Compositions and methods for regulating mapt

Abstract

The disclosure relates to small interfering RNA (siRNA) molecules targeting MAPT and adeno-associated viral (AAV) particles encoding the same for treating tauopathies.

Description

COMPOSITIONS AND METHODS FOR REGULATING MAPTRELATED APPLICATIONS

[0001] The application claims priority to U.S. Provisional Application No. 63 / 499,636 filed on May 2, 2023, U.S. Provisional Application No. 63 / 593,735 filed on October 27, 2023, U.S. Provisional Application No. 63 / 615,689 filed on December 28, 2023, and U.S. Provisional Application No. 63 / 564,249 filed on March 12, 2024; the entire contents of each of which are hereby incorporated by reference in their entirety.SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing file, entitled V2071-301 lPCT_SL.xml, was created on April 11 , 2024, and is 5,686,373 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE

[0003] The present disclosure relates generally to compositions, methods, and use of AAV capsid proteins and variants thereof for vectorized delivery of an agent, e.g., an RNA agent, that that inhibits a mutant, variant, or wild type human microtubule-associated protein tau (MAPT) gene, mRNA, and / or protein.BACKGROUND

[0004] Tauopathies, which may also be referred to herein as tau-associated diseases, are a heterogeneous group of neurodegenerative diseases characterized by the dysfunction and / or aggregation of the microtubule- associated protein tau (MAPT) which may also be referred to as Tau herein, which is encoded by the MAPT gene. Tau is normally a very soluble protein known to associate with microtubules based on the extent of its phosphorylation. In tauopathies, tau becomes hyperphosphorylated, misfolds and aggregates as neurofibrillary tangles (NFT) of paired helical filaments (PHF), twisted ribbons or straight filaments. These NFT are largely considered indicative of impending neuronal cell degeneration which can contribute to widespread neuronal cell loss, leading to a variety of behavioral and cognitive deficits, and can also be fatal. Currently, very limited treatment options are available for tauopathies, often with only symptomatic relief and supportive therapies available. As such, there is a medical need for improved compositions and methods of prevention, treatment, and diagnosis for diseases associated with aberrant tau expression, including tauopathies and related neurodegenerative disorders.SUMMARY

[0005] The present disclosure provides AAV particles comprising an AAV capsid variant encoding an agent for targeting MAPT, e.g., an RNA agent to modulate, e.g., inhibit, MAPT gene expression and / or MAPT protein production and methods of use thereof. In some embodiments, the agent for targeting MAPT, e.g., a MAPT gene, mRNA, or protein (e.g., a tau protein) is an RNA agent for targeting MAPT, e.g., a siRNA duplex for targeting MAPT. In some embodiments, the agent for targeting MAPT comprises amodulatory polynucleotide encoding a siRNA duplex for targeting MAPT. Methods for treating diseases associated MAPT expression, e.g., aberrant expression, such as tauopathies, including but not limited to Alzheimer’s disease (AD), frontotemporal dementia (FTD), and / or Dravet syndrome (DS) in a subject in need thereof.

[0006] Accordingly, in one aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises the amino acid sequence of SPH; and (iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid, e.g., a K or R. In some embodiments, position X4 of [N3] is K. In some embodiments, position X5 of [N3] is K. In some embodiments, [N3] is or comprises SKA. In some embodiments [N3] is or comprises KSG. In some embodiments, [N2]-[N3] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138, 981 or 982. In some embodiments, [N1] is present immediately subsequent to position 452, relative to a 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), relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises 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 comprises S at position 454 and G at position 455, numbered according to SEQ ID NO: 138 or 981. In some embodiments, an insert of 8 amino acids replaces the SG at positions 454-455, numbered according to SEQ ID NO: 138. In some embodiments, an insert of 6 amino acids is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138, 981, or 982.

[0007] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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, wherein position X2 is S and position X3 is G; (ii) [N2] comprises the amino acid sequence SPH; and (iii) [N3] comprises positions X4, X5, and X6, wherein position X5 is K. In some embodiments, [N1]-[N2]-[N3] is present immediately subsequent to position 452 and replaces positions 453- 455, numbered according to SEQ ID NO: 138 or 982. In some embodiments, [N1]-[N2]-[N3] is or comprises GSGSPHSKA (SEQ ID NO: 60).

[0008] In another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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, wherein position X2 is an amino acid other than S and position X3 is an amino acid other than G; (ii) [N2] comprises the amino acid sequence SPH; and (iii) [N3] comprises positions X4, X5, and X6, wherein position X4 is K. In some embodiments, [N1]-[N2]-[N3] is present immediately subsequent to position 452 and replaces positions 453-455, numbered according to SEQ ID NO: 138 or 982. In some embodiments, [N1]-[N2]-[N3] is or comprises GHDSPHKSG (SEQ ID NO: 62).

[0009] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting 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, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises the amino acid sequence of SPH; and (iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid, e.g., a K or R; wherein [N1]-[N2]-[N3] is present in hypervariable loop IV; and wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO: 138.

[0010] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting 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 of positions 203-736 of SEQ ID NO: 138.

[0011] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting 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 of positions 203-736 of SEQ ID NO: 138.

[0012] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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) in hypervariable loop IV. In some embodiments, 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 present immediately subsequent to position 455, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid E at position 451, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the 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); the amino acid E at position 451, numbered according to SEQ ID NO: 981; and the amino acid V at position 453, numbered according to SEQ ID NO: 3094 or 981.

[0013] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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) in hypervariable loop IV. In some embodiments, 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 present immediately subsequent to position 455, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid E at position 451, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid R at position 452, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the 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); the amino acid E at position 451, numbered according to SEQ ID NO: 981; the amino acid R at position 452, numbered according to SEQ ID NO: 981; and the amino acid V at position 453, numbered according to SEQ ID NO: 36 or 981.

[0014] In yet another aspect, the present disclosure provides 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 a 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 present disclosure provides 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 a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908.

[0016] In yet another aspect, the present disclosure provides 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 a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein: (a) the encoded sense strand sequencecomprises 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 present disclosure provides 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 a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908.

[0018] In yet another aspect, the present disclosure provides 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 a 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 present disclosure provides 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 a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908.

[0020] In yet another aspect, the present disclosure provides 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 a 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 present disclosure provides 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 a siRNA comprisinga sense strand sequence and an antisense strand sequence, wherein the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908.

[0022] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0023] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of SEQ ID NO: 4405.

[0024] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0025] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of SEQ ID NO: 4405.

[0026] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0027] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of SEQ ID NO: 4405.

[0028] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0029] In yet another aspect, the present disclosure provides 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 comprising the nucleotide sequence of SEQ ID NO: 4405.

[0030] In yet another aspect, the present 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 any one of SEQ ID NOs: 5173, 5195, 5184, or 3886.

[0031] In yet another aspect, the present 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 present 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 aspect, the present 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 any one of SEQ ID NOs: 5173, 5195, 5184, or 3886.

[0034] In yet another aspect, the present 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 aspect, the present 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 present 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 any one of SEQ ID NOs: 5173, 5195, 5184, or 3886.

[0037] In yet another aspect, the present 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 present 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 present 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 any one of SEQ ID NOs: 5173, 5195, 5184, or 3886.

[0040] In yet another aspect, the present 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 aspect, the present 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 provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule- associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises (a) the amino acid sequence of any of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, consecutive amino acids from any one of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30; (c) an amino acid sequence comprising at least one, two, or three, but no more than four different amino acids, relative to any one of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30; or (d) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30. In some embodiments, the amino acid sequence is present in loop IV. In some embodiments, the amino acid sequence is present immediately subsequent to position 448, 452, 453, 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0043] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule- associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises (a) the 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 one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 945-980 or 985-986; (d) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 945-980 or 985-986. In some embodiments, the amino acid sequence is present in loop IV. In some embodiments, the amino acid sequence is present immediately subsequent to position 448, 452, 453, 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

[0044] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule- associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises (a) the amino acid sequence of any of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; (c) an amino acid sequence comprising at least one, two, or three, but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; or (d) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservativesubstitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909. In some embodiments, the amino acid sequence is present in loop IV. In some embodiments, the amino acid sequence is present immediately subsequent to position 448, 452, 453, 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.

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

[0046] In yet another aspect, present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0047] In yet another aspect, present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 981.

[0048] In yet another aspect, present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0049] In yet another aspect, present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 982.

[0050] In yet another aspect, present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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 ofSPHSKA (SEQ ID NO: 941), wherein: (i) the at least 3 consecutive amino acids comprise SPH; (ii) the at least 4 consecutive amino acids comprise SPHS (SEQ ID NO: 63); (iii) the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 64); or (iv) the at least 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). In some embodiments, the amino acid sequence is present immediately subsequent to positions 455, numbered according to SEQ ID NO: 138 or 981.

[0051] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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 relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). In some embodiments, the amino acid sequence is present immediately subsequent to positions 455, numbered according to SEQ ID NO: 138 or 981.

[0052] In another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein: (i) the at least 3 consecutive amino acids comprise HDS; (ii) the at least 4 consecutive amino acids comprise HDSP (SEQ ID NO: 65); (iii) the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 66); and / or (iv) the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982; (c) a 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 with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). Insome embodiments, the amino acid sequence is present immediately subsequent to positions 453, numbered according to SEQ ID NO: 138 or 982.

[0053] In another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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 relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). In some embodiments, the amino acid sequence is present immediately subsequent to positions 453, numbered according to SEQ ID NO: 138 or 982.

[0054] In accordance with some aspects of the present disclosure, the short interfering ribonucleic acid (siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) comprises a sense strand sequence and an antisense strand sequence, wherein the antisense sequence is complementary to at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides comprising 0, 1, 2, or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3A or 19. In some embodiments, the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 4A, 5A, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Tables 4A, 5A, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides. In some embodiments, the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides from any one of the antisense strand sequences provided in Tables 4A, 5A, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides from any one of the sense strand sequences provided in Tables 4A, 5A, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides. In some embodiments, the antisense strand sequence comprises nucleotide sequence of any one of the antisense strand sequences provided in Tables 4A, 5A, 9A, or 9B; and the sense strand sequence comprises the nucleotide sequence of any one of the sense strand sequences provided in Tables 4A, 5A, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.

[0055] In accordance with some aspects of the present disclosure, the encoded polynucleotide for inhibiting expression of MAPT (e.g., human MAPT) comprises an siRNA comprising a sense strand sequence and an antisense strand sequence. In some embodiments, the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 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, 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; wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.

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

[0057] In another aspect, the present disclosure provides an AAV particle comprising a promoter operably linked a nucleic acid encoding a modulatory polynucleotide comprising an siRNA for targeting MAPT described herein.

[0058] In another aspect, the present disclosure provides a method of making an AAV particle comprising an AAV capsid protein, e.g., an AAV capsid variant, encoding an siRNA for targeting MAPT described herein. In some embodiments, the method comprises providing a host cell comprising a viral genome encoding an siRNA described herein and incubating the host cell under conditions suitable to enclose the viral genome in the AAV capsid protein, e.g., an AAV capsid variant, thereby making the AAV particle.

[0059] In yet another aspect, the present disclosure provides a method of delivering an siRNA for inhibiting MAPT to a cell. In some embodiments, the method comprises administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.

[0060] In yet another aspect, the present disclosure provides, a method of treating a subject having or diagnosed with having a genetic disorder e.g., a monogenic disorder or a polygenic disorder. In some embodiments, the method comprises administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.

[0061] In yet another aspect, the present disclosure provides, a method of treating a subject having or diagnosed with having a neurological disorder e.g., a neurodegenerative disorder. The method comprising administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.

[0062] In yet another aspect, the present disclosure provides, a method of treating a subject having or diagnosed with having a disorder associated with tau expression, e.g., aberrant tau expression. The methodcomprising administering an effective amount of an siRNA or an AAV particle comprising an AAV capsid variant described herein encoding an siRNA described herein.

[0063] In yet another aspect, the present disclosure provides, a method of treating a subject having or diagnosed with a tauopathy. The method comprising administering an effective amount of an siRNA or an AAV particle comprising an AAV capsid variant described herein encoding an siRNA described herein.

[0064] In some embodiments, the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy is Alzheimer’s disease (AD), Frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism linked to 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’s syndrome, Pick’s disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), Prion diseases, CJD, Multiple system atrophy, mild cognitive impairment, Tangle-only dementia, or Progressive subcortical gliosis.

