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 MAPT RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 606,391 filed on December 5, 2023, and U.S. Provisional Application No.63 / 667,316 filed on July 3, 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 V2071-3043PCT_SL.xml, was created on November 8, 2024, and is 3,165,764 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 a modulatory polynucleotide encoding a siRNA duplex for targeting MAPT. Methods for treating diseases associatedMAPT 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] (SEQ ID NO: 4681), wherein [N2] comprises the amino acid sequence of DWHR (SEQ ID NO: 4682) and wherein (i) [N1] comprises positions X1, X2, X3, and X4, wherein position X4is Q, K, E, S, P, R, N, H, or a conservative substitution thereof; and / or (ii) [N3] comprises positions X5, X6, and X7, wherein position X5is I, V, T, M, S, N, L, F, or a conservative substitution thereof. In some embodiments, position X4of [N1] is Q. In some embodiments, position X4of [N1] is K. In some embodiments, position X5of [N3] is I. In some embodiments, [N1] replaces positions 582-585 (e.g., T582, N583, H584, Q585), numbered according to SEQ ID NO: 138. In some embodiments, [N1] corresponds to positions 582-585 (e.g., T582, N583, T584, Q585) of SEQ ID NO: 981. In some embodiments, [N1] is present at positions 582-585, numbered according to SEQ ID NO: 981. In some embodiments, X1of [N1] is present at position 582, X2of [N1] is present at position 583, X3of [N1] is present at position 584, and X4of [N1] is present at position 585, numbered according to SEQ ID NO: 981. In some embodiments, [N2] replaces positions 586-589 (e.g., S586, A587, Q588, A589), numbered according to SEQ ID NO: 138. In some embodiments [N2] corresponds to positions 586-589 (e.g., D586, W587, H588, and R589) of SEQ ID NO: 981. In some embodiments, [N2] is present at positions 586-589, numbered according to SEQ ID NO: 981. In some embodiments [N3] replaces positions 590-592 (e.g., Q590, A591, Q592), numbered according to SEQ ID NO: 138. In some embodiments, [N3] corresponds to positions 590- 592 (e.g., I590, A591, Q592) of SEQ ID NO: 981. In some embodiments, [N3] is present at positions 590- 592, numbered according to SEQ ID NO: 981. In some embodiments, X5of [N3] is present at position 590, X6of [N3] is present at position 591, and X7of [N3] is present at position 592, numbered according to SEQ ID NO: 981. In some embodiments, [N1]-[N2] is present at positions 582-589, numbered according to SEQ ID NO: 981. In some embodiments, [N2]-[N3] is present at positions 586-592, numbered according to SEQ ID NO: 981. In some embodiments, [N1]-[N2]-[N3] is present at positions 582-592, numbered according to SEQ ID NO: 981.

[0007] 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: 4683), wherein [N2] comprises the amino acid sequence of DWHR (SEQ ID NO: 4682) and wherein (i) [N1] comprises positions X1, X2, X3, and X4, wherein position X4is Q, P, or a conservative substitution thereof; and / or (ii) [N3] comprisespositions X5, X6, and X7, wherein position X5is I, V, or a conservative substitution thereof. In some embodiments, position X4of [N1] is Q. In some embodiments, position X5of [N3] is I. In some embodiments, [N1] replaces positions 582-585 (e.g., T582, N583, H584, Q585), numbered according to SEQ ID NO: 138. In some embodiments, [N1] corresponds to positions 582-585 (e.g., T582, N583, T584, Q585) of SEQ ID NO: 981. In some embodiments, [N1] is present at positions 582-585, numbered according to SEQ ID NO: 981. In some embodiments, X1of [N1] is present at position 582, X2of [N1] is present at position 583, X3of [N1] is present at position 584, and X4of [N1] is present at position 585, numbered according to SEQ ID NO: 981. In some embodiments, [N2] replaces positions 586-589 (e.g., S586, A587, Q588, A589), numbered according to SEQ ID NO: 138. In some embodiments [N2] corresponds to positions 586-589 (e.g., D586, W587, H588, and R589) of SEQ ID NO: 981. In some embodiments, [N2] is present at positions 586- 589, numbered according to SEQ ID NO: 981. In some embodiments [N3] replaces positions 590-592 (e.g., Q590, A591, Q592), numbered according to SEQ ID NO: 138. In some embodiments, [N3] corresponds to positions 590-592 (e.g., I590, A591, Q592) of SEQ ID NO: 981. In some embodiments, [N3] is present at positions 590-592, numbered according to SEQ ID NO: 981. In some embodiments, X5of [N3] is present at position 590, X6of [N3] is present at position 591, and X7of [N3] is present at position 592, numbered according to SEQ ID NO: 981. In some embodiments, [N1]-[N2] is present at positions 582-589, numbered according to SEQ ID NO: 981. In some embodiments, [N2]-[N3] is present at positions 586-592, numbered according to SEQ ID NO: 981. In some embodiments, [N1]-[N2]-[N3] is present at positions 582-592, numbered according to SEQ ID NO: 981.

[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: (a) the amino acid sequence of any of the sequences provided in Tables 1, 2A, 2B, 9, 14, 15, 16, or 26-31; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, 14, 15, 16, or 26-31; (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 1, 2A, 2B, 9, 14, 15, 16, or 26-31; 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 1, 2A, 2B, 9, 14, 15, 16, or 26-31. In some embodiments, the amino acid sequence is present in loop VIII. In some embodiments, the amino acid sequence replaces positions 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, and / or 596 (e.g., T582, N583, H584, Q585, S586, A587, Q588, A589, Q590, A591, Q592, T593, G594, W595, and / or V596), numbered according to SEQ ID NO: 138.

[0009] 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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive amino acids from any one of SEQ ID NOs: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336; (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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336; (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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262- 265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336. In some embodiments, the amino acid sequence is present in loop VIII. In some embodiments, the amino acid sequence replaces positions 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, and / or 596 (e.g., T582, N583, H584, Q585, S586, A587, Q588, A589, Q590, A591, Q592, T593, G594, W595, and / or V596), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence replaces positions 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, and / or 596 (e.g., A581, T582, N583, H584, Q585, S586, A587, Q588, A589, Q590, A591, Q592, T593, G594, W595, and / or V596), numbered according to SEQ ID NO: 138.

[0010] 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, 6, or 7 consecutive amino acids from the amino acid sequence of TQDWHRI (SEQ ID NO: 941), wherein: (i) the at least 3 consecutive amino acids comprise TQD; (ii) the at least 4 consecutive amino acids comprise TQDW (SEQ ID NO: 4684); (iii) the at least 5 consecutive amino acids comprise TQDWH (SEQ ID NO: 4685); or (iv) the at least 6 consecutive amino acids comprise TQDWHR (SEQ ID NO: 4686); 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 138-736 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 203-736 of SEQ ID NO: 981; or (d) an amino acid sequence with at least 70% (e.g., at least 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c).

[0011] 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 TQDWHRI (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 138-736 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 203-736 of SEQ ID NO: 981; or (d) an amino acid sequence with at least 70% (e.g., at least 75, 80, 85, 90, 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c).

[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 one, two, three, four, five or all of an amino acid other than H at position 584 (e.g., T), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), and / or Q at position 590 (e.g., I), numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises an amino acid other than H at position 584 (e.g., T), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), and / or Q at position 590 (e.g., I), numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises one, two, three, four, five or all of the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 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 one, two, three, four, five or all of the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981.

[0014] 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, two,three, four, five or all of the substitutions H584T, S586D, A587W, Q588H, A589R, and / or Q590I, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the substitutions H584T, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138.

[0015] 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 T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981.

[0016] 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 the substitutions H584T, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138.

[0017] 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 positions 203-736 of SEQ ID NO: 981, or an amino acid sequence at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) thereto, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of positions 203-736 of SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of positions 138-736 of SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981.

[0018] 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 positions 138-736 of SEQ ID NO: 981, or an amino acid sequence at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) thereto, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of positions 138-736 of SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981.

[0019] 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 aminoacid sequence of SEQ ID NO: 981, or an amino acid sequence at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) thereto, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises an amino acid sequence comprising 30, 20, or 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981.

[0020] 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 SEQ ID NO: 981.

[0021] 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 encoded by the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence at least 95% identical thereto.

[0022] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid H at position 597, numbered according to SEQ ID NO: 138 or 981, and one, two, three, four, five or all of the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, I at position 590, and H at position 597, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 943.

[0023] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, I at position 590, and H at position 597, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 943.

[0024] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the substitution Q597H, numbered according to SEQ ID NO: 138; and one, two, three, four, five or all of the substitutions H584T, S586D, A587W, Q588H, A589R, and / or Q590I, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the substitutions H584T, S586D, A587W, Q588H, A589R, Q590I, and Q597H, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 943.

[0025] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the substitutions H584T, S586D, A587W, Q588H, A589R, Q590I, and Q597H, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 943.

[0026] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of TNTQDWHRIAQTGWVH (SEQ ID NO: 943). In some embodiments, the amino acid sequence of SEQ ID NO: 943 is present at positions 582 to 597, numbered according to SEQ ID NO: 138 or 981.

[0027] In another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid T at position 583 and Q at position 584, numbered according to SEQ ID NO: 138 or 981; and one, two, three, four, or all of the amino acid D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid T at position 583, Q at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 984.

[0028] In yet another aspect, the present disclosure an AAV capsid variant comprising the amino acid T at position 583, Q at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 984.

[0029] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the substitutions N583T and H584Q, numbered according to SEQ ID NO: 138; and one, two, three, four, or all of the substitutions S586D, A587W, Q588H, A589R, and / or Q590I, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the substitutions N583T, H584Q, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 984.

[0030] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the substitutions N583T, H584Q, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 984.

[0031] In yet another aspect, the present disclosure provides an AAV capsid variant comprising the amino acid sequence of TTQQDWHRIAQTGWV (SEQ ID NO: 984). In some embodiments, the amino acid sequence of SEQ ID NO: 984 is present at positions 582 to 596, numbered according to SEQ ID NO: 138 or 981.

[0032] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 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.

[0033] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 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.

[0034] 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.

[0035] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 203-736 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.

[0036] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 203-736 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 strandsequence, wherein the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908.

[0037] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 138-736 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.

[0038] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 138-736 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.

[0039] 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.

[0040] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to 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.

[0041] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 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.

[0042] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981; and (ii) a nucleicacid encoding a polynucleotide targeting human MAPT, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 4405.

[0043] 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 nucleic acid comprises the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0044] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 203-736 of SEQ ID NO: 981; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 4405.

[0045] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 203-736 of SEQ ID NO: 981; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 4405.

[0046] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 138-736 of SEQ ID NO: 981; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 4405.

[0047] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 138-736 of SEQ ID NO: 981; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 4405.

[0048] 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 nucleic acid comprises the nucleotide sequence of SEQ ID NO: 4405.

[0049] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to SEQ ID NO: 981; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the nucleic acid comprises the nucleotide sequence of SEQ ID NO: 4405.

[0050] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981; and (ii) a viral genome comprising the nucleotide sequence of any one of SEQ ID NOs: 5173, 5195, 5184, or 3886.

[0051] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0052] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0053] 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.

[0054] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 203-736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0055] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 203-736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0056] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 203- 736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0057] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 203- 736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0058] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 138-736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0059] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of amino acids 138-736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0060] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 138- 736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0061] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to amino acids 138- 736 of SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0062] 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.

[0063] 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.

[0064] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0065] In yet another aspect, the present disclosure provides an AAV particle comprising: (i) an AAV capsid variant comprising an amino acid sequence at least 95% or at least 98% identical to SEQ ID NO: 981; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0066] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant described herein and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT).

[0067] In accordance with some aspects of the present disclosure, the short interfering ribonucleic acid (siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) which 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 comprisesnucleotide 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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 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.

[0075] 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.

[0076] 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, Frontotemporal dementia (FTD), or Dravet syndrome.

