Compositions and methods for regulating mapt

Abstract

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

Description

COMPOSITIONS AND METHODS FOR REGULATING MAPTRELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 717,024 filed on November 6, 2024; the entire contents 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 V2071-3052PCT_SL.xml, was created on September 17. 2025. and is 6,211,983 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUND

[0003] 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

[0004] 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 associated MAPT expression, e.g., aberrant expression, such as tauopathies, including but not limited to Alzheimer’s disease (AD), frontotemporal dementia (FTD), and / or Dravet syndrome (DS) in a subject in need thereof.

[0005] 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 ofmicrotubule-associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises: (a) one, two, three, four, or all of the amino acid R at position 584, the amino acid T at position 86, the amino acid L at position 588, the amino acid Q at position 589, and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV.

[0006] 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) one, two, three, four, or all of the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV.

[0007] In yet another aspect, the present disclosure provides an AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide (e.g., a siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) (e.g. human MAPT), wherein the AAV capsid variant comprises: (a) the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV.

[0008] 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 R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412: and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV.

[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) one, two, three, four, or all of the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV.

[0010] 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) one, two, three, four, or all of the amino acid R at position 590, T at position 592, L at position 594, Q at position 595,and / or L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV.

[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: (a) the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV.

[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: (a) the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV.

[0013] 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: (a) one, two. three, four, or all of the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0014] 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: (a) the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0015] 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: (a) one, two, three, four or all of the amino acid R at position 590, T at position 592, L at position 594, Q at position 595,and / or L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 981 or 6411.

[0016] 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: (a) the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 981 or 6411.

[0017] 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: (a) one, two, three, four, or all of the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0018] 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: (a) the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 138.

[0019] 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: (a) one, two. three, four or all of the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 982 or 6412.

[0020] 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: (a) the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 982 or 6412.

[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: (a) the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV. In some embodiments, hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence of SEQ ID NO: 941 is present immediately subsequent to position 455, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid E at position 451, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid V at position 453, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941); the amino acid E at position 451, numbered according to SEQ ID NO: 981; the amino acid V at position 453, numbered according to SEQ ID NO: 3904 or 981; the amino acid R at position 590, numbered according to SEQ ID NO: 981; the amino acid T at position 592, numbered according to SEQ ID NO: 981; the amino acid L at position 594, numbered according to SEQ ID NO: 981: the amino acid Q at position 595, numbered according to SEQ ID NO: 981: and L at position 596, numbered according to SEQ ID NO: 981.

[0022] 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 R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and the amino acid L at position 590, numbered according to SEQ ID NO: 138: and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV. In some embodiments, hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence of SEQ ID NO: 941 is present immediately subsequent to position 455, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid E at position 451, numbered according to SEQ ID NO: 981. In some embodiments, the AAVcapsid variant comprises the amino acid R at position 452, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid V at position 453, numbered according to SEQ ID NO: 981. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941); the amino acid E at position 451, numbered according to SEQ ID NO: 981; the amino acid R at position 452, numbered according to SEQ ID NO: 981; the amino acid V at position 453, numbered according to SEQ ID NO: 36 or 981; the amino acid R at position 590, numbered according to SEQ ID NO: 981; the amino acid T at position 592, numbered according to SEQ ID NO: 981; the amino acid L at position 594, numbered according to SEQ ID NO: 981; the amino acid Q at position 595, numbered according to SEQ ID NO: 981; and L at position 596, numbered according to SEQ ID NO: 981.

[0023] 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) three, four, or all of the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV; wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO: 138. In some embodiments, hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the AAV capsid variant comprises the amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present immediately subsequent to amino acid 453, numbered according to SEQ ID NO: 982. In some embodiments, the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 203-742 of SEQ ID NO: 6412, or an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 6412. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 138-742 of SEQ ID NO: 6412, or an amino acid sequence at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6412. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 6412, or an amino acid sequence at least 95% or 98% identical thereto.

[0024] 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) three.four, or all of the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV; wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO: 138. In some embodiments, hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412. In some embodiments, the AAV capsid variant comprises the amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present immediately subsequent to amino acid 455, numbered according to SEQ ID NO: 981. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 203-742 of SEQ ID NO: 6411, or an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 6411. In some embodiments, the AAV capsid variant comprises the amino acid sequence of amino acids 138-742 of SEQ ID NO: 6411, or an amino acid sequence at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6411. In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 6411, or an amino acid sequence at least 95% or 98% identical thereto.

[0025] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412; 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.

[0026] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412; 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.

[0027] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412; and (ii) a nucleic acid encoding apolynucleotide 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: 4918, and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

[0028] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6411; 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.

[0029] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6411; 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.

[0030] 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: 6411; 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: 4918, and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

[0031] 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: 6414; 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.

[0032] 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: 6414; 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.

[0033] 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: 6413; 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.

[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: 6413; 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.

[0035] 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: 6412; 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.