[0065] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following enumerated embodiments. Enumerated Embodiments 1. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises the amino acid sequence of SPH; and (iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid, e.g., a K or R. 2. The AAV particle of embodiment 1, wherein X4, X5, or both of [N3] is a K. 3. The AAV particle of embodiment 1 or 2, wherein X4, X5, or X6 of [N3] is an R. 4. The AAV particle of any one of embodiments 1-3, wherein: (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;optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 5. The AAV particle of any one of embodiments 1-4, wherein [N3] comprises SK, KA, KS, AR, RM, VK, AS, SR, VK, KR, KK, KN, VR, RS, RK, KT, TS, KF, FG, KI, IG, KL, LG, TT, TY, KY, YG, KD, KP, TR, RG, VR, GA, SL, SS, FL, WK, SA, RA, LR, KW, RR, GK, TK, NK, AK, KV, KG, KH, KM, TG, SE, SV, SW, SN, HG, SQ, LW, MG, MA, or SG. 6. The AAV particle of any one of embodiments 1-5, wherein [N3] is or comprises SKA, KSG, ARM, VKS, ASR, VKI, KKN, VRM, RKA, KTS, KFG, KIG, KLG, KTT, KTY, KYG, SKD, SKP, TRG, VRG, KRG, GAR, KSA, KSR, SKL, SRA, SKR, SLR, SRG, SSR, FLR, SKW, SKS, WKA, VRR, SKV, SKT, SKG, GKA, TKA, NKA, SKL, SKN, AKA, KTG, KSL, KSE, KSV, KSW, KSN, KHG, KSQ, KSK, KLW, WKG, KMG, KMA, or RSG. 7. The AAV particle of any one of embodiments 1-6, wherein [N2]-[N3] comprises SPHSK (SEQ ID NO: 64), SPHKS (SEQ ID NO: 67), SPHAR (SEQ ID NO: 68), SPHVK (SEQ ID NO: 69), SPHAS (SEQ ID NO: 70), SPHKK (SEQ ID NO: 71), SPHVR (SEQ ID NO: 72), SPHRK (SEQ ID NO: 73), SPHKT (SEQ ID NO: 74), SPHKF (SEQ ID NO: 75), SPHKI (SEQ ID NO: 76), SPHKL (SEQ ID NO: 77), SPHKY (SEQ ID NO: 78), SPHTR (SEQ ID NO: 79), SPHKR (SEQ ID NO: 80), SPHGA (SEQ ID NO: 81), SPHSR (SEQ ID NO: 82), SPHSL (SEQ ID NO: 83), SPHSS (SEQ ID NO: 84), SPHFL (SEQ ID NO: 85), SPHWK (SEQ ID NO: 86), SPHGK (SEQ ID NO: 87), SPHTK (SEQ ID NO: 88), SPHNK (SEQ ID NO: 89), SPHAK (SEQ ID NO: 90), SPHKH (SEQ ID NO: 91), SPHKM (SEQ ID NO: 92), or SPHRS (SEQ ID NO: 93). 8. The AAV particle of any one of embodiments 1-7, wherein [N2]-[N3] is or comprises: (i) SPHSKA (SEQ ID NO: 941), SPHKSG (SEQ ID NO: 946), SPHARM (SEQ ID NO: 947), SPHVKS (SEQ ID NO: 948), SPHASR (SEQ ID NO: 949), SPHVKI (SEQ ID NO: 950), SPHKKN (SEQ ID NO: 954), SPHVRM (SEQ ID NO: 955), SPHRKA (SEQ ID NO: 956), SPHKFG (SEQ ID NO: 957), SPHKIG (SEQ ID NO: 958), SPHKLG (SEQ ID NO: 959), SPHKTS (SEQ ID NO: 963), SPHKTT (SEQ ID NO: 964), SPHKTY (SEQ ID NO: 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: 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 (SEQ ID NO: 103), 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); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 9. The AAV particle of any one of embodiments 1-8, wherein the AAV capsid variant 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 a G at position 455 (e.g., C, L, D, E, Y, H, V, A, N, P, or S), numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981 or 982. 10. The AAV particle of any one of embodiments 1-8, wherein the AAV capsid variant comprises the amino acid G at position 453, the amino acid S at position 454, and the amino acid G at position 455, numbered according to SEQ ID NO: 138 or 981. 11. The AAV particle of any one of embodiments 1-9, wherein the AAV capsid variant comprises the amino acid G at position 453, the amino acid H at position 454, and the amino acid D at position 455, numbered according to SEQ ID NO: 138 or 982. 12. The AAV particle of any one of embodiments 1-11, wherein [N1] comprises X1, X2, and X3, wherein at least one of X1, X2, or X3 is G. 13. The AAV particle of any one of embodiments 1-12, wherein: (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; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 14. The AAV particle of any one of embodiments 1-13, wherein [N1] comprises GS, SG, GH, HD, GQ, QD, VS, CS, GR, RG, QS, SH, MS, RN, TS, IS, GP, ES, SS, GN, AS, NS, LS, GG, KS, GT, PS, RS, GI, WS, DS, ID, GL, DA, DG, ME, EN, KN, KE, AI, NG, PG, TG, SV, IG, LG, AG, EG, SA, YD, HE, HG, RD, ND, PD, MG, QV, DD, HN, HP, GY, GM, GD, or HS. 15. The AAV particle of any one of embodiments 1-14, wherein [N1] is or comprises GSG, GHD, GQD, VSG, CSG, GRG, CSH, GQS, GSH, RVG, GSC, GLL, GDD, GHE, GNY, MSG, RNG, TSG, ISG, GPG, ESG, SSG, GNG, ASG, NSG, LSG, GGG, KSG, HSG, GTG, PSG, GSV, RSG, GIG, WSG, DSG, IDG, GLG, DAG, DGG, MEG, ENG, GSA, KNG, KEG, AIG, GYD, GHG, GRD, GND, GPD, GMG, GQV, GHN, GHP, or GHS. 16. The AAV particle of any one of embodiments 1-15, wherein [N1]-[N2] comprises (i) SGSPH (SEQ ID NO: 116), HDSPH (SEQ ID NO: 66), VGSPH (SEQ ID NO: 124), QDSPH (SEQ ID NO: 117), RGSPH (SEQ ID NO: 118), SHSPH (SEQ ID NO: 119), QSSPH (SEQ ID NO: 120), DDSPH (SEQ ID NO: 121), HESPH (SEQ ID NO: 122), NYSPH (SEQ ID NO: 123), SCSPH (SEQ ID NO: 125), LLSPH (SEQ ID NO: 126), NGSPH (SEQ ID NO: 127), PGSPH (SEQ ID NO: 128), GGSPH (SEQ ID NO: 129), TGSPH (SEQ ID NO: 130), SVSPH (SEQ ID NO: 131), IGSPH (SEQ ID NO: 132), DGSPH (SEQ ID NO: 133), LGSPH (SEQ ID NO: 134), AGSPH (SEQ ID NO: 135), EGSPH (SEQ ID NO: 136), SASPH (SEQ ID NO: 139), YDSPH (SEQ ID NO: 140), HGSPH (SEQ ID NO: 141), RDSPH (SEQ ID NO: 142), NDSPH (SEQ ID NO: 143), PDSPH (SEQ ID NO: 144), MGSPH (SEQ ID NO: 145), QVSPH (SEQ ID NO: 146), HNSPH (SEQ ID NO: 147), HPSPH (SEQ ID NO: 148), or HSSPH (SEQ ID NO: 149); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).17. The AAV particle of any one of embodiments 1-16, wherein [N1]-[N2] is or comprises: (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 (SEQ ID NO: 164), MSGSPH (SEQ ID NO: 165), RNGSPH (SEQ ID NO: 166), TSGSPH (SEQ ID NO: 167), ISGSPH (SEQ ID NO: 168), GPGSPH (SEQ ID NO: 169), ESGSPH (SEQ ID NO: 170), SSGSPH (SEQ ID NO: 171), GNGSPH (SEQ ID NO: 172), ASGSPH (SEQ ID NO: 173), NSGSPH (SEQ ID NO: 174), LSGSPH (SEQ ID NO: 175), GGGSPH (SEQ ID NO: 176), KSGSPH (SEQ ID NO: 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), GSASPH (SEQ ID NO: 192), KNGSPH (SEQ ID NO: 193), KEGSPH (SEQ ID NO: 194), AIGSPH (SEQ ID NO: 195), GYDSPH (SEQ ID NO: 196), GHGSPH (SEQ ID NO: 197), GRDSPH (SEQ ID NO: 198), GNDSPH (SEQ ID NO: 199), GPDSPH (SEQ ID NO: 989), GMGSPH (SEQ ID NO: 992), GQVSPH (SEQ ID NO: 993), GHNSPH (SEQ ID NO: 994), GHPSPH (SEQ ID NO: 997), or GHSSPH (SEQ ID NO: 1008); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 18. The AAV particle of any one of embodiments 1-17, wherein [N1]-[N2]-[N3] comprises: (i) SGSPHSK (SEQ ID NO: 1009), HDSPHKS (SEQ ID NO: 1010), VGSPHSK (SEQ ID NO: 1037), SGSPHAR (SEQ ID NO: 1011), SGSPHVK (SEQ ID NO: 1012), QDSPHKS (SEQ ID NO: 1013), SGSPHKK (SEQ ID NO: 1014), SGSPHVR (SEQ ID NO: 1015), SGSPHAS (SEQ ID NO: 1016), SGSPHRK (SEQ ID NO: 1017), SGSPHKT (SEQ ID NO: 1018), SHSPHKS (SEQ ID NO: 1019), QSSPHRS (SEQ ID NO: 1020), RGSPHAS (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), LGSPHSK (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 (SEQ ID NO: 1064), MGSPHSK (SEQ ID NO: 1065), HDSPHKH (SEQ ID NO: 1066), QVSPHKS (SEQ ID NO: 1067), HNSPHKS (SEQ ID NO: 1068), NGSPHKR (SEQ ID NO: 1069), HDSPHKY (SEQ ID NO: 1070), NDSPHKI (SEQ ID NO: 1071), HDSPHKL (SEQ ID NO: 1072), HPSPHWK (SEQ ID NO: 1073), HDSPHKM (SEQ ID NO: 1074), or HSSPHRS (SEQ ID NO: 1075); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 19. The AAV particle of any one of embodiments 1-18, wherein [N1]-[N2]-[N3] is or comprises: (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 IDNO: 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), GSGSPHSRA (SEQ ID NO: 1114), GSGSPHSKR (SEQ ID NO: 1115), GSGSPHSLR (SEQ ID NO: 1116), GSGSPHSRG (SEQ ID NO: 1117), GSGSPHSSR (SEQ ID NO: 1118), RVGSPHSKA (SEQ ID NO: 1119), GSCSPHRKA (SEQ ID NO: 1120), GSGSPHFLR (SEQ ID NO: 1121), GSGSPHSKW (SEQ ID NO: 1122), GSGSPHSKS (SEQ ID NO: 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: 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);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 20. The AAV particle of any one of embodiments 1-19, wherein [N3] comprises SK, KA, KS, or SG. 21. The AAV particle of any one of embodiments 1-20, wherein [N3] is or comprises SKA, KSG, or KYG. 22. The AAV particle of any one of embodiments 1-21, wherein [N2]-[N3] comprises SPHSK (SEQ ID NO: 64), SPHKS (SEQ ID NO: 67), or SPHKY (SEQ ID NO: 78). 23. The AAV particle of any one of embodiments 1-22, wherein [N2]-[N3] is or comprises SPHSKA (SEQ ID NO: 941). 24. The AAV particle of any one of embodiments 1-22, wherein [N2]-[N3] is or comprises SPHKSG (SEQ ID NO: 946). 25. The AAV particle of any one of embodiments 1-22, wherein [N2]-[N3] is or comprises SPHKYG (SEQ ID NO: 966). 26. The AAV particle of any one of embodiments 1-25, wherein [N1] comprises GS, SG, GH, or HD. 27. The AAV particle of any one of embodiments 1-26, wherein [N1] is or comprises GSG. 28. The AAV particle of any one of embodiments 1-26, wherein [N1] is or comprises GHD. 29. The AAV particle of any one of embodiments 1-23 or 26-27, wherein [N1]-[N2]-[N3] comprises SGSPHSK (SEQ ID NO: 1009).30. The AAV particle of any one of embodiments 1-22, 24, 26, or 28, wherein [N1]-[N2]-[N3] comprises HDSPHKS (SEQ ID NO: 1010). 31. The AAV particle of any one of embodiments 1-22 or 25-27, wherein [N1]-[N2]-[N3] comprises SGSPHKYG (SEQ ID NO: 1197). 32. The AAV particle of any one of embodiments 1-8, 10, 12-23, 26-27, or 29, wherein [N1]-[N2]-[N3] is or comprises GSGSPHSKA (SEQ ID NO: 60). 33. The AAV particle of any one of embodiments 1-9, 11-22, 24, 26, 28, or 30, wherein [N1]-[N2]-[N3] is or comprises GHDSPHKSG (SEQ ID NO: 62). 34. The AAV particle of any one of embodiments 1-8, 10, 12-22, 25-27, or 31, wherein [N1]-[N2]-[N3] is or comprises GSGSPHKYG (SEQ ID NO: 1097). 35. The AAV particle of any one of embodiments 1-34, wherein [N1]-[N2]-[N3] replaces positions 453-455, numbered according to the amino acid sequence of SEQ ID NO: 138. 36. The AAV particle of any one of embodiments 1-35, wherein the AAV capsid variant comprises 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), relative to a reference sequence numbered according to SEQ ID NO: 138. 37. The AAV particle of any one of embodiments 1-36, wherein the AAV capsid variant comprises an amino acid other than Q at position 462 (e.g., W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F), an amino acid other than N at position 463 (e.g., Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, 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), relative to a reference sequence numbered according to SEQ ID NO: 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57. 38. The AAV particle of any one of embodiments 1-37, wherein the AAV capsid variant comprises:(a) the amino acid Q at position 456, the amino acid N at position 457, the amino acid Q at position 458, and / or the amino acid Q at position 459, relative to a reference sequence numbered according to SEQ ID NO: 138; or (b) the amino acid Q at position 462, the amino acid N at position 463, the amino acid Q at position 464, and / or the amino acid Q at position 465, relative to a reference sequence numbered according to SEQ ID NO: 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57. 39. The AAV particle of any one of embodiments 1-38, wherein the AAV capsid variant further comprises [N4], wherein [N4] comprises X7 X8 X9 X10, and wherein: (a) position X7 is: Q, W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F; (b) position X8 is: N, Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, I, M, Q, or L; (c) position X9 is: Q, G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y; and (d) position X10 is: Q, H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(d). 40. The AAV particle of embodiment 39, wherein: (a) position X7 of [N4] is Q or R; (b) position X8 of [N4] is N or R; (c) position X9 of [N4] is Q or R; and (d) position X10 of [N4] is Q, L, or R. 41. The AAV particle of embodiment 39 or 40, wherein [N4] is or comprises: (i) QNQQ (SEQ ID NO: 1198), WNQQ (SEQ ID NO: 1199), QYYV (SEQ ID NO: 1200), RRQQ (SEQ ID NO: 1201), GCGQ (SEQ ID NO: 1202), LRQQ (SEQ ID NO: 1203), RNQQ (SEQ ID NO: 1204), VNQQ (SEQ ID NO: 1205), FRLQ (SEQ ID NO: 1206), FNQQ (SEQ ID NO: 1207), LLQQ (SEQ ID NO: 1208), SNQQ (SEQ ID NO: 1209), RLQQ (SEQ ID NO: 1210), LNQQ (SEQ ID NO: 1211), QRKL (SEQ ID NO: 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 (SEQ ID NO: 1230), QNTH (SEQ ID NO: 1231), RRRQ (SEQ ID NO: 1232), QYQQ (SEQ ID NO: 1233), QNDQ (SEQ ID NO: 1234), QNRH (SEQ ID NO: 1235), RDQQ (SEQ ID NO: 1236), PNLQ (SEQ ID NO: 1237), HVRQ (SEQ ID NO: 1238), PNQH (SEQID NO: 1239), HNQQ (SEQ ID NO: 1240), QSQQ (SEQ ID NO: 1241), QPAK (SEQ ID NO: 1242), QNLA (SEQ ID NO: 1243), QNQL (SEQ ID NO: 1244), QGQQ (SEQ ID NO: 1245), LNRQ (SEQ ID NO: 1246), QNPP (SEQ ID NO: 1247), QNLQ (SEQ ID NO: 1248), QDQE (SEQ ID NO: 1249), QDQQ (SEQ ID NO: 1250), HWQQ (SEQ ID NO: 1251), PNQQ (SEQ ID NO: 1252), PEQQ (SEQ ID NO: 1253), QRTM (SEQ ID NO: 1254), LHQH (SEQ ID NO: 1255), QHRI (SEQ ID NO: 1256), QYIH (SEQ ID NO: 1257), QKFE (SEQ ID NO: 1258), QFPS (SEQ ID NO: 1259), QNPL (SEQ ID NO: 1260), QAIK (SEQ ID NO: 1261), QNRQ (SEQ ID NO: 1263), QYQH (SEQ ID NO: 1264), QNPQ (SEQ ID NO: 1265), QHQL (SEQ ID NO: 1266), QSPP (SEQ ID NO: 1267), QAKL (SEQ ID NO: 1268), KSQQ (SEQ ID NO: 1269), QDRP (SEQ ID NO: 1270), QNLG (SEQ ID NO: 1271), QAFH (SEQ ID NO: 1272), QNAQ (SEQ ID NO: 1273), HNQL (SEQ ID NO: 1274), QKLN (SEQ ID NO: 1275), QNVQ (SEQ ID NO: 1276), QAQQ (SEQ ID NO: 1277), QTPP (SEQ ID NO: 1278), QPPA (SEQ ID NO: 1279), QERP (SEQ ID NO: 1280), QDLQ (SEQ ID NO: 1281), QAMH (SEQ ID NO: 1282), QHPS (SEQ ID NO: 1283), PGLQ (SEQ ID NO: 1284), QGIR (SEQ ID NO: 1285), QAPA (SEQ ID NO: 1286), QIPP (SEQ ID NO: 1287), QTQL (SEQ ID NO: 1288), QAPS (SEQ ID NO: 1289), QNTY (SEQ ID NO: 1290), QDKQ (SEQ ID NO: 1291), QNHL (SEQ ID NO: 1292), QIGM (SEQ ID NO: 1293), LNKQ (SEQ ID NO: 1294), PNQL (SEQ ID NO: 1295), QLQQ (SEQ ID NO: 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: 1313), QGHH (SEQ ID NO: 1314), QSKV (SEQ ID NO: 1315), QLPS (SEQ ID NO: 1316), IGKQ (SEQ ID NO: 1317), QAIH (SEQ ID NO: 1318), QHGL (SEQ ID NO: 1319), QFMC (SEQ ID NO: 1320), QNQM (SEQ ID NO: 1321), QHLQ (SEQ ID NO: 1322), QPAR (SEQ ID NO: 1323), QSLQ (SEQ ID NO: 1324), QSQL (SEQ ID NO: 1325), HSQQ (SEQ ID NO: 1326), QMPS (SEQ ID NO: 1327), QGSL (SEQ ID NO: 1328), QVPA (SEQ ID NO: 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: 1346), RGLQ (SEQ ID NO: 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: 1380), QNLL (SEQ ID NO: 1381), QLVI (SEQ ID NO: 1382), RTQE (SEQ ID NO: 1383), QTHQ (SEQ ID NO: 1384), QDQH (SEQ ID NO: 1385), QSQH (SEQ ID NO: 1386), VRQQ (SEQ ID NO: 1387), AWQQ (SEQ ID NO: 1388), QSVP (SEQ ID NO: 1389), QNIQ (SEQ ID NO: 1390), LDQQ (SEQ ID NO: 1391), PDQQ (SEQ ID NO: 1392), ESQQ (SEQ ID NO: 1393), QRQL (SEQ ID NO: 1394), QIIV (SEQ ID NO: 1395), 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); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, or 3 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 42. The AAV particle of any one of embodiments 39-41, wherein [N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any of SEQ ID NOs: 1800-2241; (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 43. The AAV particle of any one of embodiments 37-42, wherein [N1]-[N2]-[N3]-[N4] is or comprises GSGSPHSKAQNQQ (SEQ ID NO: 1801).44. The AAV particle of any one of embodiments 37-42, wherein [N1]-[N2]-[N3]-[N4] is or comprises GHDSPHKSGQNQQ (SEQ ID NO: 1800). 45. The AAV particle of any one of embodiments 37-42, wherein [N1]-[N2]-[N3]-[N4] is or comprises GSGSPHKYGQNQQT (SEQ ID NO: 910). 46. The AAV particle of any one of embodiments 1-45, wherein the AAV capsid variant comprises an amino acid other than T at position 450 (e.g., S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G), an amino acid other than I at position 451 (e.g., M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L), and / or an amino acid other than N at position 452 (e.g., M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S), relative to a reference sequence numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981 or 982. 47. The AAV particle of any one of embodiments 1-46, wherein the AAV capsid variant comprises: (i) the amino acid T at position 450, the amino acid I at position 451, and / or the amino acid N at position 452, relative to a reference sequence numbered according to any one of SEQ ID NOs: 138, 981, or 982; (ii) the amino acid T at position 450, the amino acid E at position 451, and / or the amino acid R at position 452, numbered according to SEQ ID NO: 36; or (iii) the amino acid T at position 450, the amino acid E at position 451, and / or the amino acid N at position 452, numbered according to SEQ ID NO: 3904. 48. The AAV particle of any one of embodiments 1-47, wherein the AAV capsid variant further comprises [N0], wherein [N0] comprises XA XB and XC, and wherein: (a) position XA is: T, S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G; (b) position XB is: I, M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L; and (c) position XC is: N, M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 49. The AAV particle of embodiment 48, wherein [N0] is or comprises 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, TII, TFP, TEK, EIN, TVN, TFN, SIN, TER, TSY, ELH, AIN, SVN, TDN, TFH, TVH, TEN, TSS, TID, TCN, NIN, TEH,AEM, AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TIY, TFS, TES, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, NAD, TIT, NCV, TIR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV, SDI, NSI, NSL, EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, NNL, or any dipeptide thereof. 50. The AAV particle of embodiment 48 or 49, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 2242-2886; (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 51. The AAV particle of any one of embodiments 48-50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TINGSGSPHSKAQNQQ (SEQ ID NO: 2242). 52. The AAV particle of any one of embodiments 48-50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TINGHDSPHKSGQNQQ (SEQ ID NO: 2243). 53. The AAV particle of any one of embodiments 48-50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TINGSGSPHKYGQNQQT (SEQ ID NO: 5246). 54. The AAV particle of any one of embodiments 1-53, wherein [N1]-[N2]-[N3] is present in loop IV of the AAV capsid variant. 55. The AAV particle of any one of embodiments 48-54, wherein [N0] and [N4] are present in loop IV of the AAV capsid variant. 56. The AAV particle of any one of embodiments 48-55, wherein [N0] is present immediately subsequent to position 449, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.57. The AAV particle of any one of embodiments 48-55, wherein [N0] is present immediately subsequent to position 449, relative to a reference sequence numbered according to the amino acid sequence of any one of SEQ ID NO: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982. 58. The AAV particle of any one of embodiments 48-57, wherein [N0] replaces positions 450, 451, and 452 (e.g., T450, I451, and N452), relative to a reference sequence numbered according to SEQ ID NO: 138. 59. The AAV particle of any one of embodiments 48-58, wherein [N0] replaces positions 450-452 (e.g., T450, I451, and N452), relative to a reference sequence numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982. 60. The AAV particle of any one of embodiments 48-59, wherein [N0] corresponds to positions 450-452 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981 or 982. 61. The AAV particle of any one of embodiments 48-60, wherein [N0] is present immediately subsequent to position 449 and wherein [N0] replaces positions 450-452 (e.g., T450, I451, and N452), relative to a reference sequence numbered according to SEQ ID NO: 138. 62. The AAV particle of any one of embodiments 48-61, wherein [N0] is present immediately subsequent to position 449 and wherein [N0] replaces positions 450-452 (e.g., T450, I451, and N452), relative to a reference sequence numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981 or 982. 63. The AAV particle of any one of embodiments 1-62, wherein [N1] is present immediately subsequent to position 452, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 64. The AAV particle of any one of embodiments 1-63, wherein [N1] is present immediately subsequent to position 452, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 65. The AAV particle of any one of embodiments 1-64, wherein [N1] replaces positions 453- 455 (e.g., G453, S454, and G455), relative to a reference sequence numbered according to SEQ ID NO: 138.66. The AAV particle of any one of embodiments 1-65, wherein [N1] replaces positions 453 (e.g., G453), relative to a reference sequence numbered according to SEQ ID NO: 138. 67. The AAV particle of any one of embodiments 1-66, wherein [N1] replaces positions 453- 455 (e.g., G453, S454, and G455), relative to a reference sequence numbered according to SEQ ID NO: 981. 68. The AAV particle of any one of embodiments 1-66 or 67, wherein [N1] replaces positions 453- 455, relative to a reference sequence numbered according to SEQ ID NO: 982. 69. The AAV particle of any one of embodiments 1-68, wherein [N1] is present immediately subsequent to position 452 and wherein [N1] replaces positions 453-455 (e.g., G453, S454, and G455), relative to a reference sequence numbered according to SEQ ID NO: 138. 70. The AAV particle of any one of embodiments 1-64, or 66, wherein [N1] is present immediately subsequent to position 452 and wherein [N1] replaces positions 453 (e.g., G453), relative to a reference sequence numbered according to SEQ ID NO: 138. 71. The AAV particle of any one of embodiments 1-64, 66, or 70, wherein [N1] is present immediately subsequent to position 452 and wherein [N1] replaces positions 453-455, relative to a reference sequence numbered according to SEQ ID NO: 981 or 982. 72. The AAV particle of any one of embodiments 1-71, wherein [N1] corresponds to positions 453-455 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981 or 982. 73. The AAV particle of any one of embodiment 1-72, 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 SEQ ID NO: 138, 981, or 982. 74. The AAV particle of any one of embodiments 1-73, wherein the AAV capsid variant comprises the amino acid H at position 454 and the amino acid D at position 455, numbered according to SEQ ID NO: 138. 75. The AAV particle of any one of embodiments 1-74, wherein the AAV capsid variant comprises a substitution at position 454 (e.g., S454H) and / or a substitution at position 455 (e.g., G455D), numbered according to SEQ ID NO: 138 or 982.76. The AAV particle of any one of embodiments 1-75, wherein the AAV capsid variant comprises the amino acid H at position 454 and the amino acid D at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455, relative to a reference sequence numbered according to SEQ ID NO: 138. 77. The AAV particle of any one of embodiments 1-71, wherein the AAV capsid variant comprises the amino acid H at position 454 and the amino acid D at position 455, relative to a reference sequence numbered according to SEQ ID NO: 982. 78. The AAV particle of any one of embodiments 1-77, wherein the AAV capsid variant comprises the amino acid H at position 454 and the amino acid D at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455, relative to a reference sequence numbered according to SEQ ID NO: 982. 79. The AAV particle of any one of embodiments 1-71, wherein the AAV capsid variant comprises the amino acid S at position 454 and the amino acid G at position 455, relative to a reference sequence numbered according to SEQ ID NO: 138. 80. The AAV particle of any one of embodiments 1-71 or 79, wherein the AAV capsid variant comprises the amino acid S at position 454 and the amino acid G at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455, relative to a reference sequence numbered according to SEQ ID NO: 138. 81. The AAV particle of any one of embodiments 1-71, 79, or 80, wherein the AAV capsid variant comprises the amino acid S at position 454 and the amino acid G at position 455, relative to a reference sequence numbered according to SEQ ID NO: 981. 82. The AAV particle of any one of embodiments 1-71 or 79-81, wherein the AAV capsid variant comprises the amino acid S at position 454 and the amino acid G at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455, relative to a reference sequence numbered according to SEQ ID NO: 981.83. The AAV particle of any one of embodiments 1-82, wherein [N2] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 84. The AAV particle of any one of embodiments 1-82, wherein [N2] corresponds to positions 456-458 (e.g., S456, P457, H458) of SEQ ID NO: 981 or 982. 85. The AAV particle of any one of embodiments 1-84, wherein [N2] corresponds to positions 456-458 (e.g., S456, P457, H458) of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 86. The AAV particle of any one of embodiments 1-85, wherein [N2]-[N3] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 87. The AAV particle of any one of embodiments 1-86, wherein [N2] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 88. The AAV particle of any one of embodiments 1-87, wherein [N2]-[N3] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 89. The AAV particle of any one of embodiments 1-88, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, S459, K460, A461) of SEQ ID NO: 981. 90. The AAV particle of any one of embodiments 1-88, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, K459, S460, G461) of SEQ ID NO: 982. 91. The AAV particle of any one of embodiments 1-88, wherein [N2] is present immediately subsequent to [N1]. 92. The AAV particle of any one of embodiments 1-64, 66, 70, or 71, wherein [N3] is present immediately subsequent to [N2] and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138.93. The AAV particle of any one of embodiments 1-64, 66, 70, 71, or 92, wherein [N3] is present immediately subsequent to [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138. 94. The AAV particle of any one of embodiments 39-93, wherein [N4] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 95. The AAV particle of any one of embodiments 39-94, wherein [N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 96. The AAV particle of any one of embodiments 39-95, wherein [N4] corresponds to positions 462-465 (e.g., Q462, N463, Q464, Q465) of SEQ ID NO: 981 or 982. 97. The AAV particle of any one of embodiments 39-96, wherein [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 98. The AAV particle of any one of embodiments 39-97, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 99. The AAV particle of any one of embodiments 39-98, wherein [N2]-[N3]-[N4] corresponds to positions 456- 465 (e.g., S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465) of SEQ ID NO: 981. 100. The AAV particle of any one of embodiments 39-99, wherein [N2]-[N3]-[N4] corresponds to positions 456-465 (e.g., S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465) of SEQ ID NO: 982. 