[0077] 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] (SEQ ID NO: 4681), wherein [N2] comprises the amino acid sequence of DWHR (SEQ ID NO: 4682) and wherein: (i) [N1] comprises positions X1, X2, X3, and X4, wherein position X4is Q, K, E, S, P, R, N, H, or a conservative substitution thereof; and / or (ii) [N3] comprises positions X5, X6, and X7, wherein position X5is I, V, T, M, S, N, L, F, or a conservative substitution thereof. 2. The AAV particle of embodiment 1, wherein the AAV capsid variant comprises the amino acid Q at position 585, numbered according to SEQ ID NO: 138 or 981. 3. The AAV particle of embodiment 1, wherein the AAV capsid variant comprises an amino acid other than Q at position 585, numbered according to SEQ ID NO: 138 or 981. 4. The AAV particle of embodiment 1 or 3, wherein the AAV capsid variant comprises the amino acid K at position 585, numbered according to SEQ ID NO: 138 or 981. 5. The AAV particle of any one of embodiments 1-4, wherein the AAV capsid variant comprises one, two, three, or all of an amino acid other than T at position 582 (e.g., S, R, A, I, C, N, K, L, or Q), an amino acid other than N at position 583 (e.g., T, G, V, S, Y, K, I, H, D, or F), an amino acid other than H at position 584 (e.g., T, N, K, D, I, S, P, A, Y, E, V, L, M, R, Q, or C), and / or an amino acid other than Q at position 585 (e.g., K, E, S, P, R, N, H), numbered according to SEQ ID NO: 138. 6. The AAV particle of any one of embodiments 1-5, wherein [N1] comprises positions X1, X2, X3, and X4, wherein position X4is Q, K, E, S, P, R, N, or H.7. The AAV particle of any one of embodiments 1-6, wherein position X4is Q or K. 8. The AAV particle of any one of embodiments 1, 2, or 5-7, wherein position X4is Q. 9. The AAV particle of any one of embodiments 1 or 3-7, wherein position X4is K. 10. The AAV particle of any one of embodiments 1-9, wherein the AAV capsid variant comprises an amino acid other than H at position 584 (e.g., T), numbered according to SEQ ID NO: 138. 11. The AAV particle of any one of embodiments 1-10, wherein the AAV capsid variant comprises the amino acid T at position 584, numbered according to SEQ ID NO: 138 or 981. 12. The AAV particle of any one of embodiments 1-11, wherein: (i) position X1is T, S, R, A, I, C, N, K, L, or Q; (ii) position X2is N, T, G, V, S, Y, K, I, H, D, or F; and / or (iii) position X3is T, N, K, D, I, S, P, A, Y, E, V, L, M, R, H, Q, or C. 13. The AAV particle of any one of embodiments 1-12, wherein [N1] comprises TN, NT, NK, SN, TT, RN, TG, TV, ST, TS, TY, AN, TK, TI, IN, TH, TD, CN, NN, KN, LN, SG, TF, RT, SY, SS, QN, ND, NP, GK, TA, VK, NY, TE, SK, NI, YN, GT, TL, TM, YT, TR, NS, IT, NA, KT, GN, HT, DT, NE, NH, YI, HN, NQ, FS, NM, NL, SM, NC, VT, KQ, TQ, DQ, IQ, SQ, PS, KE, AQ, YQ, TP, EQ, VQ, LQ, MQ, KS, IE, RQ, IK, AK, PK, NR, HQ, QQ, or CQ. 14. The AAV particle of any one of embodiments 1-13, wherein [N1] comprises TNT, TNK, TNN, SNN, SNK, SNT, TTN, TND, TTI, RNT, TTK, TTS, TTD, TNP, TTT, TGK, TTA, TVK, TNY, STK, TTE, TSK, TNI, TYN, STI, TTV, TGT, TTL, TTM, ANN, SNI, TKN, TYT, TTR, TNS, TST, TIT, INT, TNA, TKT, STN, ANT, RNN, TGN, TSN, THT, TDT, TNE, CNT, INN, NNN, KNN, LNN, TIN, TNH, STT, SNS, STS, TYI, SGT, THN, TNQ, RNI, TFS, RNS, TNM, RTT, KNT, TNL, TSM, SYT, TNC, SST, TVT, QNT, NTK, NNQ, NKQ, NNE, NTQ, NDQ, TIQ, TKQ, TSQ, TDQ, NPS, NKE, TTQ, GKQ, TAQ, VKQ, NYQ, NTP, TEQ, SKQ, NIQ, YNQ, TVQ, GTQ, NTR, TLQ, TMQ, KNQ, YTQ, NKS, NTE, NIE, TRQ, NSQ, YTK, NIK, NNK, NSK, ITK, NAK, KTK, GNQ, SNQ, HTK, DTK, NEQ, NPK, YTE, NNR, INQ, NHQ, YIQ, HNQ, ITQ, STQ, NSN, NQQ, NNP, ITE, NTN, FSQ, NNH, NMQ, NTS, NLQ, SMQ, NCQ, or VTQ15. The AAV particle of any one of embodiments 1-14, wherein [N1] is or comprises TNTQ (SEQ ID NO: 4688), TNTK (SEQ ID NO: 4689), TNNQ (SEQ ID NO: 1100), SNNQ (SEQ ID NO: 1101), TNKQ (SEQ ID NO: 1102), TNNE (SEQ ID NO: 1103), SNKQ (SEQ ID NO: 1104), SNTQ (SEQ ID NO: 1105), TTNQ (SEQ ID NO: 1106), TNDQ (SEQ ID NO: 1107), TTIQ (SEQ ID NO: 4698), RNTQ (SEQ ID NO: 4699), TTKQ (SEQ ID NO: 1110), TTSQ (SEQ ID NO: 1111), TTDQ (SEQ ID NO: 1112), TNPS (SEQ ID NO: 1113), TNKE (SEQ ID NO: 1114), TTTQ (SEQ ID NO: 1115), TGKQ (SEQ ID NO: 4706), TTAQ (SEQ ID NO: 4707), TVKQ (SEQ ID NO: 4708), TNYQ (SEQ ID NO: 4709), TNTP (SEQ ID NO: 1120), STKQ (SEQ ID NO: 4711), TTEQ (SEQ ID NO: 1122), TSKQ (SEQ ID NO: 4713), TNIQ (SEQ ID NO: 4714), TYNQ (SEQ ID NO: 1125), STIQ (SEQ ID NO: 1126), TTVQ (SEQ ID NO: 4717), TGTQ (SEQ ID NO: 1128), TNTR (SEQ ID NO: 4719), TTLQ (SEQ ID NO: 4720), TTMQ (SEQ ID NO: 4721), ANNQ (SEQ ID NO: 4722), SNIQ (SEQ ID NO: 4723), TKNQ (SEQ ID NO: 4724), TYTQ (SEQ ID NO: 4725), TNKS (SEQ ID NO: 4726), SNTE (SEQ ID NO: 4727), TNTE (SEQ ID NO: 4728), TNIE (SEQ ID NO: 4729), TTRQ (SEQ ID NO: 4730), TNSQ (SEQ ID NO: 4731), TYTK (SEQ ID NO: 4732), TTTK (SEQ ID NO: 4733), TNIK (SEQ ID NO: 4734), SNTK (SEQ ID NO: 4735), TNNK (SEQ ID NO: 4736), TNSK (SEQ ID NO: 4737), TSTK (SEQ ID NO: 4738), TITK (SEQ ID NO: 4739), INTK (SEQ ID NO: 4740), TNAK (SEQ ID NO: 4741), TKTK (SEQ ID NO: 4742), STNQ (SEQ ID NO: 4743), ANTK (SEQ ID NO: 4744), RNNQ (SEQ ID NO: 4745), TGNQ (SEQ ID NO: 4746), TSNQ (SEQ ID NO: 4747), THTK (SEQ ID NO: 4748), TDTK (SEQ ID NO: 4749), TNEQ (SEQ ID NO: 4750), CNTQ (SEQ ID NO: 4751), TNPK (SEQ ID NO: 4752), INNQ (SEQ ID NO: 4753), TYTE (SEQ ID NO: 4754), NNNQ (SEQ ID NO: 4755), KNNQ (SEQ ID NO: 4756), TNNR (SEQ ID NO: 4757), LNNQ (SEQ ID NO: 4758), TINQ (SEQ ID NO: 4759), TNHQ (SEQ ID NO: 4760), STTQ (SEQ ID NO: 4761), SNSQ (SEQ ID NO: 4762), STSQ (SEQ ID NO: 4763), TYIQ (SEQ ID NO: 4764), SGTQ (SEQ ID NO: 4765), THNQ (SEQ ID NO: 4766), TITQ (SEQ ID NO: 4767), TSTQ (SEQ ID NO: 4768), TNSN (SEQ ID NO: 4769), TNQQ (SEQ ID NO: 4770), RNIQ (SEQ ID NO: 4771), TNNP (SEQ ID NO: 4772), TITE (SEQ ID NO: 4773), TNTN (SEQ ID NO: 4774), TFSQ (SEQ ID NO: 4775), RNSQ (SEQ ID NO: 4776), INTQ (SEQ ID NO: 4777), RNTE (SEQ ID NO: 4778), TNNH (SEQ ID NO: 4779), TNMQ (SEQ ID NO: 4780), RTTQ (SEQ ID NO: 4781), SNIE (SEQ ID NO: 4782), TNTS (SEQ ID NO: 4783), KNTQ (SEQ ID NO: 4784), TNLQ (SEQ ID NO: 4785), TSMQ (SEQ ID NO: 4786), SYTQ (SEQ ID NO: 4787), TNCQ (SEQ ID NO: 4788), SSTQ (SEQ ID NO: 4789), TVTQ (SEQ ID NO: 4790), or QNTQ (SEQ ID NO: 4791). 16. The AAV particle of any one of embodiments 1-15, wherein [N1] is or comprises TNTQ (SEQ ID NO: 4688).17. The AAV particle of any one of embodiments 1-15, wherein [N1] is or comprises TNTK (SEQ ID NO: 4689). 18. The AAV particle of any one of embodiments 1-17, wherein [N1]-[N2] comprises: (i) TQDWHR (SEQ ID NO: 4686), TKDWHR (SEQ ID NO: 4792), NQDWHR (SEQ ID NO: 4793), KQDWHR (SEQ ID NO: 4794), NEDWHR (SEQ ID NO: 4795), DQDWHR (SEQ ID NO: 4796), IQDWHR (SEQ ID NO: 4797), SQDWHR (SEQ ID NO: 4798), PSDWHR (SEQ ID NO: 4799), KEDWHR (SEQ ID NO: 4800), AQDWHR (SEQ ID NO: 4801), YQDWHR (SEQ ID NO: 4802), TPDWHR (SEQ ID NO: 4803), EQDWHR (SEQ ID NO: 4804), VQDWHR (SEQ ID NO: 4805), TRDWHR (SEQ ID NO: 4806), LQDWHR (SEQ ID NO: 4807), MQDWHR (SEQ ID NO: 4808), KSDWHR (SEQ ID NO: 4809), TEDWHR (SEQ ID NO: 4810), IEDWHR (SEQ ID NO: 4811), RQDWHR (SEQ ID NO: 4812), IKDWHR (SEQ ID NO: 4813), NKDWHR (SEQ ID NO: 4814), SKDWHR (SEQ ID NO: 4815), AKDWHR (SEQ ID NO: 4816), PKDWHR (SEQ ID NO: 4817), NRDWHR (SEQ ID NO: 4818), HQDWHR (SEQ ID NO: 4819), SNDWHR (SEQ ID NO: 4820), QQDWHR (SEQ ID NO: 4821), NPDWHR (SEQ ID NO: 4822), TNDWHR (SEQ ID NO: 4823), NHDWHR (SEQ ID NO: 4824), TSDWHR (SEQ ID NO: 4825), or CQDWHR (SEQ ID NO: 4826); (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). 19. The AAV particle of any one of embodiments 1-18, wherein [N1]-[N2] comprises: (i) NTQDWHR (SEQ ID NO: 4827), NTKDWHR (SEQ ID NO: 4828), NNQDWHR (SEQ ID NO: 4829), NKQDWHR (SEQ ID NO: 4830), NNEDWHR (SEQ ID NO: 4831), TNQDWHR (SEQ ID NO: 4832), NDQDWHR (SEQ ID NO: 4833), TIQDWHR (SEQ ID NO: 4834), TKQDWHR (SEQ ID NO: 4835), TSQDWHR (SEQ ID NO: 4836), TDQDWHR (SEQ ID NO: 4837), NPSDWHR (SEQ ID NO: 4838), NKEDWHR (SEQ ID NO: 4839), TTQDWHR (SEQ ID NO: 4840), GKQDWHR (SEQ ID NO: 4841), TAQDWHR (SEQ ID NO: 4842), VKQDWHR (SEQ ID NO: 4843), NYQDWHR (SEQ ID NO: 4844), NTPDWHR (SEQ ID NO: 4845), TEQDWHR (SEQ ID NO: 4846), SKQDWHR (SEQ ID NO: 4847), NIQDWHR (SEQ ID NO: 4848), YNQDWHR (SEQ ID NO: 4849), TVQDWHR (SEQ ID NO: 4850), GTQDWHR (SEQ ID NO: 4851), NTRDWHR (SEQ ID NO: 4852), TLQDWHR (SEQ ID NO: 4853),TMQDWHR (SEQ ID NO: 4854), KNQDWHR (SEQ ID NO: 4855), YTQDWHR (SEQ ID NO: 4856), NKSDWHR (SEQ ID NO: 4857), NTEDWHR (SEQ ID NO: 4858), NIEDWHR (SEQ ID NO: 4859), TRQDWHR (SEQ ID NO: 4860), NSQDWHR (SEQ ID NO: 4861), YTKDWHR (SEQ ID NO: 4862), TTKDWHR (SEQ ID NO: 4863), NIKDWHR (SEQ ID NO: 4864), NNKDWHR (SEQ ID NO: 4865), NSKDWHR (SEQ ID NO: 4866), STKDWHR (SEQ ID NO: 4867), ITKDWHR (SEQ ID NO: 4868), NAKDWHR (SEQ ID NO: 4869), KTKDWHR (SEQ ID NO: 4870), GNQDWHR (SEQ ID NO: 4871), SNQDWHR (SEQ ID NO: 4872), HTKDWHR (SEQ ID NO: 4873), DTKDWHR (SEQ ID NO: 4874), NEQDWHR (SEQ ID NO: 4875), NPKDWHR (SEQ ID NO: 4876), YTEDWHR (SEQ ID NO: 4877), NNRDWHR (SEQ ID NO: 1287), INQDWHR (SEQ ID NO: 1288), NHQDWHR (SEQ ID NO: 1289), YIQDWHR (SEQ ID NO: 1290), HNQDWHR (SEQ ID NO: 1291), ITQDWHR (SEQ ID NO: 1292), STQDWHR (SEQ ID NO: 1293), NSNDWHR (SEQ ID NO: 1294), NQQDWHR (SEQ ID NO: 1295), NNPDWHR (SEQ ID NO: 1296), ITEDWHR (SEQ ID NO: 1297), NTNDWHR (SEQ ID NO: 1298), FSQDWHR (SEQ ID NO: 1299), NNHDWHR (SEQ ID NO: 1300), NMQDWHR (SEQ ID NO: 1301), NTSDWHR (SEQ ID NO: 1302), NLQDWHR (SEQ ID NO: 1303), SMQDWHR (SEQ ID NO: 1304), NCQDWHR (SEQ ID NO: 1305), VTQDWHR (SEQ ID NO: 5); (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). 20. The AAV particle of any one of embodiments 1-19, wherein [N1]-[N2] is or comprises: (i) TNTQDWHR (SEQ ID NO: 1307), TNTKDWHR (SEQ ID NO: 1308), TNNQDWHR (SEQ ID NO: 1309), SNNQDWHR (SEQ ID NO: 1310), TNKQDWHR (SEQ ID NO: 1311), TNNEDWHR (SEQ ID NO: 1312), SNKQDWHR (SEQ ID NO: 1313), SNTQDWHR (SEQ ID NO: 1314), TTNQDWHR (SEQ ID NO: 1315), TNDQDWHR (SEQ ID NO: 1316), TTIQDWHR (SEQ ID NO: 1317), RNTQDWHR (SEQ ID NO: 6), TTKQDWHR (SEQ ID NO: 1318), TTSQDWHR (SEQ ID NO: 1319), TTDQDWHR (SEQ ID NO: 1320), TNPSDWHR (SEQ ID NO: 1321), TNKEDWHR (SEQ ID NO: 1322), TTTQDWHR (SEQ ID NO: 1323), TGKQDWHR (SEQ ID NO: 1324), TTAQDWHR (SEQ ID NO: 1325), TVKQDWHR (SEQ ID NO: 1326), TNYQDWHR (SEQ ID NO: 1327), TNTPDWHR (SEQ ID NO: 1328), STKQDWHR (SEQ ID NO: 1329), TTEQDWHR (SEQ ID NO: 1330), TSKQDWHR (SEQ ID NO: 1331), TNIQDWHR (SEQ ID NO: 1332), TYNQDWHR (SEQ ID NO: 1333), STIQDWHR (SEQ ID NO:1334), TTVQDWHR (SEQ ID NO:4927), TGTQDWHR (SEQ ID NO: 4928), TNTRDWHR (SEQ ID NO: 1335), TTLQDWHR (SEQ ID NO: 1336), TTMQDWHR (SEQ ID NO: 4931), ANNQDWHR (SEQ ID NO: 4932), SNIQDWHR (SEQ ID NO: 1337), TKNQDWHR (SEQ ID NO: 1338), TYTQDWHR (SEQ ID NO: 4935), TNKSDWHR (SEQ ID NO: 4936), SNTEDWHR (SEQ ID NO: 1339), TNTEDWHR (SEQ ID NO: 1340), TNIEDWHR (SEQ ID NO: 4939), TTRQDWHR (SEQ ID NO: 4940), TNSQDWHR (SEQ ID NO: 1341), TYTKDWHR (SEQ ID NO: 1342), TTTKDWHR (SEQ ID NO: 4943), TNIKDWHR (SEQ ID NO: 4944), SNTKDWHR (SEQ ID NO: 1343), TNNKDWHR (SEQ ID NO:1344), TNSKDWHR (SEQ ID NO: 4947), TSTKDWHR (SEQ ID NO: 4948), TITKDWHR (SEQ ID NO:1345), INTKDWHR (SEQ ID NO: 1346), TNAKDWHR (SEQ ID NO: 4951), TKTKDWHR (SEQ ID NO: 4952), STNQDWHR (SEQ ID NO: 1347), ANTKDWHR (SEQ ID NO: 1348), RNNQDWHR (SEQ ID NO: 4955), TGNQDWHR (SEQ ID NO: 4956), TSNQDWHR (SEQ ID NO: 1349), THTKDWHR (SEQ ID NO: 1350), TDTKDWHR (SEQ ID NO: 4959), TNEQDWHR (SEQ ID NO: 4960), CNTQDWHR (SEQ ID NO: 1351), TNPKDWHR (SEQ ID NO: 1352), INNQDWHR (SEQ ID NO: 4963), TYTEDWHR (SEQ ID NO: 4964), NNNQDWHR (SEQ ID NO: 1353), KNNQDWHR (SEQ ID NO: 1354), TNNRDWHR (SEQ ID NO: 4967), LNNQDWHR (SEQ ID NO: 4968), TINQDWHR (SEQ ID NO: 1355), TNHQDWHR (SEQ ID NO: 1356), STTQDWHR (SEQ ID NO: 4971), SNSQDWHR (SEQ ID NO: 4972), STSQDWHR (SEQ ID NO: 1357), TYIQDWHR (SEQ ID NO: 1358), SGTQDWHR (SEQ ID NO: 4975), THNQDWHR (SEQ ID NO: 4976), TITQDWHR (SEQ ID NO: 1359), TSTQDWHR (SEQ ID NO: 1360), TNSNDWHR (SEQ ID NO: 4979), TNQQDWHR (SEQ ID NO: 4980), RNIQDWHR (SEQ ID NO: 1361), TNNPDWHR (SEQ ID NO: 1362), TITEDWHR (SEQ ID NO: 4983), TNTNDWHR (SEQ ID NO: 4984), TFSQDWHR (SEQ ID NO: 1363), RNSQDWHR (SEQ ID NO: 1364), INTQDWHR (SEQ ID NO: 4987), RNTEDWHR (SEQ ID NO: 4988), TNNHDWHR (SEQ ID NO: 1365), TNMQDWHR (SEQ ID NO: 1366), RTTQDWHR (SEQ ID NO: 4991), SNIEDWHR (SEQ ID NO: 4992), TNTSDWHR (SEQ ID NO: 1367), KNTQDWHR (SEQ ID NO: 1368), TNLQDWHR (SEQ ID NO: 4995), TSMQDWHR (SEQ ID NO: 4996), SYTQDWHR (SEQ ID NO: 1369), TNCQDWHR (SEQ ID NO: 1370), SSTQDWHR (SEQ ID NO: 4999), TVTQDWHR (SEQ ID NO: 5000), or QNTQDWHR (SEQ ID NO: 1371); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 56, or 7 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).21. The AAV particle of any one of embodiments 1-20, wherein [N1]-[N2] is or comprises TNTQDWHR (SEQ ID NO: 1307). 22. The AAV particle of any one of embodiments 1-20, wherein [N1]-[N2] is or comprises TNTKDWHR (SEQ ID NO: 1308). 23. The AAV particle of any one of embodiments 1-22, wherein the AAV capsid variant comprises one, two, or all of an amino acid other than Q at position 590 (e.g., I, V, T, M, S, N, L, or F), A at position 591 (e.g., Y, P, N, S, T, G, E, V, W, F, Q), and / or Q at position 592 (e.g., G, N, K, H, R, E, L, P, or M), numbered according to SEQ ID NO: 138. 24. The AAV particle of any one of embodiments 1-23, wherein the AAV capsid variant comprises an amino acid other than Q at position 590 (e.g., I, V, T, M, S, N, L, or F), numbered according to SEQ ID NO: 138. 25. The AAV particle of any one of embodiments 1-24, wherein the AAV capsid variant comprises the amino acid I at position 590, numbered according to SEQ ID NO: 138. 26. The AAV particle of any one of embodiments 1-24, wherein the AAV capsid variant comprises the amino acid V at position 590, numbered according to SEQ ID NO: 138. 27. The AAV particle of any one of embodiments 1-26, wherein the AAV capsid variant comprises the amino acid A at position 591 and / or the amino acid Q at position 592, numbered according to SEQ ID NO: 138 or 981. 28. The AAV particle of any one of embodiments 1-27, wherein [N3] comprises positions X5, X6, and X7, wherein position X5is I, V, T, M, S, N, L, or F. 29. The AAV particle of any one of embodiments 1-28, wherein position X5is I or V. 30. The AAV particle of any one of embodiments 1-25 or 27-29, wherein position X5is I. 31. The AAV particle of any one of embodiments 1-30, wherein: (i) position X6is A, Y, P, N, S, T, G, E, V, W, F, or Q; and / or (ii) position X7is Q, G, N, K, H, R, E, L, P, or M.32. The AAV particle of any one of embodiments 1-31, wherein [N3] comprises IA, IY, VP, IN, VN, VY, VA, IS, IT, TA, MA, SA, IG, IE, IV, NA, LA, IP, FA, VS, VT, IW, IF, IQ, VQ, AQ, AG, YQ, PQ, AN, NQ, SG, SQ, TQ, GQ, EQ, AK, AH, AR, AE, AL, AP, TM, SM, WQ, FQ, QQ, FM, AM, or SN. 33. The AAV particle of any one of embodiments 1-32, wherein [N3] is or comprises IAQ, IAG, IYQ, VPQ, IAN, INQ, VNQ, VYQ, VAN, ISG, ISQ, VAQ, ITQ, TAQ, MAQ, SAQ, IGQ, IEQ, IVQ, NAQ, LAQ, IAK, IAH, IPQ, IAR, IAE, IAL, IAP, FAQ, VSQ, VTM, ISM, IWQ, IFQ, IQQ, VQQ, IFM, IAM, or ISN. 34. The AAV particle of any one of embodiments 1-33, wherein [N3] is or comprises IAQ. 35. The AAV particle of any one of embodiments 1-34, wherein [N2]-[N3] comprises: (i) DWHRIA (SEQ ID NO: 1372), DWHRIY (SEQ ID NO: 5003), DWHRVP (SEQ ID NO: 5004), DWHRIN (SEQ ID NO: 1373), DWHRVN (SEQ ID NO: 1374), DWHRVY (SEQ ID NO: 5007), DWHRVA (SEQ ID NO: 5008), DWHRIS (SEQ ID NO: 7), DWHRIT (SEQ ID NO: 1376), DWHRTA (SEQ ID NO: 5011), DWHRMA (SEQ ID NO: 5012), DWHRSA (SEQ ID NO: 1377), DWHRIG (SEQ ID NO: 1378), DWHRIE (SEQ ID NO: 5015), DWHRIV (SEQ ID NO: 5016), DWHRNA (SEQ ID NO: 5017), DWHRLA (SEQ ID NO: 5018), DWHRIP (SEQ ID NO: 5019), DWHRFA (SEQ ID NO: 5020), DWHRVS (SEQ ID NO: 1379), DWHRVT (SEQ ID NO: 1380), DWHRIW (SEQ ID NO: 5023), DWHRIF (SEQ ID NO: 1306), DWHRIQ (SEQ ID NO: 5025), or DWHRVQ (SEQ ID NO: 5026); (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). 36. The AAV particle of any one of embodiments 1-35, wherein [N2]-[N3] is or comprises: (i) DWHRIAQ (SEQ ID NO: 8), DWHRIAG (SEQ ID NO: 9), DWHRIYQ (SEQ ID NO: 10), DWHRVPQ (SEQ ID NO: 22), DWHRIAN (SEQ ID NO: 23), DWHRINQ (SEQ ID NO: 24), DWHRVNQ (SEQ ID NO: 25), DWHRVYQ (SEQ ID NO: 26), DWHRVAN (SEQ ID NO: 27), DWHRISG (SEQ ID NO: 28), DWHRISQ (SEQ ID NO: 29), DWHRVAQ (SEQ ID NO: 30), DWHRITQ (SEQ ID NO: 31), DWHRTAQ (SEQ ID NO: 32), DWHRMAQ (SEQ ID NO: 33), DWHRSAQ (SEQ ID NO: 34), DWHRIGQ (SEQ ID NO: 35), DWHRIEQ (SEQ ID NO: 36), DWHRIVQ (SEQ ID NO: 37), DWHRNAQ (SEQ ID NO:38), DWHRLAQ (SEQ ID NO: 39), DWHRIAK (SEQ ID NO: 40), DWHRIAH (SEQ ID NO: 41), DWHRIPQ (SEQ ID NO: 42), DWHRIAR (SEQ ID NO: 43), DWHRIAE (SEQ ID NO: 44), DWHRIAL (SEQ ID NO: 45), DWHRIAP (SEQ ID NO: 46), DWHRFAQ (SEQ ID NO: 47), DWHRVSQ (SEQ ID NO: 48), DWHRVTM (SEQ ID NO: 49), DWHRISM (SEQ ID NO: 50), DWHRIWQ (SEQ ID NO: 51), DWHRIFQ (SEQ ID NO: 52), DWHRIQQ (SEQ ID NO: 53), DWHRVQQ (SEQ ID NO: 54), DWHRIFM (SEQ ID NO: 55), DWHRIAM (SEQ ID NO: 56), or DWHRISN (SEQ ID NO: 57); (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). 37. The AAV particle of any one of embodiments 1-36, wherein [N2]-[N3] is or comprises DWHRIAQ (SEQ ID NO: 8). 38. The AAV particle of any one of embodiments 1-37, wherein [N1]-[N2]-[N3] is or comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 343-538; (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, or 10 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). 39. The AAV particle of any one of embodiments 1-38, wherein [N1]-[N2]-[N3] is or comprises TNTQDWHRIAQ (SEQ ID NO: 343). 40. The AAV particle of any one of embodiments 1-38, wherein [N1]-[N2]-[N3] is or comprises TNTKDWHRIAQ (SEQ ID NO: 344).41. The AAV particle of any one of embodiments 1-40, wherein the AAV capsid variant comprises one, two, three, or all of an amino acid other than T at position 593 (e.g., S, N, P, A, or I), a G at position 594 (e.g., N, D, R, V, A, S, or Q), a W at position 595 (e.g., S, C, R, L, or G), and / or a V at position 596 (e.g., A, S, I, C, G, D, F, L, or T), numbered according to SEQ ID NO: 138 or 981. 42. The AAV particle of any one of embodiments 1-40, wherein the AAV capsid variant comprises the amino acid T at position 593, the amino acid G at position 594, the amino acid W at position 595, and the amino acid V at position 596, numbered according to SEQ ID NO: 138 or 981. 