 1577), KELH (sequence number 1579), KAIN (sequence number 1580), KTDN (sequence number 1581), KTFH (sequence number 1582), KTSN (sequence number 1583), ETIN (sequence number 1584), NTIN ( SEQ ID NO: 1585), KTSS (SEQ ID NO: 1587), KTCN (SEQ ID NO: 1588), KTEH (SEQ ID NO: 1589), KAEM (SEQ ID NO: 1590), KATN (SEQ ID NO: 1591), KAIK (SEQ ID NO: 1592), KTDK (SEQ ID NO: 1593), KTFK (SEQ ID NO: 1594), KSDQ (SEQ ID NO: 1595), KTEI (SEQ ID NO: 1596), KTID (SEQ ID NO: 1597), KNTN (SEQ ID NO: 1598), KTET (SEQ ID NO: 1599), KTEL (SEQ ID NO: 1600), KNIN (SEQ ID NO: 1601), KTEA (SEQ ID NO: 1602) ), KTAN (sequence number 1603), NTIY (sequence number 1604), KTFS (sequence number 1605), KTES (sequence number 1606), KTTN (sequence number 1607), KTED (sequence number 1608), KTNN (sequence number 1609), KEVH (sequence number 1610), KTIS (sequence number 1611), KTVR (sequence number 1612), KTDR (sequence number 1613), ETIK (sequence number 1614), KNHI (sequence number 1615), KESD (sequence number 1616), KTIK (sequence number 1617), KTDL (sequence number 1618), KTVP (distribution Column number 1619), KTVI (sequence number 1620), KAEH (sequence number 1621), KNCL (sequence number 1622), KTVK (sequence number 1623), KNAD (sequence number 1624), KTIT (sequence number 1625), KNCV (sequence number 1626), KNAL (sequence number 1627), KVIN (sequence number 1628), KTEF (sequence number 1629), KTRE (sequence number 1630), KQGE (sequence number 1631), KSEK (sequence number 1632), KNVN (sequence number 1633), KGGE (sequence number 1634), KEFV (sequence number 1635),KSDK (sequence number 1636), KTEQ (sequence number 1637), KEVQ (sequence number 1638), KTEY (sequence number 1639), KNCW (sequence number 1640), KTDV (sequence number 1641), KSDI (sequence number 1642), KNSI (sequence number 1643), KNSL (sequence number 1644), KEVV (sequence number 1645), KTEP (sequence number 1646), KSEL (sequence number 1647), KTWQ (sequence number 1648), KTEV (sequence number 1649), KAVN (sequence number 1650), KGVL (sequence number 1651), KTEG (sequence number 1652), KTRD (sequence number 1653), KTGN (sequence number 1654), KNAI (sequence number 1655), KAEN (sequence number 1656), KAET (sequence number 1657), KTVH (sequence number 1658), KETA (sequence number 1659), KNNL (sequence number 1660), EAIN (sequence number 1661), KSLN (sequence number 1662), KTIP (sequence number 1663), or KTIH (sequence number 1664); (ii) Any part of the amino acid sequence in (i), for example, any two or three amino acids, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 160, which are or include the same.

[0228] 162.[N0]-[N1]-[N2]-[N3]-[N4] is, (i) One amino acid sequence from sequence numbers 3239-3526 or 3591-3605; (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to embodiment 160 or 161, which are or include the same.

[0229] 163.[N0]-[N1]-[N2]-[N3]-[N4] is KTINGSGSPHSKAQNQQT (Sequence ID 5660), or an AAV particle according to any one of Embodiments 160 to 162, comprising the same.

[0230] 164. AAV particles according to any one of embodiments 160 to 162, wherein [N0]-[N1]-[N2]-[N3]-[N4] is KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589) or KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589), or includes the same.

[0231] 165. AAV particles comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and human microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant is given by the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 61) (wherein, (i)[N1] includes 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 SPH amino acid sequence; (iii)[N3] includes positions X4, X5, and X6, where position X4 is K. The AAV particle having an amino acid sequence.

[0232] 166. (i) X5 in [N3] is S, I, T, R, H, Y, L, or M; (ii) X6 in [N3] is G, A, L, E, V, R, W, N, Q, or K; The AAV particle according to Embodiment 165, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (i) or (ii), for example, a conservative substitution.

[0233] 167. AAV particles according to embodiment 165 or 166, wherein X5 is S and / or X6 is G.

[0234] 168.[N3] is an AAV particle according to any one of embodiments 165 to 167, comprising 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.

[0235] 169.[N3] is KSG, KIG, KTG, KRG, KSA, KSL, KSE, KSV, KSR, KSW, KSN, KHG, KYG, KSQ, KIV, KSK, KLW, KMG, or KMA, or an AAV particle according to any one of embodiments 165 to 168.

[0236] 170.[N3] is KSG, or an AAV particle according to any one of embodiments 165 to 169, comprising the same.

[0237] 171.[N2]-[N3] are AAV particles according to any one of Embodiments 165-170, comprising SPHKS (SEQ ID NO: 67), SPHKI (SEQ ID NO: 76), SPHKT (SEQ ID NO: 74), SPHKR (SEQ ID NO: 80), NPHKS (SEQ ID NO: 1665), SPHKH (SEQ ID NO: 91), SPHKY (SEQ ID NO: 78), SPHKL (SEQ ID NO: 77), or SPHKM (SEQ ID NO: 92).

[0238] 172. [N2]-[N3] is, (i) SPHKSG (sequence number 946), SPHKIG (sequence number 958), SPHKTG (sequence number 102), SPHKRG (sequence number 974), NPHKSG (sequence number 1666), SPHKSA (sequence number 94), SPHKSL (sequence number 104), SPHKSE (sequence number 105), SPHKSV (sequence number 106), SPHKSR (sequence number 951), SPHKSW (sequence number 107), SPHKSN (sequence number 108), SPHKHG (sequence number 109), SPHKYG (sequence number 966), SPHKSQ (sequence number 110), SPHKIV (sequence number 1667), SPHKSK (sequence number 111), SPHKLW (sequence number 112), SPHKMG (sequence number 114), or SPHKMA (sequence number 115); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of embodiments 165 to 171, which are or include such particles.

[0239] 173.[N2]-[N3] is SPHKSG (SEQ ID NO: 946), or an AAV particle according to any one of embodiments 165-172, comprising the same.

[0240] 174. The AAV particle according to any one of Embodiments 165 to 173, wherein the AAV capsid variant comprises an amino acid other than G at position 453 (e.g., A, K, W, R, L, I, M, N, T, E, Q, Y, H, F, or V) numbered according to Sequence ID No. 138 or 981.

[0241] 175. The AAV particle according to any one of Embodiments 165 to 173, wherein the AAV capsid variant comprises amino acid G at position 453, numbered according to Sequence ID No. 138 or 981.

[0242] 176. (i) Position X1 of [N1] is G, A, K, W, R, L, I, M, N, T, E, Q, Y, H, F, or V; (ii) Position X2 of [N1] is H, Y, R, Q, N, P, or D; (iii) Position X3 of [N1] is D, E, G, V, or N; The AAV particle according to any one of Embodiments 165 to 175, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (i), (ii), or (iii), such as a conservative substitution.

[0243] 177. An AAV particle according to any one of embodiments 165 to 176, wherein position X2 of [N1] is H and position X3 of [N1] is D.

[0244] 178. An AAV particle according to any one of embodiments 165 to 177, wherein position X1 of [N1] is G, position X2 of [N1] is H, and position X3 of [N1] is D.

[0245] 179.[N1] is an AAV particle according to any one of embodiments 165 to 178, comprising 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.

[0246] 180.[N1] is GHD, GYD, GHE, GRG, GQD, GRD, AHD, GND, KHD, GPD, WHD, RHD, LHD, GQV, IHD, MHD, GDD, GHN, NHD, THD, GNG, EHD, QHD, YHD, HHD, FHD, or VHD, or an AAV particle according to any one of Embodiments 165 to 179.

[0247] 181.[N1] is a GHD, or an AAV particle according to any one of embodiments 165 to 180, comprising the same.

[0248] 182.[N1]-[N2] is an AAV particle according to any one of embodiments 165 to 181, comprising HDSPH (SEQ ID NO: 66).

[0249] 183.[N1]-[N2] is, (i) GHDSPH (SEQ ID NO: 151), GYDSPH (SEQ ID NO: 196), GHESPH (SEQ ID NO: 160), GRGSPH (SEQ ID NO: 155), GHDNPH (SEQ ID NO: 1668), GQDSPH (SEQ ID NO: 152), GRDSPH (SEQ ID NO: 198), AHDSPH (SEQ ID NO: 1669), GNDSPH (SEQ ID NO: 199), KHDSPH (SEQ ID NO: 1670), GPDSPH (SEQ ID NO: 989), WHDSPH (SEQ ID NO: 1671), RHDSPH (SEQ ID NO: 1672), LHDSPH (SEQ ID NO: 1673), GQ VSPH (sequence number 993), IHDSPH (sequence number 1674), MHDSPH (sequence number 1675), GDDSPH (sequence number 159), GHNSPH (sequence number 994), NHDSPH (sequence number 1676), THDSPH (sequence number 1677), GNGSPH (sequence number 172), EHDSPH (sequence number 1678), QHDSPH (sequence number 1679), YHDSPH (sequence number 1680), HHDSPH (sequence number 1681), FHDSPH (sequence number 1682), or VHDSPH (sequence number 1683); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, or 5 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of embodiments 165 to 182, which are or include such particles.

[0250] 184.[N1]-[N2]-[N3] is, (i) GHDSPHKSG (SEQ ID NO: 62), GHDSPHKIG (SEQ ID NO: 1166), GYDSPHKSG (SEQ ID NO: 1167), GHESPHKSG (SEQ ID NO: 1168), GHDSPHKTG (SEQ ID NO: 1169), GRGSPHKRG (SEQ ID NO: 1170), GHDNPHKSG (SEQ ID NO: 1684), GQDSPHKSG (SEQ ID NO: 1078), GHDSPHKSA (SEQ ID NO: 1110), GHDSPHKSL (SEQ ID NO: 1171), GHDSPHKSE (SEQ ID NO: 1173), GRDSPHKSG (SEQ ID NO: 1174), AHDSPHKSG (SEQ ID NO: 1685), GNDSPHKSV (SEQ ID NO: 1175), AHDSPHKIG (SEQ ID NO: 1686), GHESPHKSA (SEQ ID NO: 1109), GQDSPHKIG (SEQ ID NO: 1176), GHDSPHKSV (SEQ ID NO: 1177), GHDSPHKSR (SEQ ID NO: 1112), KHDSPHKSG (SEQ ID NO: 1687), GPDSPHKIG (SEQ ID NO: 1178), GPDSPHKSG (SEQ ID NO: 1179), GHDSPHKSW (SEQ ID NO: 1180), WHDSPHKSG (SEQ ID NO: 1688), RHDSPHKSG (SEQ ID NO: 1689) GHDSPHKSN (SEQ ID NO: 1181), GHDSPHKRG (SEQ ID NO: 1107), GHDSPHKHG (SEQ ID NO: 1183), LHDSPHKSG (SEQ ID NO: 1690), GQVSPHKSG (SEQ ID NO: 1184), IHDSPHKSG (SEQ ID NO: 1691), MHDSPHKSG (SEQ ID NO: 1692), GDDSPHKSV (SEQ ID NO: 1185), GHNSPHKSG (SEQ ID NO: 1186), NHDSPHKSG (SEQ ID NO: 1693), THDSPHKSG (SEQ ID NO: 1694), GNGSPHKRG (SEQ ID NO: 1187), EHDSPHKSG (SEQ ID NO: 1695), GHDSPHKYG (SEQ ID NO: 1188), GHDSPHKSQ (SEQ ID NO: 1189), QHDSPHKSG (SEQ ID NO: 1696), RHDSPHKIV (SEQ ID NO: 1697), YHDSPHKSG (SEQ ID NO: 1698), GNDSPHKIG (SEQ ID NO: 1190), HHDSPHKSG (SEQ ID NO: 1699), GHDSPHKSK (SEQ ID NO: 1191), FHDSPHKSG (SEQ ID NO: 1700), GHDSPHKLW (SEQ ID NO: 1192), VHDSPHKSG (SEQ ID NO: 1701), GHDSPHKMG (SEQ ID NO: 1194),GHDSPHKMA (sequence number 1195), or GDDSPHKSG (sequence number 1108); (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to any one of embodiments 165 to 183, which are or include such particles.

[0251] 185.[N1]-[N2]-[N3] is GHDSPHKSG (SEQ ID NO: 62), or an AAV particle according to any one of embodiments 165 to 184, comprising the same.

[0252] 186. The AAV particle according to any one of Embodiments 165 to 185, wherein the AAV capsid variant comprises, compared to the reference sequence numbered according to Sequence ID No. 138, an amino acid other than Q at position 456 (e.g., R, P, H, K, L, V, A, E, or I), an amino acid other than N at position 457 (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q, or M), an amino acid other than Q at position 458 (e.g., R, V, K, P, Y, H, L, I, E, or M), an amino acid other than Q at position 459 (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N), and / or an amino acid other than T at position 460 (e.g., A, E, K, S, I, P, G, or N).

[0253] 187. The AAV particle according to any one of Embodiments 165 to 186, wherein the AAV capsid variant comprises, compared to the reference sequence numbered according to Sequence ID No. 982, an amino acid other than Q at position 462 (e.g., R, P, H, K, L, V, A, E, or I), an amino acid other than N at position 463 (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q, or M), an amino acid other than Q at position 464 (e.g., R, V, K, P, Y, H, L, I, E, or M), an amino acid other than Q at position 465 (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N), and / or an amino acid other than T at position 466 (e.g., A, E, K, S, I, P, G, or N).

[0254] 188. The AAV particle according to any one of Embodiments 165 to 187, wherein the AAV capsid variant comprises 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, compared to a reference sequence numbered according to Sequence ID No. 138.

[0255] 189. The AAV particle according to any one of Embodiments 165 to 188, wherein the AAV capsid variant comprises 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, compared to a reference sequence numbered according to Sequence ID No. 982.

[0256] 190. The AAV capsid variant further comprises [N4], which comprises X7, X8, X9, X10, and X11. (a) X7 is Q, R, P, H, L, K, I, G, S, M, or E; (b) X8 is N, D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M; (c)X9 is Q, R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, D; (d) X10 is Q, H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G; (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q; The AAV particle according to any one of Embodiments 165 to 189, wherein the AAV capsid variant optionally includes an amino acid modification of any of the aforementioned amino acids in (a) to (e), for example, a conservative substitution.

[0257] 191.[N4] is, (i) QNQQT (SEQ ID NO: 1417), QIRQT (SEQ ID NO: 1702), QNQHA (SEQ ID NO: 1703), QKQQT (SEQ ID NO: 1548), QSVQT (SEQ ID NO: 1704), RSQQT (SEQ ID NO: 1705), QNKLE (SEQ ID NO: 1706), QNQQK (SEQ ID NO: 1707), QHQQA (SEQ ID NO: 1708), QIQHT (SEQ ID NO: 1709), PRQQT (SEQ ID NO: 1710), HTQQT (SEQ ID NO: 1711), QRQHT (SEQ ID NO: 1712), QSQQT (SEQ ID NO: 1423), QNQQS (SEQ ID NO: 1713), RNQET (SEQ ID NO: 1714), QTQLT (SEQ ID NO: 1483), KNQQT (SEQ ID NO: 1715), QDQQT (SEQ ID NO: 1437), HNQQT (SEQ ID NO: 1431), QNQLT (SEQ ID NO: 1428), QTQQT (SEQ ID NO: 1716), QTQQI (SEQ ID NO: 1717), QSKQA (SEQ ID NO: 1718), QNQPP (SEQ ID NO: 1719), QSPQT (SEQ ID NO: 1720), QNYQT (SEQ ID NO: 1498), QNHQT (SEQ ID NO: 1436), QNRQT (SEQ ID NO: 1451), QNQQG (SEQ ID NO: 1721), QNHLT (SEQ ID NO: 1487) ), QYQHT (sequence number 1452), QNQWT (sequence number 1508), QNQHT (sequence number 1722), QTRQT (sequence number 1723), QNLHT (sequence number 1724), LNQQT (sequence number 1476), QNQET (sequence number 1725), QHLQT (sequence number 1518), LNQPT (sequence number 1726), QNQDT (sequence number 1727), RNQQT (sequence number 1728), QNLLT (sequence number 1729), QLVIT (sequence number 1730), RTQET (sequence number 1731), QTHQT (sequence number 1732), QNQPA (distribution) Column number 1733), QDQHT ​​(sequence number 1734), QSQHT (sequence number 1735), RNQQI (sequence number 1736), VRQQT (sequence number 1737), QNQHS (sequence number 1738), AWQQT (sequence number 1739), QSVPT (sequence number 1740), QNIQP (sequence number 1741), QNHLN (sequence number 1742), LDQQT (sequence number 1743), PDQQS (sequence number 1744), ESQQT (sequence number 1745), QNKQT (sequence number 1746), QRQLT (sequence number 1747), QIIVT (sequence number 1748),QKQST (sequence number 1749), QSHQT (sequence number 1750), QFVVT (sequence number 1751), QNLQT (sequence number 1433), QNQQI (sequence number 1424), QSQPT (sequence number 1752), QNEQT (sequence number 1753), QSLQT (sequence number 1521), RNRQT (sequence number 1755), QSKQT (sequence number 1756), QNPLT (sequence number 1757), RDQKT (sequence number 1758), HNQQN (sequence number 1759), QWKRT (sequence number 1760), QSQQI (sequence number 1481), QAQQT (sequence number 1467), QNHQI (sequence number 1761), QNQQA (sequence number 1762), QNQLN (sequence number) Number 1763), QTQPT (sequence number 1764), INQQT (sequence number 1565), QKQLT (sequence number 1765), RNQLA (sequence number 1766), RNQQS (sequence number 1767), ISIQT (sequence number 1768), QNQQN (sequence number 1769), QSQQS (sequence number 1770), QTVCT (sequence number 1771), QYQQI (sequence number 1772), QQIMT (sequence number 1773), QNEQS (sequence number 1774), LNHQT (sequence number 1775), QMIHT (sequence number 1776), RNHQS (sequence number 1777), QKMNT (sequence number 1778), QSQQN (sequence number 1779), QYQHA (sequence number 1470); (ii) Any part of the amino acid sequence in (i), for example, any two, three, or four amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 190, which are or include the same.

[0258] 192.[N1]-[N2]-[N3]-[N4] is, (i) The amino acid sequence of either SEQ ID NO: 201 or 3160-3237; (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 190 or 191, which are or include the same.

[0259] 193.[N1]-[N2]-[N3]-[N4] is GHDSPHKSGQNQQT (SEQ ID NO: 201), or an AAV particle according to any one of Embodiments 190 to 192, comprising the same.

[0260] 194. The AAV particle according to any one of Embodiments 165 to 193, wherein the AAV capsid variant comprises, compared to a reference sequence numbered according to Sequence ID No. 138 or 982, an amino acid other than K at position 449 (e.g., T), T at position 450 (e.g., A, S, I, V, N, E, Y, C, G, W, or Q), an amino acid other than I at position 451 (e.g., E, V, S, T, N, D, C, G, Q, L, P, A), and / or an amino acid other than N at position 452 (e.g., S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R).