101. The AAV particle of any one of embodiments 39-100, wherein [N2]-[N3]-[N4] corresponds to positions 456-465 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59.102. The AAV particle of any one of embodiments 39-101, wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 103. The AAV particle of any one of embodiments 39-102, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 452, and wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 104. The AAV particle of any one of embodiments 39-99, 102, or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465) of SEQ ID NO: 981. 105. The AAV particle of any one of embodiments 39-98 or 100-103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465) of SEQ ID NO: 982. 106. The AAV particle of any one of embodiments 39-98, or 101-103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 107. The AAV particle of any one of embodiments 1-98 or 102-104 wherein [N1]-[N2]-[N3] corresponds to positions 453-461 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461) of SEQ ID NO: 981. 108. The AAV particle of any one of embodiments 1-98, 100, 102, 103, or 105, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461) of SEQ ID NO: 982. 109. The AAV particle of any one of embodiments 40-98, 101-103, or 106, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 110. The AAV particle of any one of embodiments 39-109, wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.111. The AAV particle of any one of embodiments 39-110, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 449, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 112. The AAV particle of any one of embodiments 39-99, 102-104, 110 or 111, wherein [N0]-[N1]-[N2]-[N3]- [N4] corresponds to positions 450-465 (e.g., T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465) of SEQ ID NO: 981. 113. The AAV particle of any one of embodiments 39-98, 100-103, or 105-111, wherein [N0]-[N1]-[N2]-[N3]- [N4] corresponds to positions 450-465 (e.g., T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465) of SEQ ID NO: 982. 114. The AAV particle of any one of embodiments 48-98, 101-103, 106, or 109, wherein [N0]-[N1]-[N2]-[N3]- [N4] corresponds to positions 450-465 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 115. The AAV particle of any one of embodiments 39-113, wherein [N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 116. The AAV particle of any one of embodiments 39-115, wherein [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 117. The AAV particle of any one of embodiments 39-116, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 118. The AAV particle of any one of embodiments 1-117, wherein [N3] is present immediately subsequent to [N2]. 119. The AAV particle of any one of embodiments 1-118, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N2]-[N3].120. The AAV particle of any one of embodiments 1-119, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N1]-[N2]-[N3]. 121. The AAV particle of any one of embodiments 28-120, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N0]-[N1]-[N2]-[N3]. 122. The AAV particle of any one of embodiments 25-121, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N1]-[N2]-[N3]-[N4]. 123. The AAV particle of any one of embodiments 25-122, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N0]-[N1]-[N2]-[N3]-[N4]. 124. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid other 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 SEQ ID NO: 138. 125. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino acid N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G or S at position 460, numbered according to the amino acid sequence of SEQ ID NO: 138. 126. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid other T at position 466 (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 any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981 or 982. 127. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino acid N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G or S at position 466, numbered according to the amino acid sequence of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981 or 982. 128. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid other K at position 449 (e.g., an E, an N, or a T), numbered according to the amino acid sequence of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981, or 982.129. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino E, N, or T at position 449, numbered according to the amino acid sequence of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 138, 981 or 982. 116. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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, wherein position X2 is S and position X3 is G; (ii) [N2] comprises the amino acid sequence SPH; and (iii) [N3] comprises positions X4, X5, and X6, wherein position X5 is K. 131. The AAV particle of embodiment 130, wherein: (i) X4 of [N3] is S, T, N, or A; and (ii) X5 of [N3] is A, V, T, S, G, R, L, or N; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (i) or (ii). 132. The AAV particle of embodiment 130 or 131, wherein X4 is S and / or X5 is A. 133. The AAV particle of any one of embodiments 130-132, wherein [N3] comprises SK, TK, NK, AK, KA, KV, KT, KS, KG, KR, KL, or KN. 134. The AAV particle of any one of embodiments 130-133, wherein [N3] is or comprises SKA, SKV, SKT, SKS, SKG, SKR, TKA, NKA, SKL, SKN, or AKA. 135. The AAV particle of any one of embodiments 130-134, wherein [N3] is or comprises SKA. 136. The AAV particle of any one of embodiments 130-135, wherein [N2]-[N3] comprises SPHSK (SEQ ID NO: 64), SPHTK (SEQ ID NO: 88), SPHNK (SEQ ID NO: 89), or SPHAK (SEQ ID NO: 90). 137. The AAV particle of any one of embodiments 130-136, wherein [N2]-[N3] is or comprises: (i) SPHSKA (SEQ ID NO: 941), SPHSKV (SEQ ID NO: 101), SPHSKT (SEQ ID NO: 95), SPHSKS (SEQ ID NO: 962), SPHSKG (SEQ ID NO: 96), SPHSKR (SEQ ID NO: 978), SPHTKA (SEQ ID NO: 103),SPHNKA (SEQ ID NO: 98), SPHSKL (SEQ ID NO: 960), SPHSKN (SEQ ID NO: 99), or SPHAKA (SEQ ID NO: 100); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 138. The AAV particle of any one of embodiments 130-137, wherein [N2]-[N3] is or comprises SPHSKA (SEQ ID NO: 941). 139. The AAV particle of any one of embodiments 130-138, which comprises 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 SEQ ID NO: 138 or 981. 140. The AAV particle of any one of embodiments 130-139, which comprises the amino acid G at position 453, numbered according to SEQ ID NO: 138 or 981. 141. The AAV particle of any one of embodiments 130-140, wherein X1 of [N1] is chosen from: G, M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids. 142. The AAV particle of any one of embodiments 130-141, wherein [N1] comprises SG, GS, MS, TS, IS, ES, SS, AS, NS, VS, LS, KS, HS, PS, RS, WS, or DS. 143. The AAV particle of any one of embodiments 130-142, wherein [N1] is or comprises: GSG, MSG, TSG, ISG, ESG, SSG, ASG, NSG, VSG, LSG, KSG, HSG, PSG, RSG, WSG, or DSG. 144. The AAV particle of any one of embodiments 130-143, wherein [N1] is or comprises GSG. 145. The AAV particle of any one of embodiments 130-144, wherein [N1]-[N2] comprises SGSPH (SEQ ID NO: 116).146. The AAV particle of any one of embodiments 130-145, wherein [N1]-[N2] is or comprises: (i) GSGSPH (SEQ ID NO: 150), VSGSPH (SEQ ID NO: 153), MSGSPH (SEQ ID NO: 165), TSGSPH (SEQ ID NO: 167), ISGSPH (SEQ ID NO: 168), ESGSPH (SEQ ID NO: 170), SSGSPH (SEQ ID NO: 171), ASGSPH (SEQ ID NO: 173), NSGSPH (SEQ ID NO: 174), LSGSPH (SEQ ID NO: 175), KSGSPH (SEQ ID NO: 177), HSGSPH (SEQ ID NO: 178), PSGSPH (SEQ ID NO: 180), RSGSPH (SEQ ID NO: 182), WSGSPH (SEQ ID NO: 184), DSGSPH (SEQ ID NO: 185); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 147. The AAV particle of any one of embodiments 130-146, wherein [N1]-[N2]-[N3] is or comprises: (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), KSGSPHSKA (SEQ ID NO: 1140), GSGSPHSKG (SEQ ID NO: 1142), GSGSPHSKR (SEQ ID NO: 1115), HSGSPHSKA (SEQ ID NO: 1143), PSGSPHSKA (SEQ ID NO: 1145), RSGSPHSKA (SEQ ID NO: 1147), GSGSPHTKA (SEQ ID NO: 1148), WSGSPHSKA (SEQ ID NO: 1150), DSGSPHSKA (SEQ ID NO: 1151), GSGSPHNKA (SEQ ID NO: 1153), GSGSPHSKL (SEQ ID NO: 1113), GSGSPHSKN (SEQ ID NO: 1164), or GSGSPHAKA (SEQ ID NO: 1165); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 148. The AAV particle of any one of embodiments 130-147, wherein [N1]-[N2]-[N3] is or comprises GSGSPHSKA (SEQ ID NO: 60) or VSGSPHSKA (SEQ ID NO: 1083),.149. The AAV particle of any one of embodiments 130-148, wherein the AAV capsid variant comprises an amino acid other than Q at position 456 (e.g., R, P, H, L, K, I, G, S, M, or E), an amino acid other than N at position 457 (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M), an amino acid other than Q at position 458 (e.g., R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, or D), an amino acid other than Q at position 459 (e.g., H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G), and / or an amino acid other than T at position 460 (e.g., I, N, S, H, R, L, D, Y, A, or Q), relative to a reference sequence numbered according to SEQ ID NO: 138. 150. The AAV parrticle of any one of embodiments 130-149, wherein the AAV capsid variant comprises an amino acid other than Q at position 462 (e.g., R, P, H, L, K, I, G, S, M, or E), an amino acid other than N at position 463 (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M), an amino acid other than Q at position 464 (e.g., R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, or D), an amino acid other than Q at position 465 (e.g., H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G), and / or an amino acid other than T at position 466 (e.g., I, N, S, H, R, L, D, Y, A, or Q), relative to a reference sequence numbered according to SEQ ID NO: 981. 151. The AAV particle of any one of embodiments 130-150, wherein the AAV capsid variant comprises the amino acid Q at position 456, the amino acid N at position 457, the amino acid Q at position 458, the amino acid Q at position 459, and / or the amino acid T at position 460, relative to a reference sequence numbered according to SEQ ID NO: 138. 152. The AAV particle of any one of embodiments 130-151, wherein the AAV capsid variant comprises the amino acid Q at position 462, the amino acid N at position 463, the amino acid Q at position 464, the amino acid Q at position 465, and / or the amino acid T at position 466, numbered according to SEQ ID NO: 981 153. The AAV particle of any one of embodiments 130-152, wherein the AAV capsid variant further comprises [N4] wherein [N4] comprises X7, X8, X9, X10, and X11, wherein: (a) X7 is Q, R, P, H, L, K, I, G, S, M, or E; (b) X8 is N, D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M; (c) X9 is Q, R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, D; (d) X10 is Q, H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G; and (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(e). 154. The AAV particle of embodiment 153, wherein [N4] is or comprises:(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 (SEQ ID NO: 1448), HNQQR (SEQ ID NO: 1449), QAIKT (SEQ ID NO: 1450), QNRQT (SEQ ID NO: 1451), QYQHT (SEQ ID NO: 1452), QNPQS (SEQ ID NO: 1453), QHQLT (SEQ ID NO: 1454), QSPPT (SEQ ID NO: 1455), QAKLT (SEQ ID NO: 1456), KSQQT (SEQ ID NO: 1457), QDRPT (SEQ ID NO: 1458), QSQQL (SEQ ID NO: 1459), QAFHT (SEQ ID NO: 1460), QKQQD (SEQ ID NO: 1461), QNAQT (SEQ ID NO: 1462), HNQLT (SEQ ID NO: 1463), QNQQY (SEQ ID NO: 1464), QKLNT (SEQ ID NO: 1465), QNVQT (SEQ ID NO: 1466), QAQQT (SEQ ID NO: 1467), QNLQA (SEQ ID NO: 1468), QTPPT (SEQ ID NO: 1469), QYQHA (SEQ ID NO: 1470), QGQQA (SEQ ID NO: 1471), QPPAT (SEQ ID NO: 1472), QERPT (SEQ ID NO: 1473), QDLQT (SEQ ID NO: 1474), QAMHT (SEQ ID NO: 1475), LNQQT (SEQ ID NO: 1476), QHPST (SEQ ID NO: 1477), PGLQT (SEQ ID NO: 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: 1494), QNTHD (SEQ ID NO: 1495), PNLQI (SEQ ID NO: 1496), QERST (SEQ ID NO: 1497), QNYQT (SEQ ID NO: 1498), QRTCT (SEQ ID NO: 1499), QIGHT (SEQ ID NO: 1500), QGAIT (SEQ ID NO: 1501), QVPPT (SEQ ID NO: 1502), QVQQI (SEQ ID NO: 1503), LMRQT (SEQ ID NO: 1504), QYSVT (SEQ ID NO: 1505), QAITT (SEQ ID NO: 1506), QKTLT (SEQ ID NO: 1507), QNQWT (SEQ ID NO: 1508), QLHHT (SEQ ID NO: 1509), QNIII (SEQ ID NO: 1510), QGHHT (SEQ ID NO: 1511), QSKVT (SEQ ID NO: 1512), QLPST (SEQ ID NO: 1513), IGKQT (SEQ ID NO: 1514), QAIHT (SEQ ID NO: 1515), QHGLT (SEQ ID NO: 1516), QFMCT (SEQ ID NO: 1517), QHLQT (SEQ ID NO: 1518), QNHQN (SEQ ID NO: 1519), QPART (SEQ ID NO: 1520), QSLQT (SEQ ID NO: 1521), QSQLT (SEQ ID NO: 1522), QDRQS (SEQ ID NO: 1523), QMPST (SEQ ID NO: 1524), QGSLT (SEQ ID NO: 1525), QVPAT (SEQ ID NO: 1526), QDKQT (SEQ ID NO: 1527), HYQQT (SEQ ID NO: 1528), QVPST (SEQ ID NO: 1529), RGEQT (SEQ ID NO: 1530), PGQQT (SEQ ID NO: 1531), QSLQI (SEQ ID NO: 1532), LEQQT (SEQ ID NO: 1533), QNQST (SEQ ID NO: 1534), QKVIT (SEQ ID NO: 1535), QNNDQ (SEQ ID NO: 1536), QSVHT (SEQ ID NO: 1537), QPLGT (SEQ ID NO: 1538), HNQET (SEQ ID NO: 1539), QNLQI (SEQ ID NO: 1540),QIQQT (SEQ ID NO: 1541), QVRNT (SEQ ID NO: 1542), PSNQT (SEQ ID NO: 1543), QVGHT (SEQ ID NO: 1544), QRDIT (SEQ ID NO: 1545), QMPNT (SEQ ID NO: 1546), RGLQT (SEQ ID NO: 1547), QKQQT (SEQ ID NO: 1548), PSLQT (SEQ ID NO: 1549), QRDQT (SEQ ID NO: 1550), QAKGT (SEQ ID NO: 1551), QSAHT (SEQ ID NO: 1552), QSTMT (SEQ ID NO: 1553), QREMT (SEQ ID NO: 1554), QYRAT (SEQ ID NO: 1555), QWQQT (SEQ ID NO: 1556), QRMNT (SEQ ID NO: 1557), GDSQT (SEQ ID NO: 1558), QKIST (SEQ ID NO: 1559), PSMQT (SEQ ID NO: 1560), SPRQT (SEQ ID NO: 1561), MEQQT (SEQ ID NO: 1562), QYQNT (SEQ ID NO: 1563), QHQQT (SEQ ID NO: 1564), INQQT (SEQ ID NO: 1565), PNQQH (SEQ ID NO: 1566), ENRQT (SEQ ID NO: 1567), QTQQA (SEQ ID NO: 1568), or QNQAT (SEQ ID NO: 1569); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 155. The AAV particle of embodiment 153 or 154, wherein [N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any of SEQ ID NOs: 200 or 2887-3076; (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 156. The AAV particle of any one of embodiments 153-155, wherein [N1]-[N2]-[N3]-[N4] is or comprises GSGSPHSKAQNQQT (SEQ ID NO: 200). 157. The AAV particle of any one of embodiments 153-155, wherein [N1]-[N2]-[N3]-[N4] is or comprises VSGSPHSKAQNQQT (SEQ ID NO: 903). 158. The AAV particle of any one of embodiments 130-157, wherein the AAV capsid variant comprises 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), anamino 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), relative to a reference sequence numbered according to SEQ ID NO: 138. 159. The AAV particle of any one of embodiments 130-157, wherein the AAV capsid variant comprises: (i) the amino acid K at position 449, the amino acid T at position 450, the amino acid I at position 451, and / or the amino acid N at position 452, relative to a reference sequence numbered according to SEQ ID NO: 138 or 981; (ii) the amino acid K at position 449, the amino acid T at position 450, the amino acid E at position 451, and / or the amino acid N at position 452, relative to a reference sequence numbered according to SEQ ID NO: 3904; or (iii) the amino acid K at position 449, the amino acid T at position 450, the amino acid E at position 451, and / or the amino acid R at position 452, relative to a reference sequence numbered according to SEQ ID NO: 36. 160. The AAV particle of any one of embodiments 130-159, wherein the AAV capsid variant further comprises [N0], wherein [N0] comprises XA, XB, XC, and XD, wherein: (a) XAis K, T, E, or N; (b) Xbis T, S, E, A, N, V, Q, or G; (c) XCis I, F, E, V, L, D, S, C, T, A, N, H, R, G, or W; and (d) XDis N, I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(d). 161. The AAV particle of embodiment 160, wherein [N0] is or comprises: (i) KTIN (SEQ ID NO: 1575), KTEN (SEQ ID NO: 1586), KTER (SEQ ID NO: 1578), KTII (SEQ ID NO: 1570), KTFP (SEQ ID NO: 1571), KTEK (SEQ ID NO: 1572), KTVN (SEQ ID NO: 1573), KTFN (SEQ ID NO: 1574), TTIN (SEQ ID NO: 1576), KSIN (SEQ ID NO: 1577), KELH (SEQ ID NO: 1579), KAIN (SEQ ID NO: 1580), KTDN (SEQ ID NO: 1581), KTFH (SEQ ID NO: 1582), KTSN (SEQ ID NO: 1583), ETIN (SEQ ID NO: 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 (SEQ ID NO: 1603), NTIY(SEQ ID NO: 1604), KTFS (SEQ ID NO: 1605), KTES (SEQ ID NO: 1606), KTTN (SEQ ID NO: 1607), KTED (SEQ ID NO: 1608), KTNN (SEQ ID NO: 1609), KEVH (SEQ ID NO: 1610), KTIS (SEQ ID NO: 1611), KTVR (SEQ ID NO: 1612), KTDR (SEQ ID NO: 1613), ETIK (SEQ ID NO: 1614), KNHI (SEQ ID NO: 1615), KESD (SEQ ID NO: 1616), KTIK (SEQ ID NO: 1617), KTDL (SEQ ID NO: 1618), KTVP (SEQ ID NO: 1619), KTVI (SEQ ID NO: 1620), KAEH (SEQ ID NO: 1621), KNCL (SEQ ID NO: 1622), KTVK (SEQ ID NO: 1623), KNAD (SEQ ID NO: 1624), KTIT (SEQ ID NO: 1625), KNCV (SEQ ID NO: 1626), KNAL (SEQ ID NO: 1627), KVIN (SEQ ID NO: 1628), KTEF (SEQ ID NO: 1629), KTRE (SEQ ID NO: 1630), KQGE (SEQ ID NO: 1631), KSEK (SEQ ID NO: 1632), KNVN (SEQ ID NO: 1633), KGGE (SEQ ID NO: 1634), KEFV (SEQ ID NO: 1635), KSDK (SEQ ID NO: 1636), KTEQ (SEQ ID NO: 1637), KEVQ (SEQ ID NO: 1638), KTEY (SEQ ID NO: 1639), KNCW (SEQ ID NO: 1640), KTDV (SEQ ID NO: 1641), KSDI (SEQ ID NO: 1642), KNSI (SEQ ID NO: 1643), KNSL (SEQ ID NO: 1644), KEVV (SEQ ID NO: 1645), KTEP (SEQ ID NO: 1646), KSEL (SEQ ID NO: 1647), KTWQ (SEQ ID NO: 1648), KTEV (SEQ ID NO: 1649), KAVN (SEQ ID NO: 1650), KGVL (SEQ ID NO: 1651), KTEG (SEQ ID NO: 1652), KTRD (SEQ ID NO: 1653), KTGN (SEQ ID NO: 1654), KNAI (SEQ ID NO: 1655), KAEN (SEQ ID NO: 1656), KAET (SEQ ID NO: 1657), KTVH (SEQ ID NO: 1658), KETA (SEQ ID NO: 1659), KNNL (SEQ ID NO: 1660), EAIN (SEQ ID NO: 1661), KSLN (SEQ ID NO: 1662), KTIP (SEQ ID NO: 1663), or KTIH (SEQ ID NO: 1664); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, or 3 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 162. The AAV particle of embodiment 160 or 161, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 3239-3526 or 3591-3605; (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).163. The AAV particle of any one of embodiments 160-162, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KTINGSGSPHSKAQNQQT (SEQ ID NO: 5660). 164. The AAV particle of any one of embodiments 160-162, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589) or KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589). 165. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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, wherein position X2 is an amino acid other than S and position X3 is an amino acid other than G; (ii) [N2] comprises the amino acid sequence SPH; and (iii) [N3] comprises positions X4, X5, and X6, wherein position X4 is K. 166. The AAV particle of embodiment 165, wherein: (i) X5 of [N3] is S, I, T, R, H, Y, L, or M; and (ii) X6 of [N3] is G, A, L, E, V, R, W, N, Q, or K; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (i) or (ii). 167. The AAV particle of embodiment 165 or 166, wherein X5 is S and / or X6is G. 168. The AAV particle of any one of embodiments 165-167, wherein [N3] comprises KS, KI, KT, KR, KH, KY, KL, KM, SG, IG, TG, RG, SA, SL, SE, SV, SR, SW, SN, HG, YG, SQ, IV, SK, LW, MG, or MA. 169. The AAV particle of any one of embodiments 165-168, wherein [N3] is or comprises KSG, KIG, KTG, KRG, KSA, KSL, KSE, KSV, KSR, KSW, KSN, KHG, KYG, KSQ, KIV, KSK, KLW, KMG, or KMA. 170. The AAV particle of any one of embodiments 165-169, wherein [N3] is or comprises KSG. 171. The AAV particle of any one of embodiments 165-170, wherein [N2]-[N3] comprises SPHKS (SEQ ID NO: 67), SPHKI (SEQ ID NO: 76), SPHKT (SEQ ID NO: 74), SPHKR (SEQ ID NO: 80), NPHKS (SEQ IDNO: 1665), SPHKH (SEQ ID NO: 91), SPHKY (SEQ ID NO: 78), SPHKL (SEQ ID NO: 77), or SPHKM (SEQ ID NO: 92). 172. The AAV particle of any one of embodiments 165-171, wherein [N2]-[N3] is or comprises: (i) SPHKSG (SEQ ID NO: 946), SPHKIG (SEQ ID NO: 958), SPHKTG (SEQ ID NO: 102), SPHKRG (SEQ ID NO: 974), NPHKSG (SEQ ID NO: 1666), SPHKSA (SEQ ID NO: 94), SPHKSL (SEQ ID NO: 104), SPHKSE (SEQ ID NO: 105), SPHKSV (SEQ ID NO: 106), SPHKSR (SEQ ID NO: 951), SPHKSW (SEQ ID NO: 107), SPHKSN (SEQ ID NO: 108), SPHKHG (SEQ ID NO: 109), SPHKYG (SEQ ID NO: 966), SPHKSQ (SEQ ID NO: 110), SPHKIV (SEQ ID NO: 1667), SPHKSK (SEQ ID NO: 111), SPHKLW (SEQ ID NO: 112), SPHKMG (SEQ ID NO: 114), or SPHKMA (SEQ ID NO: 115); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 173. The AAV particle of any one of embodiments 165-172, wherein [N2]-[N3] is or comprises SPHKSG (SEQ ID NO: 946). 174. The AAV particle of any one of embodiments 165-173, 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 SEQ ID NO: 138 or 981. 175. The AAV particle of any one of embodiments 165-173, wherein the AAV capsid variant comprises the amino acid G at position 453, numbered according to SEQ ID NO: 138 or 981. 176. The AAV particle of any one of embodiments 165-175, wherein: (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; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (i), (ii), or (iii).177. The AAV particle of any one of embodiments 165-176, wherein position X2 of [N1] is H and position X3 of [N1] is D. 178. The AAV particle of any one of embodiments 165-177, wherein position X1 of [N1] is G, position X2 of [N1] is H and position X3 of [N1] is D. 179. The AAV particle of any one of embodiments 165-178, wherein [N1] comprises GH, HD, GY, GR, GQ, AH, GN, KH, GP, WH, RH, LH, IH, MH, GD, NH, TH, EH, QH, YH, HH, FH, VH, YD, HE, RG, QD, RD, ND, PD, QV, DD, HN, or NG 180. The AAV particle of any one of embodiments 165-179, wherein [N1] is or comprises 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. 181. The AAV particle of any one of embodiments 165-180, wherein [N1] is or comprises GHD. 182. The AAV particle of any one of embodiments 165-181, wherein [N1]-[N2] comprises HDSPH (SEQ ID NO: 66). 183. The AAV particle of any one of embodiments 165-182, wherein [N1]-[N2] is or comprises: (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), GQVSPH (SEQ ID NO: 993), IHDSPH (SEQ ID NO: 1674), MHDSPH (SEQ ID NO: 1675), GDDSPH (SEQ ID NO: 159), GHNSPH (SEQ ID NO: 994), NHDSPH (SEQ ID NO: 1676), THDSPH (SEQ ID NO: 1677), GNGSPH (SEQ ID NO: 172), EHDSPH (SEQ ID NO: 1678), QHDSPH (SEQ ID NO: 1679), YHDSPH (SEQ ID NO: 1680), HHDSPH (SEQ ID NO: 1681), FHDSPH (SEQ ID NO: 1682), or VHDSPH (SEQ ID NO: 1683); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 184. The AAV particle of any one of embodiments 165-183, wherein [N1]-[N2]-[N3] is or comprises: (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 (SEQ ID NO: 1195), or GDDSPHKSG (SEQ ID NO: 1108); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 185. The AAV particle of any one of embodiments 165-184, wherein [N1]-[N2]-[N3] is or comprises GHDSPHKSG (SEQ ID NO: 62).186. The AAV particle of any one of embodiments 165-185, wherein the AAV capsid variant comprises an amino acid other than Q at position 456 (e.g., R, P, H, K, L, V, A, E, or I), an amino acid other than N at position 457 (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q, or M), an amino acid other than Q at position 458 (e.g., R, V, K, P, Y, H, L, I, E, or M), an amino acid other than Q at position 459 (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N), and / or an amino acid other than T at position 460 (e.g., A, E, K, S, I, P, G, or N), relative to a reference sequence numbered according to SEQ ID NO: 138. 187. The AAV particle of any one of embodiments 165-186, wherein the AAV capsid variant comprises 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), relative to a reference sequence numbered according to SEQ ID NO: 982. 188. The AAV particle of any one of embodiments 165-187, wherein the AAV capsid variant comprises the amino acid Q at position 456, the amino acid N at position 457, the amino acid Q at position 458, the amino acid Q at position 459, and / or the amino acid T at position 460, relative to a reference sequence numbered according to SEQ ID NO: 138. 189. The AAV particle of any one of embodiments 165-188, wherein the AAV capsid variant comprises the amino acid Q at position 462, the amino acid N at position 463, the amino acid Q at position 464, the amino acid Q at position 465, and / or the amino acid T at position 466, relative to a reference sequence numbered according to SEQ ID NO: 982. 190. The AAV particle of any one of embodiments 165-189, wherein the AAV capsid variant further comprises [N4] wherein [N4] comprises X7, X8, X9, X10, and X11, wherein: (a) X7 is Q, R, P, H, L, K, I, G, S, M, or E; (b) X8 is N, D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M; (c) X9 is Q, R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, D; (d) X10 is Q, H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G; and (e) X11 is T, I, N, S, H, R, L, D, Y, A, Q; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(e).191. The AAV particle of embodiment 190, wherein [N4] is or comprises: (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 (SEQ ID NO: 1452), QNQWT (SEQ ID NO: 1508), QNQHT (SEQ ID NO: 1722), QTRQT (SEQ ID NO: 1723), QNLHT (SEQ ID NO: 1724), LNQQT (SEQ ID NO: 1476), QNQET (SEQ ID NO: 1725), QHLQT (SEQ ID NO: 1518), LNQPT (SEQ ID NO: 1726), QNQDT (SEQ ID NO: 1727), RNQQT (SEQ ID NO: 1728), QNLLT (SEQ ID NO: 1729), QLVIT (SEQ ID NO: 1730), RTQET (SEQ ID NO: 1731), QTHQT (SEQ ID NO: 1732), QNQPA (SEQ ID NO: 1733), QDQHT (SEQ ID NO: 1734), QSQHT (SEQ ID NO: 1735), RNQQI (SEQ ID NO: 1736), VRQQT (SEQ ID NO: 1737), QNQHS (SEQ ID NO: 1738), AWQQT (SEQ ID NO: 1739), QSVPT (SEQ ID NO: 1740), QNIQP (SEQ ID NO: 1741), QNHLN (SEQ ID NO: 1742), LDQQT (SEQ ID NO: 1743), PDQQS (SEQ ID NO: 1744), ESQQT (SEQ ID NO: 1745), QNKQT (SEQ ID NO: 1746), QRQLT (SEQ ID NO: 1747), QIIVT (SEQ ID NO: 1748), QKQST (SEQ ID NO: 1749), QSHQT (SEQ ID NO: 1750), QFVVT (SEQ ID NO: 1751), QNLQT (SEQ ID NO: 1433), QNQQI (SEQ ID NO: 1424), QSQPT (SEQ ID NO: 1752), QNEQT (SEQ ID NO: 1753), QSLQT (SEQ ID NO: 1521), RNRQT (SEQ ID NO: 1755), QSKQT (SEQ ID NO: 1756), QNPLT (SEQ ID NO: 1757), RDQKT (SEQ ID NO: 1758), HNQQN (SEQ ID NO: 1759), QWKRT (SEQ ID NO: 1760), QSQQI (SEQ ID NO: 1481), QAQQT (SEQ ID NO: 1467), QNHQI (SEQ ID NO: 1761), QNQQA (SEQ ID NO: 1762), QNQLN (SEQ ID NO: 1763), QTQPT (SEQ ID NO: 1764), INQQT (SEQ ID NO: 1565), QKQLT (SEQ ID NO: 1765), RNQLA (SEQ ID NO: 1766), RNQQS (SEQ ID NO: 1767), ISIQT (SEQ ID NO: 1768), QNQQN (SEQ ID NO: 1769), QSQQS (SEQ ID NO: 1770), QTVCT (SEQ ID NO: 1771), QYQQI (SEQ ID NO: 1772), QQIMT (SEQ ID NO: 1773), QNEQS (SEQ ID NO: 1774), LNHQT (SEQ ID NO: 1775), QMIHT (SEQ ID NO: 1776), RNHQS (SEQ ID NO: 1777), QKMNT (SEQ ID NO: 1778), QSQQN (SEQ ID NO: 1779), QYQHA (SEQ ID NO: 1470); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 192. The AAV particle of embodiment 190 or 191, wherein [N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any of SEQ ID NOs: 201 or 3160-3237; (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 193. The AAV particle of any one of embodiments 190-192, wherein [N1]-[N2]-[N3]-[N4] is or comprises GHDSPHKSGQNQQT (SEQ ID NO: 201). 194. The AAV particle of any one of embodiments 165-193, wherein the AAV capsid variant comprises 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), relative to a reference sequence numbered according to SEQ ID NO: 138 or 982. 