43. The AAV particle of any one of embodiments 1-42, wherein the AAV capsid variant further comprises [N4], wherein [N4] comprises positions X8, X9, X10, and X11, wherein: (i) position X8is T, S, N, P, A, or I; (ii) position X9is G, N, D, R, V, A, S, or Q; (iii) position X10is W, S, C, R, L, or G; and / or (iv) position X11is V, A, S, I, C, G, D, F, L, or T. 44. The AAV particle of embodiment 43, wherein [N4] comprises TG, TN, SN, NN, SG, PG, TD, AG, IG, NG, TR, TV, TA, TS, SV, TQ, WV, WA, WS, WI, WC, WG, CV, RV, LV, GV, WD, WF, WL, WT, GW, NW, GS, DW, GC, GR, GL, GG, RW, VW, AW, SW, or QW. 45. The AAV particle of embodiment 43 or 44, wherein [N4] comprises TGW, TNW, SNW, NNW, SGW, PGW, TGS, TDW, TGC, TGR, TGL, TGG, AGW, IGW, NGW, TRW, TVW, TAW, TSW, SVW, TQW, GWV, GWA, NWS, NWV, NWI, GWS, GWI, GWC, GWG, GSV, DWV, GCV, GRV, GLV, GGV, GWD, GWF, RWV, VWV, GWL, AWV, SWV, GWT, or QWV. 46. The AAV particle of any one of embodiments 43-45, wherein [N4] is or comprises TGWV (SEQ ID NO: 58), TGWA (SEQ ID NO: 59), TNWS (SEQ ID NO: 60), SNWV (SEQ ID NO: 61), TNWV (SEQ ID NO: 62), TNWI (SEQ ID NO: 63), NNWV (SEQ ID NO: 64), TGWS (SEQ ID NO: 65), TGWI (SEQ ID NO: 66), TGWC (SEQ ID NO: 67), TGWG (SEQ ID NO: 68), SGWV (SEQ ID NO: 69), PGWV (SEQ ID NO: 70), TGSV (SEQ ID NO:71), TDWV (SEQ ID NO: 72), TGCV (SEQ ID NO: 73), TGRV (SEQ ID NO: 74), TGLV (SEQ ID NO: 75), TGGV (SEQ ID NO: 76), AGWV (SEQ ID NO: 77), IGWV (SEQ ID NO: 78), TGWD (SEQ ID NO: 79), NGWV (SEQ ID NO: 80), TGWF (SEQ ID NO: 81), TRWV (SEQ ID NO: 82), TVWV (SEQ ID NO:83), TGWL (SEQ ID NO: 84), TAWV (SEQ ID NO: 85), TSWV (SEQ ID NO: 86), TGWT (SEQ ID NO: 87), SVWV (SEQ ID NO: 88), TQWV (SEQ ID NO: 89), or PGWG (SEQ ID NO: 90).47. The AAV particle of any one of embodiments 43-46, wherein [N4] is or comprises TGWV (SEQ ID NO: 58). 48. The AAV particle of any one of embodiments 43-47, wherein [N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 201-245, 247-250, 253-255, 257-265, 268- 274, 276-286, 288, 290-297, 299-303, 305-309, 311, 313-319, 323-328, 330-337, 339-342, 539-542, 544, 546, 547, 549-557, 559-589, 592, 593, 595, 596, 598, 599, 601-608, 610-614, 616-622, 625, 628, 630, 631, 633, 636, 638, 639-646, 649, 651-657, 667, 669, 670, 672, 673, 679-683, 685-690, 692, 693, 695, 697, 699- 701, 703-705, 708-710, 712-717, 719-723, 728-731, 733-738, 740, or 742; (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). 49. The AAV particle of any one of embodiments 43-48, wherein [N1]-[N2]-[N3]-[N4] is or comprises TNTQDWHRIAQTGWV (SEQ ID NO: 201). 50. The AAV particle of any one of embodiments 43-48, wherein [N1]-[N2]-[N3]-[N4] is or comprises TNTKDWHRIAQTGWV (SEQ ID NO: 202). 51. 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: 4683), wherein [N2] comprises the amino acid sequence of DWHR (SEQ ID NO: 4682) and wherein: (i) [N1] comprises positions X1, X2, X3, and X4, wherein position X4is Q, P, or a conservative substitution thereof; and / or (ii) [N3] comprises positions X5, X6, and X7, wherein position X5is I, V, or a conservative substitution thereof.52. The AAV particle of embodiment 51, wherein the AAV capsid variant comprises the amino acid Q at position 585, numbered according to SEQ ID NO: 138 or 981. 53. The AAV particle of embodiment 51 or 52, wherein the AAV capsid variant comprises one, two, three, or all of an amino acid other than T at position 582 (e.g., S), an amino acid other than N at position 583 (e.g., T, G, S, I, or V), an amino acid other than H at position 584 (e.g., N, I, S, A, V, or L), and / or an amino acid other than Q at position 585 (e.g., P), numbered according to SEQ ID NO: 138. 54. The AAV particle of any one of embodiments 51-53, wherein [N1] comprises positions X1, X2, X3, and X4, wherein position X4is Q or P. 55. The AAV particle of any one of embodiments 51, 52, or 54, wherein position X4is Q. 56. The AAV particle of any one of embodiments 51-55, wherein the AAV capsid variant comprises an amino acid other than H at position 584 (e.g., T), numbered according to SEQ ID NO: 138. 57. The AAV particle of any one of embodiments 51-56, wherein the AAV capsid variant comprises the amino acid T at position 584, numbered according to SEQ ID NO: 138 or 981. 58. The AAV particle of any one of embodiments 51-57, wherein: (i) position X1is T or S; (ii) position X2is N, T, G, S, I, or V; and / or (iii) position X3is T, N, I, S, A, V, or L. 59. The AAV particle of any one of embodiments 51-58, wherein [N1] comprises TN, TT, TG, ST, TS, TI, TV, TQ, NQ, IQ, SQ, AQ, VQ, TP, LQ, NT, TA, NI, GT, IT, NN, TL, NS, or VT. 60. The AAV particle of any one of embodiments 51-59, wherein [N1] comprises TNT, TTN, TTI, TTS, TTT, TTA, TNI, TTV, TGT, STT, TST, TIT, TNN, TTL, TNS, TVT, NTQ, TNQ, TIQ, TSQ, TTQ, TAQ, NIQ, TVQ, GTQ, STQ, ITQ, NTP, NNQ, TLQ, NSQ, or VTQ. 61. The AAV particle of any one of embodiments 51-60, wherein [N1] is or comprises TNTQ (SEQ ID NO: 4688), TTNQ (SEQ ID NO: 1106), TTIQ (SEQ ID NO: 4698), TTSQ (SEQ ID NO: 1111), TTTQ (SEQ ID NO: 1115), TTAQ (SEQ ID NO: 4707), TNIQ (SEQ ID NO: 4714), TTVQ (SEQ ID NO: 4717), TGTQ (SEQ ID NO: 1128), STTQ (SEQ ID NO: 4761), TSTQ (SEQ ID NO: 4768), TITQ (SEQ ID NO: 4767), TNTP(SEQ ID NO: 1120), TNNQ (SEQ ID NO: 1100), TTLQ (SEQ ID NO: 4720), TNSQ (SEQ ID NO: 4731), or TVTQ (SEQ ID NO: 4790). 62. The AAV particle of any one of embodiments 51-61, wherein [N1] is or comprises TNTQ (SEQ ID NO: 4688). 63. The AAV particle of any one of embodiments 51-62, wherein [N1]-[N2] comprises: (i) TQDWHR (SEQ ID NO: 4686), NQDWHR (SEQ ID NO: 4793), IQDWHR (SEQ ID NO: 4797), SQDWHR (SEQ ID NO: 4798), AQDWHR (SEQ ID NO: 4801), VQDWHR (SEQ ID NO: 4805), TPDWHR (SEQ ID NO: 4803), or LQDWHR (SEQ ID NO: 4807); (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). 64. The AAV particle of any one of embodiments 51-63, wherein [N1]-[N2] comprises: (i) NTQDWHR (SEQ ID NO: 4827), TNQDWHR (SEQ ID NO: 4832), TIQDWHR (SEQ ID NO: 4834), TSQDWHR (SEQ ID NO: 4836), TTQDWHR (SEQ ID NO: 4840), TAQDWHR (SEQ ID NO: 4842), NIQDWHR (SEQ ID NO: 4848), TVQDWHR (SEQ ID NO: 4850), GTQDWHR (SEQ ID NO: 4851), STQDWHR (SEQ ID NO: 1293), ITQDWHR (SEQ ID NO: 1292), NTPDWHR (SEQ ID NO: 4845), NNQDWHR (SEQ ID NO: 4829), TLQDWHR (SEQ ID NO: 4853), NSQDWHR (SEQ ID NO: 4861), VTQDWHR (SEQ ID NO: 5); (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). 65. The AAV particle of any one of embodiments 51-64, wherein [N1]-[N2] is or comprises:(i) TNTQDWHR (SEQ ID NO: 1307), TTNQDWHR (SEQ ID NO: 1315), TTIQDWHR (SEQ ID NO: 1317), TTSQDWHR (SEQ ID NO: 1319), TTTQDWHR (SEQ ID NO: 1323), TTAQDWHR (SEQ ID NO: 1325), TNIQDWHR (SEQ ID NO: 1332), TTVQDWHR (SEQ ID NO: 4927), TGTQDWHR (SEQ ID NO: 4928), STTQDWHR (SEQ ID NO: 4971), TSTQDWHR (SEQ ID NO: 1360), TITQDWHR (SEQ ID NO: 1359), TNTPDWHR (SEQ ID NO: 1328), TNNQDWHR (SEQ ID NO: 1309), TTLQDWHR (SEQ ID NO: 1336), TNSQDWHR (SEQ ID NO: 1341), TVTQDWHR (SEQ ID NO: 5000); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 56, or 7 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). 66. The AAV particle of any one of embodiments 51-65, wherein [N1]-[N2] is or comprises TNTQDWHR (SEQ ID NO: 1307). 67. The AAV particle of any one of embodiments 51-66, wherein the AAV capsid variant comprises one, two, or all of an amino acid other than Q at position 590 (e.g., I or V), A at position 591 (e.g., P, S, Y, or N), and / or Q at position 592 (e.g., G or N), numbered according to SEQ ID NO: 138. 68. The AAV particle of any one of embodiments 51-67, wherein the AAV capsid variant comprises an amino acid other than Q at position 590 (e.g., I or V), numbered according to SEQ ID NO: 138. 69. The AAV particle of any one of embodiments 51-68, wherein the AAV capsid variant comprises the amino acid I at position 590, numbered according to SEQ ID NO: 138. 70. The AAV particle of any one of embodiments 51-68, wherein the AAV capsid variant comprises the amino acid V at position 590, numbered according to SEQ ID NO: 138. 71. The AAV particle of any one of embodiments 51-70, wherein the AAV capsid variant comprises the amino acid A at position 591 and / or the amino acid Q at position 592, numbered according to SEQ ID NO: 138 or 981.72. The AAV particle of any one of embodiments 51-71, [N3] comprises positions X5, X6, and X7, wherein position X5is I or V. 73. The AAV particle of any one of embodiments 51-72, wherein position X5is I. 74. The AAV particle of any one of embodiments 51-73, wherein: (i) position X6is A, P, S, Y, or N; and / or (ii) position X7is Q, G, or N. 75. The AAV particle of any one of embodiments 51-74, wherein [N3] comprises IA, VP, VA, VS, IY, IN, IS, AQ, AG, PQ, SQ, AN, YQ, or NQ. 76. The AAV particle of any one of embodiments 51-75, wherein [N3] is or comprises IAQ, IAG, VPQ, VAQ, VSQ, IAN, IYQ, INQ, or ISQ. 77. The AAV particle of any one of embodiments 51-76, wherein [N3] is or comprises IAQ. 78. The AAV particle of any one of embodiments 51-77, wherein [N2]-[N3] comprises: (i) DWHRIA (SEQ ID NO: 1372), DWHRVP (SEQ ID NO: 5004), DWHRVA (SEQ ID NO: 5008), DWHRVS (SEQ ID NO: 1379), DWHRIY (SEQ ID NO: 5003), DWHRIN (SEQ ID NO: 1373), or DWHRIS (SEQ ID NO: 7); (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). 79. The AAV particle of any one of embodiments 51-78, wherein [N2]-[N3] is or comprises: (i) DWHRIAQ (SEQ ID NO: 8), DWHRIAG (SEQ ID NO: 9), DWHRVPQ (SEQ ID NO: 22), DWHRVAQ (SEQ ID NO: 30), DWHRVSQ (SEQ ID NO: 48), DWHRIAN (SEQ ID NO: 23), DWHRIYQ (SEQ ID NO: 10), DWHRINQ (SEQ ID NO: 24), or DWHRISQ (SEQ ID NO: 29);(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). 80. The AAV particle of any one of embodiments 51-79, wherein [N2]-[N3] is or comprises DWHRIAQ (SEQ ID NO: 8). 81. The AAV particle of any one of embodiments 51-80, wherein [N1]-[N2]-[N3] is or comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 343, 350, 352, 355, 359, 361, 364, 367, 370, 371, 373, 374, 376, 377, 378, 381, 395, 420, 454, 457, 460, 464, 481, 482, 488, 493, 494, 516, 525, 536; (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, or 10 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). 82. The AAV particle of any one of embodiments 51-81, wherein [N1]-[N2]-[N3] is or comprises TNTQDWHRIAQ (SEQ ID NO: 343). 83. The AAV particle of any one of embodiments 51-82, wherein the AAV capsid variant comprises the amino acid W at position 595, numbered according to SEQ ID NO: 138 or 981. 84. The AAV particle of any one of embodiments 51-83, wherein the AAV capsid variant comprises one, two or all of an amino acid other than T (e.g., S or N) at position 593, a G (e.g., N) a position 594, and / or V (e.g., A, I or S) at position 596, numbered according to SEQ ID NO: 138 or 981. 85. The AAV particle of any one of embodiments 51-84 wherein the AAV capsid variant comprises:(i) the amino acid T at position 593, the amino acid G at position 594, the amino acid W at position 595, and the amino acid V at position 596, numbered according to SEQ ID NO: 138 or 981; (ii) the amino acid T at position 593, the amino acid G at position 594, the amino acid W at position 595, and the amino acid A at position 596, numbered according to SEQ ID NO: 138 or 981; (iii) the amino acid S at position 593, the amino acid N at position 594, the amino acid W at position 595, and the amino acid V at position 596, numbered according to SEQ ID NO: 138 or 981; (iv) the amino acid N at position 593, the amino acid N at position 594, the amino acid W at position 595, and the amino acid V at position 596, numbered according to SEQ ID NO: 138 or 981; (v) the amino acid T at position 593, the amino acid G at position 594, the amino acid W at position 595, and the amino acid I at position 596, numbered according to SEQ ID NO: 138 or 981; or (vi) the amino acid T at position 593, the amino acid G at position 594, the amino acid W at position 595, and the amino acid S at position 596, numbered according to SEQ ID NO: 138 or 981. 86. The AAV particle of any one of embodiments 51-85 which comprises the amino acid T at position 593, the amino acid G at position 594, the amino acid W at position 595, and the amino acid V at position 596, numbered according to SEQ ID NO: 138 or 981. 87. The AAV particle of any one of embodiments 51-86, wherein the AAV capsid variant further comprises [N4], wherein [N4] comprises positions X8, X9, X10, and X11, wherein position X10is W. 88. The AAV particle of embodiment 87, wherein: (i) position X8is T, S, or N; (ii) position X9is G or N; and / or (iv) position X11is V, A, I, or S. 89. The AAV particle of embodiment 87 or 88, wherein [N4] comprises TG, SN, NN, WV, WA, WI, WS, GW, or NW. 90. The AAV particle of any one of embodiments 87-89, wherein [N4] comprises TGW, SNW, NNW, GWV, GWA, NWV, GWI, or GWS. 91. The AAV particle of any one of embodiments 87-90, wherein [N4] is or comprises TGWV (SEQ ID NO: 58), TGWA (SEQ ID NO: 59), SNWV (SEQ ID NO: 61), NNWV (SEQ ID NO: 64), TGWI (SEQ ID NO: 66), or TGWS (SEQ ID NO: 65).92. The AAV particle of any one of embodiments 87-91, wherein [N4] is or comprises TGWV (SEQ ID NO: 58). 93. The AAV particle of any one of embodiments 87-92, wherein [N1]-[N2]-[N3]-[N4] is or comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336; (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). 94. The AAV particle of any one of embodiments 87-93, wherein [N1]-[N2]-[N3]-[N4] is or comprises TNTQDWHRIAQTGWV (SEQ ID NO: 201). 95. The AAV particle of any one of embodiments 1-94, wherein [N1]-[N2]-[N3] is present in loop VIII, optionally wherein loop VIII comprises positions 580-599, numbered according to SEQ ID NO: 138 or 981. 96. The AAV particle of any one of embodiments 43-50 or 87-95, wherein [N4] is present in loop VIII, optionally wherein loop VIII comprises positions 580-599, numbered according to SEQ ID NO: 138 or 981. 97. The AAV particle of any one of embodiments 1-96, wherein [N1] replaces positions 582-585 (e.g., T582, N583, H584, Q585), numbered according to SEQ ID NO: 138. 98. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, or 85- 97, wherein [N1] corresponds to positions 582-585 (e.g., T582, N583, T584, Q585) of SEQ ID NO: 981. 99. The AAV particle of any one of embodiments 1-98, wherein [N1] is present at positions 582-585, numbered according to SEQ ID NO: 138 or 981. 100. The AAV particle of any one of embodiments 1-99, wherein [N1] corresponds to positions 582-585 (e.g., T582, N583, T584, Q585) of SEQ ID NO: 981.101. The AAV particle of any one of embodiments 1-100, wherein [N2] replaces positions 586-589 (e.g., S586, A587, Q588, A589), numbered according to the amino acid sequence of SEQ ID NO: 138. 102. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101, wherein [N2] corresponds to positions 586-589 (e.g., D586, W587, H588, R589) of SEQ ID NO: 981. 103. The AAV particle of any one of embodiments 1-102, wherein [N2] is present at positions 586-589, numbered according to SEQ ID NO: 138 or 981. 104. The AAV particle of any one of embodiments 1-103, wherein [N1]-[N2] replaces to positions 582-589 (e.g., T582, N583, H584, Q585, S586, A587, Q588, A589), numbered according to SEQ ID NO: 138. 105. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-104, wherein [N1]-[N2] corresponds to positions 582-589 (e.g., T582, N583, T584, Q585, D586, W587, H588, R589) of SEQ ID NO: 981. 106. The AAV particle of any one of embodiments 1-105, wherein [N1]-[N2] is present at positions 582-589, numbered according to SEQ ID NO: 138 or 981. 107. The AAV particle of any one of embodiments 1-106, wherein [N3] replaces positions 590-592 (e.g., Q590, A591, and Q592), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 108. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-107, wherein [N3] corresponds to positions 590-592 (e.g., I590, A591, and Q592) of SEQ ID NO: 981. 109. The AAV particle of any one of embodiments 1-108, wherein [N3] is present at positions 590-592, numbered according to SEQ ID NO: 138 or 981. 110. The AAV particle of any one of embodiments 1-109, wherein [N2]-[N3] replaces positions 586-592 (e.g., S586, A587, Q588, A589, Q590, A591, and Q592), numbered according to SEQ ID NO: 138.111. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-110, wherein [N2]-[N3] corresponds to positions 586-592 (e.g., D586, W587, H588, R589, I590, A591, and Q592) of SEQ ID NO: 981. 112. The AAV particle of any one of embodiments 1-111, wherein [N2]-[N3] is present at positions 586-592, numbered according to SEQ ID NO: 138 or 981. 113. The AAV particle of any one of embodiments 1-112, wherein [N1]-[N2]-[N3] replaces positions 582- 592 (e.g., T582, N583, H584, Q585, S586, A587, Q588, A589, Q590, A591, Q592), numbered according to SEQ ID NO: 138. 114. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-113, wherein [N1]-[N2]-[N3] corresponds to positions 582-592 (e.g., T582, N583, T584, Q585, D586, W587, H588, R589, I590, A591, Q592) of SEQ ID NO: 981. 115. The AAV particle of any one of embodiments 1-114, wherein [N1]-[N2]-[N3] is present at positions 582-592, numbered according to SEQ ID NO: 138 or 981. 116. The AAV particle of any one of embodiments 43-50 or 87-115, wherein [N4] replaces positions 593-596 (e.g., T593, G594, W595, and V596), numbered according to SEQ ID NO: 138. 117. The AAV particle of any one of embodiments 43-49 or 87-115, wherein [N4] corresponds to positions 593-596 (e.g., T593, G594, W595, and V596) of SEQ ID NO: 138 or 981. 118. The AAV particle of any one of embodiments 43-50 or 87-117, wherein [N4] is present at positions 593- 596, numbered according to SEQ ID NO: 138 or 981. 119. The AAV particle of any one of embodiments 43-50 or 87-118, wherein [N2]-[N3]-[N4] replaces positions 586-596 (e.g., S586, A587, Q588, A589, Q590, A591, Q592, T593, G594, W595, and V596), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 120. The AAV particle of any one of embodiments 43-49 or 87-119, wherein [N2]-[N3]-[N4] corresponds to positions 586-596 (e.g., D586, W587, H588, R589, I590, A591, Q592, T593, G594, W595, and V596) of SEQ ID NO: 981.121. The AAV particle of any one of embodiments 43-50 or 87-120, wherein [N2]-[N3]-[N4] is present at positions 586-596, numbered according to SEQ ID NO: 138 or 981. 122. The AAV particle of any one of embodiments 43-50 or 87-121, wherein [N1]-[N2]-[N3]-[N4] replaces positions 582-596 (e.g., T582, N583, H584, Q585, S586, A587, Q588, A589, Q590, A591, Q592, T593, G594, W595, and V596), numbered according to the amino acid sequence of SEQ ID NO: 138. 123. The AAV particle of any one of embodiments 43-49 or 87-122, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 582-596 (e.g., T582, N583, T584, Q585, D586, W587, H588, R589, I590, A591, Q592, T593, G594, W595, and V596) of SEQ ID NO: 981. 124. The AAV particle of any one of embodiments 43-50 or 87-123, wherein [N1]-[N2]-[N3]-[N4] is present at positions 582-596, numbered according to the amino acid sequence of SEQ ID NO: 138 or 981. 125. The AAV particle of any one of embodiments 1-124, wherein [N2] is present immediately subsequent to [N1]. 126. The AAV particle of any one of embodiments 1-125, wherein [N3] is present immediately subsequent to [N2]. 127. The AAV particle of any one of embodiments 43-50 or 87-126, wherein [N4] is present immediately subsequent to [N3]. 128. The AAV particle of any one of embodiments 1-127, wherein the AAV capsid variant comprises from N-terminus to C-terminus, [N1]-[N2]-[N3]. 