[0261] 195. The AAV particle according to any one of Embodiments 165 to 193, wherein the AAV capsid variant comprises 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, compared to a reference sequence numbered according to Sequence ID No. 138.

[0262] The AAV capsid variant further comprises [N0], and [N0] is X A , X B , X C , and X D (wherein (a) X A is K or T; (b) X b is T, A, S, I, V, N, E, Y, C, G, W, or Q; (c) X C is I, E, V, S, T, N, D, C, G, Q, L, P, A; (d) X D is N, S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R; Optionally, the AAV capsid variant is the AAV particle according to any one of Embodiments 165 to 195, including amino acid modifications of any of the aforementioned amino acids in (a) to (d), such as conservative substitutions.

[0263] 197. [N0] is (i) KTIN (sequence number 1575), KAIN (sequence number 1580), KTES (sequence number 1606), TTIN (sequence number 1576), KSIN (sequence number 1577), KTVN (sequence number 1573), KSIY (sequence number 1780), KTSN (sequence number 1583), KTTN (sequence number 1607), KIIN (sequence number 1781), KTIS (sequence number 1611), KAII (sequence number 1782), KTIK (sequence number 1617), KTEF (sequence number 1629), KTIT (sequence number 1625), KTNN (sequence number 1609), KTID ( SEQ ID NO: 1597), KAIS (SEQ ID NO: 1783), KTVD (SEQ ID NO: 1784), KTIE (SEQ ID NO: 1785), KTEG (SEQ ID NO: 1652), KVIN (SEQ ID NO: 1628), KAVN (SEQ ID NO: 1650), KTIY (SEQ ID NO: 1786), KTDN (SEQ ID NO: 1581), KTCN (SEQ ID NO: 1588), KNVV (SEQ ID NO: 1787), KTEL (SEQ ID NO: 1600), KTDA (SEQ ID NO: 1788), KTEV (SEQ ID NO: 1649), KSEL (SEQ ID NO: 1647), KTEM (SEQ ID NO: 1789), KTEQ (SEQ ID NO: 1637) ), KTII (sequence number 1570), KIVN (sequence number 1790), KTEK (sequence number 1572), KTEN (sequence number 1586), KIGN (sequence number 1791), KEVM (sequence number 1792), KYQV (sequence number 1793), KTEA (sequence number 1602), KATN (sequence number 1591), KTEH (sequence number 1589), KTVE (sequence number 1794), KAID (sequence number 1795), KTIM (sequence number 1796), KEVG (sequence number 1797), KSEM (sequence number 1798), KAQQ (sequence number 1799), KCGE (distribution Column number 2897), KASN (sequence number 2907), KTET (sequence number 1599), KTIG (sequence number 2917), KTDP (sequence number 3081), KELV (sequence number 3238), KELM (sequence number 3590), KNEI (sequence number 3849), KTPN (sequence number 3850), KITN (sequence number 3851), KTDI (sequence number 3852), KTDQ (sequence number 3853), KGIN (sequence number 3854), KSEI (sequence number 3855), KSEK (sequence number 1632), KWSA (sequence number 3856), KELA (sequence number 3857),KQTQ (SEQ ID NO: 3858), KGAD (SEQ ID NO: 3859), KVGE (SEQ ID NO: 3860), KANE (SEQ ID NO: 3861), KTDT (SEQ ID NO: 3862), KTCI (SEQ ID NO: 3863), KELR (SEQ ID NO: 3864), KCQI (SEQ ID NO: 3865), KGVM (SEQ ID NO: 3866), KACD (SEQ ID NO: 3867), KNEL (SEQ ID NO: 3868), KAAE (SEQ ID NO: 3869), KG QN (sequence number 3870), KNEF (sequence number 3871), KTSI (sequence number 3872), KAEH (sequence number 1621), KCDQ (sequence number 3873), KEIL (sequence number 3874), KTER (sequence number 1578), KNAI (sequence number 1655), KTDK (sequence number 1593), KTPD (sequence number 3875), KTIH (sequence number 1664), or KTEI (sequence number 1596); (ii) Any part of the amino acid sequence in (i), for example, any two or three amino acids, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 196, which are or include the same.

[0264] 198.[N0]-[N1]-[N2]-[N3]-[N4] is, (i) Any one amino acid sequence from sequence numbers 3606 to 3836; (ii) Any part of the amino acid sequence in (i), for example, any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids therein, for example, an amino acid sequence containing consecutive amino acids; (iii) An amino acid sequence having one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions compared to any of the amino acid sequences in (i); or (iv) An amino acid sequence that contains one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences in (i) AAV particles according to Embodiment 196 or 197, which are or include the same.

[0265] 199.[N0]-[N1]-[N2]-[N3]-[N4] is KTINGHDSPHKSGQNQQT (SEQ ID NO: 5828), or an AAV particle according to any one of embodiments 196 to 198, comprising the same.

[0266] 200.[N0]-[N1]-[N2]-[N3]-[N4] is KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), or an AAV particle according to any one of Embodiments 196-198, comprising the same.

[0267] 201.[N0]-[N1]-[N2]-[N3]-[N4] is KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), or an AAV particle according to any one of Embodiments 196-198, comprising the same.

[0268] 202.[N1]-[N2]-[N3] are AAV particles according to any one of embodiments 130 to 200, which are present in loop IV of the AAV capsid variant.

[0269] 203.[N0] and [N4] are AAV particles according to any one of embodiments 160-164 or 196-202, which are present in loop IV of the AAV capsid variant.

[0270] 204.[N0] is an AAV particle according to any one of Embodiments 160-164 or 196-203, located immediately after position 448 compared to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138, 981, or 982.

[0271] 205.[N0] is an AAV particle according to any one of embodiments 160-164 or 196-204, which replaces positions 449-452 (e.g., K449, T450, I451, and N452) with respect to a reference sequence numbered according to sequence number 138, 981, or 982.

[0272] 206. An AAV particle according to any one of embodiments 160-164 or 196-205, wherein [N0] is located immediately after position 448 and replaces positions 449-452 (e.g., K449, T450, I451, and N452) with respect to a reference sequence numbered according to sequence numbers 138, 981, or 982.

[0273] 207.[N0] is an AAV particle according to any one of embodiments 160-164 or 196-206, corresponding to positions 449-452 (e.g., K449, T450, I451, and N452) of sequence number 981 or 982.

[0274] 208.[N1] is an AAV particle according to any one of Embodiments 130 to 207, located immediately after position 452 compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982.

[0275] 209.[N1] is an AAV particle according to any one of Embodiments 130 to 208, which replaces positions 453 to 455 (e.g., G453, S454, and G455) with respect to a reference sequence numbered according to Sequence ID No. 138, 981, or 982.

[0276] 210.[N1] is an AAV particle according to any one of Embodiments 130 to 208, which replaces position 453 (e.g., G453) with respect to a reference sequence numbered according to Sequence ID No. 138, 981, or 982.

[0277] 211. (i) Position X1 of [N1] is replaced by position 453 (e.g., G453); (ii) Position X2 of [N1] corresponds to position 454 (e.g., S454); (iii) Position X3 of [N1] corresponds to position 455 (for example, G455), (i), (ii), and (iii) are AAV particles according to any one of embodiments 130-164 or 200-209, numbered according to Sequence ID No. 138 or Sequence ID No. 981.

[0278] 212. (i) Position X1 of [N1] corresponds to position 453 (e.g., G453); (ii) Position X2 of [N1] corresponds to position 454 (e.g., S454); (iii) Position X3 of [N1] corresponds to position 455 (for example, G455), (i), (ii), and (iii) are AAV particles according to any one of embodiments 130-164 or 200-209, numbered according to Sequence ID No. 138 or Sequence ID No. 981.

[0279] 213. (i) Position X1 of [N1] corresponds to position 453 (e.g., G453); (ii) Position X2 of [N1] is replaced by position 454 (e.g., S454); (iii) Position X3 of [N1] is replaced by position 455 (for example, G455), (i), (ii), and (iii) are AAV particles according to any one of Embodiments 165 to 209, numbered according to Sequence ID No. 138 or Sequence ID No. 982.

[0280] 214.[N1] is an AAV particle according to any one of Embodiments 165 to 209, corresponding to positions 453 to 455 (e.g., G453, H454, D455) of Sequence ID No. 982.

[0281] 215.[N1] is an AAV particle according to any one of Embodiments 165 to 209, corresponding to positions 453 to 455 (e.g., G453, S454, G455) of Sequence ID No. 138 or 981.

[0282] 216.[N2] is an AAV particle according to any one of embodiments 130 to 215, located immediately after position 455 compared to a reference sequence numbered according to the amino acid sequence of sequence number 138, 981, or 982.

[0283] 217.[N2] is an AAV particle according to any one of embodiments 130 to 216, corresponding to positions 456 to 458 (e.g., S456, P457, and H458) of sequence number 981 or 982.

[0284] 218.[N2] is an AAV particle according to any one of Embodiments 130 to 216, corresponding to position 456 to 458 (e.g., S456, P457, and H458) of any one of Sequence IDs 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36 to 59.

[0285] 219.[N2] is an AAV particle according to any one of embodiments 130 to 218, which is located immediately after [N1].

[0286] 220.[N3] is an AAV particle according to any one of embodiments 130 to 219, corresponding to positions 459 to 460 (e.g., S459, K460, A461) of sequence number 981.

[0287] 221.[N3] is an AAV particle according to any one of Embodiments 130 to 220, corresponding to positions 459-460 (e.g., S459, K460, A461) of Sequence ID No. 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, or 59.

[0288] 222.[N2]-[N3] is an AAV particle according to any one of Embodiments 130-220, located immediately after position 455 compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982.

[0289] 223.[N2]-[N3] is an AAV particle according to any one of embodiments 130-164 or 200-222, located immediately after position 455 compared to the reference sequence numbered according to the amino acid sequence of sequence number 981.

[0290] 224.[N2]-[N3] are AAV particles according to any one of embodiments 130-164 or 200-223, corresponding to positions 456-461 of sequence number 981 (e.g., S456, P457, H458, S459, K460, A461).

[0291] 225.[N2]-[N3] are AAV particles according to any one of Embodiments 130-164 or 200-223, corresponding to any one position 456-461 (e.g., S456, P457, H458, S459, K460, A461) of any one of Sequence IDs 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, or 59.

[0292] 226.[N3] is an AAV particle according to any one of embodiments 165 to 222, corresponding to positions 459 to 460 (e.g., K459, S460, G461) of sequence number 982.

[0293] 227.[N3] is an AAV particle according to any one of embodiments 165-219 or 222-226, corresponding to positions 459-460 (e.g., K459, S460, G461) of sequence number 37.

[0294] 228.[N2]-[N3] is an AAV particle according to any one of embodiments 165-222 or 227, located immediately after position 455 compared to the reference sequence numbered according to the amino acid sequence of sequence number 982.

[0295] 229.[N3] is an AAV particle according to any one of embodiments 165 to 228, replacing positions 454 and 455 (e.g., S454 and G455) numbered according to sequence number 138.

[0296] 230.[N3] is an AAV particle according to any one of Embodiments 165 to 229, which is located immediately after [N2] and replaces positions 454 and 455 (e.g., S454 and G455) numbered according to Sequence ID No. 138.

[0297] 231.[N3] is an AAV particle according to any one of Embodiments 165 to 230, which is located immediately after [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455) numbered according to Sequence ID No. 138.

[0298] 232.[N2]-[N3] are AAV particles according to any one of embodiments 165-222, 226, or 228, corresponding to positions 456-461 of sequence number 982 (e.g., S456, P457, H458, K459, S460, G461).

[0299] 233.[N2]-[N3] are AAV particles according to any one of embodiments 165-222, 226, or 228, corresponding to positions 456-461 of sequence number 37 (e.g., S456, P457, H458, K459, S460, G461).

[0300] 234.[N4] is an AAV particle according to any one of embodiments 153-164 or 190-233, located immediately after position 455 compared to the reference sequence numbered according to the amino acid sequence of sequence number 138.

[0301] 235.[N4] is replaced at positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) compared to the reference sequence numbered according to the amino acid sequence of Sequence ID No. 138, as an AAV particle according to any one of Embodiments 153-164 or 190-234.

[0302] 236.[N4] is an AAV particle according to any one of embodiments 153-164 or 190-235, corresponding to positions 462-466 ​​of sequence number 981 or 982 (e.g., Q462, N463, Q464, Q465, and T466).

[0303] 237.[N4] is an AAV particle according to any one of embodiments 153-164 or 190-235, corresponding to position 462-466 ​​of any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59.

[0304] 238.[N4] is an AAV particle according to any one of embodiments 153-164 or 190-235, corresponding to positions 456-460 of sequence number 138 (e.g., Q456, N457, Q458, Q459, and T460).

[0305] 239.[N2]-[N3]-[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 153-164 or 190-236.

[0306] 240.[N2]-[N3]-[N4] is located immediately after position 455, and [N2]-[N3]-[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) compared to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 153-164 or 190-239.

[0307] 241. AAV particle according to any one of Embodiments 153-164 or 190-240, wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460) with respect to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0308] 242. AAV particle according to any one of embodiments 153-164 or 190-241, wherein [N1]-[N2]-[N3]-[N4] is located immediately after position 452 and replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460) with respect to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0309] 243.[N1]-[N2]-[N3]-[N4] are AAV particles according to any one of Embodiments 153-164 or 190-242, corresponding to positions 453-466 of Sequence ID No. 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466).

[0310] 244.[N1]-[N2]-[N3] are AAV particles according to any one of Embodiments 153-164 or 190-243, corresponding to positions 453-461 of Sequence ID No. 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0311] 245.[N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 of Sequence ID No. 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466), and is an AAV particle according to any one of Embodiments 153-164 or 190-242.

[0312] 246.[N1]-[N2]-[N3] are AAV particles according to any one of embodiments 153-164, 190-242, or 245, corresponding to positions 453-461 of sequence number 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461).

[0313] 247.[N1]-[N2]-[N3]-[N4] corresponds to any one of the AAV particles in any one of the embodiments 153-164, 190-242, or 245, with position 453-466 of any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59.

[0314] 248.[N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) with respect to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 160-164 or 196-245.

[0315] 249.[N0]-[N1]-[N2]-[N3]-[N4] is located immediately after position 448, and [N0]-[N1]-[N2]-[N3]-[N4] is replaced by positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460) compared to the reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, an AAV particle according to any one of embodiments 160-164 or 196-248.

[0316] 250.[N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of Sequence ID No. 981 (e.g., K449, T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466), and is an AAV particle according to any one of Embodiments 160-164 or 202-249.

[0317] 251.[N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of Sequence ID No. 982 (e.g., K449, T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466), and is an AAV particle according to any one of Embodiments 202-249.

[0318] 252.[N0]-[N1]-[N2]-[N3]-[N4] corresponds to any one of the AAV particles described in any one of the embodiments 202-249, with position 449-466 corresponding to any one of sequence numbers 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59.

[0319] 253.[N4] is an AAV particle according to any one of embodiments 153-164 or 190-251, located immediately after position 461 compared to a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982.

[0320] 254.[N4] is replaced at positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) compared to a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982, as described in any one of embodiments 153-164 or 190-253 of the AAV particle.

[0321] 255.[N2]-[N3]-[N4] replaces positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) with respect to a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982, as described in any one of embodiments 153-164 or 190-254 of the AAV particle.

[0322] 256. An AAV particle according to any one of embodiments 153-164 or 190-255, wherein [N2]-[N3]-[N4] is located immediately after position 455 and replaces positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466) with respect to a reference sequence numbered according to the amino acid sequence of sequence number 981 or 982.

[0323] 257. The AAV particle according to any one of Embodiments 130 to 256, wherein the AAV capsid variant comprises [N2]-[N3] from the N-terminus to the C-terminus.

[0324] 258. The AAV particle according to any one of Embodiments 130 to 257, wherein the AAV capsid variant comprises [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0325] 259. The AAV particle according to any one of Embodiments 130 to 258, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0326] 260. The AAV particle according to any one of Embodiments 130 to 259, wherein the AAV capsid variant comprises [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0327] 261. The AAV particle according to any one of Embodiments 130 to 260, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0328] 262. AAV particles comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant is (i) For example, compared to the reference sequence of Sequence ID No. 138, at least 2-3 species, for example, in the brains of non-human primates and rodents (e.g., mice), are enriched at least 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, and optionally, at least 2-3 species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus and / or mice (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 uninbred mice); and / or (ii) It is possible to transduce neuronal cells (e.g., NeuN+ neurons or dopaminergic neurons (e.g., tyrosine hydroxylase (TH)+ neurons)) and non-neuronal cells (e.g., glial cells, oligodendrocytes (e.g., Olig2-positive oligodendrocytes), and / or astrocytes (e.g., Sox9+ astrocytes or Olig2-positive astrocytes) , the aforementioned AAV particles.

[0329] 263. AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of human microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant is (a) Any amino acid sequence of the sequences provided in Table 1A, 2A, 2B, 21-23, 25, 26, or 30; (b) an amino acid sequence containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of the sequences provided in Table 1A, 2A, 2B, 21-23, 25, 26, or 30; or (c) an amino acid sequence having at least one, two, or three, but no more than four, different amino acids compared to any one of the sequences provided in Table 1A, 2A, 2B, 21-23, 25, 26, or 30; or (d) Amino acid sequences having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions) compared to any one of the amino acid sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30 The AAV particles, including the AAV particles.

[0330] 264. AAV particles comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and human microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant is (a) Any amino acid sequence of sequence numbers 945-980 or 985-986; (b) an amino acid sequence containing at least three, four, or five consecutive amino acids from any one of sequence numbers 945-980 or 985-986; or (c) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences of sequence numbers 945-980 or 985-986; (d) Amino sequences having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to any one amino acid sequence of sequence numbers 945-980 or 985-986. The AAV particles, including the AAV particles.

[0331] 265. AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of human microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant is (a) Any amino acid sequence of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; (b) an amino acid sequence containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of sequence numbers 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; (c) an amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to any one of the amino acid sequences of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; or (d) Amino acid sequences that have at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions) compared to any one of the amino acid sequences of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909. The AAV particles, including the AAV particles.

[0332] 266. The AAV particle according to any one of Embodiments 262, 263, or 265, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of Sequence IDs 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0333] 267. The AAV particle according to any one of embodiments 262 to 266, wherein the at least three consecutive amino acids include SPH.

[0334] 268. The AAV particle according to any one of embodiments 262 to 267, wherein the at least four consecutive amino acids include SPHS (SEQ ID NO: 63).

[0335] 269. The AAV particle according to any one of embodiments 262 to 268, wherein the at least five consecutive amino acids include SPHSK (SEQ ID NO: 64).

[0336] 270. The AAV particle according to any one of embodiments 262 to 269, wherein the at least six consecutive amino acids include SPHSKA (SEQ ID NO: 941).

[0337] 271. The AAV particles according to embodiments 262 to 266, wherein the at least three consecutive amino acids include HDS.

[0338] 272. The AAV particle according to any one of embodiments 262 to 266 or 271, wherein the at least four consecutive amino acids include HDSP (SEQ ID NO: 65).