[0036] 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: 6412; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of SEQ ID NO: 4405.

[0037] 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: 6412; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of SEQ ID NO: 4408.

[0038] In yet another aspect, the present disclosure provides AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[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: 6411; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of SEQ ID NO: 4405.

[0040] 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: 6411; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of SEQ ID NO: 4408.

[0041] 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: 6414; 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 sequence of SEQ ID NO: 6414; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising 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: 982; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

[0044] 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: 6413; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of SEQ ID NO: 4405.

[0045] 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: 6412; and (ii) a viral genome comprising the nucleotide sequence of any one of SEQ ID NOs: 5173, 5195, 5184, 5864, or 3886.

[0046] 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: 6412; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0047] 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: 6412; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0048] 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: 6412; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5864.

[0049] 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: 6411; and (ii) a viral genome comprising the nucleotide sequence of any one of SEQ ID NOs: 5173, 5195, 5184, 5864, or 3886.

[0050] 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: 6411; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0051] 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: 6411; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0052] 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: 6411; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5864.

[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: 6414; and (ii) a viral genome comprising the nucleotide sequence of any one ofSEQ ID NOs: 5173, 5195, 5184, or3886.

[0054] 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: 6414; 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 SEQ ID NO: 6414; 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 the amino acid sequence of SEQ ID NO: 6413; and (ii) a viral genome comprising the nucleotide sequence of any one ofSEQ ID NOs: 5173, 5195, 5184, 5864, or 3886.

[0057] 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: 6413; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173.

[0058] 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: 6413; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 3886.

[0059] In accordance with some aspects of the present disclosure, the short interfering ribonucleic acid (siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) comprises a sense strand sequence and an antisense strand sequence, wherein the antisense sequence is complementary to at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides comprising 0, 1, 2, or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3A or 19. In some embodiments, the antisense strand sequence comprises at least 15, 16, 17. 18. 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 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 Tables5A, 9A, or 9B, wherein tire sense strand sequence and the antisense strand sequencecomprise a region of complementarity of at least 15 nucleotides. In some embodiments, the antisense strand sequence comprises at least 1, 16, 17, 18, 19, 20, 21 contiguous nucleotides from any one of the antisense strand sequences provided in Tables 5 A, 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 5A, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides. In some embodiments, the antisense strand sequence comprises nucleotide sequence of any one of the antisense strand sequences provided in Tables 5 A, 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.

[0060] In accordance with some aspects of the present disclosure, the encoded polynucleotide for inhibiting expression of MAPT (e.g., human MAPT) comprises an siRNA comprising a sense strand sequence and an antisense strand sequence. In some embodiments, the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006. 4918, 4938, 4958, 4978, 4998, 4922, 4942. 4962, 4982, 5002, 5022, 5054. 5060, 5064, 5066, 5070, 5074, 4914, 4934. 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970. 4990. 5010. 5077, 5084, 5088, 5092, 5096. 5098. 5101. 5108, 5112, 5116, 5120, 5122. 5125. 5132, 5136, 5140, 5144, or 5146; wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.

[0061] 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.

[0062] 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.

[0063] 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 tire 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] In some embodiments, the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy is Alzheimer’s disease (AD), Frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome (DS), neurodegenerative disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down’s syndrome, Pick’s disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS). Prion diseases. CJD, Multiple system atrophy, mild cognitive impairment. Tangle-only dementia, or Progressive subcortical gliosis.