195. The AAV particle of any one of embodiments 165-193, wherein the AAV capsid variant comprises the amino acid K at position 449, the amino acid T at position 450, the amino acid I at position 451, and / or the amino acid N at position 452, relative to a reference sequence numbered according to SEQ ID NO: 138. 196. The AAV particle of any one of embodiments 165-195, wherein the AAV capsid variant further comprises [N0], wherein [N0] comprises XA, XB, XC, and XD, wherein: (a) XAis K or T; (b) Xbis T, A, S, I, V, N, E, Y, C, G, W, or Q; (c) XCis I, E, V, S, T, N, D, C, G, Q, L, P, A; and (d) XDis N, S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(d).197. The AAV particle of embodiment 196, wherein [N0] is or comprises: (i) KTIN (SEQ ID NO: 1575), KAIN (SEQ ID NO: 1580), KTES (SEQ ID NO: 1606), TTIN (SEQ ID NO: 1576), KSIN (SEQ ID NO: 1577), KTVN (SEQ ID NO: 1573), KSIY (SEQ ID NO: 1780), KTSN (SEQ ID NO: 1583), KTTN (SEQ ID NO: 1607), KIIN (SEQ ID NO: 1781), KTIS (SEQ ID NO: 1611), KAII (SEQ ID NO: 1782), KTIK (SEQ ID NO: 1617), KTEF (SEQ ID NO: 1629), KTIT (SEQ ID NO: 1625), KTNN (SEQ ID NO: 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 (SEQ ID NO: 1570), KIVN (SEQ ID NO: 1790), KTEK (SEQ ID NO: 1572), KTEN (SEQ ID NO: 1586), KIGN (SEQ ID NO: 1791), KEVM (SEQ ID NO: 1792), KYQV (SEQ ID NO: 1793), KTEA (SEQ ID NO: 1602), KATN (SEQ ID NO: 1591), KTEH (SEQ ID NO: 1589), KTVE (SEQ ID NO: 1794), KAID (SEQ ID NO: 1795), KTIM (SEQ ID NO: 1796), KEVG (SEQ ID NO: 1797), KSEM (SEQ ID NO: 1798), KAQQ (SEQ ID NO: 1799), KCGE (SEQ ID NO: 2897), KASN (SEQ ID NO: 2907), KTET (SEQ ID NO: 1599), KTIG (SEQ ID NO: 2917), KTDP (SEQ ID NO: 3081), KELV (SEQ ID NO: 3238), KELM (SEQ ID NO: 3590), KNEI (SEQ ID NO: 3849), KTPN (SEQ ID NO: 3850), KITN (SEQ ID NO: 3851), KTDI (SEQ ID NO: 3852), KTDQ (SEQ ID NO: 3853), KGIN (SEQ ID NO: 3854), KSEI (SEQ ID NO: 3855), KSEK (SEQ ID NO: 1632), KWSA (SEQ ID NO: 3856), KELA (SEQ ID NO: 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), KGQN (SEQ ID NO: 3870), KNEF (SEQ ID NO: 3871), KTSI (SEQ ID NO: 3872), KAEH (SEQ ID NO: 1621), KCDQ (SEQ ID NO: 3873), KEIL (SEQ ID NO: 3874), KTER (SEQ ID NO: 1578), KNAI (SEQ ID NO: 1655), KTDK (SEQ ID NO: 1593), KTPD (SEQ ID NO: 3875), KTIH (SEQ ID NO: 1664), or KTEI (SEQ ID NO: 1596); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, or 3 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).198. The AAV particle of embodiment 196 or 197, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 3606-3836; (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 199. The AAV particle of any one of embodiments 196-198, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KTINGHDSPHKSGQNQQT (SEQ ID NO: 5828). 200. The AAV particle of any one of embodiments 196-198, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754). 201. The AAV particle of any one of embodiments 196-198, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241). 202. The AAV particle of any one of embodiments 130-200, wherein [N1]-[N2]-[N3] is present in loop IV of the AAV capsid variant. 203. The AAV particle of any one of embodiments 160-164 or 196-202, wherein [N0] and [N4] are present in loop IV of the AAV capsid variant. 204. The AAV particle of any one of embodiments 160-164 or 196-203, wherein [N0] is present immediately subsequent to position 448, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982. 205. The AAV particle of any one of embodiments 160-164 or 196-204, wherein [N0] replaces positions 449- 452 (e.g., K449, T450, I451, and N452), relative to a reference sequence numbered according to SEQ ID NO: 138, 981, or 982.206. The AAV particle of any one of embodiments 160-164 or 196-205, wherein [N0] is present immediately subsequent to position 448 and wherein [N0] replaces positions 449-452 (e.g., K449, T450, I451, and N452), relative to a reference sequence numbered according to SEQ ID NO: 138, 981, or 982. 207. The AAV particle of any one of embodiments 160-164 or 196-206, wherein [N0] corresponds to positions 449-452 (e.g., K449, T450, I451, and N452) of SEQ ID NO: 981 or 982. 208. The AAV particle of any one of embodiments 130-207, wherein [N1] is present immediately subsequent to position 452, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982. 209. The AAV particle of any one of embodiments 130-208, wherein [N1] replaces positions 453- 455 (e.g., G453, S454, and G455), relative to a reference sequence numbered according to SEQ ID NO: 138, 981, or 982. 210. The AAV particle of any one of embodiments 130-208, wherein [N1] replaces position 453 (e.g., G453), relative to a reference sequence numbered according to SEQ ID NO: 138, 981, or 982. 211. The AAV particle of any one of embodiments 130-164 or 200-209, wherein: (i) position X1 of [N1] replaces position 453 (e.g., G453); (ii) position X2 of [N1] corresponds to position 454 (e.g., S454); and (iii) position X3 of [N1] corresponds to position 455 (e.g., G455), wherein (i), (ii), and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981. 212. The AAV particle of any one of embodiments 130-164 or 200-209, wherein: (i) position X1 of [N1] corresponds to position 453 (e.g., G453); (ii) position X2 of [N1] corresponds to position 454 (e.g., S454); and (iii) position X3 of [N1] corresponds to position 455 (e.g., G455), wherein (i), (ii), and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981. 213. The AAV particle of any one of embodiments 165-209, wherein: (i) position X1 of [N1] corresponds to position 453 (e.g., G453); (ii) position X2 of [N1] replaces position 454 (e.g., S454); and (iii) position X3 of [N1] replaces position 455 (e.g., G455), wherein (i), (ii), and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 982.214. The AAV particle of any one of embodiments 165-209, wherein [N1] corresponds to positions 453-455 (e.g., G453, H454, D455) of SEQ ID NO 982. 215. The AAV particle of any one of embodiments 165-209, wherein [N1] corresponds to positions 453-455 (e.g., G453, S454, G455) of SEQ ID NO: 138 or 981. 216. The AAV particle of any one of embodiments 130-215, wherein [N2] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982. 217. The AAV particle of any one of embodiments 130-216, wherein [N2] corresponds to positions 456-458 (e.g., S456, P457, and H458) of SEQ ID NO: 981 or 982. 218. The AAV particle of any one of embodiments 130-216, wherein [N2] corresponds to positions 456-458 (e.g., S456, P457, and H458) of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 219. The AAV particle of any one of embodiments 130-218, wherein [N2] is present immediately subsequent to [N1]. 220. The AAV particle of any one of embodiments 130-219, wherein [N3] corresponds to positions 459-460 (e.g., S459, K460, A461) of SEQ ID NO 981. 221. The AAV particle of any one of embodiments 130-220, wherein [N3] corresponds to positions 459-460 (e.g., S459, K460, A461) of SEQ ID NO: 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, or 59 222. The AAV particle of any one of embodiments 130-220, wherein [N2]-[N3] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138, 981, or 982. 223. The AAV particle of any one of embodiments 130-164 or 200-222, wherein [N2]-[N3] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981.224. The AAV particle of any one of embodiments 130-164 or 200-223, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, S459, K460, A461) of SEQ ID NO: 981. 225. The AAV particle of any one of embodiments 130-164 or 200-223, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, S459, K460, A461) of any one of SEQ ID NOs: 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, or 59. 226. The AAV particle of any one of embodiments 165-222, wherein [N3] corresponds to positions 459-460 (e.g., K459, S460, G461) of SEQ ID NO: 982. 227. The AAV particle of any one of embodiments 165-219 or 222-226, wherein [N3] corresponds to positions 459-460 (e.g., K459, S460, G461) of SEQ ID NO: 37. 228. The AAV particle of any one of embodiments 165-222 or 227, wherein [N2]-[N3] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 229. The AAV particle of any one of embodiments 165-228, wherein [N3] replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138. 230. The AAV particle of any one of embodiments 165-229, wherein [N3] is present immediately subsequent to [N2] and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138. 231. The AAV particle of any one of embodiments 165-230, wherein [N3] is present immediately subsequent to [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138. 232. The AAV particle of any one of embodiments 165-222, 226, or 228, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, K459, S460, G461) of SEQ ID NO: 982. 233. The AAV particle of any one of embodiments 165-222, 226, or 228, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, K459, S460, G461) of SEQ ID NO: 37.234. The AAV particle of any one of embodiments 153-164 or 190-233, wherein [N4] is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 235. The AAV particle of any one of embodiments 153-164 or 190-234, wherein [N4] replaces positions 456- 460 (e.g., Q456, N457, Q458, Q459, and T460), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 236. The AAV particle of any one of embodiments 153-164 or 190-235, wherein [N4] corresponds to positions 462-466 (e.g., Q462, N463, Q464, Q465, and T466) of SEQ ID NO: 981 or 982. 237. The AAV particle of any one of embodiments 153-164 or 190-235, wherein [N4] corresponds to positions 462-466 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 238. The AAV particle of any one of embodiments 153-164 or 190-235, wherein [N4] corresponds to positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) of SEQ ID NO: 138. 239. The AAV particle of any one of embodiments 153-164 or 190-236, wherein [N2]-[N3]-[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 240. The AAV particle of any one of embodiments 153-164 or 190-239, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 241. The AAV particle of 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), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 242. The AAV particle of any one of embodiments 153-164 or 190-241, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 452, and wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.243. The AAV particle of any one of embodiments 153-164 or 190-242, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466) of SEQ ID NO: 981. 244. The AAV particle of any one of embodiments 153-164 or 190-243, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461) of SEQ ID NO: 981. 245. The AAV particle of any one of embodiments 153-164 or 190-242, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466) of SEQ ID NO: 982. 246. The AAV particle of any one of embodiments 153-164, 190-242, or 245, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461) of SEQ ID NO: 982. 247. The AAV particle of any one of embodiments 153-164, 190-242, or 245, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 248. The AAV particle of any one of embodiments 160-164 or 196-245, wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 249. The AAV particle of any one of embodiments 160-164 or 196-248, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 448, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449- 460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 250. The AAV particle of any one of embodiments 160-164 or 202-249, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 (e.g., K449, T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466) of SEQ ID NO: 981. 251. The AAV particle of any one of embodiments 202-249, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 (e.g., K449, T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466) of SEQ ID NO: 982.252. The AAV particle of any one of embodiments 202-249, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59. 253. The AAV particle of any one of embodiments 153-164 or 190-251, wherein [N4] is present immediately subsequent to position 461, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 254. The AAV particle of any one of embodiments 153-164 or 190-253, wherein [N4] replaces positions 462- 466 (e.g., Q462, N463, Q464, Q465, and T466), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 255. The AAV particle of any one of embodiments 153-164 or 190-254, wherein [N2]-[N3]-[N4] replaces positions 462-466 (e.g., Q462, N463, Q464, Q465, and T466), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 256. The AAV particle of any one of embodiments 153-164 or 190-255, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 462-466 (e.g., Q462, N463, Q464, Q465, and T466), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 981 or 982. 257. The AAV particle of any one of embodiments 130-256, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N2]-[N3]. 258. The AAV particle of any one of embodiments 130-257, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N1]-[N2]-[N3]. 259. The AAV particle of any one of embodiments 130-258, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N0]-[N1]-[N2]-[N3]. 260. The AAV particle of any one of embodiments 130-259, wherein the AAV capsid variant comprises from N- terminus to C-terminus, [N1]-[N2]-[N3]-[N4]. 261. The AAV particle of any one of embodiments 130-260, wherein the AAV capsid variant comprises from N-terminus to C-terminus, [N0]-[N1]-[N2]-[N3]-[N4].262. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant: (i) is enriched, e.g., at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 190, 200, 205, or 210-fold, in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., mouse), e.g., as compared to a reference sequence of SEQ ID NO: 138, optionally wherein the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 outbred mice); and / or (ii) is capable of transducing 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). 263. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises: (a) the amino acid sequence of any of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 consecutive amino acids from any one of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30; or (c) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids, relative to any one of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30; or (d) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of the sequences provided in Tables 1A, 2A, 2B, 21-23, 25, 26, or 30. 264. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises: (a) the 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; or(c) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 945-980 or 985-986; (d) an amino sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 945-980 or 985-986. 265. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises: (a) the amino acid sequence of any of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 consecutive amino acids from any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; (c) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; or (d) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909. 266. The AAV particle of 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 SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909. 267. The AAV particle of any one of embodiments 262-266, wherein the at least 3 consecutive amino acids comprise SPH. 268. The AAV particle of any one of embodiments 262-267, wherein the at least 4 consecutive amino acids comprise SPHS (SEQ ID NO: 63). 269. The AAV particle of any one of embodiments 262-268, wherein the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 64). 270. The AAV particle of any one of embodiments 262-269, wherein the at least 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941).271. The AAV particle of embodiment 262-266, wherein the at least 3 consecutive amino acids comprise HDS. 272. The AAV particle of any one of embodiments 262-266 or 271, wherein the at least 4 consecutive amino acids comprise HDSP (SEQ ID NO: 65). 273. The AAV particle of any one of embodiments 262-266, 271, or 272, wherein the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 66). 274. The AAV particle of any one of embodiments 262-266 or 271-273, wherein the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2). 275. The AAV particle of any one of embodiments 262-267, wherein: (i) the at least 3 consecutive amino acids comprise SPH; (ii) the at least 4 consecutive amino acids comprise SPHK (SEQ ID NO: 3876); (iii) the at least 5 consecutive amino acids comprise SPHKY (SEQ ID NO: 78); and / or (iv) the at least 6 consecutive amino acids comprise SPHKYG (SEQ ID NO: 966). 276. The AAV particle of embodiment 262, 263, 265, or 266, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909. 277. The AAV particle of any one of embodiments 262-270 or 276, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941). 278. The AAV particle of any one of embodiments 262-266, 271-274, or 276, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2). 279. The AAV particle of any one of embodiments 262-267, 275, or 276, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four modifications,e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SPHKYG (SEQ ID NO: 966). 280. The AAV particle of embodiment 262 or 263, wherein the AAV capsid variant comprises: (i) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272); (ii) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589); (iii) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754); (iv) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241); (v) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100); or (vi) an amino acid sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062). 281. The AAV particle of any one of embodiments 262, 263, 265, 266, or 276, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 200, 201, 941, 943, 204, 208, 404, or 903- 909. 282. The AAV particle of any one of embodiments 262-270, 276, 277, or 281, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941). 283. The AAV particle of any one of embodiments 262-266, 271-275, 276, 278, or 281, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2).284. The AAV particle of any one of embodiments 262-267, 275, 276, or 281, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of SPHKYG (SEQ ID NO: 966). 285. The AAV particle of any one of embodiments 262, 263 or 280, wherein the AAV capsid variant comprises: (i) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589); (ii) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754); (iii) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241); (iv) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100); (v) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062); (vi) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272); (vii) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTEKVSGSPHSKAQNQQT (SEQ ID NO: 3274); (viii) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTINGSGSPHKSGQNKTS (SEQ ID NO: 5440); (ix) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTSNASGSPHSKAHNQQT (SEQ ID NO: 3382); (x) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KNSIGSGSPHSKAQNQQT (SEQ ID NO: 3421); (xi) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTVNGHDSPHKSGQRPST (SEQ ID NO: 4478); (xii) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KAENGSGSPHSKAQNQQT (SEQ ID NO: 3487); or (xiii) an amino acid sequence comprising at least one, two, or three but no more than four different amino acids relative to the amino acid sequence of KTINGSGSPHKSGQNQQP (SEQ ID NO: 4081).286. The AAV particle of any one of embodiments 1-129, 262, 263, 265-279, or 281-284, wherein the AAV capsid variant comprises the amino acid sequence of any of SEQ ID NOs: 200, 201, 941, 943, 204, 208, 404, or 903-909. 287. The AAV particle of 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 of ERVSGSPHSKA (SEQ ID NO: 3877), optionally wherein the amino acid sequence is present immediately subsequent to position 450 and replaces positions 451- 455, numbered according to SEQ ID NO: 138. 288. The AAV particle of 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 of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460, numbered according to SEQ ID NO: 138. 289. The AAV particle of 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 of AEIGHDSPHKSG (SEQ ID NO: 3878), optionally wherein the amino acid sequence is present immediately subsequent to position 449 and replaces positions 450-455, numbered according to SEQ ID NO: 138. 290. The AAV particle of 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 of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460, (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138. 291. The AAV particle of any one of embodiments 262, 263, 271-274, 276, 278, 280, 281, 283, 285, or 286, which comprises the amino acid sequence of EKMSGSPHSKA (SEQ ID NO: 6401), optionally wherein the amino acid sequence is present immediately subsequent to position 450 and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455), numbered according to SEQ ID NO: 138. 292. The AAV particle of 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 of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), optionally wherein the amino acid sequence is present immediately subsequent to position 448and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138. 293. The AAV particle of 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 of HDSPHSKAQNL (SEQ ID NO: 6402), optionally wherein the amino acid sequence is present immediately subsequent to position 453 and replaces positions 456-458 (e.g., Q456, N457, Q458), numbered according to SEQ ID NO: 138. 294. The AAV particle of 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 of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138. 295. The AAV particle of 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 of VNGHDSPHSKA (SEQ ID NO: 6403), optionally wherein the amino acid sequence is present immediately subsequent to position 450 and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455), numbered according to SEQ ID NO: 138. 296. The AAV particle of 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 of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138. 297. The AAV particle of 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 of ENVSGSPHSKA (SEQ ID NO: 3879), optionally wherein the amino acid sequence is present immediately subsequent to position 450 and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455), numbered according to SEQ ID NO: 138; corresponds to positions 451 to 461 of SEQ ID NO: 3904; or is present at positions 451 to 461 numbered according to SEQ ID NO: 3904or 981. 298. The AAV particle of 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 of KTENVSGSPHSKAQNQQT (SEQID NO: 3272), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138; corresponds to positions 449 to 466 of SEQ ID NO: 3904; or is present at positions 449 to 466 numbered according to SEQ ID NO: 3904or 981. 299. The AAV particle of 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, wherein the AAV capsid variant comprises an amino acid sequence encoded by: the nucleotide sequence of SEQ ID NO: 942; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 942; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942. 300. The AAV particle of 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, wherein the AAV capsid variant comprises an amino acid sequence encoded by: the nucleotide sequence of SEQ ID NO: 3; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 3; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3. 301. The AAV particle of 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, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 942; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 942; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942. 302. The AAV particle of 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, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 3; a nucleotide sequence comprising at least one, two,three, four, five, six, or seven modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 3; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3. 303. The AAV particle of any one of embodiments 262-302, wherein the amino acid sequence is present in loop IV of the AAV capsid variant. 304. The AAV particle of any one of embodiments 262-303, wherein the amino acid sequence is present immediately subsequent to position 448, 449, 450, 451, 452, 453, 454, or 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 305. The AAV particle of any one of embodiments 262-304, wherein the amino acid sequence replaces amino acids 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, and / or 460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and / or T460), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 306. The AAV particle of any one of embodiments 262-305, wherein the amino acid sequence is present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 307. The AAV particle of any one of embodiments 262-306, wherein the amino acid sequence is present immediately subsequent to position 453, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 308. The AAV particle of 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 present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 309. The AAV particle of 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, wherein the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO:941), wherein the amino acid sequence is present immediately subsequent to position 455 (e.g., present at positions 456-461), numbered according to the amino acid sequence of SEQ ID NO: 981. 310. The AAV particle of 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 SEQ ID NOs: 36, 138, or 981. 311. The AAV particle of any one of embodiments 308-310, 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 SEQ ID NOs: 36, 138, or 981. 312. The AAV particle of any one of embodiments 308-311, wherein the AAV capsid variant further comprises the substitutions I451E, N452R, and G453V, numbered according to any one of SEQ ID NOs: 36, 138, or 981. 313. The AAV particle of any one of embodiments 308-312, wherein the AAV capsid variant comprises: (i) E at position 451, R at position 452, and V at position 453, numbered according to any one of SEQ ID NOs: 36, 138, or 981; and (ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to any one of SEQ ID NOs: 36, 138, or 981 (e.g., at amino acids 456-461, numbered according to SEQ ID NO: 36 or 981). 314. The AAV particle of embodiment 308 or 309, which further comprises an amino acid other than I at position 451, an amino acid other than N at position 452, and / or G at position 453, numbered according to SEQ ID NO: 39 or 138. 315. The AAV particle of any one of embodiments 308, 309, or 314, which further comprises E at position 451, K at position 452, and / or M at position 453, numbered according to SEQ ID NO: 138 or 39. 316. The AAV particle of any one of embodiments 308, 309, 314, or 315, which further comprises the substitutions I451E, N452K, and G453M, numbered according to SEQ ID NO: 39 or 138. 