[0339] 273. The AAV particle according to any one of embodiments 262-266, 271, or 272, wherein the at least five consecutive amino acids include HDSPH (SEQ ID NO: 66).

[0340] 274. The AAV particle according to any one of embodiments 262-266 or 271-273, wherein the at least six consecutive amino acids include HDSPHK (SEQ ID NO: 2).

[0341] 275. (i) The three consecutive amino acids include SPH; (ii) The at least four consecutive amino acids include SPHK (SEQ ID NO: 3876); (iii) The at least five consecutive amino acids include SPHKY (SEQ ID NO: 78); and / or (iv) The AAV particle according to any one of embodiments 262 to 267, wherein the at least six consecutive amino acids include SPHKYG (SEQ ID NO: 966).

[0342] 276. The AAV particle according to Embodiments 262, 263, 265, or 266, wherein the AAV capsid variant comprises an amino acid sequence having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to any one amino acid sequence of SEQ ID NOs. 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0343] 277. The AAV particle according to any one of Embodiments 262 to 270 or 276, wherein the AAV capsid variant comprises an amino acid sequence having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0344] 278. The AAV particle according to any one of embodiments 262-266, 271-274, or 276, wherein the AAV capsid variant comprises an amino acid sequence having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions) compared to the amino acid sequence of HDSPHK (SEQ ID NO: 2).

[0345] 279. The AAV particle according to any one of embodiments 262-267, 275, or 276, wherein the AAV capsid variant comprises an amino acid sequence having at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of SPHKYG (SEQ ID NO: 966).

[0346] 280. The AAV capsid variant is (i) An amino acid sequence that has at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272); (ii) An amino acid sequence that has at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589); (iii) An amino acid sequence that has at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754); (iii) An amino acid sequence that has at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241); (v) An amino acid sequence that has at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100); (vi) An amino acid sequence that has at least one, two, or three, but no more than four, modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062). AAV particles according to embodiment 262 or 263, including the AAV particles described in embodiment 262 or 263.

[0347] 281. The AAV particle according to any one of Embodiments 262, 263, 265, 266, or 276, wherein the AAV capsid variant comprises an amino acid sequence containing at least one, two, or three, but no more than four, different amino acids compared to any one amino acid sequence of Sequence ID No. 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0348] 282. The AAV particle according to any one of embodiments 262-270, 276, 277, or 281, wherein the AAV capsid variant comprises an amino acid sequence containing at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0349] 283. The AAV particle according to any one of embodiments 262-266, 271-275, 276, 278, or 281, wherein the AAV capsid variant comprises an amino acid sequence containing at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of HDSPHK (SEQ ID NO: 2).

[0350] 284. The AAV particle according to any one of embodiments 262-267, 275, 276, or 281, wherein the AAV capsid variant comprises an amino acid sequence containing at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of SPHKYG (SEQ ID NO: 966).

[0351] 285. The AAV capsid variant is (i) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589); (ii) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754); (iii) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241); (iv) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100); (v) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062); (vi) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272); (vii) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTEKVSGSPHSKAQNQQT (SEQ ID NO: 3274); (viii) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTINGSGSPHKSGQNKTS (SEQ ID NO: 5440); (ix) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTSNASGSPHSKAHNQQT (SEQ ID NO: 3382); (x) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KNSIGSGSPHSKAQNQQT (SEQ ID NO: 3421); (xi) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of (SEQ ID NO: 4478); (xii) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of (sequence number 3487); or (xiii) An amino acid sequence that contains at least one, two, or three, but no more than four, different amino acids compared to the amino acid sequence of KTINGSGSPHKSGQNQQP (Sequence ID 4081). AAV particles according to any one of embodiments 262, 263, or 280, including the AAV particles described therein.

[0352] 286. The AAV particle according to any one of Embodiments 1 to 129, 262, 263, 265 to 279, or 281 to 284, wherein the AAV capsid variant comprises any of the amino acid sequences of SEQ ID NOs: 200, 201, 941, 943, 204, 208, 404, or 903 to 909.

[0353] 287. The AAV particle according to any one of embodiments 262, 263, 267-270, 276, 277, 280-282, 285, or 286, wherein the AAV capsid variant comprises the amino acid sequence ERVSGSPHSKA (SEQ ID NO: 3877), and optionally the amino acid sequence is located immediately after position 450 and replaces positions 451-455, as numbered according to SEQ ID NO: 138.

[0354] 288. The AAV particle according to any one of embodiments 262, 263, 267-270, 276, 277, 280-282, or 285-287, wherein the AAV capsid variant comprises the amino acid sequence KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589), and optionally the amino acid sequence is located immediately after position 448, numbered according to SEQ ID NO: 138, and replaces positions 449-460.

[0355] 289. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, or 286, wherein the AAV capsid variant comprises the amino acid sequence AEIGHDSPHKSG (SEQ ID NO: 3878), and optionally the amino acid sequence is located immediately after position 449 and replaces positions 450-455, as numbered according to SEQ ID NO: 138.

[0356] 290. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, 286, or 289, wherein the AAV capsid variant comprises the amino acid sequence KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), and optionally the amino acid sequence is located immediately after position 448 and replaced by positions 449-460, (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138.

[0357] AAV particles according to any one of embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, or 286, comprising the amino acid sequence 291.EKMSGSPHSKA (SEQ ID NO: 6401), wherein the amino acid sequence is located immediately after position 450, numbered according to SEQ ID NO: 138, and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455).

[0358] 292. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, 286, or 291, wherein the AAV capsid variant comprises the amino acid sequence KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), and optionally the amino acid sequence is located immediately after position 448, numbered according to SEQ ID NO: 138, and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460).

[0359] 293. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, or 286, wherein the AAV capsid variant comprises the amino acid sequence HDSPHSKAQNL (SEQ ID NO: 6402), and optionally the amino acid sequence is located immediately after position 453, numbered according to SEQ ID NO: 138, and replaces positions 456-458 (e.g., Q456, N457, Q458).

[0360] 294. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, 286, or 293, wherein the AAV capsid variant comprises the amino acid sequence KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100), and optionally the amino acid sequence is located immediately after position 448, numbered according to SEQ ID NO: 138, and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460).

[0361] 295. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, or 286, wherein the AAV capsid variant comprises the amino acid sequence VNGHDSPHSKA (SEQ ID NO: 6403), and optionally the amino acid sequence is located immediately after position 450, numbered according to SEQ ID NO: 138, and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455).

[0362] 296. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, 286, or 295, wherein the AAV capsid variant comprises the amino acid sequence KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062), and optionally the amino acid sequence is located immediately after position 448, numbered according to SEQ ID NO: 138, and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460).

[0363] 297. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, or 286, wherein the AAV capsid variant comprises the amino acid sequence ENVSGSPHSKA (SEQ ID NO: 3879), and optionally the amino acid sequence is located immediately after position 450, numbered according to SEQ ID NO: 138, and replaced by positions 451-455 (e.g., I451, N452, G453, S454, G455); corresponding to positions 451-461 of SEQ ID NO: 3904; or located at positions 451-461, numbered according to SEQ ID NO: 3904 or 981.

[0364] 298. The AAV particle according to any one of Embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, 286, or 295, wherein the AAV capsid variant comprises the amino acid sequence KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272), and optionally the amino acid sequence is located immediately after position 448, numbered according to SEQ ID NO: 138, and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460); corresponds to positions 449-466 of SEQ ID NO: 3904; or is located at positions 449-466, numbered according to SEQ ID NO: 3904 or 981.

[0365] 299. The AAV capsid variant is the nucleotide sequence of SEQ ID NO: 942; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, compared to the nucleotide sequence of SEQ ID NO: 942; or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but 10 or fewer, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 942. AAV particles according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, or 286-288, comprising an amino acid sequence encoded by a nucleotide sequence.

[0366] 300. The AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 3; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, compared to the nucleotide sequence of SEQ ID NO: 3; or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but 10 or fewer, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 3. AAV particles according to any one of Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, or 290, comprising the amino acid sequence.

[0367] 301. The nucleotide sequence encoding the AAV capsid variant is the nucleotide sequence of SEQ ID NO: 942; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, compared to the nucleotide sequence of SEQ ID NO: 942; or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, but 10 or fewer, compared to the nucleotide sequence of SEQ ID NO: 942 AAV particles according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, or 299, comprising a nucleotide sequence containing the following different nucleotides.

[0368] 302. The nucleotide sequence encoding the AAV capsid variant is the nucleotide sequence of SEQ ID NO: 3; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, e.g., substitutions, but 10 or fewer modifications, e.g., substitutions, compared to the nucleotide sequence of SEQ ID NO: 3; or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but 10 or fewer different nucleotides compared to the nucleotide sequence of SEQ ID NO: 3. AAV particles according to any one of Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, or 300, including a row.

[0369] 303. The amino acid sequence is present in loop IV of the AAV capsid variant, as described in any one of embodiments 262 to 302, of the AAV particle.

[0370] 304. An AAV particle according to any one of Embodiments 262 to 303, wherein the amino acid sequence is located immediately after position 448, 449, 450, 451, 452, 453, 454, or 455 compared to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0371] 305. An AAV particle according to any one of Embodiments 262 to 304, wherein the amino acid sequence is replaced with 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) compared to a reference sequence numbered according to the amino acid sequence of Sequence ID No. 138.

[0372] 306. The AAV particle according to any one of embodiments 262 to 305, wherein the amino acid sequence is located immediately after position 455 compared to the reference sequence numbered according to the amino acid sequence of sequence number 138.

[0373] 307. The AAV particle according to any one of embodiments 262 to 306, wherein the amino acid sequence is located immediately after position 453 compared to the reference sequence numbered according to the amino acid sequence of sequence number 138.

[0374] 308. The AAV particle according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, or 303-307, wherein the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455 compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0375] 309. The AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), the amino acid sequence being located immediately after position 455 (for example, located at positions 456-461), numbered according to the amino acid sequence of SEQ ID NO: 981, and is an AAV particle according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, or 303-308.

[0376] 310. The AAV particle according to Embodiment 308 or 309, wherein the AAV capsid variant further comprises an amino acid other than I at position 451, an amino acid other than N at position 452, and an amino acid other than G at position 453, numbered according to any one of Sequence ID No. 36, 138, or 981.

[0377] 311. The AAV particle according to any one of embodiments 308 to 310, wherein the AAV capsid variant further comprises E at position 451, R at position 452, and V at position 453, numbered according to any one of sequence numbers 36, 138, or 981.

[0378] 312. The AAV particle according to any one of embodiments 308 to 311, further comprising substitutions I451E, N452R, and G453V, which are numbered according to any one of sequence numbers 36, 138, or 981.

[0379] 313. The AAV capsid variant is (i) E at position 451, R at position 452, and V at position 453, numbered according to one of sequence numbers 36, 138, or 981; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455 (for example, at amino acids 456-461, numbered according to SEQ ID NO: 36, 138, or 981), AAV particle according to any one of embodiments 308 to 312.

[0380] 314. AAV particles according to Embodiment 308 or 309, further comprising an amino acid other than I at position 451, an amino acid other than N at position 452, and / or G at position 453, as numbered according to Sequence ID No. 39 or 138.

[0381] 315. An AAV particle according to any one of Embodiments 308, 309, or 314, further comprising E at position 451, K at position 452, and / or M at position 453, numbered according to Sequence ID No. 138 or 39.

[0382] 316. AAV particles according to any one of Embodiments 308, 309, 314, or 315, further comprising substitutions I451E, N452K, and G453M, numbered according to Sequence ID No. 39 or 138.

[0383] 317. (i) E at position 451, K at position 452, and M at position 453, numbered according to sequence number 39 or 138; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to SEQ ID NO: 39 or 138. AAV particles according to any one of embodiments 308, 309, or 314-316, including the above.

[0384] 318. AAV particles according to Embodiment 308 or 309, further comprising an amino acid other than S at position 454, an amino acid other than G at position 455, and / or Q at position 458, numbered according to Sequence ID No. 138.

[0385] 319. An AAV particle according to any one of Embodiments 308, 309, or 318, further comprising H at position 454, D at position 455, and / or L at position 458, numbered according to Sequence ID No. 138.

[0386] 320. AAV particles according to any one of Embodiments 308, 309, 318, or 319, further comprising substitutions S454H, G455D, and Q458L, numbered according to Sequence ID No. 138.

[0387] 321. (i) H at position 454, D at position 455, and / or L at position 458, numbered according to sequence number 138; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, which is numbered according to SEQ ID NO: 138. AAV particles according to any one of embodiments 308, 309, or 318-320, including the following:

[0388] 322. AAV particles according to Embodiment 308 or 309, 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, numbered according to Sequence ID No. 52 or 138.

[0389] 323. An AAV particle according to any one of Embodiments 308, 309, or 322, further comprising V at position 451, H at position 454, and / or D at position 455, numbered according to Sequence ID No. 52 or 138.

[0390] 324. The AAV particle according to any one of Embodiments 308, 309, 322, or 323, wherein the AAV capsid variant further comprises substitutions I451V, S454H, and / or G455D, numbered according to Sequence ID No. 52 or 138.

[0391] 325. The AAV capsid variant is (i) V at position 451, H at position 454, and / or D at position 455, numbered according to sequence number 52 or 138; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is located immediately after position 455, numbered according to SEQ ID NO: 52 or 138. AAV particles according to any one of embodiments 308, 309, or 322-324, including the following:

[0392] 326. The AAV particle according to Embodiment 308 or 309, wherein the AAV capsid variant comprises an amino acid other than I at position 451 and / or G at position 453, numbered according to Sequence ID No. 138.

[0393] 327. The AAV particle according to any one of Embodiments 308, 309, or 326, wherein the AAV capsid variant comprises E at position 451 and / or V at position 453, numbered according to Sequence ID No. 138 or 3904.

[0394] 328. The AAV capsid variant is (i) Numbered according to sequence number 3904 or 138, E at position 451 and V at position 453; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is numbered according to SEQ ID NO: 3904 or 138, and is located at positions 456-461 immediately after position 455. AAV particles according to any one of embodiments 308, 309, 326, or 327, including the following:

[0395] 329. The AAV capsid variant is (i) an amino acid sequence of SPHSKA (sequence number 941) numbered according to sequence number 3905 or 138, with E at position 451, K at position 452, and V at position 453; and the amino acid sequence of SPHSKA (sequence number 941), the amino acid sequence being numbered according to sequence number 3905 or 138, with the amino acid sequence located at positions 456-461 immediately following position 455; (ii) The amino acid sequence of SPHSKA (Sequence ID 941), numbered according to Sequence ID 4, with S at position 451, A at position 453, and H at position 462; and the amino acid sequence of SPHSKA (Sequence ID 941), the amino acid sequence located at positions 456-461 immediately after position 455, numbered according to Sequence ID 4 or 138; (iii) an amino acid sequence of SPHSKA (sequence number 941) numbered according to sequence number 5 or 138, with N at position 450, S at position 451, and I at position 452; or (iv) an amino acid sequence of SPHSKA (sequence number 941) numbered according to sequence number 7 or 138, with A at position 450 and E at position 451, wherein the amino acid sequence is numbered according to sequence number 7 or 138, with the amino acid sequence located at positions 456-461 immediately after position 455. AAV particles according to embodiment 308 or 309, including the AAV particles described in embodiment 308 or 309.

[0396] 330. The AAV capsid variant contains any one amino acid sequence of SEQ ID NOs: 3241, 3272, 3274, 3382, 3421, 3487, 3589, and 4100, and optionally (i) The amino acid sequence is located immediately after position 448, numbered according to Sequence ID No. 138, and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460); or (ii) The amino acid sequence is located at positions 449-466 and is numbered according to any one of the following sequence numbers: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982. AAV particles according to any one of Embodiments 308, 309, or 329.

[0397] 331. The AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), which is numbered in comparison to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, located immediately after position 453 (for example, at positions 454-459), in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46. AAV particles listed in any one of the following categories: ~50, 52, 54~78, 83~88, 90~98, 100~103, 105~111, 113~129, 165~211, 213~222, 226~242, 245~249, 251~266, 271~274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, or 302~307.

[0398] 332. The AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), which is numbered in comparison to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982, located immediately after position 453, in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54- AAV particles listed in any one of the following: 78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, or 331.

[0399] 333. The AAV capsid variant is (i) V at position 451, R at position 463, P at position 464, and S at position 465, numbered according to sequence number 6 or 982; (ii) The amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is numbered in comparison to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 6 or 982, and is located immediately after position 453, at positions 454-459. AAV particles according to Embodiment 332, including the AAV particles described in Embodiment 332.

[0400] 334. The AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 1754, 4062, 4100, or 4478, and optionally (i) The amino acid sequence is located immediately after position 448, numbered according to Sequence ID No. 138, and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460); or (ii) The amino acid sequence is located at positions 449-466 and is numbered according to one of the following sequence numbers: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982. AAV particles according to Embodiment 332 or 333.

[0401] 335. The AAV capsid variant comprises the amino acid sequence of SPHKSG (SEQ ID NO: 946), which is numbered in comparison to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982, located immediately after position 455 (for example, at positions 456-461), in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50. AAV particles as described in any one of the following: 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331, or 332.

[0402] 336. The AAV capsid variant is (i) The amino acid sequence of SPHKSG (SEQ ID NO: 946), numbered according to SEQ ID NO: 3906, with K at position 464, T at position 465, and S at position 466; and the amino acid sequence of SPHKSG (SEQ ID NO: 946), the amino acid sequence being numbered compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 3906, immediately after position 455, located at positions 456-461; or (ii) The amino acid sequence of P at position 466 and SPHKSG (sequence number 946), which is numbered according to sequence number 8, and is located at positions 456-461 immediately after position 455, compared to the reference sequence numbered according to the amino acid sequence of sequence number 8. AAV particles according to Embodiment 335.

[0403] 337. The AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 4081 or 5440, and optionally (i) The amino acid sequence is located immediately after position 448, numbered according to Sequence ID No. 138, and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460); or (ii) The amino acid sequence is located at positions 449-466 and is numbered according to one of the following sequence numbers: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982. AAV particles according to Embodiment 335 or 336.

[0404] 338. The AAV capsid variant is (i) the amino acid sequence of HDSPHSKA (SEQ ID NO: 5519) located immediately after position 453; and (ii) Deletion of amino acid SG at positions 454 and 455; AAV particles according to any one of Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, or 331-337, including (i) and (ii) which are numbered according to Sequence ID No. 138.

[0405] 339. The AAV capsid variant further comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941) located immediately after position 455, which includes amino acids HD at positions 454 and 455 and is numbered in comparison to SEQ ID NO: 138, in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, and 8. AAV particles listed in any one of the following ranges: 3-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, or 331-338.

[0406] 340. The AAV particle according to any one of Embodiments 331 to 339, wherein the AAV capsid variant further comprises an amino acid other than T at position 450, an amino acid other than I at position 451, and an amino acid other than N at position 452, numbered according to Sequence ID No. 138 or 982.

[0407] 341. The AAV particle according to any one of embodiments 331 to 340, wherein the AAV capsid variant further comprises A at position 450, E at position 451, and I at position 452, numbered according to Sequence ID No. 138 or 982.