[0070] 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 Embodiments1. 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) one, tw o. three, four, or all of an amino acid other than H at position 584, S at position 586, Q at position 588, A at position 589, and / or Q at position 590, numbered according to SEQ ID NO: 138 or 6414; and (b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV.2. 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 (MAPI) (e g. human MAPT), wherein the AAV capsid variant comprises:(a) one, tw o. three, four, or all of an amino acid other than H at position 584, S at position 586, Q at position 588, A at position 589, and / or Q at position 590, numbered according to SEQ ID NO: 138 or 6414; and (b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV.3. Tire AAV particle of embodiment 1 or 2, wherein the AAV capsid variant comprises:(i) an amino acid other than H at position 590, S at position 592, Q at position 594, A at position 595, and Q at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; or(ii) an amino acid other than H at position 584, S at position 586, Q at position 588, A at position 589, and Q at position 590. numbered according to SEQ ID NO: 138 or 6414.4. Tire AAV particle of any one of embodiments 1-3, wherein the AAV capsid variant comprises:(i) one, two, three, four, or all of the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and / or L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; or(ii) one. two, three, four, or all of the amino acid R at position 584, T at position 586, L at position 588. Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138 or 6414.5. 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) one, two, three, four, or all of the amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138 or 6414; and(b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV.6. 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) one, two, three, four, or all of the amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and / or L at position 590, numbered according to SEQ ID NO: 138 or 6414; and(b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV.7. The AAV capsid variant of any one of embodiments 1-6. wherein the AAV capsid variant comprises:(i) the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982, 6411, or 6412; or(ii) the amino acid R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414.8. 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 R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414; and(b) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV.9. 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 R at position 584, T at position 586, L at position 588, Q at position 589, and L at position 590, numbered according to SEQ ID NO: 138 or 6414; and(b) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV.10. The AAV particle of any one of embodiments 1-9, wherein hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138.11. The AAV particle of any one of embodiments 1. 3-5, 7, 8. or 10, wherein the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present immediately subsequent to amino acid 453, numbered according to SEQ ID NO: 138.12. The AAV particle of any one of embodiments 1, 3-5, 7, 8, 10, or 11, wherein the amino acid sequence HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.13. The AAV particle of any one of embodiments 1, 3-5, 7, 8, or 10-12, wherein tire AAV capsid variant comprises an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 6412.14. The AAV particle of any one of embodiments 1, 3-5, 7, 8, or 10-13, wherein tire AAV capsid variant comprises an amino acid sequence at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6412.15. The AAV particle of any one of embodiments 1, 3-5, 7, 8, or 10-14, wherein the AAV capsid variant comprises an amino acid sequence at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 6412.16. The AAV particle of any one of embodiments 1, 3-5, 7, 8, or 10-15, wherein the AAV capsid variant comprises the amino acid sequence of amino acids 203-742 of SEQ ID NO: 6412.17. The AAV particle of any one of embodiments 1. 3-5, 7, 8, or 10-16, wherein tire AAV capsid variant comprises the amino acid sequence of amino acids 138-742 of SEQ ID NO: 6412.18. The AAV particle of any one of embodiments 1, 3-5, 7, 8, or 10-16, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 6412.19. The AAV particle of any one of any one of embodiments 2-4, 6. 7, 9, or 10, wherein the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present immediately subsequent to amino acid 455, numbered according to SEQ ID NO: 138.20. The AAV particle of any one of embodiments 2-4, 6, 7, 9, 10, or 19, wherein the amino acid sequence SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.21. The AAV particle of any one of embodiments 2-4, 6, 7, 9, 10, 19, or 20, wherein the AAV capsid variant comprises an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 6411.22. The AAV particle of any one of embodiments 2-4. 6, 7, 9. 10, or 19-21, wherein the AAV capsid variant comprises an amino acid sequence at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6411.23. The AAV particle of any one of embodiments 2-4. 6, 7, 9, 10, or 19-22, wherein the AAV capsid variant comprises an amino acid sequence at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 6411.24. The AAV particle of any one of embodiments 2-4. 6, 7, 9, 10, or 19-23, wherein the AAV capsid variant comprises the amino acid sequence of amino acids 203-742 of SEQ ID NO: 6411.25. The AAV particle of any one of embodiments 2-4, 6, 7, 9, 10, or 19-24, wherein the AAV capsid variant comprises the amino acid sequence of amino acids 138-742 of SEQ ID NO: 6411.26. The AAV particle of any one of embodiments 2-4. 6, 7, 9, 10, or 19-25, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 6411.27. The AAV particle of any one of embodiments 2-4, 6, 7, 9, 10, or 19-26, wherein the AAV capsid variant further comprises the amino acid E at position 451, numbered according to SEQ ID NO: 981.28. The AAV particle of any one of claims 2-4, 6, 7, 9, 10, or 19-27, wherein the AAV capsid variant comprises the amino acid V at position 453, numbered according to SEQ ID NO: 981.29. The AAV particle of any one of claims 2-4, 6, 7, 9, 10, or 19-28, wherein the AAV capsid variant comprises the amino acid R at position 452, numbered according to SEQ ID NO: 981.30. The AAV particle of any one of embodiments 1. 3-5, 7, 8, or 10-17, wherein tire nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 6416, or a nucleotide sequence at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.31. The AAV particle of any one of embodiments 2-4, 6, 7, 9, 10, or 19-29, wherein tire nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 6415, or a nucleotide sequence at least 75%, 80%. 85%. 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.32. The AAV particle of any one of embodiments 1-31, wherein the AAV capsid variant has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.33. The AAV particle of any one of embodiments 1-32, wherein the AAV capsid variant transduces a brain region (e.g., a putamen, caudate or motor cortex), optionally wherein the level of transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 100-fold greater as compared to a reference sequence of SEQ ID NO: 138, c.g., when measured by an assay, c.g., an immunohistochemistry’ assay or a qPCR assay, c.g., as described in Example 2.34. The AAV particle of any one of embodiments 1-33, wherein the AAV capsid variant delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 100, 200, 300, or 400-fold, as compared to a reference sequence of SEQ ID NO: 138, c.g., when measured by an assay, c.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2), optionally wherein the brain region is a caudate or motor cortex.35. The AAV particle of any one of embodiments 1-34, wherein the AAV capsid variant shows preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG) and / or the liver.36. The AAV particle of any one embodiments 1-35, wherein the AAV capsid variant is capable of transducing at least 10%, 15%, 20%. 25%. 