129. The AAV particle of any one of embodiments 43-50 or 87-128, wherein the AAV capsid variant comprises from N-terminus to C-terminus, [N1]-[N2]-[N3]-[N4]. 130. 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 1, 2A, 2B, 9, 14, 15, 16, or 26-31;(b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive amino acids from any one of the sequences provided in Tables 1, 2A, 2B, 9, 14, 15, 16, or 26-31; 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 1, 2A, 2B, 9, 14, 15, 16, or 26-31; 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 1, 2A, 2B, 9, 14, 15, 16, or 26-31. 131. 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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive amino acids from any one of SEQ ID NOs: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336; (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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336; 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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336. 132. The AAV particle of embodiment 130 or 131, wherein the AAV capsid variant does not comprise at least 3, 4, 5, 6, 7, 8, or 9 consecutive amino acids from TNHQSAQAQ (SEQ ID NO: 92), optionally wherein the TNHQSAQAQ (SEQ ID NO: 92) corresponds to positions 582-592 of SEQ ID NO: 138. 133. The AAV particle of any one of embodiments 130-132, wherein the AAV capsid variant does not comprise: TNH, TNHQ (SEQ ID NO: 4760), TNHQS (SEQ ID NO: 93), TNHQSA (SEQ ID NO: 94), TNHQSAQ (SEQ ID NO: 95), TNHQSAQA (SEQ ID NO: 96), TNHQSAQAQ (SEQ ID NO: 92), NHQ, NHQS (SEQ ID NO: 97), NHQSA (SEQ ID NO: 98), NHQSAQ (SEQ ID NO: 99), NHQSAQA (SEQ ID NO: 100), NHQSAQAQ (SEQ ID NO: 101), HQS, HQSA (SEQ ID NO: 102), HQSAQ (SEQ ID NO: 103),HQSAQA (SEQ ID NO: 104), HQSAQAQ (SEQ ID NO: 105), QSA, QSAQ (SEQ ID NO: 106), QSAQA (SEQ ID NO: 107), QSAQAQ (SEQ ID NO: 108), SAQA (SEQ ID NO: 109), or SAQAQ (SEQ ID NO: 110). 134. The AAV particle of any one of embodiments 130-124, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive amino acids from any one of SEQ ID NOs: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336. 135. The AAV particle of any one of embodiments 130-134, wherein the 3 consecutive amino acids comprise TQD. 136. The AAV particle of any one of embodiments 130-135, wherein the at least 4 consecutive amino acids comprise TQDW (SEQ ID NO: 4684). 137. The AAV particle of any one of embodiments 130-136, wherein the at least 5 consecutive amino acids comprise TQDWH (SEQ ID NO: 4685). 138. The AAV particle of any one of embodiments 130-137, wherein the at least 6 consecutive amino acids comprise TQDWHR (SEQ ID NO: 4686). 139. The AAV particle of embodiment 130-138, wherein the at least 7 consecutive amino acids comprise TQDWHRI (SEQ ID NO: 941). 140. The AAV particle of any one of embodiments 130-134, wherein the at least 3 consecutive amino acids comprise TNT. 141. The AAV particle of any one of embodiments 130-134 or 140, wherein the at least 4 consecutive amino acids comprise TNTQ (SEQ ID NO: 4688). 142. The AAV particle of any one of embodiments 130-134, 140, or 141, wherein the at least 5 consecutive amino acids comprise TNTQD (SEQ ID NO: 111).143. The AAV particle of any one of embodiments 130-134 or 140-142, wherein the at least 6 consecutive amino acids comprise TNTQDW (SEQ ID NO: 112). 144. The AAV particle of embodiment 130-134 or 140-143, wherein the at least 7 consecutive amino acids comprise TNTQDWH (SEQ ID NO: 113). 145. The AAV particle of any one of embodiments 130-134 or 140-144, wherein the at least 8 consecutive amino acids comprise TNTQDWHR (SEQ ID NO: 1307). 146. The AAV particle of any one of embodiments 130-134 or 140-145, wherein the at least 9 consecutive amino acids comprise TNTQDWHRI (SEQ ID NO: 746). 147. The AAV particle of any one of embodiments 130-146, 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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336. 148. The AAV particle of any one of embodiments 130-147, 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 TQDWHRI (SEQ ID NO: 941). 149. The AAV particle of any one of embodiments 130-147, 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 TNTQDWHRI (SEQ ID NO: 746). 150. The AAV particle of any one of embodiments 130-149, 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 ATNTQDWHRIAQT (SEQ ID NO: 744).151. The AAV particle of any one of embodiments 130-150, 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: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336. 152. The AAV particle of any one of embodiments 130-149 or 151, 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 TQDWHRI (SEQ ID NO: 941). 153. The AAV particle of any one of embodiments 130-149, 151, or 152, 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 relative to the amino acid sequence of TNTQDWHRI (SEQ ID NO: 746). 154. The AAV particle of any one of embodiments 130-153, 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 relative to the amino acid sequence of ATNTQDWHRIAQT (SEQ ID NO: 744). 155. The AAV particle of any one of embodiments 1-154, wherein the AAV capsid variant comprises the amino acid sequence of any of SEQ ID NOs: 201, 205-209, 211-214, 216, 219, 220, 230, 232, 237, 238, 255, 262-265, 274, 283, 286, 290, 291, 293, 301, 306, 307, 308, 309, 314, or 336. 156. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-155, wherein the AAV capsid variant comprises the amino acid sequence of TQDWHRI (SEQ ID NO: 941), optionally wherein the amino acid sequence replaces positions 584-590, numbered according to SEQ ID NO: 138. 157. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-156, which comprises the amino acid sequence of TQDWHRI (SEQ ID NO: 941), optionally wherein the amino acid sequence corresponds to positions 584-590 of SEQ ID NO: 981. 158. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-149, 151-153, or 155-157, comprising 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 thenucleotide 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. 159. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-158, comprising an amino acid sequence encoded by: the nucleotide sequence of SEQ ID NO: 747; 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: 747; 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: 747. 160. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-149, 151-153, or 155-158, wherein the nucleotide sequence encoding the 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. 161. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-160, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 747; 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: 747; 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: 747. 162. The AAV particle of any one of embodiments 130-161, wherein the amino acid sequence is present in loop VIII, optionally wherein loop VIII comprises positions 580-599, numbered according to SEQ ID NO: 138 or 981. 163. The AAV particle of any one of embodiments 130-153, wherein the amino acid sequence replaces positions 584, 585, 586, 587, 588, 589, and / or 590 (e.g., H584, Q585, S586, A587, Q588, A589, and / or Q590), numbered according to the amino acid sequence of SEQ ID NO: 138.164. The AAV particle of any one of embodiments 130-163, wherein the amino acid sequence is present at positions 584, 585, 586, 587, 588, 589, and / or 590, numbered according to the amino acid sequence of SEQ ID NO: 138 or 981. 165. The AAV particle of any one of embodiments 130-164, wherein the amino acid sequence corresponds to positions 584-590 (e.g., T584, Q585, D586, W587, H588, R589, and / or I590), numbered according to the amino acid sequence of SEQ ID NO: 981. 166. The AAV particle of any one of embodiments 121-165, wherein the amino acid sequence replaces positions 582, 583, 584, 585, 586, 587, 588, 589, and / or 590 (e.g., T582, N583, H584, Q585, S586, A587, Q588, A589, and / or Q590), numbered according to the amino acid sequence of SEQ ID NO: 138. 167. The AAV particle of any one of embodiments 121-166, wherein the amino acid sequence is present at positions 582, 583, 584, 585, 586, 587, 588, 589, and / or 590, numbered according to the amino acid sequence of SEQ ID NO: 138 or 981. 168. The AAV particle of any one of embodiments 121-167, wherein the amino acid sequence replaces positions 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, and / or 596 (e.g., T582, N583, H584, Q585, S586, A587, Q588, A589, Q590, A591, Q592, T593, G594, W595, and / or V5965), numbered according to the amino acid sequence of SEQ ID NO: 138. 169. The AAV particle of any one of embodiments 121-168, wherein the amino acid sequence is present at positions 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, and / or 596, numbered according to the amino acid sequence of SEQ ID NO: 138 or 981. 170. The AAV particle of any one of embodiments 1-169, wherein the AAV capsid variant comprises one, two, three, four, five or all of an amino acid other than H at position 584 (e.g., T), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), and / or Q at position 590 (e.g., I), numbered according to SEQ ID NO: 138. 171. 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, two, three, four, five or all of an amino acid other than H atposition 584 (e.g., T), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), and / or Q at position 590 (e.g., I), numbered according to SEQ ID NO: 138. 172. The AAV particle of any one of embodiments 1-171, wherein the AAV capsid variant comprises one, two, three, four, five or all of the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. 173. 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, two, three, four, five or all of the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. 174. The AAV particle of any one of embodiments 1-173, wherein the AAV capsid variant comprises one, two, three, four, five or all of the substitutions H584T, S586D, A587W, Q588H, A589R, and / or Q590I, numbered according to SEQ ID NO: 138. 175. 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, two, three, four, five or all of the substitutions H584T, S586D, A587W, Q588H, A589R, and / or Q590I, numbered according to SEQ ID NO: 138. 176. The AAV particle of any one of embodiments 1-175, wherein the AAV capsid variant comprises an amino acid other than H at position 584 (e.g., T), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), and Q at position 590 (e.g., I), numbered according to SEQ ID NO: 138. 177. The AAV particle of any one of embodiments 1-176, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981. 178. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-98, or 100-164, which corresponds to positions 584, 586, 587, 588, 589, and 590 of SEQ ID NO: 981.179. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-178, which corresponds to positions 582, 583, 584, 586, 587, 588, 589, and 590 of SEQ ID NO: 981. 180. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, or 101-179, which corresponds to positions 582, 583, 584, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, and 596 of SEQ ID NO: 981. 181. The AAV particle of any one of embodiments 1-181, wherein the AAV capsid variant comprises the substitutions H584T, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138. 182. 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 T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981. 183. 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 substitutions H584T, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138. 184. The AAV particle of any one of embodiments 1-183, wherein the AAV capsid variant further comprises an amino acid other than A position 581, numbered according to SEQ ID NO: 138 or 981. 185. The AAV particle of any one of embodiments 1-184, wherein the AAV capsid variant further comprises a T at position 581 or a V at position 581, numbered according to SEQ ID NO: 138 or 981. 186. The AAV particle of any one of embodiments 1-185, wherein the AAV capsid variant comprises the substitutions A581T or A581V, numbered according to SEQ ID NO: 138 or 981. 187. The AAV particle of any one of embodiments 1, 3-7, 9-15, 17-20, 22-38, 40-48, 50, 130-134, 147, 151, 155, 162, 163, 166-177, or 181-186, wherein the AAV capsid variant comprises an amino acid other than Q at position 585, numbered according to SEQ ID NO: 138.188. The AAV particle of any one of embodiments 1, 3-7, 9-15, 17-20, 22-38, 40-48, 50, 130-134, 147, 151, 155, 162, 163, 166-177, 181-187, wherein the AAV capsid variant comprises the amino acid K at position 585, numbered according to SEQ ID NO: 138. 189. 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, IV, and / or VI; and / or (ii) a substitution at position K449, e.g., a K449R substitution, numbered according to SEQ ID NO: 138. 190. The AAV particle of any one of the preceding embodiments, 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: 138. 191. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises 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. 192. 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 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 193. 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. 194. 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 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 195. 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 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.196. 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. 197. The AAV particle of any one of embodiments 1-196, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 138-736, e.g., a VP2, of SEQ ID NO: 981, or a sequence with at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 198. The AAV particle of any one of embodiments 1-197, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 203-736, e.g., a VP3, of SEQ ID NO: 981, or a sequence with at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 199. The AAV particle of any one of embodiments 1-198, 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 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 200. The AAV particle of any one of embodiments 1-199, 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 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 201. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, 101-186, or 189-200, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, 6, or 7 consecutive amino acids from the amino acid sequence of TQDWHRI (SEQ ID NO: 941), wherein: (i) the at least 3 consecutive amino acids comprise TQD; (ii) the at least 4 consecutive amino acids comprise TQDW (SEQ ID NO: 4684); (iii) the at least 5 consecutive amino acids comprise TQDWH (SEQ ID NO: 4685); (iv) the at least 6 consecutive amino acids comprise TQDWHR (SEQ ID NO: 4686); or (v) the at least 7 consecutive amino acids comprise TQDWHRI (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 138-736 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 203-736 of SEQ ID NO: 981; or (d) an amino acid sequence with at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c).202. The AAV particle of any one of embodiments 1-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, 101-186, or 189-201, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, 6, 3, 4, 5, 6, or 7 consecutive amino acids from the amino acid sequence of TQDWHRI (SEQ ID NO: 941), wherein: (i) the at least 3 consecutive amino acids comprise TQD; (ii) the at least 4 consecutive amino acids comprise TQDW (SEQ ID NO: 4684); (iii) the at least 5 consecutive amino acids comprise TQDWH (SEQ ID NO: 4685); (iv) the at least 6 consecutive amino acids comprise TQDWHR (SEQ ID NO: 4686); or (v) the at least 7 consecutive amino acids comprise TQDWHRI (SEQ ID NO: 941); wherein the AAV capsid variant comprises an amino acid sequence at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 981. 203. The AAV particle of any one of embodiments 11-3, 5-8, 10-16, 18-21, 23-39, 42-49, 51-69, 71-83, 85- 99, 101-186, or 189-202, wherein the AAV capsid variant comprises one or two, but no more than three substitutions relative to the amino acid sequence of TQDWHRI (SEQ ID NO: 941), wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981. 204. The AAV particle of any one of embodiments 1-203, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NO: 981, or an amino acid sequence with at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 205. The AAV particle of any one of embodiments 1-204, 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. 206. The AAV particle of any one of embodiments, 1-205, 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. 207. The AAV particle of any one of embodiments 1-206, wherein the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence with at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.208. The AAV particle of any one of the preceding embodiments 1-207, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence with at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 209. The AAV particle of any one of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant is codon optimized. 210. 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 embodiments 1-3, 5-8, 10- 16, 18-21, 23-39, 42-49, 51-69, 71-83, 85-99, 101-186, or 189, and further comprising an amino acid sequence at least 95% identical to SEQ ID NO: 981. 211. 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 SEQ ID NO: 981. 212. 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 encoded by the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence at least 95% identical thereto. 213. 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 positions 203-736 of SEQ ID NO: 981, or an amino acid sequence at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) thereto, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 981. 214. The AAV particle of embodiment 213, wherein the AAV capsid variant comprises the amino acid sequence of positions 203-736 of SEQ ID NO: 981. 215. 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 positions 203-736 of SEQ ID NO: 981. 216. 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 positions 138-736 of SEQ ID NO: 981, or an amino acid sequence at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) thereto, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 981. 217. The AAV particle any one of embodiments 213-216, wherein the AAV capsid variant comprises the amino acid sequence of positions 138-736 of SEQ ID NO: 981. 218. 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 positions 138-736 of SEQ ID NO: 981. 219. 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 SEQ ID NO: 981, or an amino acid sequence at least 80% (e.g., at least 85, 90, 95, 96, 97, 98, or 99%) thereto, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 981. 