317. The AAV particle of any one of embodiments 308, 309, or 314-316, which comprises: (i) E at position 451, K at position 452, and M at position 453, numbered according to SEQ ID NO: 39 or 138; and(ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 39 or 138. 318. The AAV particle of embodiment 308 or 309, which further comprises 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 SEQ ID NO: 138. 319. The AAV particle of any one of embodiments 308, 309, or 318, which further comprises H at position 454, D at position 455, and / or L at position 458, numbered according to SEQ ID NO: 138. 320. The AAV particle of any one of embodiments 308, 309, 318, or 319, which further comprises the substitutions S454H, G455D, and Q458L, numbered according to SEQ ID NO: 138. 321. The AAV particle of any one of embodiments 308, 309, or 318-320, which comprises: (i) H at position 454, D at position 455, and / or L at position 458, numbered according to SEQ ID NO: 138; and (ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138. 322. The AAV particle of embodiment 308 or 309, which further comprises 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 SEQ ID NO: 52 or 138. 323. The AAV particle of any one of embodiments 308, 309, or 322, which further comprises V at position 451, H at position 454, and / or D at position 455, numbered according to SEQ ID NO: 52 or 138. 324. The AAV particle of any one of embodiments 308, 309, 322, or 323, wherein the AAV capsid variant further comprises the substitutions I451V, S454H, and / or G455D, numbered according to SEQ ID NO: 52 or 138. 325. The AAV particle of any one of embodiments 308, 309, or 322-324, wherein the AAV capsid variant comprises: (i) V at position 451, H at position 454, and / or D at position 455, numbered according to SEQ ID NO: 52 or 138; and(ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 52 or 138. 326. The AAV particle of 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 SEQ ID NO: 138. 327. The AAV particle of 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 SEQ ID NO: 138 or 3904. 328. The AAV particle of any one of embodiments 308, 309, 326, or 327, wherein the AAV capsid variant comprises: (i) E at position 451 and V at position 453, numbered according to SEQ ID NO: 3904 or 138; and (ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, at positions 456-461, numbered according to SEQ ID NO: 3904 or 138. 329. The AAV particle of embodiment 308 or 309, wherein the AAV capsid variant comprises: (i) E at position 451, K at position 452, and V at position 453, numbered according to SEQ ID NO: 3905 or 138; and the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, at positions 456-461, numbered according to SEQ ID NO: 3905 or 138; (ii) S at position 451, A at position 453, and H at position 462, numbered according to SEQ ID NO: 4; and the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, at positions 456-461, numbered according to SEQ ID NO: 4 or 138; (iii) N at position 450, S at position 451, and I at position 452, numbered according to SEQ ID NO: 5 or 138; and the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, at positions 456-461, numbered according to SEQ ID NO: 5 or 138; or (iv) A at position 450 and E at position 451, numbered according to SEQ ID NO: 7 or 138; and the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, at positions 456-461, numbered according to SEQ ID NO: 7 or 138. 330. The AAV particle of any one of embodiments 308, 309, or 329, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 3241, 3272, 3274, 3382, 3421, 3487, 3589, 4100, optionally wherein:(i) the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138; or (ii) the amino acid sequence is present at positions 449-466, numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981, or 982. 331. The AAV particle of 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, or 302-307, wherein the AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453 (e.g., at positions 454-459), numbered relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 332. The AAV particle of 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, wherein the AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 333. The AAV particle of embodiment 332, wherein the AAV capsid variant comprises: (i) V at position 451, R at position 463, P at position 464, and S at position 465, numbered according to SEQ ID NO: 6 or 982; (ii) the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, at positions 454-459, numbered relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 6 or 982. 334. The AAV particle of embodiment 332 or 333, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 1754, 4062, 4100, or 4478, optionally wherein: (i) the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138; or (ii) the amino acid sequence is present at positions 449-466, numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981 or 982.335. The AAV particle of 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, or 332, wherein the AAV capsid variant comprises the amino acid sequence of SPHKSG (SEQ ID NO: 946), wherein the amino acid sequence is present immediately subsequent to position 455 (e.g., at positions 456-461), numbered relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 336. The AAV particle of embodiment 335, wherein the AAV capsid variant comprises: (i) K at position 464, T at position 465, and S at position 466, numbered according SEQ ID NO: 3906; and the amino acid sequence of SPHKSG (SEQ ID NO: 946), wherein the amino acid sequence is present immediately subsequent to position 455, at positions 456-461, numbered relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 3906; or (ii) P at position 466, numbered according SEQ ID NO: 8; and the amino acid sequence of SPHKSG (SEQ ID NO: 946), wherein the amino acid sequence is present immediately subsequent to position 455, at positions 456-461, numbered relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 8. 337. The AAV particle of embodiment 335 or 336, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 4081 or 5440, optionally wherein: (i) the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138; or (ii) the amino acid sequence is present at positions 449-466, numbered according to any one of SEQ ID NOs: 3904, 3905, 3906, 4, 5, 6, 7, 8, 36-59, 981 or 982. 338. The AAV particle of 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, wherein the AAV capsid variant comprises: (i) the amino acid sequence of HDSPHSKA (SEQ ID NO: 5519), which is present immediately subsequent to position 453; and (ii) a deletion of amino acids SG at position 454 and 455; wherein (i) and (ii) are numbered according to SEQ ID NO: 138.339. The AAV particle of 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 331-338, wherein the AAV capsid variant comprises the amino acids HD at position 454 and 455, and further comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), which is present immediately subsequent to position 455, numbered relative to SEQ ID NO: 138. 340. The AAV particle of any one of embodiments 331-339, 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 SEQ ID NO: 138 or 982. 341. The AAV particle of any one of embodiments 331-340, wherein the AAV capsid variant further comprises A at position 450, E at position 451, and I at position 452, numbered according to SEQ ID NO: 138 or 982. 342. The AAV particle of any one of embodiments 331-341, wherein the AAV capsid variant further comprises the substitutions T450A, I451E, and N452I, numbered according to SEQ ID NO: 138 or 982. 343. The AAV particle of any one of embodiments 331-342, wherein the AAV capsid variant comprises: (i) A at position 450, E at position 451, and I at position 452, numbered according to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of HDSPHK (SEQ ID NO: 2), which is present immediately subsequent to positions 453, numbered according to SEQ ID NO: 138 or 982. 344. The AAV particle of 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 present immediately subsequent to position 455, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 345. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 982.346. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 981. 347. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 37, and optionally further comprising: (i) one, two, or all of 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, numbered according to SEQ ID NO: 138 or 37; (ii) one, two, or all of A at position 450, E at position 451, and / or I at position 452, numbered according to SEQ ID NO: 138 or 37. 348. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting 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), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of any one of SEQ ID NO: 36, 38-55, 57, or 59. 349. The AAV particle of embodiment 348, which comprises the amino acid E at position 451, numbered according to SEQ ID NO: 3904, 981, or 138. 350. The AAV particle of embodiment 348 or 349, which comprises the amino acid V at position 453, numbered according to SEQ ID NO: 3904, 981, or 138. 351. The AAV particle of any one of embodiments 348-350, which comprises the amino acid E at position 451 and the amino acid V at position 453, numbered according to SEQ ID NO: 3904, 981, or 138. 352. The AAV particle of any one of embodiments 348-351, which comprises the amino acid R at position 452, numbered according to SEQ ID NO: 36, 981, or 138.353. The AAV particle of any one of embodiments 348-352, which comprises the amino acid E at position 451, the amino acid R at position 452, and the amino acid V at position 453, numbered according to SEQ ID NO: 36, 981, or 138. 354. The AAV particle, of any one of the preceding embodiments, wherein the AAV capsid variant further comprises: (i) a modification, e.g., an insertion, substitution (e.g., conservative substitution), and / or deletion, in loop I, II, VI and / or VIII; and / or (ii) a substitution at position K449, e.g., a K449R substitution, numbered according to SEQ ID NO: 138. 355. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises: (i) an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 138; or (ii) an amino acid sequence comprising at least one, two or three, but no more than 30, 20 or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 138. 356. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 138, or an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 357. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 138. 358. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 137, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 359. The AAV particle of any one of the preceding embodiments, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 137, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 360. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof.361. The AAV particle of any one of embodiments 1-360, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 138-742, e.g., a VP2, of SEQ ID NO: 981, 982, 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 362. The AAV particle of any one of embodiments 1-360, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 203-742, e.g., a VP3, of SEQ ID NO: 981, 982, 3904, 3905, 3906, 4, 5, 6, 7, 8, or 36-59, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 363. The AAV particle of any one of embodiments 1-360, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 138-736, e.g., a VP2, of SEQ ID NO: 138, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 364. The AAV particle of any one of embodiments 1-360, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 203-736, e.g., a VP3, of SEQ ID NO: 138, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 365. The AAV particle of 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, 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), wherein: (i) the at least 3 consecutive amino acids comprise SPH; (ii) the at least 4 consecutive amino acids comprise SPHS (SEQ ID NO: 63); (iii) the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 64); or (iv) the at least 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981; (b) a VP2 protein comprising the amino acid sequence of positions 138- 736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c).366. The AAV particle of 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 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), wherein: (i) the at least 3 consecutive amino acids comprise SPH; (ii) the at least 4 consecutive amino acids comprise SPHS (SEQ ID NO: 63); (iii) the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 64); or (iv) the at least 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941); wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 981. 367. The AAV particle of 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, wherein the AAV capsid variant comprises one or two, but no more than three substitutions relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 981; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 981; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). 368. The AAV particle of 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 365-367, wherein the AAV capsid variant comprises one or two, but no more than three substitutions relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981. 369. The AAV particle of any one of embodiments 365-368, wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138 or 981.370. The AAV particle of 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, 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 HDSPHK (SEQ ID NO: 2), wherein: (i) the at least 3 consecutive amino acids comprise HDS; (ii) the at least 4 consecutive amino acids comprise HDSP (SEQ ID NO: 65); (iii) the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 66); or (iv) the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 138- 736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982; (c) a 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 with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). 371. The AAV particle of 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, or 370, 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 HDSPHK (SEQ ID NO: 2), wherein: (i) the at least 3 consecutive amino acids comprise HDS; (ii) the at least 4 consecutive amino acids comprise HDSP (SEQ ID NO: 65); (iii) the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 66); or (iv) the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2); wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 982. 372. The AAV particle of 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, wherein the AAV capsid variant comprises one or two, but no more than three substitutions relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982;(b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-742 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-742 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). 373. The AAV particle of 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, 370-372, wherein the AAV capsid variant comprises one or two, but no more than three substitutions relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the AAV capsid variant comprises an amino acid sequence 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. 374. The AAV particle of any one of embodiments 370-373, wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to SEQ ID NO: 138 or 982. 375. The AAV particle of any one of embodiments 1-373, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NO: 981 or 982, or an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 376. The AAV particle of any one of embodiments 1-375, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 981 or 982. 377. The AAV particle of any one of embodiments, 1-376, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three, but not more than 30, 20 or 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 981 or 982. 378. The AAV particle of 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 375-377, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981, or an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.379. The AAV particle of 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 375-377, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 981. 380. The AAV particle of 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 one, two or three, but not more than 30, 20 or 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 981. 381. The AAV particle of 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, or 370-377, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 382. The AAV particle of 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, 370-377, or 381, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 982. 383. The AAV particle of 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, 370-377, 381, or 382, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three, but not more than 30, 20 or 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 982.384. The AAV particle of any one of embodiments 1-383, wherein the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 983 or 984, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 385. The AAV particle of any one of the preceding embodiments 1-384, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NOs: 983 or 984, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 386. The AAV particle of any one of the preceding 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, 375-380, 384, or 385, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 387. The AAV particle of any one of the preceding 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, 370-377, 381, or 382-385, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 388. The AAV particle of any one of the preceding embodiments, wherein the nucleotide sequence encoding the AAV capsid variant is codon optimized. 389. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981. 390. The AAV particle of embodiment 389, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence at least 90%, 95%, or 99% identical thereto.391. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982. 392. The AAV particle of embodiment 391, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence at least 90%, 95%, or 99% identical thereto. 393. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 36-59, 3904, 3905, 3906, 4, 5, 6, 7, or8. 394. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), comprising an amino acid sequence encoded by the nucleotide sequence of any one of SEQ ID NOs: 9, 3907, 3908, 3909, 3910, 3911, 3912, 3913, 3914, 3915, 3916, or 22-35, or a nucleotide sequence at least 95% identical thereto. 395. The AAV particle of embodiment 393 or 394, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of any one of SEQ ID NOs: 9, 3907, 3908, 3909, 3910, 3911, 3912, 3913, 3914, 3915, 3916, or 22-35, or a nucleotide sequence at least 95% identical thereto. 396. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138. 397. The AAV particle of any one of embodiments 1-396, wherein the AAV capsid variant transduces a brain region, e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN), optionally wherein the level of transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65-fold greater as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 3.398. The AAV particle of any one of embodiments 1-397, wherein the AAV capsid variant transduces a brain region, e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN), optionally wherein the level of transduction is at least 30, 35, 40, 45, 50, 55, 60, or 65-fold greater as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 3. 399. The AAV particle of any one of embodiments 1-398, wherein the AAV capsid variant is enriched at least about 3, 4, 5, 6, 7, 8, 9, or 10-fold, in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 2. 400. The AAV particle of any one of embodiments 1-399, wherein the AAV capsid variant is enriched at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85-fold, in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 2. 401. The AAV particle of any one of embodiments 1-400, wherein the AAV capsid variant is enriched in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., mouse), e.g., as compared to a reference sequence of SEQ ID NO: 138. 402. The AAV particle of any one of embodiments 1-401, wherein the AAV capsid variant is enriched at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 190, 200, 205, or 210-fold, in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., mouse), compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 2 or 5. 403. The AAV particle of embodiment 401 or 402, wherein the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 outbred mice). 404. The AAV particle of any one of embodiments 1-403, wherein the AAV capsid variant delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 10, 12, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 3 or 7).405. The AAV particle of any one of embodiments 1-404, wherein the AAV capsid variant delivers an increased level of viral genomes to a brain region, optionally wherein the level of viral genomes is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 3 or 7). 406. The AAV particle of any one of embodiments 1-405, wherein the AAV capsid variant is capable of transducing: (i) is capable of transducing at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85, 90%, or 95% of cells in a brain region (e.g., a putamen, caudate, 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)) , e.g., when measured by an assay as described in Example 11; (ii) is capable of transducing at least 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% of astrocytes (e.g., Sox9+ astrocytes) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g., when measured by an assay as described in Example 11; and / or (iii) is capable of transducing at least 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, or 70% of neurons (e.g., NeuN+ neurons) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g., when measured by an assay as described in Example 11. 407. The AAV particle of any one of embodiments 399-406, wherein the brain region is a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN). 408. The AAV particle of any one of embodiments 1-407, wherein the AAV capsid variant is enriched at least about 5, 10, 15, 20, 25, 30, or 35-fold, in the spinal cord compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 2 or 7, optionally wherein the region of the spinal cord is a thoracic spinal cord region, cervical spinal cord region, C5 ventral horn region, lumbar spinal cord region, or L5 ventral horn region. 409. The AAV particle of any one of claims 1-408, 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., the cervical spinal cord, the thoracic spinal cord, or the lumbar spinal cord), e.g., when measured by an assay as described in Example 11. 410. The AAV particle of any one of embodiments 1-409, wherein the AAV capsid variant shows preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG). 411. The AAV particle of any one of embodiments 1-410, wherein the AAV capsid variant shows preferential transduction in a brain region relative to the liver. 412. The AAV particle of any one of embodiments 1-411, wherein the AAV capsid variant shows preferential transduction in a brain region relative to the transduction in the heart. 413. The AAV particle of any one of embodiments 1-412, wherein the AAV capsid variant shows preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG) and the heart. 414. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing neuronal cells, e.g., NeuN+ neurons or dopaminergic neurons (e.g., dopaminergic neurons in the substantia nigra), e.g., tyrosine hydroxylase (TH)+ neurons. 415. The AAV particle of any one of the preceding 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). 416. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing non-neuronal cells, e.g., glial cells (e.g., oligodendrocytes or astrocytes). 417. The AAV particle of embodiment 416, wherein the non-neuronal cells comprise glial cells, oligodendrocytes (e.g., Olig2 positive oligodendrocytes), or astrocytes (e.g., Olig2 positive astrocytes or Sox9+ astrocytes). 418. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing Olig2 positive cells, e.g., Olig2 positive astrocytes or Olig2 positive oligodendrocytes. 419. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing Sox9+ cells, e.g., Sox9+ astrocytes.420. The AAV particle of any one of the preceding embodiments, wherein the encoded polynucleotide for inhibiting MAPT comprises an a siRNA, a shRNA, a pre-miRNA, a pri-miRNA, a miRNA, a stRNA, a lncRNA, a piRNA, an antisense oligonucleotide agent (ASO), or a snoRNA. 421. The AAV particle of any one the preceding embodiments, wherein the encoded polynucleotide for inhibiting MAPT comprises an a siRNA comprises a sense strand sequence and antisense strand sequence. 422. The AAV particle of embodiment 420 or 421, wherein the encoded siRNA binds to a 3’ UTR of MAPT (e.g., human MAPT). 423. The AAV particle of any one of embodiments 420-422, wherein the encoded siRNA binds to a coding region of MAPT (e.g., human MAPT). 424. The AAV particle of any one of embodiments 420-423, wherein the encoded siRNA binds to a 5’ UTR of MAPT (e.g., human MAPT). 425. The AAV particle of any one of embodiments 420-424, wherein the MAPT is a human MAPT gene, a non-human primate MAPT gene, or a mouse MAPT gene. 426. The AAV particle of any one embodiments 420-425, wherein the antisense strand comprises at least one mismatch with the target mRNA. 427. The AAV particle of any one of embodiments 420-426, wherein the encoded siRNA comprises a sense strand sequence and an antisense strand sequence, wherein the antisense sequence is complementary to at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides comprising 0, 1, 2, or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3A or 19. 428. The AAV particle of any one of embodiments 421-427, wherein the encoded antisense strand is complementary to at least 15, 16, 17, 18, 19, 20, or 21, contiguous nucleotides with 0, 1, 2, or 3 mismatches to an exon of a MAPT sequence, wherein the exon comprises nucleotides 1277 to 1332 of SEQ ID NO: 5024, nucleotides 1712-1977 of SEQ ID NO: 5024, or nucleotides 2266-6644 of SEQ ID NO: 5024.429. The AAV particle of any one of embodiments 421-428, wherein the encoded antisense strand is complementary to at least 15, 16, 17, or 18, contiguous nucleotides with 0, 1, 2, or 3 mismatches to nucleotides 1300-1317, 1305-1322, 1860-1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584- 2601, 2633-2650, or 2634-2653 of SEQ ID NO: 5024. 430. The AAV particle of any one of embodiments 421-429, wherein the encoded sense strand comprises: (i) at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides comprising 0, 1, 2, or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3A or 19; (ii) at least 15, 16, 17, 18, 19, 20, or 21, contiguous nucleotides with 0, 1, 2, or 3 mismatches to an exon of a MAPT sequence, wherein the exon comprises nucleotides 1277 to 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, contiguous nucleotides with 0, 1, 2, or 3 mismatches to nucleotides 1300-1317, 1305-1322, 1860-1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584-2601, 2633- 2650, or 2634-2653 of SEQ ID NO: 5024. 