30%, 40%, 50%, 55%, 60%, or 65% of neurons (e.g., NeuN+ neurons) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex).37. The AAV particle of any one of embodiments 1-36, wherein the AAV capsid variant is capable of transducing at least 70%, 75%, 80%, 85%, 90%, or 95% of astrocytes (e.g., Sox9+ astrocytes) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g.. when measured by an assay as described in Example 2.38. The AAV particle of any one of embodiments 1-37, wherein the AAV capsid variant is capable of transducing at least 90% or 95% of neurons, e.g., motor neurons (e.g., ChAT+ neurons) in tire spinal cord (e.g., the cervical spinal cord, the thoracic spinal cord, or the lumbar spinal cord), e.g., when measured by an assay as described in Example 2.39. The AAV particle of any one of embodiments 1-38, wherein the AAV capsid variant is capable of transducing at least 90%, 95%, or 98% of astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., tire cervical spinal cord, the thoracic spinal cord, or the lumbar spinal cord), e.g., when measured by an assay as described in Example 2.40. The AAV particle of any one of embodiments 1-39, wherein the AAV capsid variant is capable of transducing at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% of cells in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, cerebellar cortex, cerebellum, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)), e.g., when measured by an assay as described in Example 2.41. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing neuronal cells, e.g., NeuN+ neurons or dopaminergic neurons (e.g., dopaminergic neurons in the substantia nigra), e.g., tyrosine hydroxylase (TH)+ neurons.42. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing NeuN+ cells (e.g., NeuN+ neurons) and / or TH+ cells (e.g., TH+ neurons, e.g., dopaminergic neurons).43. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing non-neuronal cells, e.g., glial cells (e.g., oligodendrocytes or astrocytes).44. The AAV particle of embodiment 416, wherein the non-neuronal cells comprise glial cells, oligodendrocytes (e.g., Olig2 positive oligodendrocytes), or astrocytes (e.g., Olig2 positive astrocytes or Sox9+ astrocytes).45. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing Olig2 positive cells, e g., Olig2 positive astrocytes or Olig2 positive oligodendrocytes.46. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant is capable of transducing Sox9+ cells, e.g., Sox9+ astrocytes.47. The AAV particle of any one of the preceding embodiments, wherein the encoded polynucleotide for inhibiting MAPT comprises an a siRNA, a shRNA, a pre-miRNA, a pri-miRNA, a miRNA, a stRNA, a IncRNA, a piRNA, an antisense oligonucleotide agent (ASG), or a snoRNA.48. The AAV particle of any one the preceding embodiments, w herein the encoded polynucleotide for inhibiting MAPT comprises an a siRNA comprises a sense strand sequence and antisense strand sequence.49. The AAV particle of embodiment 47 or 48, wherein the encoded siRNA binds to a 3’ UTR of MAPT (e.g., human MAPT).50. The AAV particle of any one of embodiments 47-49, wherein the encoded siRNA binds to a coding region of MAPT (e.g., human MAPT).51. The AAV particle of any one of embodiments 47-50, wherein the encoded siRNA binds to a 5 ’ UTR of MAPT (e.g., human MAPT).52. The AAV particle of any one of embodiments 47-51, wherein the MAPT is a human MAPT gene, a nonhuman primate MAPT gene, or a mouse MAPT gene.53. The AAV particle of any one embodiments 47-52, wherein the antisense strand comprises at least one mismatch with the target mRNA.54. The AAV particle of any one of embodiments 47-53, 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 3 A or 19.55. The AAV particle of any one of embodiments 4854, 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: 5024.56. The AAV particle of any one of embodiments 48-55, 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: 5024.57. The AAV particle of any one of embodiments 48-56, 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 3 A 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: 5024.58. The AAV particle of any one of embodiments 48-57, 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 5A, 9A, or 9B.59. The AAV particle of any one of embodiments 48-58, 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 5 A, 9A, or 9B.60. The AAV particle of any one of embodiments 48-59, 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 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 5A, 9A, or 9B. w herein tire sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.61. The AAV particle of embodiment 460, 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.62. The AAV particle of any one of embodiments 48-61, 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 tire 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 tire 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: 4527.63. The AAV particle of any one of embodiments 48-62, 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 tire 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 tire 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 tire 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: 4527.64. The AAV particle of any one of embodiments 48-63, wherein:(i) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 5641, 5649, 5655, 5718, 5724, 5730, 5736, 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: 5638, 5644, 5652, 5658, 5721, 5727, 5733, 5740, 5744, 5748, 5752, 5756, 5760, 5764, 5766, 5768, 5770, 5774, 5776, 5778, 5780, 5784, 5788, 5792, 5796, 5800, 5804, 5808, 5812, 5816, 5820, 5824, 5829, 5833, 5837, 5839, 5841, 5843, 5845, 5847, 5849, 5851, 5853, 5855, 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.65. The AAV particle of any one of embodiments 60-64, wherein the region of complementarity comprises at least 18. 19, or 20 nucleotides.66. The AAV particle of any one of embodiments 48-65, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 5641, 5649, 5655, 5718, 5724, 5730, 5736, 4908, 4920, 4924, or 4912.67. The AAV particle of any one of embodiments 48-66, wherein the encoded sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 5638, 5644, 5652, 5658, 5721, 5727, 5733, 5740, 5744, 5748, 5752, 5756, 5760, 5764, 5766, 5768, 5770, 5774, 5776, 5778, 5780, 5784, 5788, 5792, 5796, 5800, 5804, 5808, 5812, 5816, 5820, 5824, 5829, 5833, 5837, 5839, 5841, 5843, 5845, 5847, 5849, 5851, 5853, 5855, 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982. 5002, 5022, 4910, 4930, 4950, 4970, 4990. or 5010.68. The AAV particle of any one of embodiments 48-67, wherein:(i) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641 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: 5638, 5740, 5766, 5784, 5812, or 5839;(ii) the encoded antisense strand sequence comprises at least 19, 20. or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 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: 5644, 5744, 5768, 5788, 5816, or 5841;(iii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 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: 5652, 5748, 5770, 5792, 5820, or 5843;(iv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5718 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: 5658, 5752, 5774, 5796, 5824, 5845;(v) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 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: 5721, 5756, 5776, 5800, 5829, or 5847;(vi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 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: 5727, 5760, 5778, 5804, 5833, 5849;(vii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5736 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: 5733, 5764, 5780, 5808, 5837, or 5851;(viii) 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. 5006. or 5853;(ix) 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, 4998, or 5855;(x) the encoded antisense strand sequence comprises at least 19. 