220. The AAV particle of any one of embodiments 213-219, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981. 221. The AAV particle of any one of the preceding embodiments, which comprises an amino acid other than Q at position 597, numbered according to SEQ ID NO: 138 or 981. 222. The AAV particle of any one of the preceding embodiments, which comprises the amino acid H at position 597, numbered according to SEQ ID NO: 138 or 981.223.The AAV particle of any one of embodiments 1-176 or 189-200, 204-209, 221, or 222, wherein the AAV capsid variant comprises: (i) an amino acid other than N at position 583 (e.g., T), an amino acid H at position 584 (e.g., T or Q), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), and Q at position 590 (e.g., I), numbered according to SEQ ID NO: 138; (ii) an amino acid other than H at position 584 (e.g., T), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), Q at position 590 (e.g., I or V), and A at position 591 (e.g., P or W), numbered according to SEQ ID NO: 138; or (iii) an amino acid other than H at position 584 (e.g., T), S at position 586 (e.g., D), A at position 587 (e.g., W), Q at position 588 (e.g., H), A at position 589 (e.g., R), Q at position 590 (e.g., I), and Q at position 597 (e.g., H), numbered according to SEQ ID NO: 138. 224. The AAV particle of any one of embodiments 1-176 or 189-200, 204-209, or 220-223, wherein the AAV capsid variant comprises: (i) the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, V at position 590, and P at position 591, numbered according to SEQ ID NO: 138 or 981; (ii) the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, I at position 590, and H at position 597, numbered according to SEQ ID NO: 138 or 981; (iii) the amino acid T at position 583, T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981; (iv) the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and V at position 590, numbered according to SEQ ID NO: 138 or 981; (v) the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, I at position 590, and W at position 591, numbered according to SEQ ID NO: 138 or 981; or (vi) the amino acid T at position 583, Q at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981. 225. The AAV particle of any one of embodiments 1-176 or 189-200, 204-209, or 220-224, wherein the AAV capsid variant comprises: (i) the substitutions H584T, S586D, A587W, Q588H, A589R, Q590V, and A591P, numbered according to SEQ ID NO: 138; (ii) the substitutions H584T, S586D, A587W, Q588H, A589R, Q590I, and Q597H, numbered according to SEQ ID NO: 138;(iii) the substitutions N583T, H584T, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138; (iv) the substitutions H584T, S586D, A587W, Q588H, A589R, and Q590V, numbered according to SEQ ID NO: 138; (v) the substitutions H584T, S586D, A587W, Q588H, A589R, Q590I, and A591W, numbered according to SEQ ID NO: 138; or (vi) the substitutions N583T, H584Q, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138. 226. The AAV particle of any one of embodiments 1-176 or 189-200, 204-209, or 220-225, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NO: 208, 216, 232, 241, 943, or 984; optionally wherein: (i) the amino acid sequence of SEQ ID NO: 943 is present at positions 582-597, numbered according to SEQ ID NO: 138 or 981; or (ii) the amino acid sequences of any one of SEQ ID NOs: 208, 216, 232, 241, or 984 are present at positions 582-596, numbered according to SEQ ID NO: 138 or 981. 227. An AAV capsid variant comprising the amino acid H at position 597, numbered according to SEQ ID NO: 138 or 981, and one, two, three, four, five or all of the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. 228. An AAV capsid variant comprising the substitution Q597H, numbered according to SEQ ID NO: 138; and one, two, three, four, five or all of the substitutions H584T, S586D, A587W, Q588H, A589R, and / or Q590I, numbered according to SEQ ID NO: 138. 229. The AAV capsid variant of embodiment 227 or 228, comprising the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, I at position 590, and H at position 597, numbered according to SEQ ID NO: 138 or 981. 230. The AAV capsid variant of any one of embodiments 227-229, comprising the substitutions H584T, S586D, A587W, Q588H, A589R, Q590I, and Q597H, numbered according to SEQ ID NO: 138.231. The AAV capsid variant of any one of embodiments 227-230, which comprises the amino acid sequence of SEQ ID NO: 943, optionally wherein the amino acid sequence of SEQ ID NO: 943 is present at positions 582-597, numbered according to SEQ ID NO: 138 or 981. 232. An AAV capsid variant comprising the amino acid T at position 583 and Q at position 584, numbered according to SEQ ID NO: 138 or 981; and one, two, three, four, or all of the amino acid D at position 586, W at position 587, H at position 588, R at position 589, and / or I at position 590, numbered according to SEQ ID NO: 138 or 981. 233. An AAV capsid variant comprising the substitutions N583T and H584Q, numbered according to SEQ ID NO: 138; and one, two, three, or four or all of the substitutions S586D, A587W, Q588H, A589R, and / or Q590I, numbered according to SEQ ID NO: 138. 234. The AAV capsid variant of embodiment 232 or 233, which comprises the amino acid T at position 583, Q at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO: 138 or 981. 235. The AAV capsid variant of any one of embodiments 232-234, comprising the substitutions N583T, H584Q, S586D, A587W, Q588H, A589R, and Q590I, numbered according to SEQ ID NO: 138. 236. The AAV capsid variant of any one of embodiments 232-235, which comprises the amino acid sequence of SEQ ID NO: 984, optionally wherein the amino acid sequence of SEQ ID NO: 984 is present at positions 582-596, numbered according to SEQ ID NO: 138 or 981. 237. The AAV capsid variant of any one of embodiments 227-236, which further comprises the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or 981, or an amino acid sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to positions 203-736 of SEQ ID NO: 138 or 981. 238. The AAV capsid variant of any one of embodiments 227-237, which further comprises the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or 981, or an amino acid sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to positions 138-736 of SEQ ID NO: 138 or 981.239. The AAV capsid variant of any one of embodiments 227-238, which further comprises the amino acid sequence SEQ ID NO: 138 or 981, or an amino acid sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138 or 981. 240. An AAV particle comprising the AAV capsid variant of any one of embodiments 227-239, and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT). 241. The AAV particle of any one of embodiments 1-226 or 240, which has 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. 242. The AAV particle of any one of embodiments 1-226, 240, or 241, which transduces a brain region, e.g., sensory cortex, motor cortex, putamen, thalamus, caudate, hippocampus, cerebellum, optionally wherein the level of transduction is at least 39, 50, 100, 120, 132, 146, 150, 161, 174, 175, 200, 225, 250, 275, 283, 300, 350, 400, 450, 500, 525, 528, or 550-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 or ddPCR assay, e.g., as described in Example 2. 243. The AAV particle of any one of embodiments 1-226 or 240-242, wherein the AAV capsid variant is enriched at least about 10, 14, 20, 24, 50, 100, 150, 200, 250, 300, 350, 400, 425, 450, or 460-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 3. 244. The AAV particle of any one of embodiments 1-226 or 240-243, wherein the AAV capsid variant is enriched at least about 200, 300, 400, 425, 450, or 460-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. 245. The AAV particle of any one of embodiments 1-226 or 240-244, 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. 246. The AAV particle of any one of embodiments 1-226 or 240-245, wherein the AAV capsid variant is enriched at least about 2, 3, 5, 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 1 or 4. 247. The AAV particle of embodiment 245 or 246, wherein the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., outbred mice). 248. The AAV particle of any one of embodiments 1-226 or 240-247, wherein the AAV capsid variant is enriched at least about 2, 3, 4, 5, 10, 15, 17, 20, 50, 75, 100, 103, 107, 125, 150, 200, 250, 300, 350, 400, 450, 500, 750, 1000, 1200-fold, in the brain compared to a reference sequence of SEQ ID NO: 981, e.g., when measured by an assay as described in Example 3. 249. The AAV particle of any one of embodiments 1-226 or 240-248, which delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 39, 50, 100, 120, 132, 146, 150, 161, 174, 175, 200, 225, 250, 275, 283, 300, 350, 400, 450, 500, 525, 528, or 550-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR, a ddPCR, or a qPCR assay (e.g., as described in Example 2). 250. The AAV particle of any one of embodiments 1-226 or 240-249, which delivers an increased level of viral genomes to a brain region, optionally wherein the level of viral genomes is increased by at least 2, 5, 7, 10, 15, 19, 20, 22, or 25-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). 251. The AAV particle of embodiment 249 or 250, wherein the brain region is a sensory cortex, motor cortex, putamen, thalamus, caudate, hippocampus, and / or cerebellum. 252. The AAV particle of any one of embodiments 1-226 or 240-251, wherein the AAV capsid variant is enriched at least about 5, 10, 50, 100, 115, 120, 150, 175, 200, 207, 225, 250, or 275-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 2. 253. The AAV particle of any one of embodiments 1-226 or 240-252, 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.254. The AAV particle of any one of embodiments 1-226 or 240-253, wherein the encoded polynucleotide for inhibiting MAPT comprises an a siRNA comprises a sense strand sequence and antisense strand sequence. 255. The AAV particle of embodiment 254, wherein the encoded siRNA binds to a 3’ UTR of MAPT (e.g., human MAPT). 256. The AAV particle of embodiment 254 or 255, wherein the encoded siRNA binds to a coding region of MAPT (e.g., human MAPT). 257. The AAV particle of any one of embodiments 254-256, wherein the encoded siRNA binds to a 5’ UTR of MAPT (e.g., human MAPT). 258. The AAV particle of any one of embodiments 254-257, wherein the MAPT is a human MAPT gene, a non-human primate MAPT gene, or a mouse MAPT gene. 259. The AAV particle of any one embodiments 254-258, wherein the antisense strand comprises at least one mismatch with the target mRNA. 260. The AAV particle of any one of embodiments 254-259, 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. 261. The AAV particle of any one of embodiments 254-260, 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. 262. The AAV particle of any one of embodiments 254-261, 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: 5024.263. The AAV particle of any one of embodiments 254-262, 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. 264. The AAV particle of any one of embodiments 254-263, 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. 265. The AAV particle of any one of embodiments 254-264, 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. 266. The AAV particle of any one of embodiments 254-263, 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. 267. The AAV particle of embodiment 266, 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. 268. The AAV particle of any one of embodiments 254-267, 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 nucleotidesdiffering 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 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: 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 nucleotidesdiffering 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: 4527.269. The AAV particle of any one of embodiments 254-268, 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. 270. The AAV particle of any one of embodiments 254-267, 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. 271. The AAV particle of any one of embodiments 266-270, wherein the region of complementarity comprises at least 18, 19, or 20 nucleotides. 272. The AAV particle of any one of embodiments 254-271, 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. 273. The AAV particle of any one of embodiments 254-272, 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. 274. The AAV particle of any one of embodiments 254-273, 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 least19, 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. 275. The AAV particle of any one of embodiments 254-274, 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. 276. The AAV particle of any one of embodiments 254-274, 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: 4918.277. The AAV particle of any one of embodiments 254-274, 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. 278. The AAV particle of any one of embodiments 254-274, 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. 279. The AAV particle of any one of embodiments 254-274, 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. 280. The AAV particle of any one of embodiments 254-274, 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. 281. The AAV particle of any one of embodiments 254-274, 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. 282. The AAV particle of any one of embodiments 254-274, 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. 283. The AAV particle of any one of embodiments 254-282, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, or 4912. 284. The AAV particle of any one of embodiments 254-283, 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. 285. The AAV particle of any one of embodiments 254-284, 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. 286. The AAV particle of any one of embodiments 254-275 or 283-285, 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. 287. The AAV particle of any one of embodiments 254-274, 276, or 283-285, 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. 288. The AAV particle of any one of embodiments 254-274, 277, or 283-285, 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. 289. The AAV particle of any one of embodiments 254-274, 278, or 283-285, 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. 290. The AAV particle of any one of embodiments 254-274, 279, or 283-285, 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. 291. The AAV particle of any one of embodiments 254-274, 280, or 283-285, 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. 292. The AAV particle of any one of embodiments 254-274, 281, or 283-285, 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. 293. The AAV particle of any one of embodiments 254-274 or 282-285, 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. 294. The AAV particle of any one of embodiments 254-293 wherein the encoded antisense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4908, 4920, 4924, or 4912. 295. The AAV particle of any one of embodiments 254-294, 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. 296. The AAV particle of any one of embodiments 254-295, 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 5074.297. The AAV particle of any one of embodiments 254-275, 283-286, or 294-296, 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. 298. The AAV particle of any one of embodiments 254-274, 276, 283-285, 287, or 294-296, 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. 299. The AAV particle of any one of embodiments 254-274, 277, 283-285, 288, or 294-296, 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. 300. The AAV particle of any one of embodiments 254-274, 278, 283-285, 289, or 294-296, 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. 301. The AAV particle of any one of embodiments 254-274, 279, 283-285, 290, or 294-296, 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. 302. The AAV particle of any one of embodiments 254-274, 280, 283-285, 291, or 294-296, 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. 303. The AAV particle of any one of embodiments 254-274, 281, 283-285, 292, or 294-296, 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. 304. The AAV particle of any one of embodiments 254-274, 282-285, or 293-296, 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. 305. The AAV particle of any one of embodiments 254-304, 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. 306. The AAV particle of any one of embodiments 254-305, 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 the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxx) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5100 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5107 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5111 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxiii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5115 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxiv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5119 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5121 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103;(lxxvi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5124 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxvii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5131 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5135 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5139 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxx) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5143 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; or (lxxxi) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5145 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127. 307. The AAV particle of any one of embodiments 254-275, 283-286, 294-297, 305, or 306, wherein 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. 308. The AAV particle of any one of embodiments 254-274, 276, 283-285, 287, 294-296, 298, 305, or 306, wherein 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. 309. The AAV particle of any one of embodiments 254-274, 277, 283-285, 288, 294-296, 299, 305, or 306, wherein 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: 4921.310. The AAV particle of any one of embodiments 254-274, 278, 283-285, 289, 294-296, 300, 305, or 306, wherein 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. 311. The AAV particle of any one of embodiments 254-274, 279, 283-285, 290, 294-296, 301, 305, or 306, wherein 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. 312. The AAV particle of any one of embodiments 254-274, 280, 283-285, 291, 294-296, 302, 305, or 306, wherein 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. 313. The AAV particle of any one of embodiments 254-274, 281, 283-285, 292, 294-296, 303, 305, or 306, wherein 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. 