431. The AAV particle of any one of embodiments 421-430, wherein the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 4A, 5A, 9A, or 9B. 432. The AAV particle of any one of embodiments 421-431, wherein the encoded sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Tables 4A, 5A, 9A, or 9B. 433. The AAV particle of any one of embodiments 421-432, wherein the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 4A, 5A, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Tables 4A, 5A, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides. 434. The AAV particle of embodiment 433, wherein the region of complementarity is 15-30, 19-21, or 25-30 nucleotides in length, e.g., 17, 18, 20, 21, 22, 25, or 30 nucleotides in length.435. The AAV particle of any one of embodiments 421-434, wherein: (i) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4502- 4505; (ii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998; (iii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4495- 4499; (iv) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one 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 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480- 4484; (vi) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (vii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4694 andthe encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4492; (viii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4691 and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4485- 4489; (ix) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (x) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4506- 4510; (xi) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (xii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4687 and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4477; (xiii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4712 and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4521; (xiv) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing 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 contiguous nucleotides differing 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 contiguous nucleotides differing by 3, 2, 1, or 0 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 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4527. 436. The AAV particle of any one of embodiments 421-435, wherein: (i) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4502-4505; (ii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous 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 contiguous nucleotides differing from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998; (iii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4495-4499; (iv) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one 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 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480-4484; (vi) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (vii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4694 and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4492;(viii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4691 and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4485-4489; (ix) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (x) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4506-4510; (xi) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (xii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4687 and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4477; (xiii) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4712 and the encoded sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4521; (xiv) the encoded antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous 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 contiguous 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 contiguous 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 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4527. 437. The AAV particle of any one of embodiments 421-436, wherein:(i) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and (ii) the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 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, 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; wherein the encoded sense strand sequence and the encoded antisense strand sequence comprise a region of complementarity of at least 15 nucleotides. 438. The AAV particle of any one of embodiments 433-437, wherein the region of complementarity comprises at least 18, 19, or 20 nucleotides. 439. The AAV particle of any one of embodiments 421-438, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, or 4912. 440. The AAV particle of any one of embodiments 421-439, wherein the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010. 441. The AAV particle of any one of embodiments 421-440, wherein: (i) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998; (iii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022;(iv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (v) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (vi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122; (vii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132, 5136, 5140, 5144, or 5146; (viii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5077, 5084, 5088, 5092, 5096, or 5098; or (ix) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074. 442. The AAV particle of any one of embodiments 421-441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4906. 443. The AAV particle of any one of embodiments 421-441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4918.444. The AAV particle of any one of embodiments 421-441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4922. 445. The AAV particle of any one of embodiments 421-441 wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4966. 446. The AAV particle of any one of embodiments 421-441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4970. 447. The AAV particle of any one of embodiments 421-441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4978. 448. The AAV particle of any one of embodiments 421-441, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4982. 449. The AAV particle of any one of embodiments 421-441, wherein: (i) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4910; (ii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4914;(iii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5054; (iv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4926; (v) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4930; (vi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4934; (vii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4938; (viii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4942; (ix) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5060; (x) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4946; (xi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4950; (xii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4954;(xiii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958; (xiv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4962; (xv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5064; (xvi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4974; (xvii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5066; (xviii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4986; (xix) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4990; (xx) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4994; (xxi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequencecomprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4998; (xxii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5002; (xxiii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5070; (xxiv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5006; (xxv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5010; (xxvi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5014; (xxvii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958; (xxviii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5022; (xxvii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5074;(xxix) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5077; (xxx) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5084; (xxxi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5088; (xxxii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5092; (xxxiii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5096; (xxxiv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5098; (xxxv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5101; (xxxvi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5108; (xxxvii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequencecomprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5112; (xxxviii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5116; (xxxix) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5120; (xl) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5122; (xli) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5125; (xlii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5132; (xliii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5136; (xliv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5140; (xlv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5144; or(xlvi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5146. 450. The AAV particle of any one of embodiments 421-449, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, or 4912. 451. The AAV particle of any one of embodiments 421-450, wherein the encoded sense strand sequence comprises at least 20 contiguous nucleotides of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010. 452. The AAV particle of any one of embodiments 421-451, wherein: (i) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998; (iii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (iv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (v) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014;(vi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122; (vii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132, 5136, 5140, 5144, or 5146; (viii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5077, 5084, 5088, 5092, 5096, or 5098; or (ix) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074. 453. The AAV particle of any one of embodiments 421-442 or 450-452, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4906. 454. The AAV particle of any one of embodiments 421-441, 443, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4918. 455. The AAV particle of any one of embodiments 421-441, 444, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4922. 456. The AAV particle of any one of embodiments 421-441, 445, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO:4908 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4966. 457. The AAV particle of any one of embodiments 421-441, 446, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4970. 458. The AAV particle of any one of embodiments 421-441, 447, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4978. 459. The AAV particle of any one of embodiments 421-441, 448, or 450-452, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4982. 460. The AAV particle of any one of embodiments 421-441, or 449-452, wherein: (i) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4910; (ii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4914; (iii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5054; (iv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4926; (v) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4930;(vi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4934; (vii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4938; (viii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4942; (ix) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5060; (x) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4946; (xi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4950; (xii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4954; (xiii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958; (xiv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4962; (xv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5064; (xvi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4974;(xvii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5066; (xviii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4986; (xix) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4990; (xx) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4994; (xxi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4998; (xxii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5002; (xxiii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5070; (xxiv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5006; (xxv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5010; (xxvi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5014; (xxvii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958;(xxviii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5022; (xxvii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5074; (xxix) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5077; (xxx) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5084; (xxxi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5088; (xxxii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5092; (xxxiii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5096; (xxxiv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5098; (xxxv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5101; (xxxvi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5108; (xxxvii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5112;(xxxviii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5116; (xxxix) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5120; (xl) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5122; (xli) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5125; (xlii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5132; (xliii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5136; (xliv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5140; (xlv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5144; or (xlvi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5146. 461. The AAV particle of any one of embodiments 421-460, wherein the encoded antisense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4908, 4920, 4924, or 4912. 462. The AAV particle of any one of embodiments 421-461, wherein the encoded sense strand sequence comprises at the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006,4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010. 463. The AAV particle of any one of embodiments 421-462, wherein: (i) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises the nucleotide sequence of any one 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 the nucleotide sequence of any one 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 the nucleotide sequence of any one 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 the nucleotide sequence of any one 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 the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (vi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122; (vii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132, 5136, 5140, 5144, or 5146; (viii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the encoded sense strand sequence comprises the nucleotide sequence of any one 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; and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074.464. The AAV particle of any one of embodiments 421-442, 450-452, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4906. 465. The AAV particle of 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. 466. The AAV particle of 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. 467. The AAV particle of any one of embodiments 421-441, 445, 450-452, 456, or 461-463, wherein the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4966. 468. The AAV particle of 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. 469. The AAV particle of 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. 470. The AAV particle of any one of embodiments 421-441, 448, 450-452, 459, 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: 4982. 471. The AAV particle of any one of embodiments 421-441, 449-452, or 460-463, wherein: (i) 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: 4910; (ii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and 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 SEQ ID NO: 5104; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5112; (xxxviii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and 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; and 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; and 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 SEQ ID NO: 5128; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5125; (xlii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5132; (xliii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and 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; and 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; and 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; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146. 472. The AAV particle of any one of embodiments 421-471, wherein: (i) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4700 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4502-4505; (ii) 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 any one 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 the nucleotide sequence of any one of SEQ ID NOs: 4495-4499; (iv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the encoded sense strand sequence comprises the nucleotide sequence of any one 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 contiguous 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 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480-4484; (vi) 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 any one of SEQ ID NOs: 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 the nucleotide sequence of any one of SEQ ID NOs: 4485-4489; (ix) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916 and the encoded sense strand sequence comprises the nucleotide sequence of any one 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 the nucleotide sequence of any one of SEQ ID NOs: 4506-4510; (xi) 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 any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (xii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4687 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4477; (xiii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4712 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4521; (xiv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4696 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4494; or(xv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4718 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4527. 473. The AAV particle of any one of embodiments 421-427, wherein (i) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4420 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (ii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4905 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (iii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4421 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (iv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4909 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (v) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4422 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (vi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4913 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (vii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4423 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (viii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4917 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (ix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4424 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (x) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4921 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923;(xi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4410 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (xii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4925 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (xiii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4411 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (xiv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4929 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (xv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4412 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xvi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4933 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xvii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4413 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (xviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4937 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4419; (xix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4414 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (xx) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4941 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (xxi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4415 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434;(xxii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4945 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (xxiii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4416 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (xxiv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4949 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (xxv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4417 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xxvi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4953 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xxvii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4418 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (xxviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4957 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (xxix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4419 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (xxx) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4961 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (xxxi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4420 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (xxxii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4965 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907;(xxxii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4421 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (xxxiii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4969 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (xxxiv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4422 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xxxv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4973 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xxxvi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4423 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (xxxvii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4977 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (xxxviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4424 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (xxxix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4981 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (xl) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4425 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (xli) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4985 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (xlii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4426 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435;(xliii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4989 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (xliv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4427 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xlv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4993 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xlvi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4428 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (xlvii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4997 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (xlviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4429 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (xlix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5001 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (l) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4430 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (li) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5005 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (lii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4431 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (liii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5009 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911;(liv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4432 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (lv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5013 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (lvi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4433 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (lvii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5021 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (lviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5053 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5059 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lx) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5063 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5065 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5069 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxiii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5073 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxiv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5076 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079;(lxv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5083 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxvi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5087 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxvii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5091 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5095 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5097 and...