20, or 21 contiguous nucleotides from tire 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;(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 tire 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:(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 any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014;(xiii) 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;(xiv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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;(xv) 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(xvi) 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 5074.69. The AAV particle of any one of embodiments 48-68, 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: 4906.70. The AAV particle of any one of embodiments 48-68, 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: 4918.71. The AAV particle of any one of embodiments 48-68, 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: 4922.72. The AAV particle of any one of embodiments 48-68 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: 4966.73. The AAV particle of any one of embodiments 48-68, 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: 4970.74. The AAV particle of any one of embodiments 48-68, 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: 4978.75. The AAV particle of any one of embodiments 48-68, wherein the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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: 4982.76. The AAV particle of any one of embodiments 48-68, wherein:(i) tire 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 tire nucleotide sequence of SEQ ID NO: 4938;(viii) the encoded antisense strand sequence comprises at least 19. 20, or 21 contiguous nucleotides from tire 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 tire 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 tire nucleotide sequence of SEQ ID NO: 4974;(xvii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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 tire nucleotide sequence of SEQ ID NO: 4990;(xx) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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 tire nucleotide sequence of SEQ ID NO: 5070;(xxiv) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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 tire nucleotide sequence of SEQ ID NO: 5014;(xxvii) the encoded antisense strand sequence comprises at least 19. 20, or 21 contiguous nucleotides from tire 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 tire 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 tire nucleotide sequence of SEQ ID NO: 5077;(xxx) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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 tire nucleotide sequence of SEQ ID NO: 5092;(xxxiii) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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 tire nucleotide sequence of SEQ ID NO: 5101;(xxxvi) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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 tire nucleotide sequence of SEQ ID NO: 5120;(xl) the encoded antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from tire 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 tire 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 tire 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 tire 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 tire nucleotide sequence of SEQ ID NO:5146.77. The AAV particle of any one of embodiments 48-76, wherein the encoded antisense strand sequence comprises at least 20 contiguous nucleotides of any one of SEQ ID NOs: 5641, 5649, 5655, 5718, 5724, 5730, 5736, 4908, 4920, 4924, or 4912.78. The AAV particle of any one of embodiments 48-77, wherein the encoded sense strand sequence comprises at least 20 contiguous nucleotides of any one of SEQ ID NOs: 5638, 5644, 5652, 5658, 5721, 5727, 5733, 5740, 5744, 5748. 5752, 5756, 5760, 5764, 5766, 5768, 5770. 5774, 5776, 5778, 5780, 5784, 5788, 5792, 5796, 5800, 5804, 5808, 5812, 5816, 5820, 5824, 5829, 5833, 5837, 5839, 5841, 5843, 5845, 5847, 5849, 5851, 5853, 5855, 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010.79. The AAV particle of any one of embodiments 48-78, wherein:(i) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5638, 5740, 5766, 5784, 5812, or 5839;(ii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5644, 5744. 5768, 5788, 5816, or5841;(iii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5652, 5748, 5770, 5792, 5820, or 5843;(iv) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5658, 5752, 5774, 5796, 5824, or 5845;(v) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5721, 5756, 5776, 5800, 5829, or 5847;(vi) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5727, 5760, 5778, 5804, 5833, 5849;(vii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5733, 5764, 5780, 5808, 5837, or 5851;(viii) 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, 5006, or 5853;(ix) 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, 4998, or 5855;(x) 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;(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 any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010;(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 any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014;(xiii) the encoded antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and tire encoded sense strand sequence comprises at least 20contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122;(xiv) 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;(xv) 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(xvi) 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 5074.80. The AAV particle of any one of embodiments 48-69 or 77-79, 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: 4906.81. The AAV particle of any one of embodiments 48-68, 70, or 77-79, 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: 4918.82. The AAV particle of any one of embodiments 48-68, 71, or 77-79, 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: 4922.83. The AAV particle of any one of embodiments 48-68, 72, or 77-79, 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: 4966.84. The AAV particle of any one of embodiments 48-68, 73, or 77-79, 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: 4970.85. The AAV particle of any one of embodiments 48-68, 74, or 77-79, 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: 4978.86. The AAV particle of any one of embodiments 48-68, 75, or 77-79, 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: 4982.87. The AAV particle of any one of embodiments 48-68, or 76-79, 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 tire 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: 5146.88. The AAV particle of any one of embodiments 48-68 or 77-79, wherein:(i) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5638;(ii) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5740;(iii) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5766;(iv) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5784;(v) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5812;(vi) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5839;(vii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5644;(viii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5744;(ix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5768;(x) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5788;(xi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5816;(xii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5841;(xiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5652;(xiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5748;(xv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5770;(xvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5792;(xvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5820;(xviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5843;(xix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5658:(xx) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5752;(xxi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5774:(xxii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5796;(xxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5824:(xxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5845;(xxv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5721;(xxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5756;(xxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5776;(xxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5800:(xxix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5829;(xxx) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5847:(xxxi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5727;(xxxii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5760:(xxxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5778;(xxxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5804:(xxxv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5833;(xxxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5849;(xxxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5733;(xxxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5764;(xxxix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5780:(xl) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5808;(xli) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5837:(xlii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5851;(xliii) 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: 5853: or(xliv) 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: 5855.89. The AAV particle of any one of embodiments 48-88, wherein the encoded antisense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5641, 5649, 5655. 