[0408] 342. The AAV particle according to any one of embodiments 331 to 341, further comprising substitutions T450A, I451E, and N452I, numbered according to Sequence ID No. 138 or 982, for the AAV capsid variant.

[0409] 343. The AAV capsid variant is (i) A at position 450, E at position 451, and I at position 452, numbered according to sequence number 138 or 982; and (ii) The amino acid sequence of HDSPHK (Sequence ID 2) located immediately after position 453, numbered according to Sequence ID 138 or 982. AAV particles according to any one of embodiments 331 to 342, including the AAV particles described.

[0410] 344. The AAV particle according to any one of Embodiments 1-22, 25-27, 31, 34-42, 45-50, 51-63, 69, 79, 83-86, 94-98, 102, 103, 110, 111, 118-129, 262-267, 275, 276, 281, 284, 286, or 303-307, wherein the AAV capsid variant comprises the amino acid sequence of SPHKYG (SEQ ID NO: 966), wherein the amino acid sequence is located immediately after position 455 compared to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0411] 345. An AAV particle comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), and the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 982.

[0412] 346. An AAV particle comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), and the amino acid sequence is located immediately after position 455, numbered according to the amino acid sequence of SEQ ID NO: 981.

[0413] 347. AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), the amino acid sequence is located immediately after position 453, numbered according to the amino acid sequence of SEQ ID NO: 37, and optionally (i) One, two, or all of the following amino acids numbered according to Sequence ID No. 138 or 37: an amino acid other than T at position 450, an amino acid other than I at position 541, and / or an amino acid other than N at position 452; (ii) One, two, or all of the following, numbered according to sequence number 138 or 37: A at position 450, E at position 451, and / or I at position 452. The AAV particles further include the AAV particles.

[0414] 348. An AAV particle comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence SPHSKA (SEQ ID NO: 941), and the amino acid sequence is located immediately after position 455, numbered according to any one of the amino acid sequences of SEQ ID NOs: 36, 38-55, 57, or 59.

[0415] 349. AAV particles according to Embodiment 348, comprising amino acid E at position 451, numbered according to Sequence ID No. 3904, 981, or 138.

[0416] 350. AAV particles according to Embodiment 348 or 349, comprising amino acid V at position 453, numbered according to Sequence ID No. 3904, 981, or 138.

[0417] 351. An AAV particle according to any one of Embodiments 348 to 350, comprising amino acid E at position 451 and amino acid V at position 453, numbered according to Sequence ID No. 3904, 981, or 138.

[0418] 352. An AAV particle according to any one of embodiments 348 to 351, comprising amino acid R at position 452, numbered according to Sequence ID No. 36, 981, or 138.

[0419] 353. An AAV particle according to any one of Embodiments 348 to 352, comprising amino acid E at position 451, amino acid R at position 452, and amino acid V at position 453, numbered according to Sequence ID No. 36, 981, or 138.

[0420] 354. The AAV capsid variant is (i) Modifications in loops I, II, VI and / or VIII, e.g., insertions, substitutions (e.g., conservative substitutions), and / or deletions; and / or (ii) Substitution at position K449, numbered according to sequence number 138, e.g., K449R substitution AAV particles as described in any one of the prior embodiments, further comprising:

[0421] 355. The AAV capsid variant is (i) an amino acid sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but 30, 20, or 10 or fewer modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of SEQ ID NO: 138; or (ii) An amino acid sequence that contains at least one, two, or three different amino acids compared to the amino acid sequence of SEQ ID NO: 138, but no more than 30, 20, or 10 different amino acids. AAV particles as described in any one of the prior embodiments, including:

[0422] 356. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 138, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith.

[0423] 357. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 138.

[0424] 358. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of Sequence ID No. 137, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0425] 359. An AAV particle according to any one of the prior embodiments, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of Sequence ID No. 137, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith.

[0426] 360. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant comprises a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof.

[0427] 361. The AAV particle according to any one of Embodiments 1 to 360, wherein the AAV capsid variant includes an amino acid sequence corresponding to VP2 at positions 138 to 742 of SEQ ID NOs. 981, 982, 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36 to 59, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith.

[0428] 362. The AAV particle according to any one of Embodiments 1 to 360, wherein the AAV capsid variant includes an amino acid sequence corresponding to VP3 at positions 203 to 742 of SEQ ID NOs. 981, 982, 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36 to 59, for example, or a sequence having at least 80% (for example, at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith.

[0429] 363. The AAV particle according to any one of Embodiments 1 to 360, wherein the AAV capsid variant includes an amino acid sequence corresponding to positions 138-736 of SEQ ID NO: 138, for example, VP2, or a sequence having at least 80% (for example, at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0430] 364. The AAV particle according to any one of Embodiments 1 to 360, wherein the AAV capsid variant includes an amino acid sequence corresponding to positions 203-736 of SEQ ID NO: 138, for example, VP3, or a sequence having at least 80% (for example, at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

[0431] 365. The AAV capsid variant comprises 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), (i) The three consecutive amino acids include SPH; (ii) The at least four consecutive amino acids include SPHS (SEQ ID NO: 63); (iii) The at least five consecutive amino acids include SPHSK (SEQ ID NO: 64); or (iv) The at least six consecutive amino acids include SPHSKA (SEQ ID NO: 941); The AAV capsid variant is (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 VP3 protein containing the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) at least 90% (e.g., less) of any of the amino acid sequences in (a) to (c). AAV particles according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, or 354, comprising amino acid sequences having sequence identity of approximately 95, 96, 97, 98, or 99%.

[0432] 366. The AAV capsid variant comprises 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), (i) The three consecutive amino acids include SPH; (ii) The at least four consecutive amino acids include SPHS (SEQ ID NO: 63); (iii) The at least five consecutive amino acids include SPHSK (SEQ ID NO: 64); or (iv) The at least six consecutive amino acids include SPHSKA (SEQ ID NO: 941); The AAV particle according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, or 365, wherein the AAV capsid variant contains an amino acid sequence that is at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of Sequence ID No. 981.

[0433] 367. The AAV capsid variant contains one or two, but no more than three, substitutions compared to the amino acid sequence of SPHSKA (SEQ ID NO: 941), and the AAV capsid variant is (a) VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981; (b) VP2 protein containing the amino acid sequence at positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981; (c) VP3 protein containing the amino acid sequence at positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) An amino acid sequence having at least 90% (for example, at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a) to (c). AAV particles according to any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, 365, or 366, including the AAV particles described in any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, 365, or 366.

[0434] 368. The AAV capsid variant contains one or two, but no more than three, substitutions compared to the amino acid sequence of SPHSKA (SEQ ID NO: 941), and the AAV capsid variant contains an amino acid sequence that is at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981, as described in Embodiments 1-23, 26-29. AAV particles as described in any one of the following: 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, or 365-367.

[0435] 369. An AAV particle according to any one of embodiments 365 to 368, wherein the amino acid sequence is located immediately after position 455, as numbered according to sequence number 138 or 981.

[0436] 370. The AAV capsid variant comprises 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), (i) The at least three consecutive amino acids include HDS; (ii) The at least four consecutive amino acids include HDSP (SEQ ID NO: 65); (iii) The at least five consecutive amino acids include HDSPH (SEQ ID NO: 66); or (iv) The at least six consecutive amino acids include HDSPHK (SEQ ID NO: 2); The AAV capsid variant is (a) a VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein containing the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982; (c) a VP3 protein containing the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 982; or (d) any of the amino acid sequences in (a) to (c) and at least 90% (for example, at least about 95, 96, 97, 98, or 99%). AAV particles according to any one of Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, or 354, comprising an amino acid sequence having sequence identity of %).

[0437] 371. The AAV capsid variant comprises 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), (i) The at least three consecutive amino acids include HDS; (ii) The at least four consecutive amino acids include HDSP (SEQ ID NO: 65); (iii) The at least five consecutive amino acids include HDSPH (SEQ ID NO: 66); or (iv) The at least six consecutive amino acids include HDSPHK (SEQ ID NO: 2); The AAV capsid variant contains an amino acid sequence that is at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 982, in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 10 AAV particles listed in any one of the following categories: 0-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, or 370.

[0438] 372. The AAV capsid variant contains one or two, but no more than three, substitutions compared to the amino acid sequence of HDSPHK (SEQ ID NO: 2), and the AAV capsid variant is (a) VP1 protein containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) VP2 protein containing the amino acid sequence at positions 138-736 in SEQ ID NO: 138 or positions 138-742 in SEQ ID NO: 982; (c) VP3 protein containing the amino acid sequence at positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 982; or (d) An amino acid sequence having at least 90% (for example, at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a) to (c). AAV particles according to any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, 370, or 371, including the AAV particles described in any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-242, 245-242, 251-246, 271, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, 370, or 371.

[0439] 373. The AAV capsid variant contains one or two, but no more than three, substitutions compared to the amino acid sequence of HDSPHK (SEQ ID NO: 2), and the AAV capsid variant contains an amino acid sequence that is at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 982, as in Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42. AAV particles listed in any one of the following categories: 44, 46-50, 52, 54-78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, 370-372.

[0440] 374. An AAV particle according to any one of embodiments 370 to 373, wherein the amino acid sequence is located immediately after position 453, numbered according to sequence number 138 or 982.

[0441] 375. The AAV particle according to any one of Embodiments 1 to 373, wherein the AAV capsid variant comprises one amino acid sequence 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 therewith.

[0442] 376. The AAV particle according to any one of Embodiments 1 to 375, wherein the AAV capsid variant comprises an amino acid sequence having at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but 30, 20, or 10 or fewer modifications, e.g., substitutions (e.g., conservative substitutions), compared to the amino acid sequence of SEQ ID NO: 981 or 982.

[0443] 377. The AAV particle according to any one of Embodiments 1 to 376, wherein the AAV capsid variant comprises an amino acid sequence that includes at least one, two, or three, but no more than 30, 20, or 10, different amino acids compared to the amino acid sequence of SEQ ID NO: 981 or 982.

[0444] 378. The AAV capsid variant includes the amino acid sequence of SEQ ID NO: 981, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith, in embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94- AAV particles listed in any one of the following: 99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, 365-368, or 375-377.

[0445] 379. The AAV capsid variant comprises an amino acid sequence that, compared to the amino acid sequence of SEQ ID NO: 981, includes at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 30, 20, or 10 modifications, e.g., substitutions (e.g., conservative substitutions), as described in Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71. AAV particles listed in any one of the following categories: 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, 365-368, or 375-377.

[0446] 380. The AAV particle according to any one of Embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94-99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, 365-368, or 375-379, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 1, 2, or 3, but no more than 30, 20, or 10 different amino acids compared to the amino acid sequence of Sequence ID No. 981.

[0447] 381. The AAV capsid variant includes the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith, as described in Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88. AAV particles listed in any one of the following ranges: 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, or 370-377.

[0448] 382. The AAV capsid variant comprises an amino acid sequence that, compared to the amino acid sequence of SEQ ID NO: 982, includes at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but 30, 20, or 10 or fewer modifications, e.g., substitutions (e.g., conservative substitutions), as described in Embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54- AAV particles listed in any one of the following categories: 78, 83-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, 370-377, or 381.

[0449] 383. The AAV capsid variant includes an amino acid sequence that contains at least 1, 2, or 3, but no more than 30, 20, or 10, different amino acids compared to the amino acid sequence of Sequence ID No. 982, in embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 83-88, 90-98, 100- AAV particles as described in any one of the following: 103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, 370-377, 381, or 382.

[0450] 384. The AAV particle according to any one of Embodiments 1 to 383, wherein the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 983 or 984, or an amino acid sequence encoded by a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith.

[0451] 385. An AAV particle according to any one of the prior embodiments 1 to 384, wherein the nucleotide sequence encoding the AAV 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 therewith.

[0452] 386. The nucleotide sequence encoding the AAV capsid variant includes the nucleotide sequence of Sequence ID No. 983, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith, including nucleotide sequences 1-23, 26-29, 32, 35-43, 46-51, 54-71, 79-89, 94- AAV particles as described in any one of the prior embodiments: 99, 102-104, 106-112, 115-164, 203-209, 212, 216-224, 234-243, 248-250, 253-270, 276, 277, 281, 282, 286-288, 299, 301, 303-309, 354, 365-368, 375-380, 384, or 385.

[0453] 387. The nucleotide sequence encoding the AAV capsid variant includes the nucleotide sequence of Sequence ID No. 984, or a nucleotide sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity therewith, according to prior embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-78, 8 AAV particles listed in any one of the following ranges: 3-88, 90-98, 100-103, 105-111, 113-129, 165-211, 213-222, 226-242, 245-249, 251-266, 271-274, 276, 278, 280, 281, 283, 285, 286, 289, 290, 300, 302-307, 331-339, 354, 370-377, 381, or 382-385.

[0454] 388. The AAV particle according to any one of the prior embodiments, wherein the nucleotide sequence encoding the AAV capsid variant is codon-optimized.

[0455] 389. An AAV particle comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of Sequence ID No. 981.

[0456] 390. The AAV particle according to Embodiment 389, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of Sequence ID No. 983, or a nucleotide sequence that is at least 90%, 95%, or 99% identical thereto.

[0457] 391. An AAV particle comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.

[0458] 392. The AAV particle according to Embodiment 391, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of Sequence ID No. 984, or a nucleotide sequence that is at least 90%, 95%, or 99% identical thereto.

[0459] 393. AAV particles comprising a nucleic acid encoding a polynucleotide (e.g., siRNA) for inhibiting the expression of an AAV capsid variant and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV capsid variant comprises one amino acid sequence of SEQ ID NOs. 36-59, 3904, 3905, 3906, 4, 5, 6, 7, or 8.

[0460] 394. AAV particles comprising nucleic acids encoding polynucleotides (e.g., siRNA) for inhibiting the expression of AAV capsid variants and microtubule-associated protein tau (MAPT) (e.g., human MAPT), wherein the AAV particles comprise any one nucleotide sequence of SEQ ID NOs. 9, 3907, 3908, 3909, 3910, 3911, 3912, 3913, 3914, 3915, 3916, or 22-35, or an amino acid sequence encoded by a nucleotide sequence that is at least 95% identical thereto.

[0461] 395. The AAV particle according to Embodiment 393 or 394, wherein the nucleotide sequence encoding the AAV capsid variant includes one of the nucleotide sequences of SEQ ID NOs: 9, 3907, 3908, 3909, 3910, 3911, 3912, 3913, 3914, 3915, 3916, or 22-35, or a nucleotide sequence that is at least 95% identical thereto.

[0462] 396. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant has increased directivity to CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells, or spinal cord tissue, compared to the directivity of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.

[0463] 397. The AAV particle according to any one of Embodiments 1 to 396, wherein the AAV capsid variant transduces a brain region, e.g., 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), and optionally the level of transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65 times higher than the reference sequence of Sequence ID No. 138 when measured by, for example, an assay, e.g., an immunohistochemical assay or a qPCR assay, e.g., one described in Example 3.

[0464] 398. The AAV particle according to any one of Embodiments 1 to 397, wherein the AAV capsid variant transduces a brain region, e.g., 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), and optionally the level of transduction is at least 30, 35, 40, 45, 50, 55, 60, or 65 times higher than the reference sequence of Sequence ID No. 138 when measured by, for example, an assay, e.g., an immunohistochemical assay or a qPCR assay, e.g., one described in Example 3.

[0465] 399. The AAV particle according to any one of Embodiments 1 to 398, wherein the AAV capsid variant is concentrated at least about 3, 4, 5, 6, 7, 8, 9, or 10 times in the brain compared to the reference sequence of SEQ ID NO: 138, as measured by the assay described in Example 2, for example.

[0466] 400. The AAV particles according to any one of Embodiments 1 to 399, wherein the AAV capsid variant is concentrated at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 times in the brain compared to the reference sequence of SEQ ID NO: 138, as measured by the assay described in Example 2, for example.

[0467] 401. The AAV particles according to any one of Embodiments 1 to 400, wherein the AAV capsid variant is enriched in at least two to three types, for example, in the brains of non-human primates and rodents (e.g., mice), when compared to the reference sequence of Sequence ID No. 138.

[0468] 402. The AAV particles according to any one of Embodiments 1 to 401, wherein the AAV capsid variant is concentrated at least 2 to 3 times, for example, by assays described in Example 2 or 5, compared to the reference sequence of SEQ ID NO: 138, in the brains of non-human primates and rodents (e.g., mice), for example, by about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 190, 200, 205, or 210 times, in the brains of non-human primates and rodents (e.g., mice).

[0469] 403. The AAV particles according to Embodiment 401 or 402, wherein at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callitris jacchus, and / or mice (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 uninbred mice).

[0470] 404. The AAV particle according to any one of Embodiments 1 to 403, wherein the AAV capsid variant delivers an increased level of payload to a brain region, and optionally the level of the payload increases by at least 10, 12, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 times when measured by an assay, e.g., qRT-PCR or qPCR assay (e.g., as described in Example 3 or 7), compared to the reference sequence of SEQ ID NO: 138.

[0471] 405. The AAV particle according to any one of Embodiments 1 to 404, wherein the AAV capsid variant delivers an increased level of viral genome to a brain region, and optionally 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 when measured by an assay, e.g., qRT-PCR or qPCR assay (e.g., as described in Example 3 or 7), compared to the reference sequence of SEQ ID NO: 138.

[0472] 406. The AAV capsid variant is (i) For example, as measured by the assay described in Example 11, it is possible to transduce at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of cells in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, cerebellar cortex, cerebellum, dentate nucleus, and / or lateral geniculate nucleus (LGN)); (ii) For example, as measured by the assay described in Example 11, it is possible to transduce at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% 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); and / or (iii) For example, as measured by the assay described in Example 11, it is possible to transduce at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% 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), AAV particles according to any one of Embodiments 1 to 405.

[0473] 407. The AAV particle according to any one of Embodiments 399 to 406, 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).

[0474] 408. The AAV particle according to any one of Embodiments 1 to 407, wherein the AAV capsid variant, when measured by the assay described in Example 2 or 7, is concentrated at least about 5, 10, 15, 20, 25, 30, or 35 times in the spinal cord compared to the reference sequence of Sequence ID No. 138, and optionally the region of the spinal cord is the thoracic region, the cervical region, the C5 anterior horn region, the lumbar region, or the L5 anterior horn region.

[0475] 409. The AAV particle according to any one of claims 1 to 408, wherein the AAV capsid variant is capable of transducing at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, or 95%, 96%, or 97% of astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., cervical, thoracic, or lumbar spinal cord) as measured by the assay described in Example 11, for example.

[0476] 410. The AAV particle according to any one of Embodiments 1 to 409, wherein the AAV capsid variant exhibits preferential transduction in brain regions compared to transduction in dorsal root ganglia (DRGs).

[0477] 411. The AAV particle according to any one of Embodiments 1 to 410, wherein the AAV capsid variant exhibits preferential transduction in the brain region compared to the liver.

[0478] 412. The AAV particle according to any one of Embodiments 1 to 411, wherein the AAV capsid variant exhibits preferential transduction in brain regions compared to transduction in the heart.

[0479] 413. The AAV particle according to any one of Embodiments 1 to 412, wherein the AAV capsid variant exhibits preferential transduction in brain regions compared to transduction in dorsal root ganglia (DRGs) and the heart.