314. The AAV particle of any one of embodiments 254-313, wherein 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. 315. The AAV particle of any one of embodiments 254-314, wherein 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. 316. The AAV particle of any one of embodiments 254-315, wherein: (i) the sense strand and the antisense strand comprise one mismatch; and / or (ii) the antisense strand and the target sequence comprise one mismatch.317. The AAV particle of any one of claims 254-316, wherein the polynucleotide for inhibiting MAPT (e.g., human MAPT) further comprises a modulatory polynucleotide, wherein the modulatory polynucleotide comprises the siRNA. 318. The AAV particle of embodiment 317, wherein the encoded 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. 319. The AAV particle of embodiment 318, wherein: (i) the encoded 5’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4878-4886; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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 encoded loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4887- 4896; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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 encoded 3’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4897-4904; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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. 320. The AAV particle of embodiment 318 or 319, wherein: (i) the nucleotide sequence encoding the 5’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 4353-4361, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, orseven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4353-4361; 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: 4353-4361; (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 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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. 321. The AAV particle of any one of embodiments 318-320, wherein: (i) the encoded 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4879; a nucleotide sequence at least 70%, 75%, 80%, 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 different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the encoded loop region comprises the nucleotide sequence of SEQ ID NO: 4887; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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) the encoded 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4898; a nucleotide sequence at least 70%, 75%, 80%, 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 sequencecomprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898. 322. The AAV particle of any one of embodiments 318-320, wherein: (i) the encoded 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4879; a nucleotide sequence at least 70%, 75%, 80%, 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 encoded loop region comprises the nucleotide sequence of SEQ ID NO: 4888; a nucleotide sequence at least 70%, 75%, 80%, 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; and (iii) the encoded 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4898; a nucleotide sequence at least 70%, 75%, 80%, 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. 323. The AAV particle of any one of embodiments 318-320, wherein: (i) the encoded 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4879; a nucleotide sequence at least 70%, 75%, 80%, 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 encoded loop region comprises the nucleotide sequence of SEQ ID NO: 4887; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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) the encoded 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4899; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 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. 324. The AAV particle of any one of embodiments 318-320, wherein: (i) the encoded 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 70%, 75%, 80%, 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 encoded loop region comprises the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 70%, 75%, 80%, 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; and (iii) the encoded 3’ flanking region comprises the nucleotide sequence of of SEQ ID NO: 4900; a nucleotide sequence at least 70%, 75%, 80%, 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. 325. The AAV particle of any one of embodiments 318-324, which 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. 326. The AAV particle of any one of embodiments 317-320, 324, or 325, wherein the encoded modulatory polynucleotide comprises:(i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 327. The AAV particle of any one of embodiments 317-320, or 324-326, where the nucleotide sequence encoding the modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 328. The AAV particle of any one of embodiments 317-320, 324, or 325, where the encoded modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 329. The AAV particle of any one of embodiments 317-320, 324, 325, or 328, where the nucleotide sequence encoding the modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 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 comprisingone, 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 70%, 75%, 80%, 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: 4919; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 70%, 75%, 80%, 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. 330. The AAV particle of any one of embodiments 317-320, 324, or 325, where the encoded modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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 differentnucleotides 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. 331. The AAV particle of any one of embodiments 317-320, 324, 325, or 330, where the nucleotide sequence encoding the modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 332. The AAV particle of any one of embodiments 317-320, 322, or 325, wherein the encoded modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 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: 4966;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 333. The AAV particle of any one of embodiments 317-320, 322, 325, or 332, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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: 4373.334. The AAV particle of any one of embodiments 317-320, 322, or 325, wherein the encoded modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 335. The AAV particle of any one of embodiments 317-320, 322, or 325, or 334, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 336. The AAV particle of any one of embodiments 317-320, 322, or 325, wherein the encoded modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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: 4898.337. The AAV particle of any one of embodiments 317-320, 322, or 325, or 336, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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. 338. The AAV particle of any one of embodiments 317-320, 322, or 325, wherein the encoded modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 nucleotidesrelative 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 70%, 75%, 80%, 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. 339. The AAV particle of any one of embodiments 317-320, 322, or 325, or 338, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises: (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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: 4373.340. The AAV particle of any one of embodiments 317-339, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. 341. The AAV particle of any one of embodiments 317-320, 324-327, or 340, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4405, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. 342. The AAV particle of any one of embodiments 317-320, 324, 325, 328, 329, or 340, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4408, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. 343. The AAV particle of any one of embodiments 317-320, 324, 325, 330, 331, or 340, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4409, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. 344. The AAV particle of any one of embodiments 317-320, 322, 325, 332, 333, or 340, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4390, or nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. 345. The AAV particle of any one of embodiments 317-320, 322, 325, 334, 335, or 340, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4391, or nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. 346. The AAV particle of any one of embodiments 317-320, 322, 325, 336, 337, or 340, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4393, or nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.347. The AAV particle of any one of embodiments 317-320, 322, 325, 338-340, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4394, or nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. 348. The AAV particle of any one of embodiments 1-226 or 240-347, which comprises a viral genome comprising a promoter operably linked to the nucleic acid encoding the polynucleotide for inhibiting MAPT (e.g., human MAPT) . 349. The AAV particle of embodiment 348, wherein the promoter is a ubiquitous promoter. 350. The AAV particle of embodiment 348, wherein the promoter is a cell or tissue specific promoter. 351. The AAV particle of any one of embodiments 348-350, wherein the promoter 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. 352. The AAV particle of any one of embodiments 348-351, wherein the promoter comprises a CBA promoter or a variant thereof. 353. The AAV particle of any one of embodiments 348-351, wherein the promoter comprises a synapsin promoter or a variant thereof. 354. The AAV particle of any one of embodiments 348-353, wherein the promoter 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 80%, 85%, 92% 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the nucleotide sequences provided in Table 2. 355. The AAV particle of any one of embodiments 348-352 or 354, 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 with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5199. 356. The AAV particle of any one of embodiments 348-351, 353, or 354, 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 with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3883. 357. The AAV particle of any one of embodiments 348-356, wherein the viral genome further comprises a polyA signal sequence,. 358. The AAV particle of embodiment 357, 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 with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4476. 359. The AAV particle of any one of embodiments 348-358, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence. 360. The AAV particle of embodiment 359, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197, 5200, 4469, or 4470; 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, 5200, 4469, or 4470; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197, 5200, 4469, or 4470.361. The AAV particle of any one of embodiments 348-360, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA. 362. The AAV particle of embodiment 361 wherein 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 4469; 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 or 4469; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197 or 4469. 363. The AAV particle of any one of embodiments 348-362, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA. 364. The AAV particle of embodiment 363, wherein the ITR sequence positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 4470; 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 4470; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5200 or 4470. 365. The AAV particle of any one of embodiments 348-364, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA and an ITR sequence positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA. 366. The AAV particle of any one of embodiments 363-365, wherein: (i) the ITR positioned 5’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA 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; and (ii) the ITR positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA 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 sequencecomprising 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. 367. The AAV particle of any one of embodiments 363-365, wherein: (i) the ITR positioned 5’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA 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; and (ii) the ITR positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA 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. 368. The AAV particle of any one of embodiments 348-367, wherein the viral genome further comprises an enhancer, a Kozak sequence, an intron region, and / or an exon region. 369. The viral genome of embodiment 368, wherein the enhancer comprises: (i) a CMVie enhancer; or (ii) 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%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4471 or 4472. 370. The AAV particle of embodiment 368 or 369, 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 with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4471. 371. The AAV particle of any one of embodiments 368-370, which comprises a CMVie enhancer or variant thereof; and a CBA promoter or variant thereof; optionally wherein the CMVie enhancer or variant thereof is present 5’ relative to the CBA promoter or variant thereof.372. The AAV particle of any one of embodiments 368-371, wherein the enhancer and promoter comprise the nucleotide sequence of SEQ ID NO: 4473 or 4474; 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: 4473 or 4474; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4473 or 4474. 373. The AAV particle of any one of embodiments 368-372, wherein the intron comprises: (i) a human beta glob intron (hBG intron); or (ii) 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%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4475. 374. The AAV particle of any one of embodiments 348-373, wherein the viral genome further comprises a filler sequence. 375. The AAV particle of embodiment 374, wherein the filler sequence comprises the nucleotide sequence of SEQ ID NO: 3885; 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: 3885; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3885. 376. The AAV particle of any one of embodiments 348-375, wherein the viral genome further comprises a nucleotide sequence encoding a 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. 377. The AAV particle of embodiment 376, wherein the encoded miR binding site modulates, e.g., reduces, expression of the encoded polynucleotide in a cell or tissue of the DRG, liver, heart, hematopoietic lineage, or a combination thereof. 378. The AAV particle of any one of embodiments 348-377, wherein the viral genome comprises at least 1-5 copies of the encoded miR binding site, e.g., at least 1, 2, 3, 4, or 5 copies, optionally wherein the at least 1-5 copies are continuous (e.g., not separated by a spacer) or the at least 1-5 copies are separated by a spacer.379. The AAV particle of any one of embodiments 348-378, wherein the viral genome is self-complementary. 380. The AAV particle of any one of embodiments 348-378, wherein the viral genome is single stranded. 381. The AAV particle of any one of embodiments 1-380, which further comprises a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 and a Rep52 protein). 382. The AAV particle of any one of embodiments 348-381, wherein the viral genome comprises in 5’ to 3’ order: (i) an ITR; (ii) a promoter (e.g., a synapsin promoter or variant thereof); (iv) an intron (e.g., an hBG intron or variant thereof); (v) a nucleic acid sequence encoding a modulatory polynucleotide (e.g. the modulatory polynucleotide of any one of embodiments 253-283); (vi) a polyA signal sequence; and (vii) an ITR. 383. The AAV particle of any one of embodiments 348-382, wherein the viral genome comprises in 5’ to 3’ order: (i) an ITR; (ii) an enhancer (e.g., a CMVie enhancer or variant thereof); (iii) a promoter (e.g., a CBA promoter or variant thereof); (iv) an intron (e.g., an hBG intron or variant thereof); (v) a nucleic acid sequence encoding a modulatory polynucleotide (e.g. the modulatory polynucleotide of any one of embodiments 253-283); (vi) a polyA signal sequence; and (vii) an ITR. 384. The AAV particle of any one of embodiments 348-351, 353, 354, 356-366, 368-370, 373-379, 381, or 382, wherein the viral genome comprises in 5’ to 3’ order: (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) 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; (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. 385. The AAV particle of any one of embodiments 348-352, 354, 355, 356-366, or 368-383, wherein the viral genome comprises in 5’ to 3’ order: (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. 386. The AAV particle of any one of embodiments 348-352, 354, 355, 356-366, 368-383, or 385, wherein the viral genome comprises in 5’ to 3’ order: (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 tenmodifications, 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: 4405, 4408, 4409, 4390, 4391, 4393, or 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. 387. The AAV particle of any one of embodiments 348-352, 354, 355, 356-366, 368-383, or 385, wherein the viral genome comprises in 5’ to 3’ order: (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 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. 388. The AAV particle of any one of embodiments 348-351, 353, 354, 356-366, 368-370, 373-379, 381, 382, or 384, wherein the viral genome comprises in 5’ to 3’ order: (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; (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 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. 389. The AAV particle of any one of embodiments 348-352, 354, 355, 356-366, 368-383, or 385, wherein the viral genome comprises in 5’ to 3’ order: (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 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: 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. 390. The AAV particle of any one of embodiments 348-352, 354, 355, 356-366, 368-383, or 385, wherein the viral genome comprises in 5’ to 3’ order: (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: 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. 391. The AAV particle of any one of embodiments 348-352, 354, 355, 356-366, 368-383, or 385, wherein the viral genome comprises in 5’ to 3’ order: (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 c...