5718. 5724, 5730, 5736, 4908, 4920, 4924, or 4912.90. The AAV particle of any one of embodiments 48-89, wherein the encoded sense strand sequence comprises at the nucleotide sequence of any one of SEQ ID NOs: 5638, 5644, 5652, 5658, 5721, 5727,5733, 5740. 5744. 5748. 5752, 5756, 5760, 5764, 5766. 5768. 5770. 5774, 5776, 5778, 5780, 5784. 5788.5792, 5796, 5800, 5804, 5808, 5812, 5816, 5820, 5824, 5829, 5833, 5837, 5839, 5841, 5843, 5845, 5847, 5849, 5851, 5853, 5855, 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010.91. The AAV particle of any one of embodiments 48-90, wherein:(i) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5641 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5638, 5740, 5766, 5784, 5812, or 5839;(ii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5644, 5744, 5768, 5788, 5816. or 5841;(iii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5652, 5748, 5770, 5792, 5820, or 5843;(iv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5658, 5752, 5774, 5796. 5824. or 5845;(v) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5721, 5756, 5776, 5800, 5829, or 5847;(vi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5727, 5760, 5778, 5804. 5833. 5849;(vii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5733, 5764, 5780, 5808, 5837, or 5851;(viii) 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. 5006, or 5853;(ix) 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, 4998, or 5855;(x) 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;(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: 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;(xiii) 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;(xiv) 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;(xv) 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(xvi) 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 5074.92. The AAV particle of any one of embodiments 48-69, 77-80, or 89-91, 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: 4906.93. The AAV particle of any one of embodiments 48-68, 70, 77-79, 81, or 89-91, 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: 4918.94. The AAV particle of any one of embodiments 48-68, 71, 77-79, 82, or 89-91, 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: 4922.95. The AAV particle of any one of embodiments 48-68, 72, 77-79, 83, or 89-91, 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: 4966.96. The AAV particle of any one of embodiments 48-68, 73, 77-79, 84, or 89-91, 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: 4970.97. The AAV particle of any one of embodiments 48-68, 74, 77-79, 84, or 89-91, 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: 4978.98. The AAV particle of any one of embodiments 48-68, 75, 77-79, 85, or 89-91, 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: 4982.99. The AAV particle of any one of embodiments 48-68, 76-79, 86, or 89-91, 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: 5146.100. The AAV particle of any one of embodiments 48-68, 77-79, or 88-491, wherein:(i) the encoded antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5638;(ii) tire encoded antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5740;(iii) the encoded antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5766;(iv) the encoded antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5784;(v) the encoded antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5812;(vi) the encoded antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5839;(vii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5644;(viii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5744;(ix) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5768;(x) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and tire encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5788;(xi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5816:(xii) the encoded antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5649 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5841;(xiii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5652;(xiv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5748:(xv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5770;(xvi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5792;(xvii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5820;(xviii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5843;(xix) tire encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5658;(xx) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5752;(xxi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5774;(xxii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5796;(xxiii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5824;(xxiv) the encoded antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5718 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5845;(xxv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5721;(xxvi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5756;(xxvii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and tire encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5776;(xxviii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5800;(xxix) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5829;(xxx) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5847;(xxxi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5727;(xxxii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5760;(xxxiii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5778;(xxxiv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5804;(xxxv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5833;(xxxvi) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5849;(xxxvii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5733;(xxxviii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5764;(xxxix) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5780;(xl) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5808;(xli) the encoded antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5837;(xlii) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5851;(xliii) 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: 5853; or (xliv) the encoded antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and tire encoded sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5855.101. The AAV particle of any one of embodiments 48-87 or 88-99, wherein:(i) tire 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 the nucleotide sequence of SEQ ID NO: 4690 and the encoded sense strand sequence comprises 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 tire 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: 4527.102. The AAV particle of any one of embodiments 48-99, or 101, 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 tire 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 tire 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 tire 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 tire 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;(1) tire 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;(Iv) 