[0480] 414. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is capable of transducing neuronal cells, for example, NeuN+ neurons or dopaminergic neurons (for example, dopaminergic neurons in the substantia nigra), for example, tyrosine hydroxylase (TH)+ neurons.

[0481] 415. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is capable of transducing NeuN+ cells (e.g., NeuN+ neurons) and / or TH+ (e.g., TH+ neurons, e.g., dopaminergic neurons).

[0482] 416. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is capable of transducing non-neuronal cells, such as glial cells (e.g., oligodendrocytes or astrocytes).

[0483] 417. The AAV particle according to Embodiment 416, wherein the non-neuronal cells include glial cells, oligodendrocytes (e.g., Olig2-positive oligodendrocytes), or astrocytes (e.g., Olig2-positive astrocytes or Sox9+ astrocytes).

[0484] 418. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is capable of transducing Olig2-positive cells, such as Olig2-positive astrocytes or Olig2-positive oligodendrocytes.

[0485] 419. The AAV particle according to any one of the prior embodiments, wherein the AAV capsid variant is capable of transducing Sox9+ cells, such as Sox9+ astrocytes.

[0486] 420. AAV particles according to any one of the prior embodiments, wherein the polynucleotide encoded for inhibiting MAPT comprises siRNA, shRNA, pre-miRNA, pri-miRNA, miRNA, stRNA, lncRNA, piRNA, antisense oligonucleotide agent (ASO), or snoRNA.

[0487] 421. The AAV particle according to any one of the prior embodiments, wherein the polynucleotide encoded for inhibiting MAPT comprises an siRNA and comprises a sense strand sequence and an antisense strand sequence.

[0488] 422. The AAV particle according to Embodiment 420 or 421, wherein the encoded siRNA binds to the 3'UTR of MAPT (e.g., human MAPT).

[0489] 423. An AAV particle according to any one of embodiments 420 to 422, wherein the encoded siRNA is bound to the coding region of MAPT (e.g., human MAPT).

[0490] 424. An AAV particle according to any one of embodiments 420 to 423, wherein the encoded siRNA binds to the 5'UTR of MAPT (e.g., human MAPT).

[0491] 425. The AAV particle according to any one of embodiments 420 to 424, wherein the MAPT is a human MAPT gene, a non-human primate MAPT gene, or a mouse MAPT gene.

[0492] 426. The AAV particle according to any one of embodiments 420 to 425, wherein the antisense strand includes at least one mismatch with the target mRNA.

[0493] 427. The AAV particle according to any one of Embodiments 420 to 426, wherein the encoded siRNA comprises a sense strand sequence and an antisense strand sequence, the antisense sequence being complementary to at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides, including 0, 1, 2, or 3 mismatches of a MAPT sequence, which includes the nucleotide sequence of Sequence ID No. 5024 or the nucleotide sequences provided in Table 3A or 19.

[0494] 428. The AAV particle according to any one of embodiments 421 to 427, wherein the encoded antisense strand is complementary to at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides having 0, 1, 2, or 3 mismatches with the exons of the MAPT sequence, and the exons include nucleotides 1277 to 1332 of SEQ ID NO: 5024, nucleotides 1712 to 1977 of SEQ ID NO: 5024, or nucleotides 2266 to 6644 of SEQ ID NO: 5024.

[0495] 429. An AAV particle according to any one of embodiments 421 to 428, wherein the coded antisense strand is complementary to at least 15, 16, 17, or 18 consecutive nucleotides having 0, 1, 2, or 3 mismatches with nucleotides 1300-1317, 1305-1322, 1860-1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584-2601, 2633-2650, or 2634-2653 of Sequence ID No. 5024.

[0496] 430. The sense chain to be coded is (i) At least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides containing 0, 1, 2, or 3 mismatches of the MAPT sequence, which includes the nucleotide sequence of SEQ ID NO: 5024 or the nucleotide sequence provided in Table 3A or 19; (ii) A sequence of at least 15, 16, 17, 18, 19, 20, or 21 nucleotides having 0, 1, 2, or 3 mismatches with the exons of the MAPT sequence, wherein the exons include nucleotides 1277-1332 of SEQ ID NO: 5024, nucleotides 1712-1977 of SEQ ID NO: 5024, or nucleotides 2266-6644 of SEQ ID NO: 5024; or (iii) At least 15, 16, 17, or 18 consecutive nucleotides having 0, 1, 2, or 3 mismatches with nucleotides 1300-1317, 1305-1322, 1860-1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584-2601, 2633-2650, or 2634-2653 of sequence number 5024. AAV particles according to any one of embodiments 421 to 429, including the AAV particles described.

[0497] 431. An AAV particle according to any one of Embodiments 421 to 430, wherein the coded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Table 4A, 5A, 9A, or 9B.

[0498] 432. An AAV particle according to any one of Embodiments 421 to 431, wherein the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Table 4A, 5A, 9A, or 9B.

[0499] 433. The AAV particle according to any one of embodiments 421 to 432, wherein the coded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Table 4A, 5A, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Table 4A, 5A, 9A, or 9B, and the sense strand sequence and the antisense strand sequence comprise a complementary region of at least 15 nucleotides.

[0500] 434. The AAV particle according to Embodiment 433, wherein the complementary region has a length of 15-30, 19-21, or 25-30 nucleotides, for example, a length of 17, 18, 20, 21, 22, 25, or 30 nucleotides.

[0501] 435. (i) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4700, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4502 to 4505; (ii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4918, 4938, 4958, 4978, or 4998; (iii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4697, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4495 to 4499; (iv) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4906, 4926, 4946, 4966, 4986, or 5006; (v) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4690, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4480 to 4484; (vi) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4922, 4942, 4962, 4982, 5002, or 5022; (vii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4694, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4492; (viii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4691, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of Sequence ID Nos. 4485 to 4489; (ix) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4916, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4914, 4934, 4954, 4974, 4994, or 5014; (x) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4701, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4506 to 4510; (xi) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4910, 4930, 4950, 4970, 4990, or 5010; (xii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4687, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4477; (xiii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4712, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4521; (xiv) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4696, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4494; or (xv) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 4718 by 3, 2, 1, or 0 nucleotides, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 4527, AAV particle according to any one of embodiments 421 to 434.

[0502] 436. (i) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4700, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4502 to 4505; (ii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that are different from any one of the nucleotide sequences of SEQ ID NO: 4918, 4938, 4958, 4978, or 4998; (iii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4697, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4495 to 4499; (iv) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4908, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4906, 4926, 4946, 4966, 4986, or 5006; (v) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4690, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4480 to 4484; (vi) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4924, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4922, 4942, 4962, 4982, 5002, or 5022; (vii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4694, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4492; (viii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4691, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from any one of the nucleotide sequences of Sequence ID Nos. 4485 to 4489; (ix) The coded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4916, and the coded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4914, 4934, 4954, 4974, 4994, or 5014; (x) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4701, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from any one of the nucleotide sequences of Sequence ID Nos. 4506 to 4510; (xi) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4912, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4910, 4930, 4950, 4970, 4990, or 5010; (xii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4687, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4477; (xiii) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4712, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4521; (xiv) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4696, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4494; or (xv) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4718, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4527. AAV particles according to any one of embodiments 421 to 435.

[0503] 437. (i) The coded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides of any one of sequence numbers 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; (ii) The sense strand sequences to be coded are sequence numbers 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 5074, 4914, 4934, 4954, 4974, 4994, Containing at least 19, 20, or 21 consecutive nucleotides of any one of the following: 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144, or 5146; The encoded sense strand sequence and the encoded antisense strand sequence include a complementary region of at least 15 nucleotides. AAV particle according to any one of embodiments 421 to 436.

[0504] 438. The AAV particle according to any one of embodiments 433 to 437, wherein the complementary region comprises at least 18, 19, or 20 nucleotides.

[0505] 439. The AAV particle according to any one of embodiments 421 to 438, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides of any one of sequence numbers 4908, 4920, 4924, or 4912.

[0506] 440. An AAV particle according to any one of embodiments 421 to 439, wherein the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of sequence numbers 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010.

[0507] 441. (i) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4908, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4918, 4938, 4958, 4978, or 4998; (iii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of Sequence ID No. 4922, 4942, 4962, 4982, 5002, or 5022; (iv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4912, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4910, 4930, 4950, 4970, 4990, or 5010; (v) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4916, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4914, 4934, 4954, 4974, 4994, or 5014; (vi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5104; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5101, 5108, 5112, 5116, 5120, or 5122; (vii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5125, 5132, 5136, 5140, 5144, or 5146; (viii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5077, 5084, 5088, 5092, 5096, or 5098; ​​or (ix) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5054, 5060, 5064, 5066, 5070, or 5074. AAV particles according to any one of embodiments 421 to 440.

[0508] 442. The AAV particle according to any one of Embodiments 421 to 441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4906.

[0509] 443. The AAV particle according to any one of Embodiments 421 to 441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4918.

[0510] 444. The AAV particle according to any one of Embodiments 421 to 441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4922.

[0511] 445. The AAV particle according to any one of Embodiments 421 to 441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4966.

[0512] 446. The AAV particle according to any one of Embodiments 421 to 441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4970.

[0513] 447. The AAV particle according to any one of Embodiments 421 to 441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4978.

[0514] 448. The AAV particle according to any one of Embodiments 421 to 441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4982.

[0515] 449. (i) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4910; (ii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4914; (iii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5054; (iv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4926; (v) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4930; (vi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4934; (vii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4938; (viii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4942; (ix) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5060; (x) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4946; (xi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4950; (xii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4954; (xiii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4958; (xiv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4962; (xv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5064; (xvi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4974; (xvii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5066; (xviii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4986; (xix) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4990; (xx) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4994; (xxi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4998; (xxii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5002; (xxiii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5070; (xxiv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5006; (xxv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5010; (xxvi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5014; (xxvii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4958; (xxviii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5022; (xxvii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5074; (xxix) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5077; (xxx) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5084; (xxxi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5088; (xxxii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5092; (xxxiii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5096; (xxxiv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5098; (xxxv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5101; (xxxvi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5108; (xxxvii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5112; (xxxviii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5116; (xxxix) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5120; (xl) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5122; (xli) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5125; (xlii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5132; (xliii) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5136; (xliv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5140; (xlv) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5144; or (xlvi) The encoded antisense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises at least 19, 20, or 21 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5146, AAV particle according to any one of Embodiments 421 to 441.

[0516] 450. An AAV particle according to any one of embodiments 421 to 449, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides of any one of sequence numbers 4908, 4920, 4924, or 4912.

[0517] 451. An AAV particle according to any one of Embodiments 421 to 450, wherein the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of sequence numbers 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010.

[0518] 452. (i) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4908, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4918, 4938, 4958, 4978, or 4998; (iii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of Sequence ID No. 4922, 4942, 4962, 4982, 5002, or 5022; (iv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4912, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4910, 4930, 4950, 4970, 4990, or 5010; (v) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4916, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 4914, 4934, 4954, 4974, 4994, or 5014; (vi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5104; the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5101, 5108, 5112, 5116, 5120, or 5122; (vii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5125, 5132, 5136, 5140, 5144, or 5146; (viii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5077, 5084, 5088, 5092, 5096, or 5098; ​​or (ix) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises at least 20 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NO: 5054, 5060, 5064, 5066, 5070, or 5074. AAV particle according to any one of embodiments 421 to 451.

[0519] 453. An AAV particle according to any one of Embodiments 421-442 or 450-452, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4906.

[0520] 454. An AAV particle according to any one of embodiments 421-441, 443, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4918.

[0521] 455. An AAV particle according to any one of embodiments 421-441, 444, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4922.

[0522] 456. An AAV particle according to any one of embodiments 421-441, 445, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4966.

[0523] 457. An AAV particle according to any one of embodiments 421-441, 446, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4970.

[0524] 458. An AAV particle according to any one of embodiments 421-441, 447, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4978.

[0525] 459. An AAV particle according to any one of embodiments 421-441, 448, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4982.

[0526] 460. (i) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4910; (ii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4914; (iii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5054; (iv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4926; (v) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4930; (vi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4934; (vii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4938; (viii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4942; (ix) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5060; (x) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4946; (xi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4950; (xii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4954; (xiii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4958; (xiv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4962; (xv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5064; (xvi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4916; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4974; (xvii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5066; (xviii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4986; (xix) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4990; (xx) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4916; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4994; (xxi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4998; (xxii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5002; (xxiii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5070; (xxiv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5006; (xxv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5010; (xxvi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5014; (xxvii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4958; (xxviii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5022; (xxvii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5074; (xxix) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5077; (xxx) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5084; (xxxi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5088; (xxxii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5092; (xxxiii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5096; (xxxiv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5098; (xxxv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5101; (xxxvi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5108; (xxxvii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5112; (xxxviii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5116; (xxxix) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5120; (xl) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5122; (xli) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5125; (xlii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5132; (xliii) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5136; (xliv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5140; (xlv) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5144; or (xlvi) The encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the encoded antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5146, AAV particles according to any one of embodiments 421 to 441 or 449 to 452.

[0527] 461. The AAV particle according to any one of embodiments 421 to 460, wherein the coded antisense strand sequence comprises one nucleotide sequence of sequence numbers 4908, 4920, 4924, or 4912.

[0528] 462. An AAV particle according to any one of Embodiments 421 to 461, wherein the encoded sense strand sequence comprises one nucleotide sequence of sequence numbers 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010.

[0529] 463. (i) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998; (iii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (iv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (v) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (vi) The encoded antisense strand sequence comprises the nucleotide sequence of sequence number 5104; the encoded sense strand sequence comprises one of the nucleotide sequences of sequence numbers 5101, 5108, 5112, 5116, 5120, or 5122; (vii) The encoded antisense strand sequence comprises the nucleotide sequence of sequence number 5128; the encoded sense strand sequence comprises one of the nucleotide sequences of sequence numbers 5125, 5132, 5136, 5140, 5144, or 5146; (viii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 5077, 5084, 5088, 5092, 5096, or 5098; ​​or (ix) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074. AAV particle according to any one of embodiments 421 to 462.

[0530] 464. An AAV particle according to any one of embodiments 421-442, 450-452, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of sequence number 4908, and the encoded sense strand sequence comprises the nucleotide sequence of sequence number 4906.

[0531] 465. An AAV particle according to any one of embodiments 421-441, 443, 450-452, 454, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4918.

[0532] 466. An AAV particle according to any one of embodiments 421-441, 444, 450-452, 455, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924, and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4922.

[0533] 467. An AAV particle according to any one of embodiments 421-441, 445, 450-452, 456, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of sequence number 4908, and the encoded sense strand sequence comprises the nucleotide sequence of sequence number 4966.

[0534] 468. An AAV particle according to any one of embodiments 421-441, 446, 450-452, 457, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912, and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4970.

[0535] 469. An AAV particle according to any one of embodiments 421-441, 447, 450-452, 458, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4978.

[0536] 470. An AAV particle according to any one of embodiments 421-441, 448, 450-452, 459, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of sequence number 4924, and the encoded sense strand sequence comprises the nucleotide sequence of sequence number 4982.

[0537] 471. (i) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4910; (ii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4914; (iii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5054; (iv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4926; (v) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4930; (vi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4934; (vii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4938; (viii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4942; (ix) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5060; (x) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4946; (xi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4950; (xii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4954; (xiii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xiv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4962; (xv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5064; (xvi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4974; (xvii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5066; (xviii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4986; (xix) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4990; (xx) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4994; (xxi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4998; (xxii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5002; (xxiii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5070; (xxiv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5006; (xxv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5010; (xxvi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5014; (xxvii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xxviii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5022; (xxvii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5074; (xxix) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5077; (xxx) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5084; (xxxi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5088; (xxxii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5092; (xxxiii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5096; (xxxiv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5098; (xxxv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5101; (xxxvi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5108; (xxxvii) The encoded antisense strand sequence comprises the nucleotide sequence of sequence number 5104; the encoded sense strand sequence comprises the nucleotide sequence of sequence number 5112; (xxxviii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5116; (xxxix) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5120; (xl) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5122; (xli) The encoded antisense strand sequence comprises the nucleotide sequence of sequence number 5128; the encoded sense strand sequence comprises the nucleotide sequence of sequence number 5125; (xlii) The encoded antisense strand sequence comprises the nucleotide sequence of sequence number 5128; the encoded sense strand sequence comprises the nucleotide sequence of sequence number 5132; (xliii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5136; (xlv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5140; (xliv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5144; or (xlvi) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146, AAV particles according to any one of embodiments 421-441, 449-452, or 460-463.

[0538] 472. (i) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4700, and the encoded sense strand sequence comprises one nucleotide sequence from SEQ ID NOs: 4502 to 4505; (ii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998; (iii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4697, and the encoded sense strand sequence comprises one nucleotide sequence from SEQ ID NOs: 4495 to 4499; (iv) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (v) The encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 4690, and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 consecutive nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4480 to 4484; (vi) The encoded antisense strand sequence comprises the nucleotide sequence of Sequence ID No. 4924, and the encoded sense strand sequence comprises one of the nucleotide sequences of Sequence ID No. 4922, 4942, 4962, 4982, 5002, or 5022; (vii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4694, and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4492; (viii) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4691, and the encoded sense strand sequence comprises one nucleotide sequence from SEQ ID NOs: 4485 to 4489; (ix) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (x) The encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4701, and the encoded sense strand sequence comprises one of the nucleotide sequences of SEQ ID NOs: 4506 to 4510; (xi) The encoded antisense strand sequence comprises the nucleotide sequence of S...

Claims

1. AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting the expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant is given by the following formula: [N1]-[N2]-[N3] (wherein, (i) [N1] includes X1, X2, and X3, where at least one of X1, X2, or X3 is G; (ii) [N2] contains the amino acid sequence of SPH; (iii) [N3] comprises X4, X5, and X6, where at least one of X4, X5, or X6 is a basic amino acid, e.g., K or R. The amino acid sequence includes [N1]-[N2]-[N3], which is located in the hypervariable loop IV; The AAV particle wherein the AAV capsid variant contains an amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203-736 of SEQ ID NO:

138.

2. [N3] is SKA, KSG, ARM, VKS, ASR, VKI, KKN, VRM, RKA, KTS, KFG, KIG, KLG, KTT, KT Y, KYG, SKD, SKP, TRG, VRG, KRG, GAR, KSA, KSR, SKL, SRA, SKR, SLR, SRG, SSR, FLR AAV particles according to claim 1, comprising 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.

3. [N2]-[N3] are SPHSKA (sequence number 941), SPHKSG (sequence number 946), SPHARM (sequence number 947), SPHVKS (sequence number 948), SPHASR (sequence number 949), SPHVKI (sequence number 950), SPHKKN (sequence number 954), SPHVRM (sequence number 955), SPHRKA (sequence number 956), SPHKFG (sequence number 957), SPHKIG (sequence number 958), SPHKLG (sequence number 959), SPHKTS (sequence number 963), SPHKTT (sequence number 964), SPHKTY (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: 94), 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: 968) 61), 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: 95), SPHSKG (SEQ ID NO: 96), SPHGKA (SEQ ID NO: 97), SPHNKA (SEQ ID NO: 98), SPHSKN (SEQ ID NO: 99), SPHAKA (SEQ ID NO: 100), SPHSKV (SEQ ID NO: 101), SPHKTG (SEQ ID NO: 102), SPHTKA (SEQ ID NO: 100) 3) AAV particles according to claim 1 or 2, comprising SPHKSL (SEQ ID NO: 104), SPHKSE (SEQ ID NO: 105), SPHKSV (SEQ ID NO: 106), SPHKSW (SEQ ID NO: 107), SPHKSN (SEQ ID NO: 108), SPHKHG (SEQ ID NO: 109), SPHKSQ (SEQ ID NO: 110), SPHKSK (SEQ ID NO: 111), SPHKLW (SEQ ID NO: 112), SPHWKG (SEQ ID NO: 113), SPHKMG (SEQ ID NO: 114), SPHKMA (SEQ ID NO: 115), or SPHRSG (SEQ ID NO: 976).