Claims

We claim:

1. An adeno-associated virus (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 [N2] comprises the amino acid sequence of DWHR (SEQ ID NO: 4682) and wherein: (i) [N1] comprises positions X1, X2, X3, and X4, wherein position X4is Q, K, E, S, P, R, N, or H; and / or (ii) [N3] comprises positions X5, X6, and X7, wherein position X5is I, V, T, M, S, N, L, or F; wherein [N1]-[N2]-[N3] is present in hypervariable loop VIII; 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 [N1] comprises positions X1, X2, X3, and X4, wherein: (i) position X1is T, S, R, A, I, C, N, K, L, or Q; (ii) position X2is N, T, G, V, S, Y, K, I, H, D, or F; (iii) position X3is T, N, K, D, I, S, P, A, Y, E, V, L, M, R, H, Q, or C; and (iv) position X4is Q, K, E, S, P, R, N, or H.

3. The AAV particle of claim 1 or 2, wherein: (i) [N1] comprises TNTQ (SEQ ID NO: 4688), TNTK (SEQ ID NO: 4689), TNNQ (SEQ ID NO: 1100), SNNQ (SEQ ID NO: 1101), TNKQ (SEQ ID NO: 1102), TNNE (SEQ ID NO: 1103), SNKQ (SEQ ID NO: 1104), SNTQ (SEQ ID NO: 1105), TTNQ (SEQ ID NO: 1106), TNDQ (SEQ ID NO: 1107), TTIQ (SEQ ID NO: 4698), RNTQ (SEQ ID NO: 4699), TTKQ (SEQ ID NO: 1110), TTSQ (SEQ ID NO: 1111), TTDQ (SEQ ID NO: 1112), TNPS (SEQ ID NO: 1113), TNKE (SEQ ID NO: 1114), TTTQ (SEQ ID NO: 1115), TGKQ (SEQ ID NO: 4706), TTAQ (SEQ ID NO: 4707), TVKQ (SEQ ID NO: 4708), TNYQ (SEQ ID NO: 4709), TNTP (SEQ ID NO: 1120), STKQ (SEQ ID NO: 4711), TTEQ (SEQ ID NO: 1122), TSKQ (SEQ ID NO: 4713), TNIQ (SEQ ID NO: 4714), TYNQ (SEQ ID NO: 1125), STIQ (SEQ ID NO: 1126), TTVQ (SEQ ID NO: 4717), TGTQ (SEQ ID NO: 1128), TNTR (SEQ ID NO: 4719), TTLQ (SEQ ID NO: 4720), TTMQ (SEQ ID NO: 4721), ANNQ (SEQ ID NO: 4722), SNIQ (SEQ ID NO: 4723), TKNQ (SEQ ID NO: 4724), TYTQ (SEQ ID NO: 4725), TNKS (SEQ ID NO: 4726), SNTE (SEQ ID NO: 4727), TNTE (SEQ ID NO: 4728), TNIE (SEQ ID NO: 4729), TTRQ (SEQ ID NO: 4730), TNSQ (SEQ ID NO: 4731), TYTK (SEQ ID NO: 4732), TTTK (SEQ ID NO: 4733), TNIK (SEQ ID NO: 4734), SNTK (SEQ ID NO: 4735), TNNK (SEQ ID NO: 4736), TNSK (SEQ ID NO: 4737), TSTK (SEQ ID NO: 4738), TITK (SEQ ID NO: 4739), INTK (SEQ ID NO: 4740), TNAK (SEQ ID NO: 4741), TKTK (SEQ ID NO: 4742), STNQ (SEQ ID NO: 4743),ANTK (SEQ ID NO: 4744), RNNQ (SEQ ID NO: 4745), TGNQ (SEQ ID NO: 4746), TSNQ (SEQ ID NO: 4747), THTK (SEQ ID NO: 4748), TDTK (SEQ ID NO: 4749), TNEQ (SEQ ID NO: 4750), CNTQ (SEQ ID NO: 4751), TNPK (SEQ ID NO: 4752), INNQ (SEQ ID NO: 4753), TYTE (SEQ ID NO: 4754), NNNQ (SEQ ID NO: 4755), KNNQ (SEQ ID NO: 4756), TNNR (SEQ ID NO: 4757), LNNQ (SEQ ID NO: 4758), TINQ (SEQ ID NO: 4759), TNHQ (SEQ ID NO: 4760), STTQ (SEQ ID NO: 4761), SNSQ (SEQ ID NO: 4762), STSQ (SEQ ID NO: 4763), TYIQ (SEQ ID NO: 4764), SGTQ (SEQ ID NO: 4765), THNQ (SEQ ID NO: 4766), TITQ (SEQ ID NO: 4767), TSTQ (SEQ ID NO: 4768), TNSN (SEQ ID NO: 4769), TNQQ (SEQ ID NO: 4770), RNIQ (SEQ ID NO: 4771), TNNP (SEQ ID NO: 4772), TITE (SEQ ID NO: 4773), TNTN (SEQ ID NO: 4774), TFSQ (SEQ ID NO: 4775), RNSQ (SEQ ID NO: 4776), INTQ (SEQ ID NO: 4777), RNTE (SEQ ID NO: 4778), TNNH (SEQ ID NO: 4779), TNMQ (SEQ ID NO: 4780), RTTQ (SEQ ID NO: 4781), SNIE (SEQ ID NO: 4782), TNTS (SEQ ID NO: 4783), KNTQ (SEQ ID NO: 4784), TNLQ (SEQ ID NO: 4785), TSMQ (SEQ ID NO: 4786), SYTQ (SEQ ID NO: 4787), TNCQ (SEQ ID NO: 4788), SSTQ (SEQ ID NO: 4789), TVTQ (SEQ ID NO: 4790), or QNTQ (SEQ ID NO: 4791); and / or (ii) [N3] comprises IAQ, IAG, IYQ, VPQ, IAN, INQ, VNQ, VYQ, VAN, ISG, ISQ, VAQ, ITQ, TAQ, MAQ, SAQ, IGQ, IEQ, IVQ, NAQ, LAQ, IAK, IAH, IPQ, IAR, IAE, IAL, IAP, FAQ, VSQ, VTM, ISM, IWQ, IFQ, IQQ, VQQ, IFM, IAM, or ISN 4. The AAV particle of any one of claims 1-3, wherein: (i) [N1]-[N2] comprises TNTQDWHR (SEQ ID NO: 1307), TNTKDWHR (SEQ ID NO: 1308), TNNQDWHR (SEQ ID NO: 1309), SNNQDWHR (SEQ ID NO: 1310), TNKQDWHR (SEQ ID NO: 1311), TNNEDWHR (SEQ ID NO: 1312), SNKQDWHR (SEQ ID NO: 1313), SNTQDWHR (SEQ ID NO: 1314), TTNQDWHR (SEQ ID NO: 1315), TNDQDWHR (SEQ ID NO: 1316), TTIQDWHR (SEQ ID NO: 1317), RNTQDWHR (SEQ ID NO: 6), TTKQDWHR (SEQ ID NO: 1318), TTSQDWHR (SEQ ID NO: 1319), TTDQDWHR (SEQ ID NO: 1320), TNPSDWHR (SEQ ID NO: 1321), TNKEDWHR (SEQ ID NO: 1322), TTTQDWHR (SEQ ID NO: 1323), TGKQDWHR (SEQ ID NO: 1324), TTAQDWHR (SEQ ID NO: 1325), TVKQDWHR (SEQ ID NO: 1326), TNYQDWHR (SEQ ID NO: 1327), TNTPDWHR (SEQ ID NO: 1328), STKQDWHR (SEQ ID NO: 1329), TTEQDWHR (SEQ ID NO: 1330), TSKQDWHR (SEQ ID NO: 1331), TNIQDWHR (SEQ ID NO: 1332), TYNQDWHR (SEQ ID NO: 1333), STIQDWHR (SEQ ID NO: 1334), TTVQDWHR (SEQ ID NO: 4927), TGTQDWHR (SEQ ID NO: 4928), TNTRDWHR (SEQ ID NO: 1335), TTLQDWHR (SEQ ID NO: 1336), TTMQDWHR (SEQ ID NO: 4931), ANNQDWHR (SEQ ID NO: 4932), SNIQDWHR (SEQ ID NO: 1337), TKNQDWHR (SEQ ID NO: 1338), TYTQDWHR (SEQ ID NO: 4935), TNKSDWHR (SEQ ID NO: 4936), SNTEDWHR (SEQ ID NO: 1339), TNTEDWHR (SEQ ID NO: 1340), TNIEDWHR (SEQ ID NO: 4939), TTRQDWHR (SEQ ID NO: 4940), TNSQDWHR (SEQ ID NO: 1341), TYTKDWHR (SEQ ID NO: 1342), TTTKDWHR (SEQ ID NO: 4943), TNIKDWHR (SEQ ID NO: 4944),SNTKDWHR (SEQ ID NO: 1343), TNNKDWHR (SEQ ID NO: 1344), TNSKDWHR (SEQ ID NO: 4947), TSTKDWHR (SEQ ID NO: 4948), TITKDWHR (SEQ ID NO: 1345), INTKDWHR (SEQ ID NO: 1346), TNAKDWHR (SEQ ID NO: 4951), TKTKDWHR (SEQ ID NO: 4952), STNQDWHR (SEQ ID NO: 1347), ANTKDWHR (SEQ ID NO: 1348), RNNQDWHR (SEQ ID NO: 4955), TGNQDWHR (SEQ ID NO: 4956), TSNQDWHR (SEQ ID NO: 1349), THTKDWHR (SEQ ID NO: 1350), TDTKDWHR (SEQ ID NO: 4959), TNEQDWHR (SEQ ID NO: 4960), CNTQDWHR (SEQ ID NO: 1351), TNPKDWHR (SEQ ID NO: 1352), INNQDWHR (SEQ ID NO: 4963), TYTEDWHR (SEQ ID NO: 4964), NNNQDWHR (SEQ ID NO: 1353), KNNQDWHR (SEQ ID NO: 1354), TNNRDWHR (SEQ ID NO: 4967), LNNQDWHR (SEQ ID NO: 4968), TINQDWHR (SEQ ID NO: 1355), TNHQDWHR (SEQ ID NO: 1356), STTQDWHR (SEQ ID NO: 4971), SNSQDWHR (SEQ ID NO: 4972), STSQDWHR (SEQ ID NO: 1357), TYIQDWHR (SEQ ID NO: 1358), SGTQDWHR (SEQ ID NO: 4975), THNQDWHR (SEQ ID NO: 4976), TITQDWHR (SEQ ID NO: 1359), TSTQDWHR (SEQ ID NO: 1360), TNSNDWHR (SEQ ID NO: 4979), TNQQDWHR (SEQ ID NO: 4980), RNIQDWHR (SEQ ID NO: 1361), TNNPDWHR (SEQ ID NO: 1362), TITEDWHR (SEQ ID NO: 4983), TNTNDWHR (SEQ ID NO: 4984), TFSQDWHR (SEQ ID NO: 1363), RNSQDWHR (SEQ ID NO: 1364), INTQDWHR (SEQ ID NO: 4987), RNTEDWHR (SEQ ID NO: 4988), TNNHDWHR (SEQ ID NO: 1365), TNMQDWHR (SEQ ID NO: 1366), RTTQDWHR (SEQ ID NO: 4991), SNIEDWHR (SEQ ID NO: 4992), TNTSDWHR (SEQ ID NO: 1367), KNTQDWHR (SEQ ID NO: 1368), TNLQDWHR (SEQ ID NO: 4995), TSMQDWHR (SEQ ID NO: 4996), SYTQDWHR (SEQ ID NO: 1369), TNCQDWHR (SEQ ID NO: 1370), SSTQDWHR (SEQ ID NO: 4999), TVTQDWHR (SEQ ID NO: 5000), or QNTQDWHR (SEQ ID NO: 1371); (ii) [N2]-[N3] comprises DWHRIAQ (SEQ ID NO: 8), DWHRIAG (SEQ ID NO: 9), DWHRIYQ (SEQ ID NO: 10), DWHRVPQ (SEQ ID NO: 22), DWHRIAN (SEQ ID NO: 23), DWHRINQ (SEQ ID NO: 24), DWHRVNQ (SEQ ID NO: 25), DWHRVYQ (SEQ ID NO: 26), DWHRVAN (SEQ ID NO: 27), DWHRISG (SEQ ID NO: 28), DWHRISQ (SEQ ID NO: 29), DWHRVAQ (SEQ ID NO: 30), DWHRITQ (SEQ ID NO: 31), DWHRTAQ (SEQ ID NO: 32), DWHRMAQ (SEQ ID NO: 33), DWHRSAQ (SEQ ID NO: 34), DWHRIGQ (SEQ ID NO: 35), DWHRIEQ (SEQ ID NO: 36), DWHRIVQ (SEQ ID NO: 37), DWHRNAQ (SEQ ID NO: 38), DWHRLAQ (SEQ ID NO: 39), DWHRIAK (SEQ ID NO: 40), DWHRIAH (SEQ ID NO: 41), DWHRIPQ (SEQ ID NO: 42), DWHRIAR (SEQ ID NO: 43), DWHRIAE (SEQ ID NO: 44), DWHRIAL (SEQ ID NO: 45), DWHRIAP (SEQ ID NO: 46), DWHRFAQ (SEQ ID NO: 47), DWHRVSQ (SEQ ID NO: 48), DWHRVTM (SEQ ID NO: 49), DWHRISM (SEQ ID NO: 50), DWHRIWQ (SEQ ID NO: 51), DWHRIFQ (SEQ ID NO: 52), DWHRIQQ (SEQ ID NO: 53), DWHRVQQ (SEQ ID NO: 54), DWHRIFM (SEQ ID NO: 55), DWHRIAM (SEQ ID NO: 56), or DWHRISN (SEQ ID NO: 57); and / or (iii) [N1]-[N2]-[N3] comprises the amino acid sequence of any one of SEQ ID NOs: 343-538.