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;(Ivi) 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;(Ivii) 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;(Iviii) 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;(Ixi) 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;(Ixii) 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;(Ixiii) 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;(Ixiv) 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;(Ixv) 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;(Ixvi) 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;(Ixvii) 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;(Ixviii) 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;(Ixix) 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;(Ixx) 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;(Ixxi) 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;(Ixxii) 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;(Ixxiii) 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;(Ixxiv) 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;(Ixxv) 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;(Ixxvi) 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;(Ixxvii) 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;(Ixxviii) 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;(Ixxix) 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;(Ixxx) 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(Ixxxi) 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: 5127.103. The AAV particle of any one of embodiments 48-69, 77-80, 89-92, 101, or 102, 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: 4905.104. The AAV particle of any one of embodiments 48-68, 70, 77-79, 81, 89-91, 93, 101, or 102, 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: 4917.105. The AAV particle of any one of embodiments 48-68, 71, 77-80, 82, 89-91, 94, 101, or 102, 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: 4921.106. The AAV particle of any one of embodiments 48-68, 72, 77-80, 83, 89-91, 95, 101, or 102, 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: 4965.107. The AAV particle of any one of embodiments 48-68, 73, 77-80, 84, 89-91, 96, 101, or 102, 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: 4969.108. The AAV particle of any one of embodiments 48-68, 74, 77-80, 85, 89-91, 97, 101, or 102, 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: 4977.109. The AAV particle of any one of embodiments 48-68, 75, 77-80, 86, 89-91, 98, 101, or 102, 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: 4981.110. The AAV particle of any one of embodiments 48-68, 77-80, 88, 98, or 99, wherein:(i) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5637;(ii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5739;(iii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5765;(iv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5783;(v) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5811;(vi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5838;(vii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5643;(viii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5743;(ix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5767;(x) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5787;(xi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5815;(xii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5840;(xiii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5651;(xiv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5747;(xv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5769;(xvi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5791;(xvii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5819;(xviii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5842;(xix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5657;(xx) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5751;(xxi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5773;(xxii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5795;(xxiii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5823;(xxiv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5844;(xxv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5720;(xxvi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5755;(xxvii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5775;(xxviii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5799;(xxix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5827;(xxx) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5846;(xxxi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5726;(xxxii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5759;(xxxiii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5777;(xxxiv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5803;(xxxv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5832;(xxxvi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5848;(xxxvii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5732;(xxxviii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5763;(xxxix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5779;(xl) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5807;(xli) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5836;(xlii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5850;(xliii) 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: 5852; or(xliv) 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: 5854.111. The AAV particle of any one of embodiments 48-110, wherein the sense strand sequence, the antisense strand sequence, or both the encoded sense strand sequence and the encoded 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.112. The AAV particle of any one of embodiments 48-111, wherein the encoded sense strand sequence, the encoded antisense strand sequence, or both the encoded sense strand sequence and the encoded 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 tire antisense strand sequence, of 1 or 2 nucleotides.113. The AAV particle of any one of embodiments 48-112, wherein:(i) the encoded sense strand and the encoded antisense strand comprise one mismatch; and / or (ii) the encoded antisense strand and the target sequence comprise one mismatch.114. The AAV particle of any one of embodiments 48-113, wherein the encoded polynucleotide for inhibiting MAPT (e.g., human MAPT) further comprises a modulatory polynucleotide, wherein the modulatory polynucleotide comprises the siRNA.115. The AAV particle of embodiment 114, 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.116. The AAV particle of embodiment 115, 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%, 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 70%, 75%, 80%, 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 70%, 75%, 80%, 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: 4897-4904.117. The AAV particle of embodiment 115 or 116, wherein:(i) the nucleotide sequence encoding the 5’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395; or a nucleotide sequence comprising one, two, three, four, five, six. or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395;(ii) the nucleotide sequence encoding the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4362-4371; a nucleotide sequence at least 70%, 75%, 80%, 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 70%, 75%, 80%, 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: 4372-4379.118. The AAV particle of any one of embodiments 115-117, 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%, 92%, 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 comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprises 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%, 92%, 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: 4898.119. The modulatory polynucleotide of any one of embodiments 115-118, 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%, 92%, 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%, 92%, 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%, 92%, 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: 4898.120. The AAV particle of any one of embodiments 115-119, 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%, 92%, 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%, 92%, 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%, 92%, 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: 4899.121. The AAV particle of any one of embodiments 115-120, 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%, 92%, 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%, 92%, 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 SEQ ID NO: 4900, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 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 sequencecomprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900.122. The AAV particle of any one of embodiments 115-120, wherein:(i) the encoded 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4884, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95% 96%. 