Claims

We claim:

1. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting 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, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises the amino acid sequence of SPH; and (iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid, e.g., a K or R; wherein [N1]-[N2]-[N3] is present in hypervariable loop IV; and wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:

138.

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

3. The AAV particle of claim 1 or 2, wherein [N2]-[N3] comprises SPHSKA (SEQ ID NO: 941), SPHKSG (SEQ ID NO: 946), SPHARM (SEQ ID NO: 947), SPHVKS (SEQ ID NO: 948), SPHASR (SEQ ID NO: 949), SPHVKI (SEQ ID NO: 950), SPHKKN (SEQ ID NO: 954), SPHVRM (SEQ ID NO: 955), SPHRKA (SEQ ID NO: 956), SPHKFG (SEQ ID NO: 957), SPHKIG (SEQ ID NO: 958), SPHKLG (SEQ ID NO: 959), SPHKTS (SEQ ID NO: 963), SPHKTT (SEQ ID NO: 964), SPHKTY (SEQ ID NO: 965), SPHKYG (SEQ ID NO: 966), SPHSKD (SEQ ID NO: 967), SPHSKP (SEQ ID NO: 968), SPHTRG (SEQ ID NO: 972), SPHVRG (SEQ ID NO: 973), SPHKRG (SEQ ID NO: 974), SPHGAR (SEQ ID NO: 975), SPHKSA (SEQ ID NO: 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: 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 (SEQ ID NO: 103), 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. The AAV particle of any one of claims 1-3, wherein [N1] comprises GSG, GHD, VSG, GQD, CSG, GRG, CSH, GQS, GSH, RVG, GSC, GLL, GDD, GHE, GNY, MSG, RNG, TSG, ISG, GPG, ESG, SSG, GNG, ASG, NSG, LSG, GGG, KSG, HSG, GTG, PSG, GSV, RSG, GIG, WSG, DSG, IDG, GLG, DAG, DGG, MEG, ENG, GSA, KNG, KEG, AIG, GYD, GHG, GRD, GND, GPD, GMG, GQV, GHN, GHP, or GHS.

5. The AAV particle of any one of claims 1-4, wherein [N1]-[N2]-[N3] comprises: (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), GSGSPHSRA (SEQ ID NO: 1114), GSGSPHSKR (SEQ ID NO: 1115), GSGSPHSLR (SEQ ID NO: 1116), GSGSPHSRG (SEQ ID NO: 1117), GSGSPHSSR (SEQ ID NO: 1118), RVGSPHSKA (SEQ ID NO: 1119), GSCSPHRKA (SEQ ID NO: 1120), GSGSPHFLR (SEQ ID NO: 1121), GSGSPHSKW (SEQ ID NO: 1122), GSGSPHSKS (SEQ ID NO: 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: 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).