5. The AAV particle of any one of claims 1-5, which further comprises [N4], wherein [N4] comprises TGWV (SEQ ID NO: 58), TGWA (SEQ ID NO: 59), TNWS (SEQ ID NO: 60), SNWV (SEQ ID NO: 61), TNWV (SEQ ID NO: 62), TNWI (SEQ ID NO: 63), NNWV (SEQ ID NO: 64), TGWS (SEQ ID NO: 65), TGWI (SEQ ID NO: 66), TGWC (SEQ ID NO: 67), TGWG (SEQ ID NO: 68), SGWV (SEQ ID NO: 69), PGWV (SEQ ID NO: 70), TGSV (SEQ ID NO:71), TDWV (SEQ ID NO: 72), TGCV (SEQ ID NO: 73), TGRV (SEQ ID NO: 74), TGLV (SEQ ID NO: 75), TGGV (SEQ ID NO: 76), AGWV (SEQ ID NO: 77), IGWV (SEQ ID NO: 78), TGWD (SEQ ID NO: 79), NGWV (SEQ ID NO: 80), TGWF (SEQ ID NO: 81), TRWV (SEQ ID NO: 82), TVWV (SEQ ID NO:83), TGWL (SEQ ID NO: 84), TAWV (SEQ ID NO: 85), TSWV (SEQ ID NO: 86), TGWT (SEQ ID NO: 87), SVWV (SEQ ID NO: 88), TQWV (SEQ ID NO: 89), or PGWG (SEQ ID NO: 90).

6. The AAV particle of claim 5, wherein [N1]-[N2]-[N3]-[N4] comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 201-245, 247-250, 253-255, 257-265, 268- 274, 276-286, 288, 290-297, 299-303, 305-309, 311, 313-319, 323-328, 330-337, 339-342, 539-542, 544, 546, 547, 549-557, 559-589, 592, 593, 595, 596, 598, 599, 601-608, 610-614, 616-622, 625, 628, 630, 631, 633, 636, 638, 639-646, 649, 651-657, 667, 669, 670, 672, 673, 679-683, 685-690, 692, 693, 695, 697, 699- 701, 703-705, 708-710, 712-717, 719-723, 728-731, 733-738, 740, or 742; (ii) TNTQDWHRIAQTGWV (SEQ ID NO: 201); or (iii) TNTKDWHRIAQTGWV (SEQ ID NO: 202).

7. The AAV particle of any one of claims 1-6, wherein hypervariable loop VIII comprises positions 580-599 numbered according to SEQ ID NO:

981.

8. The AAV particle of any one of claims 5-7, wherein: (i) [N1] is present at amino acids 582-585, numbered according to SEQ ID NO: 138 or 981; (ii) [N2] is present at amino acids 586-589, numbered according to SEQ ID NO: 138 or 981; (iii) [N3] is present at amino acids 590-592, numbered according to SEQ ID NO: 138 or 981; (iv) [N4] is present at amino acids 593-596, numbered according to SEQ ID NO: 138 or 981; and / or (v) [N1]-[N2]-[N3]-[N4] is present at amino acids 582-596, numbered according to the amino acid sequence of SEQ ID NO: 138 or 981.

9. An adeno-associated virus (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 with at least 95% sequence identity to positions 203-736 of SEQ ID NO: 981, wherein the AAV capsid variant comprises the amino acid T at position 584, D at position 586, W at position 587, H at position 588, R at position 589, and I at position 590, numbered according to SEQ ID NO:

981.

10. The AAV particle of claim 9, wherein the AAV capsid variant comprises: (i) an amino acid sequence at least 98% identical to amino acids 203-736 of SEQ ID NO: 981; (ii) an amino acid sequence at least 95% or at least 98% identical to amino acids 138-736 of SEQ ID NO: 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:

981.

11. The AAV particle of claim 9 or 10, wherein the AAV capsid variant comprises: (i) the amino acid sequence of amino acids 203-736 of SEQ ID NO: 981; (ii) the amino acid sequence of amino acids 138-736 of SEQ ID NO: 981; and / or (iii) the amino acid sequence of SEQ ID NO:

981.

12. The AAV particle of any one of claims 1-11, which comprises one, two, three, four, five, six, or all of the following properties: (i) 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., sensory cortex, motor cortex, putamen, thalamus, caudate, hippocampus, cerebellum optionally wherein the level of transduction is at least 39, 50, 100, 120, 132, 146, 150, 161, 174, 175, 200, 225, 250, 275, 283, 300, 350, 400, 450, 500, 525, 528, or 550-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 or ddPCR assay, e.g., as described in Example 2; (iii) is enriched at least about 10, 14, 20, 24, 50, 100, 150, 200, 250, 300, 350, 400, 425, 450, or 460- 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 3; (iv) is enriched at least about 200, 300, 400, 425, 450, or 460-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; (v) is enriched at least about 2, 3, 5, 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 1 or 4; (vi) is enriched at least about 2, 3, 4, 5, 10, 15, 17, 20, 50, 75, 100, 103, 107, 125, 150, 200, 250, 300, 350, 400, 450, 500, 750, 1000, 1200-fold, in the brain compared to a reference sequence of SEQ ID NO: 981, e.g., when measured by an assay as described in Example 3; (vi) delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 39, 50, 100, 120, 132, 146, 150, 161, 174, 175, 200, 225, 250, 275, 283, 300, 350, 400, 450, 500, 525, 528, or 550-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR, a ddPCR, or a qPCR assay (e.g., as described in Example 2); (v) delivers an increased level of viral genomes to a brain region, optionally wherein the level of viral genomes is increased by at least 2, 5, 7, 10, 15, 19, 20, 22, or 25-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); and / or (vi) is enriched at least about 5, 10, 50, 100, 115, 120, 150, 175, 200, 207, 225, 250, or 275-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 2.

13. The AAV particle of any one of claims 1-12, 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.

14. The AAV particle of claim 13, 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.

15. The AAV particle of claim 13 or 14, 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.

16. The AAV particle of any one of claims 13-15, 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.

17. The AAV particle of any one of claims 13-16, 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.

18. The AAV particle of any one of claims 13-17, 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.

19. An adeno-associated virus (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.

20. The AAV particle of any one of claims 13-19, 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.

21. The AAV particle of any one of claims 1-20, wherein the encoded polynucleotide for inhibiting human MAPT further comprises a modulatory polynucleotide, wherein the modulatory polynucleotide comprises the siRNA.

22. The AAV particle of claim 21, wherein the encoded 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.

23. The AAV particle of claim 22, wherein: (A) (i) the encoded 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 encoded 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 encoded 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: 4353-4361, 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: 4353- 4361; 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: 4353-4361; (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.

24. The AAV particle of any one of claims 21-23, wherein the encoded 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 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; (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 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.

25. The AAV particle of any one of claims 22-24, 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.

26. The AAV particle of any one of claims 21-25, wherein the encoded 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 SEQID 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 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: 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.

27. The AAV particle of any one of claims 21-28, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises in 5’ to 3’ order: (A) (i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence comprising SEQ ID NO: 4905; (iii) a nucleotide sequence encoding 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) a nucleotide sequence encoding the antisense strand sequence comprising SEQ ID NO: 4907; and (v) a nucleotide sequence encoding 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 sequencecomprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375; (B) (i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence comprising SEQ ID NO: 4917; (iii) a nucleotide sequence encoding 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) a nucleotide sequence encoding the antisense strand sequence comprising SEQ ID NO: 4919; and (v) a nucleotide sequence encoding 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 nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence comprising SEQ ID NO: 4921; (iii) a nucleotide sequence encoding 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) a nucleotide sequence encoding the antisense strand sequence comprising SEQ ID NO: 4923; and(v) a nucleotide sequence encoding 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 nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence comprising SEQ ID NO: 4965; (iii) a nucleotide sequence encoding 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) a nucleotide sequence encoding the antisense strand sequence comprising SEQ ID NO: 4907; and (v) a nucleotide sequence encoding 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 nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence comprising SEQ ID NO: 4969;(iii) a nucleotide sequence encoding 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) a nucleotide sequence encoding the antisense strand sequence comprising SEQ ID NO: 4911; and (v) a nucleotide sequence encoding 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 nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence comprising SEQ ID NO: 4977; (iii) a nucleotide sequence encoding 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) a nucleotide sequence encoding the antisense strand sequence comprising SEQ ID NO: 4919; and (v) a nucleotide sequence encoding 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 nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence comprising SEQ ID NO: 4981; (iii) a nucleotide sequence encoding 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) a nucleotide sequence encoding the antisense strand sequence comprising SEQ ID NO: 4923; and (v) a nucleotide sequence encoding 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.

28. The AAV particle of any one of claims 21-27, 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.

29. An adeno-associated virus (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 nucleic acid comprises the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

30. The AAV particle of any one of claims 1-29, which comprises a viral genome comprising a promoter operably linked to the nucleic acid encoding the polynucleotide for inhibiting human MAPT.

31. The AAV particle of claim 30, 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) is 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.

32. The AAV particle of claim 30 or 31, 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.

33. The AAV particle of claim 32, 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 4469; 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 or 4469; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197 or 4469; (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 4470; 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 4470; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5200 or 4470; (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.

34. The AAV particle of any one of claims 30-33, wherein the viral genome is self-complementary or single stranded.

35. The AAV particle of any one of claims 30-34, 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 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) 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 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: 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.

36. The AAV particle of any one of claims 30-35, 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 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; 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 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; (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 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: 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 tenmodifications, 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 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: 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 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: 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.

37. The AAV particle of any one of claims 30-36, wherein the viral genome 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 4439-4468, 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 4439-4468.

38. An adeno-associated virus (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, 3886, 5195, 1375, or 5184.

39. A cell comprising the AAV particle of any one of claims 1-38, 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.

40. A method of making the AAV particle of any one of claims 1-38, comprising: (i) providing a host cell comprising a AAV viral genome and a nucleotide sequence encoding an AAV capsid variant; (ii) incubating the host cell under conditions suitable to enclose the viral genome in the AAV capsid variant; thereby making the AAV particle.

41. A pharmaceutical composition comprising the AAV particle of any one of claims 1-38, and a pharmaceutically acceptable excipient.

42. 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 41 or the AAV particle of any one of claims 1-38, thereby delivering the siRNA for inhibiting MAPT expression to the cell.

43. The method of claim 42, wherein the cell is: (i) a mammalian cell or an insect cell; (ii) a cell of a brain region or a spinal cord region (e.g., a CNS cell); (iii) a cell of the brain or the spinal cord (e.g., a cell of a cortex, sensory cortex, motor cortex, putamen, thalamus, caudate, hippocampus, cerebellum, and / or brainstem); (iv) a neuron or an astrocyte; and / or (v) in a subject.

44. The method of claim 43, 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.

45. 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 41 or the AAV particle of any one of claims 1-38.

46. The method of claim 44 or 45, 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.

47. The method of claim 64 or 65, 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.

48. The method of any one of claims 45-47, 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.

49. The method of any one of claims 45-48, 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.

50. The pharmaceutical composition of claim 41 or the AAV particle of any one of claims 1-38, for use in a method of delivering an siRNA for inhibiting MAPT expression to a cell.

51. The pharmaceutical composition of claim 41 or the AAV particle of any one of claims 1-38, 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.

52. Use of the pharmaceutical composition of claim 41 or the AAV particle of any one of claims 1-38, in the manufacture of a medicament for delivering an siRNA for inhibiting MAPT expression to a cell.

53. Use of the pharmaceutical composition of claim 41 or the AAV particle of any one of claims 1-38, 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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