4. [N1] is an AAV particle according to any one of claims 1 to 3, comprising 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.

5. [N1] - [N2] - [N3] is (i) GSGSPHSKA (SEQ ID NO: 60), GHDSPHKSG (SEQ ID NO: 62), VSGSPHSKA (SEQ ID NO: 1083), GSGSPHARM (SEQ ID NO: 1076), GSGSPHVKS (SEQ ID NO: 1077), GQDSPHKSG (SEQ ID NO: 1078), GSGSPHASR (SEQ ID NO: 1079), GSGSPHVKI (SEQ ID NO: 1080), GSGSPHKKN (SEQ ID NO: 1081), GSGSPHVRM (SEQ ID NO: 1082), CSGSPHSKA (SEQ ID NO: 1084), GSGSPHRKA (SEQ ID NO: 1085), CSGSPHKTS ( SEQ ID NO: 1086), CSHSPHKSG (SEQ ID NO: 1087), GQSSPHRSG (SEQ ID NO: 1088), GRGSPHASR (SEQ ID NO: 1089), GRGSPHSKA (SEQ ID NO: 1090), GSGSPHKFG (SEQ ID NO: 1091), GSGSPHKIG (SEQ ID NO: 1092), GSGSPHKLG (SEQ ID NO: 1093), GSGSPHKTS (SEQ ID NO: 1094), GSGSPHKTT (SEQ ID NO: 1095), GSGSPHKTY (SEQ ID NO: 1096), GSGSPHKYG (SEQ ID NO: 1097), GSGSPHSKD (SEQ ID NO: 1098), GSGSPHSKP (SEQ ID NO: 1099), GSGSPHTRG (SEQ ID NO: 1100), GSGSPHVRG (SEQ ID NO: 1101), GSHSPHKRG (SEQ ID NO: 1102), GSHSPHKSG (SEQ ID NO: 1103), VSGSPHASR (SEQ ID NO: 1104), VSGSPHGAR (SEQ ID NO: 1105), VSGSPHKFG (SEQ ID NO: 1106), GHDSPHKRG (SEQ ID NO: 1107), GDDSPHKSG (SEQ ID NO: 1108), GHESPHKSA (SEQ ID NO: 1109), GHDSPHKSA (SEQ ID NO: 1110), GNYSPHKIG ( SEQ ID NO: 1111), GHDSPHKSR (SEQ ID NO: 1112), GSGSPHSKL (SEQ ID NO: 1113), GSGSPHRA (SEQ ID NO: 1114), GSGSPHSKR (SEQ ID NO: 1115), GSGSPHLR (SEQ ID NO: 1116), GSGSPHRG (SEQ ID NO: 1117), GSGSPHSR (SEQ ID NO: 1118), RVGSPHKA (SEQ ID NO: 1119), GSCSPHRKA (SEQ ID NO: 1120), GSGSPHFLR (SEQ ID NO: 1121), GSGSPHSKW (SEQ ID NO: 1122), GSGSPHKS (SEQ ID NO: 1123),GLLSPHWKA (SEQ ID NO: 1124), GSGSPHVRR (SEQ ID NO: 1125), GSGSPHSKV (SEQ ID NO: 1126), MSGSPHSKA (SEQ ID NO: 1127), RNGSPHKA (SEQ ID NO: 1128), TSGSPHKA (SEQ ID NO: 1129), ISGSPHKA (SEQ ID NO: 1130), GPGSPHKA (SEQ ID NO: 1131), GSGSPHSKT (SEQ ID NO: 1132), ESGSPHKA (SEQ ID NO: 1133), SSGSPHKA (SEQ ID NO: 1134), GNGSPHKA (SEQ ID NO: 1135), ASGSPHKA ( SEQ ID NO: 1136), NSGSPHSKA (SEQ ID NO: 1137), LSGSPHSKA (SEQ ID NO: 1138), GGGSPHSKA (SEQ ID NO: 1139), KSGSPHSKA (SEQ ID NO: 1140), GGGSPHSKS (SEQ ID NO: 1141), GSGSPHSKG (SEQ ID NO: 1142), HSGSPHSKA (SEQ ID NO: 1143), GTGSPHSKA (SEQ ID NO: 1144), PSGSSPHSKA (SEQ ID NO: 1145), GSVSPHGKA (SEQ ID NO: 1146), RSGSPHSKA (SEQ ID NO: 1147), GSGSPHTKA (SEQ ID NO: 1148), GIGSPHHSKA (SEQ ID NO: 1149), WSGSPHSKA (SEQ ID NO: 1150), DSGSPHSKA (SEQ ID NO: 1151), IDGSPHHSKA (SEQ ID NO: 1152), GSGSPHNKKA (SEQ ID NO: 1153), GLGSPHSKS (SEQ ID NO: 1154), DAGSPHSKA (SEQ ID NO: 1155), DGGSPHSKA (SEQ ID NO: 1156), MEGSPHSKA (SEQ ID NO: 1157), ENGSPHSKA (SEQ ID NO: 1158), GSASPHSKA (SEQ ID NO: 1159), GNGSPHSKS (SEQ ID NO: 1160), KNGSPHSKA ( SEQ ID NO: 1161), KEGSPHSKA (SEQ ID NO: 1162), AIGSPHSKA (SEQ ID NO: 1163), GSGSPHSKN (SEQ ID NO: 1164), GSGSPHAKA (SEQ ID NO: 1165), GHDSPHKIG (SEQ ID NO: 1166), GYDSPHKSG (SEQ ID NO: 1167), GHESPHKSG (SEQ ID NO: 1168), GHDSPHKTG (SEQ ID NO: 1169), GRGSPHKRG (SEQ ID NO: 1170), GQDSPHKSG (SEQ ID NO: 1078), GHDSPHKSL (SEQ ID NO: 1171), GHGSPHSKA (SEQ ID NO: 1172),GHDSPHKSE (Sequence No. 1173), VSGSPHSKA (Sequence No. 1083), GRDSPHKSG (Sequence No. 1174), GNDSPHKSV (Sequence No. 1175), GQDSPHKIG (Sequence No. 1176), GHDSPHKSV (Sequence No. 1177), GPDSPHKIG (Sequence No. 1178), GPDSPHKSG (Sequence No. 1179), GHDSPHKSW (Sequence No. 1180), GHDSPHKSN (Sequence No. 1181), GMGSPHSKT (Sequence No. 1182), GHDSPHKHG (Sequence No. 1183), GQVSPHKSG (Sequence No. SEQ ID NO. 1184), GDDSPHKSV (SEQ ID NO. 1185), GHNSPHKSG (SEQ ID NO. 1186), GNGSPHKRG (SEQ ID NO. 1187), GHDSPHKYG (SEQ ID NO. 1188), GHDSPHKSQ (SEQ ID NO. 1189), GNDSPHKIG (SEQ ID NO. 1190), GHDSPHKSK (SEQ ID NO. 1191), GHDSPHKLW (SEQ ID NO. 1192), GHPSPHWKG (SEQ ID NO. 1193), GHDSPHKMG (SEQ ID NO. 1194), GHDSPHKMA (SEQ ID NO. 1195), or GHSSPHRSG (SEQ ID NO. 1196); or, (ii) GSGSPHSKA (SEQ ID NO: 60), GHDSPHKSG (SEQ ID NO: 62), or VSGSPHSKA (SEQ ID NO: 1083) AAV particles according to any one of claims 1 to 4, including the AAV particles described in any one of claims 1 to 4.

6. (i) [N0] (where [N0] is TIN, TEN, TER, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW, ANN, IPE, ADM, I EY, ADY, IET, MEW, CEY, RIN, MEI, LEY, ADW, IEI, DIM, FEQ, MEF, CDQ, LPE, IEN, MES, AEI, VEY, IIN , TSN, IEV, MEM, AEV, MDA, VEW, AEQ, LEW, MEL, MET, MEA, IES, MEV, CEI, ATN, MDG, QEV, ADQ, NMN, I EM, ISN, TGN, QQQ, HDW, IEG, TII, TFP, TEK, EIN, TVN, TFN, SIN, TSY, ELH, AIN, SVN, TDN, TFH, TVH, TSS, TID, TCN, NIN, TEH, AEM, AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TIY, TFS, TE S, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, NAD, TIT, NCV, TIR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV, SDI, NS I, NSL, EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, or NNL); and / or (ii) [N4] (wherein [N4] is QNQQ (sequence number 1198), WNQQ (sequence number 1199), QYYV (sequence number 1200), RRQQ (sequence number 1201), GCGQ (sequence number 1202), LRQQ (sequence number 1203), RNQQ (sequence number 1204), VNQQ (sequence number 1205), FRLQ (sequence number 1206), FNQQ (sequence number 1207), LLQQ (sequence number 1208), SNQQ (sequence number 1209), RLQQ (sequence number 1210), LNQQ (sequence number 1211), QRKL (sequence number 1212), LRRQ ( SEQ ID NO: 1213), QRLR (SEQ ID NO: 1214), QRRL (SEQ ID NO: 1215), RRLQ (SEQ ID NO: 1216), RLRQ (SEQ ID NO: 1217), SKRQ (SEQ ID NO: 1218), QLYR (SEQ ID NO: 1219), QLTV (SEQ ID NO: 1220), QNKQ (SEQ ID NO: 1221), KNQQ (SEQ ID NO: 1222), QKQQ (SEQ ID NO: 1223), QTQQ (SEQ ID NO: 1224), QNHQ (SEQ ID NO: 1225), QHQQ (SEQ ID NO: 1226), QNQH (SEQ ID NO: 1227), QHRQ (SEQ ID NO: 1228), LTQQ (SEQ ID NO: 1229) ), QNQW (Sequence ID 1230), QNTH (Sequence ID 1231), RRRQ (Sequence ID 1232), QYQQ (Sequence ID 1233), QNDQ (Sequence ID 1234), QNRH (Sequence ID 1235), RDQQ (Sequence ID 1236), PNLQ (Sequence ID 1237), HVRQ (Sequence ID 1238), PNQH (Sequence ID 1239), HNQQ (Sequence ID 1240), QSQQ (Sequence ID 1241), QPAK (Sequence ID 1242), QNLA (Sequence ID 1243), QNQL (Sequence ID 1244), QGQQ (Sequence ID 1245), LNRQ (Sequence ID 1245) Column number 1246), QNPP (sequence number 1247), QNLQ (sequence number 1248), QDQE (sequence number 1249), QDQQ (sequence number 1250), HWQQ (sequence number 1251), PNQQ (sequence number 1252), PEQQ (sequence number 1253), QRTM (sequence number 1254), LHQH (sequence number 1255), QHRI (sequence number 1256), QYIH (sequence number 1257), QKFE (sequence number 1258), QFPS (sequence number 1259), QNPL (sequence number 1260), QAIK (sequence number 1261), QNRQ (sequence number 1263),QYQH (Sequence ID 1264), QNPQ (Sequence ID 1265), QHQL (Sequence ID 1266), QSPP (Sequence ID 1267), QAKL (Sequence ID 1268), KSQQ (Sequence ID 1269), QDRP (Sequence ID 1270), QNLG (Sequence ID 1271), QAFH (Sequence ID 1272), QNAQ (Sequence ID 1273), HNQL (Sequence ID 1274), QKLN (Sequence ID 1275), QNVQ (Sequence ID 1276), QAQQ (Sequence ID 1277), QTPP (Sequence ID 1278), QPPA (Sequence ID 1279), QERP (Sequence ID Number 1280), QDLQ (Sequence ID 1281), QAMH (Sequence ID 1282), QHPS (Sequence ID 1283), PGLQ (Sequence ID 1284), QGIR (Sequence ID 1285), QAPA (Sequence ID 1286), QIPP (Sequence ID 1287), QTQL (Sequence ID 1288), QAPS (Sequence ID 1289), QNTY (Sequence ID 1290), QDKQ (Sequence ID 1291), QNHL (Sequence ID 1292), QIGM (Sequence ID 1293), LNKQ (Sequence ID 1294), PNQL (Sequence ID 1295), QLQQ (Sequence ID 1296), QRMS (SEQ ID NO: 1297), QGIL (SEQ ID NO: 1298), QDRQ (SEQ ID NO: 1299), RDWQ (SEQ ID NO: 1300), QERS (SEQ ID NO: 1301), QNYQ (SEQ ID NO: 1302), QRTC (SEQ ID NO: 1303), QIGH (SEQ ID NO: 1304), QGAI (SEQ ID NO: 1305), QVPP (SEQ ID NO: 1306), QVQQ (SEQ ID NO: 1307), LMRQ (SEQ ID NO: 1308), QYSV (SEQ ID NO: 1309), QAIT (SEQ ID NO: 1310), QKTL (SEQ ID NO: 1311), QLHH (SEQ ID NO: 1312), QNII (SEQ ID NO: 1307NII (SEQ ID NO: 1307), QNII (SEQ ID NO: 1307), QNII (SEQ ID NO: 1307), QNII (SEQ ID NO: 1307), QNII (SEQ ID NO: 1307), QNII (SEQ ID NO: 1307), QNII (SEQ ID NO: 1307), QNII (SEQ ID NO: 1307), QNII (SEQ ID NO: 13 Number 1313), QGHH (Sequence ID 1314), QSKV (Sequence ID 1315), QLPS (Sequence ID 1316), IGKQ (Sequence ID 1317), QAIH (Sequence ID 1318), QHGL (Sequence ID 1319), QFMC (Sequence ID 1320), QNQM (Sequence ID 1321), QHLQ (Sequence ID 1322), QPAR (Sequence ID 1323), QSLQ (Sequence ID 1324), QSQL (Sequence ID 1325), HSQQ (Sequence ID 1326), QMPS (Sequence ID 1327), QGSL (Sequence ID 1328), QVPA (Sequence ID 1329),HYQQ (SEQ ID NO: 1330), QVPS (SEQ ID NO: 1331), RGEQ (SEQ ID NO: 1332), PGQQ (SEQ ID NO: 1333), LEQQ (SEQ ID NO: 1334), QNQS (SEQ ID NO: 1335), QKVI (SEQ ID NO: 1336), QNND (SEQ ID NO: 1337), QSVH (SEQ ID NO: 1338), QPLG (SEQ ID NO: 1339), HNQE (SEQ ID NO: 1340), QIQQ (SEQ ID NO: 1341), QVRN (SEQ ID NO: 1342), PSNQ (SEQ ID NO: 1343), QVGH (SEQ ID NO: 1344), QRDI (SEQ ID NO: 1345), QMPN (SEQ ID NO: 1340) Number 1346), RGLQ (Sequence ID 1347), PSLQ (Sequence ID 1348), QRDQ (Sequence ID 1349), QAKG (Sequence ID 1350), QSAH (Sequence ID 1351), QSTM (Sequence ID 1352), QREM (Sequence ID 1353), QYRA (Sequence ID 1354), QRQQ (Sequence ID 1355), QWQQ (Sequence ID 1356), QRMN (Sequence ID 1357), GDSQ (Sequence ID 1358), QKIS (Sequence ID 1359), PSMQ (Sequence ID 1360), SPRQ (Sequence ID 1361), MEQQ (Sequence ID 1362), QYQN (Sequence ID 1363), QIRQ (Sequence ID 1364), QSVQ (Sequence ID 1365), RSQQ (Sequence ID 1366), QNKL (Sequence ID 1367), QIQH (Sequence ID 1368), PRQQ (Sequence ID 1369), HTQQ (Sequence ID 1370), QRQH (Sequence ID 1371), RNQE (Sequence ID 1372), QSKQ (Sequence ID 1373), QNQP (Sequence ID 1374), QSPQ (Sequence ID 1375), QTRQ (Sequence ID 1376), QNLH (Sequence ID 1377), QNQE (Sequence ID 1378), LNQP (Sequence ID Number 1379), QNQD (Sequence ID 1380), QNLL (Sequence ID 1381), QLVI (Sequence ID 1382), RTQE (Sequence ID 1383), QTHQ (Sequence ID 1384), QDQH (Sequence ID 1385), QSQH (Sequence ID 1386), VRQQ (Sequence ID 1387), AWQQ (Sequence ID 1388), QSVP (Sequence ID 1389), QNIQ (Sequence ID 1390), LDQQ (Sequence ID 1391), PDQQ (Sequence ID 1392), ESQQ (Sequence ID 1393), QRQL (Sequence ID 1394), QIII (Sequence ID 1395),(Including QKQS (SEQ ID NO: 1396), QSHQ (SEQ ID NO: 1397), QFVV (SEQ ID NO: 1398), QSQP (SEQ ID NO: 1399), QNEQ (SEQ ID NO: 1400), INQQ (SEQ ID NO: 1401), RNRQ (SEQ ID NO: 1402), RDQK (SEQ ID NO: 1403), QWKR (SEQ ID NO: 1404), ENRQ (SEQ ID NO: 1405), QTQP (SEQ ID NO: 1406), QKQL (SEQ ID NO: 1407), RNQL (SEQ ID NO: 1408), ISIQ (SEQ ID NO: 1409), QTVC (SEQ ID NO: 1410), QQIM (SEQ ID NO: 1411), LNHQ (SEQ ID NO: 1412), QNQA (SEQ ID NO: 1413), QMIH (SEQ ID NO: 1414), RNHQ (SEQ ID NO: 1415), or QKMN (SEQ ID NO: 1416)) AAV particles according to any one of claims 1 to 5, further comprising:

7. [N0]-[N1]-[N2]-[N3]-[N4] is, (i) any one amino acid sequence from SEQ ID NOs. 2242 to 2886; or (ii) TENVSGSPHHSKAQNQQ (Sequence ID 2283), TERVSGSPHHSKAQNQQ (Sequence ID 2272), TINGSGSPHSKAQNQQ (Sequence ID 2242), or TINGHDSPHKSGQNQQ (Sequence ID 2243) AAV particles according to claim 6, including the AAV particles described in claim 6.

8. (i) [N0] is located at amino acids 450–452, numbered according to sequence numbers 981, 982, or 138; (ii) [N1] is located at amino acids 453–455, numbered according to sequence numbers 981, 982, or 138; (iii)[N2] is located at amino acids 456-458, numbered according to sequence number 981 or 982; (iv)[N3] is located at amino acids 459–461, numbered according to sequence number 981 or 982; (v) [N4] is located at amino acids 462–465, numbered according to sequence number 981 or 982; and / or (vi) [N0]-[N1]-[N2]-[N3]-[N4] are numbered according to sequence number 981 or 982 and are located at amino acids 450-465. AAV particles according to claim 6 or 7

9. AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting the expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant is (i) The amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV; and (ii) An amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203-736 of SEQ ID NO: 138 The AAV particles, including the AAV particles.