6. The AAV particle of any one of claims 1-5, which further comprises: (i) [N0], wherein [N0] comprises TIN, TEN, TER, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW, ANN, IPE, ADM, IEY, ADY, IET, MEW, CEY, RIN, MEI, LEY, ADW, IEI, DIM, FEQ, MEF, CDQ, LPE, IEN, MES, AEI, VEY, IIN, TSN, IEV, MEM, AEV, MDA, VEW, AEQ, LEW, MEL, MET, MEA, IES, MEV, CEI, ATN, MDG, QEV, ADQ, NMN, IEM, ISN, TGN, QQQ, HDW, IEG, TII, TFP, TEK, EIN, TVN, TFN, SIN, TSY, ELH, AIN, SVN, TDN, TFH, TVH, TSS, TID, TCN, NIN, TEH, AEM, AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TIY, TFS, TES, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, NAD, TIT, NCV, TIR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV, SDI, NSI, NSL, EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, or NNL; and / or (ii) [N4], wherein [N4] comprises QNQQ (SEQ ID NO: 1198), WNQQ (SEQ ID NO: 1199), QYYV (SEQ ID NO: 1200), RRQQ (SEQ ID NO: 1201), GCGQ (SEQ ID NO: 1202), LRQQ (SEQ ID NO: 1203), RNQQ (SEQ ID NO: 1204), VNQQ (SEQ ID NO: 1205), FRLQ (SEQ ID NO: 1206), FNQQ (SEQ ID NO: 1207), LLQQ (SEQ ID NO: 1208), SNQQ (SEQ ID NO: 1209), RLQQ (SEQ ID NO: 1210), LNQQ (SEQ ID NO: 1211), QRKL (SEQ ID NO: 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 (SEQ ID NO: 1230), QNTH (SEQ ID NO: 1231), RRRQ (SEQ ID NO: 1232), QYQQ (SEQ ID NO: 1233), QNDQ (SEQ ID NO: 1234), QNRH (SEQ ID NO: 1235), RDQQ (SEQ ID NO: 1236), PNLQ (SEQ ID NO: 1237), HVRQ (SEQ ID NO: 1238), PNQH (SEQ ID NO: 1239), HNQQ (SEQ ID NO: 1240), QSQQ (SEQ ID NO: 1241), QPAK (SEQ ID NO: 1242), QNLA (SEQ ID NO: 1243), QNQL (SEQ ID NO: 1244), QGQQ (SEQ ID NO: 1245), LNRQ (SEQ ID NO: 1246), QNPP (SEQ ID NO: 1247), QNLQ (SEQ ID NO: 1248), QDQE (SEQ ID NO: 1249), QDQQ (SEQ ID NO: 1250), HWQQ (SEQ ID NO: 1251), PNQQ (SEQ ID NO: 1252), PEQQ (SEQ ID NO: 1253), QRTM (SEQ ID NO: 1254), LHQH (SEQ ID NO: 1255), QHRI (SEQ ID NO: 1256), QYIH (SEQ ID NO: 1257), QKFE (SEQ ID NO: 1258), QFPS (SEQ ID NO: 1259), QNPL (SEQ ID NO: 1260), QAIK (SEQ ID NO: 1261), QNRQ (SEQ ID NO: 1263), QYQH (SEQ ID NO: 1264), QNPQ (SEQ ID NO: 1265), QHQL (SEQ ID NO: 1266), QSPP (SEQ ID NO: 1267), QAKL (SEQ ID NO: 1268), KSQQ (SEQ ID NO: 1269), QDRP (SEQ ID NO: 1270), QNLG (SEQ ID NO: 1271), QAFH (SEQ ID NO: 1272), QNAQ (SEQ ID NO: 1273), HNQL (SEQ ID NO: 1274), QKLN (SEQ ID NO: 1275), QNVQ (SEQ ID NO: 1276), QAQQ (SEQ ID NO: 1277), QTPP (SEQ ID NO: 1278), QPPA (SEQ ID NO: 1279), QERP (SEQ ID NO: 1280), QDLQ (SEQ ID NO: 1281), QAMH (SEQ ID NO: 1282), QHPS (SEQ ID NO: 1283), PGLQ (SEQ ID NO: 1284), QGIR (SEQ ID NO: 1285), QAPA (SEQ ID NO: 1286), QIPP (SEQ ID NO: 1287), QTQL (SEQ ID NO: 1288), QAPS (SEQ ID NO: 1289), QNTY (SEQ ID NO: 1290), QDKQ (SEQ ID NO: 1291), QNHL (SEQ ID NO: 1292), QIGM (SEQ ID NO: 1293), LNKQ (SEQ ID NO: 1294), PNQL (SEQ ID NO: 1295), QLQQ (SEQ ID NO: 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: 1313), QGHH (SEQ ID NO: 1314), QSKV (SEQ ID NO: 1315), QLPS (SEQ ID NO: 1316), IGKQ (SEQ ID NO: 1317), QAIH (SEQ ID NO: 1318), QHGL (SEQ ID NO: 1319), QFMC (SEQ ID NO: 1320), QNQM (SEQ ID NO: 1321), QHLQ (SEQ ID NO: 1322), QPAR (SEQ ID NO: 1323), QSLQ (SEQ ID NO: 1324), QSQL (SEQ ID NO: 1325), HSQQ (SEQ ID NO: 1326), QMPS (SEQ ID NO: 1327), QGSL (SEQ ID NO: 1328), QVPA (SEQ ID NO: 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: 1346), RGLQ (SEQ ID NO: 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 IDNO: 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: 1380), QNLL (SEQ ID NO: 1381), QLVI (SEQ ID NO: 1382), RTQE (SEQ ID NO: 1383), QTHQ (SEQ ID NO: 1384), QDQH (SEQ ID NO: 1385), QSQH (SEQ ID NO: 1386), VRQQ (SEQ ID NO: 1387), AWQQ (SEQ ID NO: 1388), QSVP (SEQ ID NO: 1389), QNIQ (SEQ ID NO: 1390), LDQQ (SEQ ID NO: 1391), PDQQ (SEQ ID NO: 1392), ESQQ (SEQ ID NO: 1393), QRQL (SEQ ID NO: 1394), QIIV (SEQ ID NO: 1395), 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).

7. The AAV particle of claim 6, wherein [N0]-[N1]-[N2]-[N3]-[N4] comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 2242-2886; or (ii) TENVSGSPHSKAQNQQ (SEQ ID NO: 2283), TERVSGSPHSKAQNQQ (SEQ ID NO: 2272), TINGSGSPHSKAQNQQ (SEQ ID NO: 2242), or TINGHDSPHKSGQNQQ (SEQ ID NO: 2243).

8. The AAV particle of claim 6 or 7, wherein: (i) [N0] is present at amino acids 450-452, numbered according to SEQ ID NO: 981, 982, or 138; (ii) [N1] is present at amino acids 453-455, numbered according to SEQ ID NO: 981, 982, or 138; (iii) [N2] is present at amino acids 456-458, numbered according to SEQ ID NO: 981 or 982; (iv) [N3] is present at amino acids 459-461, numbered according to SEQ ID NO: 981 or 982; (v) [N4] is present at amino acids 462-465, numbered according to SEQ ID NO: 981 or 982; and / or (vi) [N0]-[N1]-[N2]-[N3]-[N4] is present at amino acids 450-465, numbered according to SEQ ID NO: 981 or 982.

9. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting 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 of positions 203-736 of SEQ ID NO:

138.

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

981.

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

981.

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

981.

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

981.

14. The AAV particle of any one of claims 1-13, wherein the AAV capsid variant comprises: (i) an amino acid sequence 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 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 at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 3904, 36, or 981.

15. The AAV particle of any one of claims 1-14, wherein the AAV capsid variant comprises: (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) the amino acid sequence of SEQ ID NO: 3904, 36, or 981.

16. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting 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 of positions 203-736 of SEQ ID NO:

138.

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

982.

18. The AAV particle of any one of claims 1-9, 16, or 17, wherein the AAV capsid variant comprises: (i) an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 982, 37, or 6; (ii) an amino acid sequence at least 95% or at least 98% identical to amino acids138-742 of SEQ ID NO: 982, 37, or 6; and / or (iii) an amino acid sequence at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 982, 37, or 6.

19. The AAV particle of any one of claims 1-9 or 16-18, wherein the AAV capsid variant comprises: (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) the amino acid sequence of SEQ ID NO: 982, 37, or 6.

20. The AAV particle of any one of claims 1-19, wherein hypervariable loop IV comprises amino acids 449- 460, numbered according to SEQ ID NO:

138.

21. The AAV particle of any one of claims 1-20, wherein the AAV capsid variant: (i) has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138; (ii) transduces a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)), optionally wherein the level of transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65-fold greater as compared to a reference sequence of SEQ ID NO: 138, e.g., whenmeasured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 3 or 7; (iii) is enriched 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-fold, in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1 or 4; (iv) has increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, of at least two to three species, e.g., a non-human primate and rodent (e.g., Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 outbred mice), relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138; (v) is enriched at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100-fold, in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 outbred mice), compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 2, 5, or 8; (vi) delivers an increased level of a payload to a brain region, optionally wherein 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-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2 or 8), optionally wherein the brain region is a midbrain region (e.g., the hippocampus or thalamus), frontal cortex, temporal cortex, motor cortex, cerebral cortex, caudate, putamen, dentate nucleus, substantia nigra, or the brainstem; (vii) delivers an increased level of viral genomes to a brain region, optionally wherein the level of viral genomes is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2 or 8), optionally wherein the brain region is a putamen, caudate, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)); (viii) is enriched at least about 5, 10, 15, 20, 25, 30, or 35-fold, in the spinal cord compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1 or 8, optionally wherein the region of the spinal cord is a thoracic spinal cord region, cervical spinal cord region, C5 ventral horn region, lumbar spinal cord region, or L5 ventral horn region; (ix) shows preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG) and / or the liver; (x) is capable of transducing neuronal cells and / or non-neuronal cells (e.g., astrocytes);(xi) is capable of transducing at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85, 90%, or 95% of cells in a brain region (e.g., a putamen, caudate, 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)) , e.g., when measured by an assay as described in Example 11; (xii) is capable of transducing at least 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% of astrocytes (e.g., Sox9+ astrocytes) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g., when measured by an assay as described in Example 11; (xiii) is capable of transducing at least 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, or 70% of neurons (e.g., NeuN+ neurons) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g., when measured by an assay as described in Example 11; and / or (xiv) 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., the cervical spinal cord, the thoracic spinal cord, or the lumbar spinal cord), e.g., when measured by an assay as described in Example 11.

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

23. The AAV particle of claim 22, wherein: (i) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 4A, 5A, 9A, or 9B; and / or (ii) the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Tables 4A, 5A, 9A, or 9B; wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.

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

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

26. The AAV particle of any one of claims 22-25, wherein: (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; (viii) 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: 4910; (ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4914; (x) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5054; (xi) 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: 4926; (xii) 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: 4930; (xiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and 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; and 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; and 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; and 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; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4946; (xviii) 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: 4950; (xix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4954; (xx) 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: 4958; (xxi) 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: 4962; (xxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and 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; and 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; and 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; and 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; and 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; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4994; (xxviii) 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: 4998; (xxix) 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: 5002; (xxx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and 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; and 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; and 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; and 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; and 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; and 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; and 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; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5077; (xxxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and 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; and 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; and 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; and 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; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5098; (xliii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5101; (xliv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and 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; and 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; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5116; (xlvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and 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; and 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; and 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; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5132; (li) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and 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; and 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; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5144; or (liv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146.

27. The AAV particle of any one of claims 22-26, wherein: (i) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4905; (ii) 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: 4917; (iii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4921; (iv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4965; (v) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911 and the nucleotide sequence encoding the sense strand sequence comprises 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 comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4981.

28. 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 a 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.

29. 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 a 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.

30. 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 a 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.

31. The AAV particle of any one of claims 22-30, wherein: (i) the sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence comprise at least 15-30, 19-21, or 25-30 nucleotides in length, e.g., 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 comprise an overhang, e.g., an overhang at the 5’ end of the sense strand sequence and / or at the 3’ end of the antisense strand sequence, of 1 or 2 nucleotides; (iii) the sense strand and the antisense strand comprise one mismatch; and / or (iv) the antisense strand and the target sequence comprise one mismatch.

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

33. The AAV particle of claim 32, wherein the modulatory polynucleotide further comprises one, two, three or all of: (i) a 5’ flanking region; (ii) a loop region; and (iii) a 3’ flanking region.

34. The AAV particle of claim 33, wherein: (A) (i) the 5’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4878- 4886; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886;(ii) the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4887-4896; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; and / or (iii) the 3’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4897- 4904; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904; and / or (B) (i) the nucleotide sequence encoding the 5’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395; (ii) the nucleotide sequence encoding the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4362-4371; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4362-4371; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4362-4371; and / or (iii) the nucleotide sequence encoding the 3’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 4372-4379; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4372-4379; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4372-4379.

35. The AAV particle of any one of claims 32-34, wherein the modulatory polynucleotide comprises:(A) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4887; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; (B) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprisingone, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; (C) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4887; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4899, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4899; or (D) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4891, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4900, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotidesrelative to the nucleotide sequence of SEQ ID NO: 4900, or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900.

36. The AAV particle of any one of claims 32-35, wherein the modulatory polynucleotide comprises in 5’ to 3’ order: (i) the 5’ flanking region, sense strand sequence, loop region, antisense strand sequence, and 3’ flanking region; or (ii) the 5’ flanking region, antisense strand sequence, loop region, sense strand sequence, and 3’ flanking region.

37. The AAV particle of any one of claims 32-36, wherein the modulatory polynucleotide comprises in 5’ to 3’ order: (A) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4906; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4908; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900; (B) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three,four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4918; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4920; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900; (C) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4922; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4924; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900; (D) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotidesequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4966; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; (E) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4970; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898;(F) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4978; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; or (G) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4982; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO:4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898.

38. The AAV particle of any one of claims 32-37, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises in 5’ to 3’ order: (A) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4905; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4907; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375; (B) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4917; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4919; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375; (C) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4921; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4923; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375; (D) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4965;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373; (E) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4969; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373; (F) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two,three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4977; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373; or (G) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4981; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373.

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

40. 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 comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

41. 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 comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

42. 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 comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

43. The AAV particle of any one of claims 1-42, which comprises a viral genome comprising a promoter operably linked to the nucleic acid encoding the polynucleotide for inhibiting human MAPT.

44. The AAV particle of claim 43, wherein the promoter: (i) is a ubiquitous promoter; (ii) is a cell or tissue specific promoter; (iii) is chosen from human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) immediate- early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), a cardiovascular promoter (e.g., αMHC,cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a functional fragment, e.g., a truncation, or a functional variant thereof; (iii) is a CBA promoter or variant thereof; (iv) a synapsin promoter or variant thereof; (v) comprises the nucleotide sequence of any one of the nucleotide sequences provided in Table 2; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to any one of the nucleotide sequences provided in Table 2; or a nucleotide sequence with at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the nucleotide sequences provided in Table 2; (vi) comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5199; or (vii) comprises the nucleotide sequence of SEQ ID NO: 3883; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 3883; or a nucleotide sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3883.

45. The AAV particle of claim 43 or 44, wherein the viral genome further comprises: (i) at least one or two inverted terminal repeat (ITR) sequences, optionally wherein the AAV viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA and / or an ITR sequence positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA; (ii) a polyadenylation (polyA) signal sequence; (iii) an enhancer, a Kozak sequence, an intron region, and / or an exon region; and / or (iv) a nucleotide sequence encoding a microRNA (miR) binding site, e.g., a miR binding site that modulates, e.g., reduces expression of payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed; optionally wherein the encoded miR binding site modulates, e.g., reduces expression of the payload encoded by the viral genome in a cell or tissue of the DRG, liver, heart, hematopoietic lineage, or a combination thereof.

46. The AAV particle of claim 45, wherein: (i) the ITR positioned 5’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197 or 5503; a nucleotide sequence comprising at leastone, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197 or 5503; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197 or 5503; (ii) the ITR positioned 3’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 5504; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200 or 5504; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5200 or 5504; (iii) the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 4476; (iv) the enhancer comprises a CMVie enhancer or variant thereof; (v) the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471 or 4472; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471 or 4472; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4471 or 4472; and / or (vi) the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4475.

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

48. The AAV particle of any one of claims 43-47, wherein the viral genome comprises in 5’ to 3’ order: (A) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (B) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 3883; at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 3883; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence 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 comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; or (C) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4469; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4469; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4472; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4472; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4472; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or anucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4470; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4470.

49. The AAV particle of any one of claims 43-48, which comprises in 5’ to 3’ order: (A) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4405, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or anucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (B) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 3883; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 3883; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4405, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence 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 comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (C) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4408, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (D) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than tenmodifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4409, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (E) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4390, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (F) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4391, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and(vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (G) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4393, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; or (H) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or anucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence 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 modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4394, or nucleotide sequence 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 one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.

50. The AAV particle of any one of claims 43-49, which comprises the nucleotide sequence of any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194, 3886-3893, or 5473-5502, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194 or 5473- 5502.

51. 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, 3886, 5195, or 5184.

52. 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, 3886, 5195, or 5184.

53. 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, 3886, 5195, or 5184.

54. A cell comprising the AAV particle of any one of claims 1-53, optionally wherein, the cell is: (a) a mammalian cell or an insect cell; (b) a cell of a brain region or a spinal cord region (e.g., a CNS cell); (c) a cell of the brain or the spinal cord (e.g., a cell of a putamen, caudate, 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) a neuron or an astrocyte.

55. A method of making the AAV particle of any one of claims 1-53, comprising: (i) providing a host cell comprising a AAV viral genome; (ii) incubating the host cell under conditions suitable to enclose the viral genome in an AAV capsid protein; thereby making the AAV particle.

56. A pharmaceutical composition comprising the AAV particle of any one of claims 1-53, and a pharmaceutically acceptable excipient.

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

58. The method of claim 57, wherein the cell is: (a) a mammalian cell or an insect cell;(b) a cell of a brain region or a spinal cord region (e.g., a CNS cell); (c) a cell of the brain or the spinal cord (e.g., a cell of a putamen, caudate, 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) a neuron or an astrocyte; and / or (e) in a subject.

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

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

61. The method of claim 59 or 60, wherein the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy is Alzheimer’s disease (AD), Frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism linked to 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’s syndrome, Pick’s disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), Prion diseases, CJD, Multiple system atrophy, mild cognitive impairment, Tangle-only dementia, or Progressive subcortical gliosis.

62. The method of claim 60 or 61, wherein treating comprises prevention of progression of the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy in the subject in the subject.

63. The method of any one of claims 60-62, further comprising performing a blood test, an imaging test (e.g., a PET scan or a PET scan in combination with biomarker, e.g., serum biomarker staining), a CNS biopsy sample, or an aqueous cerebral spinal fluid biopsy, optionally wherein the blood test, imaging test, biopsysample, or aqueous cerebral spinal fluid biopsy is performed prior to, during, or after treatment with the AAV particle, modulatory polynucleotide, siRNA, or pharmaceutical composition.

64. The method of any one of claims 60-63, wherein the pharmaceutical composition or AAV particle are administered to the subject: (i) intravenously, via intra-cisterna magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly; (ii) via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration; (iii) intravenously.

65. The pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, for use in a method of delivering an siRNA for inhibiting MAPT expression to a cell.

66. The pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, for use in the treatment of a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy.

67. Use of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, in the manufacture of a medicament for delivering an siRNA for inhibiting MAPT expression to a cell.

68. Use of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, in the manufacture of a medicament for treating a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy.

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