10. The AAV particle according to claim 9, wherein the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located immediately after amino acid 455, as numbered according to SEQ ID NO:

981.

11. The AAV particle according to claim 9 or 10, wherein the AAV capsid variant further comprises amino acid E at position 451, numbered according to Sequence ID No.

981.

12. The AAV particle according to any one of claims 9 to 11, wherein the AAV capsid variant comprises amino acid V at position 453, numbered according to Sequence ID No.

981.

13. The AAV particle according to any one of claims 9 to 12, wherein the AAV capsid variant comprises amino acid R at position 452, numbered according to Sequence ID No.

981.

14. The aforementioned AAV capsid variant is (i) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 203–742 of SEQ ID NO: 3904, 36, or 981; (ii) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 3904, 36, or 981; 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: 3904, 36, or 981 AAV particles according to any one of claims 1 to 13, including the AAV particles described in any one of claims 1 to 13.

15. The AAV capsid variant is (i) The amino acid sequence of amino acids 203–742 of SEQ ID NO: 3904, 36, or 981; (ii) The amino acid sequence of amino acids 138–742 of SEQ ID NO: 3904, 36, or 981; and / or (iii) Amino acid sequence of SEQ ID NO: 3904, 36, or 981 AAV particles according to any one of claims 1 to 14, including the AAV particles described in any one of claims 1 to 14.

16. AAV particles comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting the expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant is (i) The amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV; and (ii) An amino acid sequence that is at least 95% identical to the amino acid sequence at positions 203-736 of SEQ ID NO: 138 The AAV particles, including the AAV particles.

17. The AAV particle according to claim 16, wherein the amino acid sequence of HDSPHK (SEQ ID NO: 2) is located immediately after amino acid 453, numbered according to SEQ ID NO:

982.

18. The AAV capsid variant is (i) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NOs. 982, 37, or 6; (ii) an amino acid sequence that is at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 982, 37, or 6; 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 NOs. 982, 37, or 6. AAV particles according to any one of claims 1 to 9, 16, or 17, comprising:

19. The AAV capsid variant is (i) The amino acid sequence of amino acids 203–742 of SEQ ID NO: 982, 37, or 6; (ii) The amino acid sequence of amino acids 138-742 of SEQ ID NO: 982, 37, or 6; and / or (iii) Amino acid sequence of SEQ ID NO: 982, 37, or 6 AAV particles according to any one of claims 1 to 9 or 16 to 18, comprising:

20. The AAV particle according to any one of claims 1 to 19, wherein the hypervariable loop IV comprises amino acids 449 to 460, numbered according to Sequence ID No.

138.

21. The AAV capsid variant is (i) Compared to the reference sequence containing the amino acid sequence of Sequence ID No. 138, it has increased directivity to CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells, or spinal cord tissue; (ii) Transducing a brain region (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or lateral geniculate nucleus (LGN)) optionally such transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65 times higher than the reference sequence of Sequence ID No. 138, as measured by an assay, e.g., an immunohistochemical assay or a qPCR assay, e.g., as described in Example 3 or 7; (iii) For example, when measured by the assay described in Example 1 or 4, it is concentrated at least about 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or 210 times in the brain compared to the reference sequence of SEQ ID NO: 138; (iv) Compared to the reference sequence containing the amino acid sequence of Sequence ID No. 138, it has increased directivity to at least two to three types of CNS cells or tissues of non-human primates and rodents (e.g., Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mice (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 non-inbred mice), such as brain cells, brain tissue, spinal cord cells, or spinal cord tissue; (v) For example, when measured by the assay described in Example 2, 5, or 8, it is enriched at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times in the brains of at least two to three species, e.g., non-human primates and rodents (e.g., Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus), and / or mice (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 non-inbred mice), compared to the reference sequence of Sequence ID No. 138; (vi) Deliver an increased level of payload to a brain region, optionally such that 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 Sequence ID No. 138, and optionally such brain region is a midbrain region (e.g., hippocampus or thalamus), prefrontal cortex, temporal cortex, motor cortex, cerebral cortex, caudate nucleus, putamen, dentate nucleus, substantia nigra, or brainstem; (vii) Deliver an increased level of viral genome to a brain region, optionally such that the level of 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 Sequence ID No. 138, when measured by an assay, e.g., qRT-PCR or qPCR assay (e.g., as described in Example 2 or 8), optionally such brain region is the putamen, caudate nucleus, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or lateral geniculate nucleus (LGN)); (viiii) For example, when measured by the assay described in Example 1 or 8, the spinal cord is enriched at least about 5, 10, 15, 20, 25, 30, or 35 times compared to the reference sequence of Sequence ID No. 138, and the region of the spinal cord is optionally the thoracic region, the cervical region, the C5 anterior horn region, the lumbar region, or the L5 anterior horn region; (ix) It exhibits preferential transduction in brain regions compared to transduction in the dorsal root ganglia (DRG) and / or liver; (x) It is possible to transduce neuronal cells and / or non-neuronal cells (e.g., astrocytes); (xi) For example, as measured by the assay described in Example 11, it is possible to transduce at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of cells in brain regions (e.g., putamen, caudate nucleus, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, cerebellar cortex, cerebellum, dentate nucleus, and / or lateral geniculate nucleus (LGN)); (xi) For example, as measured by the assay described in Example 11, it is possible to transduce at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% 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); (xiii) For example, as measured by the assay described in Example 11, it is possible to transduce at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% 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); and / or (xiv) For example, as measured by the assay described in Example 11, it is possible to transduce at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, or 95%, 96%, or 97% of astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., cervical, thoracic, or lumbar). AAV particle according to any one of claims 1 to 20.

22. The AAV particle according to any one of claims 1 to 21, wherein the nucleic acid encodes a siRNA comprising a sense strand and an antisense strand, and the antisense strand sequence is fully or partially complementary to human MAPT.

23. (i) The antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Table 4A, 5A, 9A, or 9B; and / or (ii) The sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Table 4A, 5A, 9A, or 9B; The AAV particle according to claim 22, wherein the sense strand sequence and the antisense strand sequence include a complementary region of at least 15 nucleotides.

24. (i) The antisense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908, and the sense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) The antisense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4920, and the sense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of Sequence ID No. 4918, 4938, 4958, 4978, or 4998; (iv) The antisense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924, and the sense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (v) The antisense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of Sequence ID No. 4694 by 3, 2, 1, or 0 nucleotides, and the sense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of Sequence ID No. 4492 by 3, 2, 1, or 0 nucleotides; (vi) The antisense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4916, and the sense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (viiii) The antisense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of Sequence ID No. 4912, and the sense strand sequence comprises at least 18, 19, 20, or 21 consecutive nucleotides that differ by 3, 2, 1, or 0 nucleotides from any one of the nucleotide sequences of Sequence ID No. 4910, 4930, 4950, 4970, 4990, or 5010; (ix) The antisense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of Sequence ID No. 4687 by 3, 2, 1, or 0 nucleotides, and the sense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of Sequence ID No. 4477 by 3, 2, 1, or 0 nucleotides; (x) The antisense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of Sequence ID No. 4712 by 3, 2, 1, or 0 nucleotides, and the sense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of Sequence ID No. 4521 by 3, 2, 1, or 0 nucleotides; (xi) The antisense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 4696 by 3, 2, 1, or 0 nucleotides, and the sense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 4494 by 3, 2, 1, or 0 nucleotides; or (xi) The antisense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 4718 by 3, 2, 1, or 0 nucleotides, and the sense strand sequence comprises at least 18 or 19 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 4527 by 3, 2, 1, or 0 nucleotides. AAV particles according to claim 22 or 23, comprising:

25. (i) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908, and the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4906; (ii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920, and the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4918; (iii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4922; (iv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908, and the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4966; (v) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912, and the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4970; (vi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920, and the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4978; (vii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924, and the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4982; (viiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4910; (ix) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4914; (x) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5054; (xi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4926; (xi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4930; (xiiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4934; (xiv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4938; (xv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4942; (xvi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5060; (xvii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4946; (xviiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4950; (xix) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4954; (xx) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4958; (xxi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4962; (xxii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5064; (xxiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4974; (xxiv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5066; (xxv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4986; (xxvi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4990; (xxvii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4994; (xxviiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4998; (xxix) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5002; (xxx) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5070; (xxxi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4908; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5006; (xxxii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4912; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5010; (xxxiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4916; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5014; (xxxiv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4920; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4958; (xxxv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 4924; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5022; (xxxvi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5057; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5074; (xxxvii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5077; (xxxviiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5084; (xxxix) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5088; (xl) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5092; (xli) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5096; (xlii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5080; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5098; (xliiii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5104; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5101; (xlv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5108; (xlv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5112; (xlvi) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5116; (xlviii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5120; (xlviii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5122; (xlix) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5125; (l) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5132; (i) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5136; (lii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5128; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of Sequence ID No. 5140; (liii) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5144; or (lv) The antisense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises at least 20 consecutive nucleotides from the nucleotide sequence of SEQ ID NO: 5146. AAV particle according to any one of claims 22 to 24.

26. (i) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908, and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4906; (ii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920, and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4918; (iii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924, and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4922; (iv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908, and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4966; (v) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912, and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4970; (vi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920, and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4978; (vii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924, and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4982; (viiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4910; (ix) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4914; (x) The antisense strand sequence comprises the nucleotide sequence of Sequence ID No. 5057; the sense strand sequence comprises the nucleotide sequence of Sequence ID No. 5054; (xi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4926; (xi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4930; (xiiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4934; (xiv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4938; (xv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4942; (xvi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5060; (xvii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4946; (xviiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4950; (xix) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4954; (xx) The antisense strand sequence comprises the nucleotide sequence of Sequence ID No. 4920; the sense strand sequence comprises the nucleotide sequence of Sequence ID No. 4958; (xxi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4962; (xxii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5064; (xxiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4974; (xxiv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5066; (xxv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4986; (xxvi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4990; (xxvii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4994; (xxviiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4998; (xxix) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5002; (xxx) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5070; (xxxi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5006; (xxxii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5010; (xxxiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5014; (xxxiv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xxxv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5022; (xxxvi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5074; (xxxvii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5077; (xxxviiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5084; (xxxix) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5088; (xl) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5092; (xli) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5096; (xlii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5098; (xliiii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5101; (xlv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5108; (xlv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5112; (xlvi) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5116; (xlviii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5120; (xlviii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5122; (xlix) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5125; (l) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5132; (i) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5136; (lii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5140; (liii) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5144; or (lv) The antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146. AAV particle according to any one of claims 22 to 25.

27. (i) The nucleotide sequence encoding the antisense strand sequence includes the nucleotide sequence of Sequence ID No. 4907, and the nucleotide sequence encoding the sense strand sequence includes the nucleotide sequence of Sequence ID No. 4905; (ii) The nucleotide sequence encoding the antisense strand sequence includes the nucleotide sequence of SEQ ID NO: 4919, and the nucleotide sequence encoding the sense strand sequence includes the nucleotide sequence of SEQ ID NO: 4917; (iii) The nucleotide sequence encoding the antisense strand sequence includes the nucleotide sequence of SEQ ID NO: 4923, and the nucleotide sequence encoding the sense strand sequence includes the nucleotide sequence of SEQ ID NO: 4921; (iv) The nucleotide sequence encoding the antisense strand sequence includes the nucleotide sequence of SEQ ID NO: 4907, and the nucleotide sequence encoding the sense strand sequence includes the nucleotide sequence of SEQ ID NO: 4965; (v) The nucleotide sequence encoding the antisense strand sequence includes the nucleotide sequence of SEQ ID NO: 4911, and the nucleotide sequence encoding the sense strand sequence includes the nucleotide sequence of SEQ ID NO: 4969; (vi) The nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919, and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4977; or (vii) The nucleotide sequence encoding the antisense strand sequence includes the nucleotide sequence of SEQ ID NO: 4923, and the nucleotide sequence encoding the sense strand sequence includes the nucleotide sequence of SEQ ID NO: 4981. AAV particle according to any one of claims 22 to 26.

28. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 3904; and (ii) A nucleic acid encoding a polynucleotide that targets human MAPT, wherein the encoded polynucleotide includes siRNA comprising a sense strand sequence and an antisense strand sequence, (a) The coded sense strand sequence includes sequence number 4906, and the coded antisense strand sequence includes sequence number 4908; (b) The coded sense strand sequence includes sequence number 4978, and the coded antisense strand sequence includes sequence number 4920; or (c) The coded sense strand sequence includes sequence number 4918, and the coded antisense strand sequence includes sequence number 4920. the nucleic acid AAV particles, including those mentioned above.

29. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 36; and (ii) A nucleic acid encoding a polynucleotide that targets human MAPT, wherein the encoded polynucleotide includes siRNA comprising a sense strand sequence and an antisense strand sequence, (a) The coded sense strand sequence includes sequence number 4906, and the coded antisense strand sequence includes sequence number 4908; (b) The coded sense strand sequence includes sequence number 4978, and the coded antisense strand sequence includes sequence number 4920; or (c) The coded sense strand sequence includes sequence number 4918, and the coded antisense strand sequence includes sequence number 4920. the nucleic acid AAV particles, including those mentioned above.

30. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 982; and (ii) A nucleic acid encoding a polynucleotide that targets human MAPT, wherein the encoded polynucleotide includes siRNA comprising a sense strand sequence and an antisense strand sequence, (a) The coded sense strand sequence includes sequence number 4906, and the coded antisense strand sequence includes sequence number 4908; (b) The coded sense strand sequence includes sequence number 4978, and the coded antisense strand sequence includes sequence number 4920; or (c) The coded sense strand sequence includes sequence number 4918, and the coded antisense strand sequence includes sequence number 4920. the nucleic acid AAV particles, including those mentioned above.

31. (i) The sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence each comprises at least 15 to 30, 19 to 21, or 25 to 30 nucleotides in length, for example, 17, 18, 20, 21, 22, 25, or 30 nucleotides in length; (ii) The sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence include one or two nucleotide overhangs, for example, an overhang at the 5' end of the sense strand sequence and / or at the 3' end of the antisense strand sequence. (iii) The sense chain and antisense chain include one mismatch; and / or (iv) The antisense strand and target sequence contain one mismatch, AAV particle according to any one of claims 22 to 30.

32. The AAV particle according to any one of claims 1 to 31, wherein the polynucleotide for inhibiting the MAPT (e.g., human MAPT) further comprises a regulatory polynucleotide, and the regulatory polynucleotide comprises siRNA.

33. The aforementioned regulatory polynucleotide is (i) 5' flanking region; (ii) Loop region; and (iii) 3' Flanking area The AAV particle according to claim 32, further comprising one, two, three or all of the above.

34. (A)(i) The 5' flanking region comprises any one nucleotide sequence from sequence numbers 4878 to 4886; a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to any of the nucleotide sequences from sequence numbers 4878 to 4886; or a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to any of the nucleotide sequences from sequence numbers 4878 to 4886; (ii) The loop region includes any nucleotide sequence of sequence numbers 4887 to 4896; a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to any nucleotide sequence of sequence numbers 4887 to 4896; or a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to any nucleotide sequence of sequence numbers 4887 to 4896; and / or (iii) The 3' flanking region comprises any one nucleotide sequence from sequence numbers 4897 to 4904; a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence having 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications compared to any of the nucleotide sequences from sequence numbers 4897 to 4904; or a nucleotide sequence having 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications compared to any of the nucleotide sequences from sequence numbers 4897 to 4904; and / or (B)(i) The nucleotide sequence encoding the 5' flanking region includes any of the nucleotide sequences of SEQ ID NOs. 5387, 4354, 4355 or 5390-5395, or any nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to any of the nucleotide sequences of SEQ ID NOs. 5387, 4354, 4355 or 5390-5395; or a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to any of the nucleotide sequences of SEQ ID NOs. 5387, 4354, 4355 or 5390-5395; (ii) The nucleotide sequence encoding the loop region includes any of the nucleotide sequences of SEQ ID NOs. 4362 to 4371; a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence that includes 1, 2, 3, or 4, but not more than 5, different nucleotides compared to any of the nucleotide sequences of SEQ ID NOs. 4362 to 4371; or a nucleotide sequence that includes 1, 2, 3, or 4, but not more than 5, modifications compared to any of the nucleotide sequences of SEQ ID NOs. 4362 to 4371; and / or (iii) The nucleotide sequence encoding the 3' flanking region includes any of the nucleotide sequences of SEQ ID NOs: 4372-4379; a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to any of the nucleotide sequences of SEQ ID NOs: 4372-4379; or a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to any of the nucleotide sequences of SEQ ID NOs: 4372-4379. AAV particle according to claim 33.

35. The aforementioned regulatory polynucleotide is (A)(i) a nucleotide sequence of sequence number 4879, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4879, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4879; or a 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4879; (ii) the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4887, a nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4887; or a loop region containing a nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4887; and (iii) A nucleotide sequence of sequence number 4898, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4898, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4898, or a 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of sequence number 4898; (B) (i) a nucleotide sequence of sequence number 4879, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4879, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4879; or a 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of sequence number 4879; (ii) the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4888, a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4888; or a loop region containing a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4888; and (iii) A nucleotide sequence of sequence number 4898, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4898, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4898, or a 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of sequence number 4898; (C)(i) a nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4879; or a 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4879; (ii) the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4887, a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4887; or a loop region containing a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4887; and (iii) A nucleotide sequence of sequence number 4899, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4899, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4899, or a 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of sequence number 4899; or (D)(i) A nucleotide sequence of sequence number 4880, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4880, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4880; or a 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of sequence number 4880; (ii) the nucleotide sequence of SEQ ID NO: 4891, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4891, a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4891; or a loop region containing a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4891; and (iii) A nucleotide sequence of sequence number 4900, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4900, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of sequence number 4900, or a 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to sequence number 4900 AAV particles according to any one of claims 32 to 34, including the AAV particles described in any one of claims 32 to 34.

36. The regulatory polynucleotide is arranged in the order 5' to 3': (i) the 5' flanking region, the sense strand arrangement, the loop region, the antisense strand arrangement, and the 3' flanking region; or (ii) The 5' flanking region, the antisense chain arrangement, the loop region, the sense chain arrangement, and the 3' flanking region AAV particles according to any one of claims 32 to 35, including the AAV particles described in any one of claims 32 to 35.

37. The regulatory polynucleotide is arranged in the order 5' to 3': (A)(i) Nucleotide sequence of SEQ ID NO: 4880; Nucleotide sequence identical to SEQ ID NO: 4880 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4880; or 5' flanking region containing nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4880; (ii) Sense strand sequence of sequence number 4906; (iii) Nucleotide sequence of sequence number 4891; Nucleotide sequence identical to sequence number 4891 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 different nucleotides compared to the nucleotide sequence of sequence number 4891; or Loop region containing nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 modifications compared to the nucleotide sequence of sequence number 4891; (iv) Antisense strand sequence of sequence number 4908; and (v) Nucleotide sequence of SEQ ID NO: 4900; Nucleotide sequence identical to SEQ ID NO: 4900 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4900; or 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to SEQ ID NO: 4900; (B) (i) Nucleotide sequence of SEQ ID NO: 4880; Nucleotide sequence identical to SEQ ID NO: 4880 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4880; or 5' flanking region containing nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4880; (ii) Sense chain sequence of sequence number 4918; (iii) Nucleotide sequence of sequence number 4891; Nucleotide sequence identical to sequence number 4891 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 different nucleotides compared to the nucleotide sequence of sequence number 4891; or Loop region containing nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 modifications compared to the nucleotide sequence of sequence number 4891; (iv) Antisense strand sequence of sequence number 4920; and (v) Nucleotide sequence of SEQ ID NO: 4900; Nucleotide sequence identical to SEQ ID NO: 4900 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4900; or 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to SEQ ID NO: 4900; (C)(i) Nucleotide sequence of SEQ ID NO: 4880; Nucleotide sequence identical to SEQ ID NO: 4880 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4880; or 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4880; (ii) Sense strand sequence of sequence number 4922; (iii) Nucleotide sequence of sequence number 4891; Nucleotide sequence identical to sequence number 4891 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 different nucleotides compared to the nucleotide sequence of sequence number 4891; or Loop region containing nucleotide sequence containing 1, 2, 3, or 4 but no more than 5 modifications compared to the nucleotide sequence of sequence number 4891; (iv) Antisense strand sequence of sequence number 4924; and (v) Nucleotide sequence of SEQ ID NO: 4900; Nucleotide sequence identical to SEQ ID NO: 4900 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4900; or 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to SEQ ID NO: 4900; (D)(i) The nucleotide sequence of SEQ ID NO: 4879; the nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879; the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4879; or the 5' flanking region containing the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4879; (ii) Sense strand sequence of sequence number 4966; (iii) The nucleotide sequence of sequence number 4888; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4888; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of sequence number 4888; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of sequence number 4888; (iv) Antisense strand sequence containing the nucleotide sequence of Sequence ID No. 4908; and (v) Sequence ID 4898; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to Sequence ID 4898; a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of Sequence ID 4898; the 3' flanking region of a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of Sequence ID 4898; (E)(i) The nucleotide sequence of SEQ ID NO: 4879; the nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879; the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4879; or the 5' flanking region containing the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4879; (ii) Sense strand sequence of sequence number 4970; (iii) The nucleotide sequence of sequence number 4888; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4888; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of sequence number 4888; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of sequence number 4888; (iv) Antisense strand sequence containing the nucleotide sequence of Sequence ID No. 4912; and (v) Sequence ID 4898; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to Sequence ID 4898; a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of Sequence ID 4898; the 3' flanking region of a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of Sequence ID 4898; (F)(i) The nucleotide sequence of SEQ ID NO: 4879, the nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4879; or the 5' flanking region containing the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4879; (ii) Sense strand sequence of sequence number 4978; (iii) The nucleotide sequence of sequence number 4888; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4888; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of sequence number 4888; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of sequence number 4888; (iv) Antisense strand sequence containing the nucleotide sequence of Sequence ID No. 4920; and (v) Sequence ID 4898, a nucleotide sequence identical to Sequence ID 4898 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%, of the nucleotide sequence of Sequence ID 4898, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of Sequence ID 4898, or the 3' flanking region of a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of Sequence ID 4898; or (G) (i) the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4879; or a 5' flanking region containing a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4879; (ii) Sense strand sequence of sequence number 4982; (iii) The nucleotide sequence of sequence number 4888; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4888; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of sequence number 4888; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of sequence number 4888; (iv) Antisense strand sequence containing the nucleotide sequence of Sequence ID No. 4924; and (v) nucleotide sequences identical to SEQ ID NO: 4898 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; nucleotide sequences containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4898; 3' flanking regions of nucleotide sequences containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4898 AAV particles according to any one of claims 32 to 36, including the AAV particles described in any one of claims 32 to 36.

38. The nucleotide sequence encoding the aforementioned regulatory polynucleotide is, in order from 5' to 3': (A)(i) Nucleotide sequence of SEQ ID NO: 4355; Nucleotide sequence identical to SEQ ID NO: 4355 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4355; or 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4355; (ii) Sense strand sequence of sequence number 4905; (iii) The nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4366; a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4366; or a loop region containing a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4366; (iv) Antisense strand sequence of sequence number 4907; and (v) Nucleotide sequence of SEQ ID NO: 4375; Nucleotide sequence identical to SEQ ID NO: 4375 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4375; or 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to SEQ ID NO: 4375; (B) (i) the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4355; a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4355; or a 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4355; (ii) Sense strand sequence of sequence number 4917; (iii) The nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4366; a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4366; or a loop region containing a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4366; (iv) Antisense strand sequence of sequence number 4919; and (v) Nucleotide sequence of SEQ ID NO: 4375; Nucleotide sequence identical to SEQ ID NO: 4375 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4375; or 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to SEQ ID NO: 4375; (C)(i) Nucleotide sequence of SEQ ID NO: 4355; Nucleotide sequence identical to SEQ ID NO: 4355 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4355; or 5' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4355; (ii) Sense strand sequence of sequence number 4921; (iii) The nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4366; a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4366; or a loop region containing a nucleotide sequence containing 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4366; (iv) Antisense strand sequence of sequence number 4923; and (v) Nucleotide sequence of SEQ ID NO: 4375; Nucleotide sequence identical to SEQ ID NO: 4375 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%; Nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4375; or 3' flanking region containing a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to SEQ ID NO: 4375; (D)(i) The nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4354; or a 5' flanking region containing a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4354; (ii) Sense strand sequence of sequence number 4965; (iii) The nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4363; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4363; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4363; (iv) Antisense strand sequence containing the nucleotide sequence of Sequence ID No. 4907; and (v) Sequence ID 4373, a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to Sequence ID 4373, a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of Sequence ID 4373, or the 3' flanking region of a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of Sequence ID 4373; (E)(i) The nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4354; or a 5' flanking region containing a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4354; (ii) Sense strand sequence of sequence number 4969; (iii) The nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4363; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4363; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4363; (iv) Antisense strand sequence containing the nucleotide sequence of sequence number 4911; and (v) Sequence ID 4373, a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to Sequence ID 4373, a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of Sequence ID 4373, or the 3' flanking region of a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of Sequence ID 4373; (F)(i) The nucleotide sequence of SEQ ID NO: 4354, the nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4354; or the 5' flanking region containing the nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4354; (ii) Sense strand sequence of sequence number 4977; (iii) The nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4363; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4363; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4363; (iv) Antisense strand sequence containing the nucleotide sequence of Sequence ID No. 4919; and (v) Sequence ID 4373, a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to Sequence ID 4373, a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of Sequence ID 4373, or the 3' flanking region of a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of Sequence ID 4373; or (G) (i) the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4354; or a 5' flanking region containing a nucleotide sequence that contains 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4354; (ii) Sense strand sequence of sequence number 4981; (iii) The nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4363; a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4363; or a loop region containing a nucleotide sequence that contains 1, 2, 3, or 4, but no more than 5, modifications compared to the nucleotide sequence of SEQ ID NO: 4363; (iv) Antisense strand sequence containing the nucleotide sequence of Sequence ID No. 4923; and (v) A nucleotide sequence identical to SEQ ID NO: 4373 by at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 4373; a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 different nucleotides compared to the nucleotide sequence of SEQ ID NO: 4373; the 3' flanking region of a nucleotide sequence containing 1, 2, 3, 4, 5, 6, or 7 but no more than 10 modifications compared to the nucleotide sequence of SEQ ID NO: 4373 AAV particles according to any one of claims 32 to 37, including the AAV particles described in any one of claims 32 to 37.

39. The AAV particle according to any one of claims 32 to 38, wherein the nucleotide sequence encoding the adjustable polynucleotide includes one of the nucleotide sequences of SEQ ID NOs: 4405, 4408, 4409, 4390, 4391, 4393, 4394, 4380-4389, 4392, 4395-4404, 4406, or 4407, or a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.

40. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 3904; and (ii) Nucleic acids encoding polynucleotides that target human MAPT, containing one of the nucleotide sequences of sequence numbers 4405, 4408, or 4393. AAV particles, including those mentioned above.

41. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 36; and (ii) Nucleic acids encoding polynucleotides that target human MAPT, containing one of the nucleotide sequences of sequence numbers 4405, 4408, or 4393. AAV particles, including those mentioned above.

42. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 982; and (ii) Nucleic acids encoding polynucleotides that target human MAPT, containing one of the nucleotide sequences of sequence numbers 4405, 4408, or 4393. AAV particles, including those mentioned above.

43. AAV particle according to any one of claims 1 to 42, comprising a viral genome including a promoter functionally linked to the nucleic acid encoding a polynucleotide for inhibiting the human MAPT.

44. The aforementioned promoter is (i) It is a ubiquitous promoter; (ii) A cell or tissue-specific promoter; (iii) Human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β-glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG-binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mG Selected from luR2), neurofilamentous light chain (NFL) or neurofilamentous heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk), and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), cardiovascular promoters (e.g., αMHC, cTnT, and CMV-MLC2k), liver promoters (e.g., hAAT, TBG), skeletal muscle promoters (e.g., desmin, MCK, C512) or their functional fragments, e.g., cleaved or functional variants; (iii) CBA promoter or a variant thereof; (iv) synapsin promoter or a variant thereof; (v) Any nucleotide sequence provided in Table 2; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to any one of the nucleotide sequences provided in Table 2; or a nucleotide sequence having at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity with any one of the nucleotide sequences provided in Table 2; (vi) The nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 5199; or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 5199; or (vii) The nucleotide sequence of SEQ ID NO: 3883; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 3883; or a nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 3883 AAV particle according to claim 43.

45. The aforementioned viral genome is (i) at least one or two terminal inverted repeat (ITR) sequences, wherein the AAV virus genome optionally comprises an ITR sequence located 5' relative to the regulatory polynucleotide or the nucleic acid encoding the siRNA and / or an ITR sequence located 3' relative to the regulatory polynucleotide or the nucleic acid encoding the siRNA; (ii) Polyadenylated (poly-A) signal sequence; (iii) Enhancer, Kozak sequence, intron region, and / or exon region; and / or (iv) A nucleotide sequence encoding a microRNA (miR) binding site, for example, a nucleotide sequence encoding a miR binding site that modulates, for example, reduces the expression of a payload encoded by the viral genome in cells or tissues expressing the corresponding miRNA, wherein the encoded miR binding site optionally modulates, for example, reduces the expression of the payload encoded by the viral genome in cells or tissues of DRG, liver, heart, hematopoietic lineage, or a combination thereof. AAV particles according to claim 43 or 44, further comprising:

46. (i) The ITR located at 5' with respect to the nucleic acid encoding the regulatory polynucleotide or the siRNA comprises the nucleotide sequence of SEQ ID NO: 5197 or 5503; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5197 or 5503; or a nucleotide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 5197 or 5503; (ii) The ITR located at 3' with respect to the nucleic acid encoding the regulatory polynucleotide or the siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 5504; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5200 or 5504; or a nucleotide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 5200 or 5504; (iii) The polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 4476; or a nucleotide sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 4476; (iv) The enhancer includes the CMVie enhancer or a variant thereof; (v) The enhancer comprises the nucleotide sequence of SEQ ID NO: 4471 or 4472; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471 or 4472; or a nucleotide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 4471 or 4472; and / or (vi) The intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 4475; or a nucleotide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 4475. AAV particle according to claim 45.

47. The AAV particle according to any one of claims 43 to 46, wherein the viral genome is self-complementary or single-stranded.

48. The aforementioned viral genome is in the order of 5' to 3': (A)(i) An ITR wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence with at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 5197; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modulopolynucleotide, wherein the nucleotide sequence includes one of sequence numbers 4380-4409 or 5027-5050, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is a nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (B)(i) An ITR wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence with at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 5197; (ii) A promoter comprising the nucleotide sequence of SEQ ID NO: 3883; at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10 modifications, e.g., substitutions, insertions, or deletions; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3883; (iii) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (iv) A nucleotide sequence encoding a regulatory polynucleotide, wherein the nucleotide sequence includes one of sequence numbers 4380-4409 or 5027-5050, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (v) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vi) ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions; or (C)(i) An ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4469; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 4469, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4472; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4472; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4472; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modulopolynucleotide, wherein the nucleotide sequence includes one of sequence numbers 4380-4409 or 5027-5050, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4470; or a nucleotide sequence that, compared to SEQ ID NO: 4470, includes at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions. AAV particles according to any one of claims 43 to 47, including the AAV particles described in any one of claims 43 to 47.

49. In the order of 5' to 3': (A)(i) An ITR wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence with at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 5197; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modifiable polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4405, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is a nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (B)(i) An ITR wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence with at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 5197; (ii) A promoter comprising the nucleotide sequence of SEQ ID NO: 3883; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 3883; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3883; (iii) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (iv) A nucleotide sequence encoding a regulatory polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4405, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (v) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vi) an ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions; (C)(i) An ITR, wherein the ITR is a nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5197, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modifiable polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4408, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is a nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (D)(i) An ITR wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5197, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modifiable polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4409, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is a nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (E)(i) An ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5197, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modifiable polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4390, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is a nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (F)(i) An ITR wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5197, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modifiable polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4391, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is a nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (G)(i) An ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5197, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modifiable polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4393, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or an ITR comprising a nucleotide sequence with at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions compared to SEQ ID NO: 5200; or (H)(i) An ITR wherein the ITR is the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or an ITR comprising a nucleotide sequence that, compared to SEQ ID NO: 5197, includes at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions; (ii) an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4471; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) A promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 5199; or a promoter comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4475; or an intron comprising a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) A nucleotide sequence encoding a modifiable polynucleotide, wherein the nucleotide sequence includes SEQ ID NO: 4394, or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) A polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions, compared to SEQ ID NO: 4476; or the polyA signal sequence comprising a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) ITR, wherein the ITR is the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence that, compared to SEQ ID NO: 5200, includes at least 1, 2, 3, 4, 5, 6, or 7, but no more than 10, modifications, e.g., substitutions, insertions, or deletions. AAV particles according to any one of claims 43 to 48, including the AAV particles described in any one of claims 43 to 48.

50. AAV particles according to any one of claims 43 to 49, comprising any one nucleotide sequence of sequence numbers 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194, 3886-3893, or 5473-5502, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to any one of sequence numbers 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194, or 5473-5502.

51. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 3904; and (ii) Viral genome containing the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, or 5184 AAV particles, including those mentioned above.

52. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 36; and (ii) Viral genome containing the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, or 5184 AAV particles, including those mentioned above.

53. (i) AAV capsid variants containing the amino acid sequence of SEQ ID NO: 982; and (ii) Viral genome containing the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, or 5184 AAV particles, including those mentioned above.

54. A cell comprising AAV particles according to any one of claims 1 to 53, wherein the cell is (a) Mammalian cells or insect cells; (b) Cells from the brain or spinal cord region (e.g., CNS cells); (c) Cells of the brain or spinal cord (e.g., cells of the putamen, caudate nucleus, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, lateral geniculate nucleus (LGN), cervical spinal cord, lumbar spinal cord, and / or thoracic spinal cord); or (d) Neurons or astrocytes The cells, including the cells.

55. A method for producing AAV particles according to any one of claims 1 to 53, (i) To provide host cells containing the AAV virus genome; (ii) Incubating the host cells under conditions suitable for encapsulating the viral genome in the AAV capsid protein. A method comprising, wherein, the AAV particles are produced.

56. A pharmaceutical composition comprising AAV particles according to any one of claims 1 to 53 and a pharmaceutically acceptable excipient.

57. A method for delivering siRNA to cells for inhibiting MAPT expression, comprising administering an effective amount of the pharmaceutical composition according to claim 56 or AAV particles according to any one of claims 1 to 53 to the cells, thereby delivering siRNA to the cells for inhibiting MAPT expression.

58. The aforementioned cells are (a) Mammalian cells or insect cells; (b) Cells from the brain or spinal cord region (e.g., CNS cells); (c) Cells of the brain or spinal cord (e.g., cells of the putamen, caudate nucleus, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, lateral geniculate nucleus (LGN), cervical spinal cord, lumbar spinal cord, and / or thoracic spinal cord); (d) Neurons or astrocytes; and / or (e) those in the subject The method according to claim 57.

59. The method according to claim 58, wherein the subject has or has been diagnosed with a hereditary disorder (e.g., monogenic disorder or polygenic disorder); a neurological disorder (e.g., neurodegenerative disorder); tau expression, e.g., a disorder associated with abnormal tau expression; and / or tauopathy.

60. A method for treating a subject having or diagnosed with a genetic disorder (e.g., monogenic or polygenic disorder); a neurological disorder (e.g., neurodegenerative disorder); tau expression, e.g., a disorder associated with abnormal tau expression; and / or tauopathy, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 56 or AAV particles according to any one of claims 1 to 53.

61. The method according to claim 59 or 60, wherein the hereditary disorder, the neurological disorder (e.g., neurodegenerative disorder), the disorder associated with tau expression (e.g., abnormal tau expression), and / or the tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome (DS), neurodegenerative disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion disease, CJD, multiple system atrophy, mild cognitive impairment, entangled dementia, or progressive subcortical gliosis.

62. The method according to claim 60 or 61, wherein the treatment includes preventing the progression of the hereditary disorder, the neurological disorder (e.g., neurodegenerative disorder), the tau expression (e.g., abnormal tau expression) in the subject, and / or the progression of the tauopathy.

63. The method according to any one of claims 60 to 62, further comprising performing a blood test, an imaging test (e.g., a PET scan or a biomarker, e.g., a PET scan combined with serum biomarker staining), a CNS biopsy sample, or an aqueous cerebrospinal fluid biopsy, wherein the blood test, the imaging test, the biopsy sample, or the aqueous cerebrospinal fluid biopsy is optionally performed before, during, or after the treatment with the AAV particles, the regulatory polynucleotide, the siRNA, or the pharmaceutical composition.

64. The pharmaceutical composition or the AAV particles are used in the target. (i) intravenously, via intracisional injection (ICM), intracerebral, intrathecal, intraventricular, intraparenchymal, or intramuscular; (ii) via focused ultrasound (FUS), for example, focused ultrasound-MB combined with intravenous administration of microbubbles, or via MRI-guided FUS combined with intravenous administration; (iii) In the vein The method according to any one of claims 60 to 63, which is administered.

65. A pharmaceutical composition according to claim 56 or an AAV particle according to any one of claims 1 to 53, for use in a method of delivering siRNA to cells to inhibit MAPT expression.

66. A pharmaceutical composition according to claim 56 or AAV particles according to any one of claims 1 to 53 for use in the treatment of hereditary disorders, neurological disorders (e.g., neurodegenerative disorders), disorders related to tau expression (e.g., abnormal tau expression), and / or tauopathy.

67. Use of the pharmaceutical composition according to claim 56 or the AAV particles according to any one of claims 1 to 53 in the manufacture of a drug for delivering siRNA to cells to inhibit MAPT expression.

68. Use of the pharmaceutical composition according to claim 56 or the AAV particles according to any one of claims 1 to 53 in the manufacture of a drug for treating hereditary disorders, neurological disorders (e.g., neurodegenerative disorders), disorders related to tau expression (e.g., abnormal tau expression), and / or tauopathy.

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