97%, 98%, 99% identical to SEQ ID NO: 4884, 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: 4884; 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: 4884;(ii) the encoded loop region comprises the nucleotide sequence of SEQ ID NO: 4893, a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%, 92%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4893, 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: 4893; 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: 4893; and (iii) the encoded 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4903, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4903, 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: 4903, or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4903.123. The AAV particle of any one of embodiments 115-120, wherein:(i) the encoded 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 4882. a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4882, 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: 4882; 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: 4882;(ii) the encoded loop region comprises the nucleotide sequence of SEQ ID NO: 4893. a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4893, 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: 4893; 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: 4893; 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%, 92%, 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, or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4898.124. The AAV particle of any one of embodiments 115-123, wherein the encoded 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.125. The AAV particle of any one of embodiments 114-117, 121, or 124, w herein 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: 4900.126. The AAV particle of any one of embodiments 114-117, 121, 124-125, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:(i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence of 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 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) a nucleotide sequence encoding the antisense strand sequence of 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 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: 4375.127. The AAV particle of any one of embodiments 114-117, 121, or 124, 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: 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: 4900.128. The AAV particle of any one of embodiments 114-117, 121, 124, or 127, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:(i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence of 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 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) a nucleotide sequence encoding the antisense strand sequence of 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 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: 4375.129. The AAV particle of any one of embodiments 114-117, 121, or 124, 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: 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 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: 4900.130. The AAV particle of any one of embodiments 114-117, 121, 124, or 129, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:(i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence of 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 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 differentnucleotides 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 of 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 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: 4375.131. The AAV particle of any one of embodiments 114-117, 119, or 124, 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: 4898.132. The AAV particle of any one of embodiments 114-117, 119, 124, or 131, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:(i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence of 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 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) nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907; and(v) a nucleotide sequence encoding 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: 4373.133. The AAV particle of any one of embodiments 114-117, 119, or 124, 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: 4898.134. The AAV particle of any one of embodiments 114-117, 119, 124, or 133, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:(i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence of 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 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) nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911; and(v) a nucleotide sequence encoding 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: 4373.135. The AAV particle of any one of embodiments 114-117, 119, or 124, 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: 4898.136. The AAV particle of any one of embodiments 114-117, 119, 124, or 125, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:(i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence of 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 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) a nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919; and(v) a nucleotide sequence encoding 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: 4373.137. The AAV particle of any one of embodiments 114-117, 119, or 124, 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 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 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 ofSEQ 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: 4898.138. The AAV particle of any one of embodiments 114-117, 119, 124, or 137, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:(i) a nucleotide sequence encoding 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) a nucleotide sequence encoding the sense strand sequence of 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 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) a nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923; and(v) a nucleotide sequence encoding 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: 4373.139. The AAV particle of any one of embodiments 114-138, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises any one of SEQ ID NOs: 4380-4409, 5027-5050, 5632-5635, or 5661-5716, or a nucleotide sequence at least 70%. 75%. 80%. 85%. 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.140. The AAV particle of any one of embodiments 114-123, or 139, wherein the nucleotide sequence encoding tire modulatory’ polynucleotide comprises any one of SEQ ID NOs: 5632-5635 or 5661-5716, or anucleotide sequence at least 70%. 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%. or 99% identical thereto.141. The AAV particle of any one of embodiments 114-117, 121, or 124-126, 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.142. The AAV particle of any one of embodiments 114-117, 121, 124, 127, or 128, 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.143. The AAV particle of any one of embodiments 114-117, 121, 124, 129, or 130, 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.144. The AAV particle of any one of embodiments 114-117, 119, 124, 131, or 132, 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.145. The AAV particle of any one of embodiments 114-117, 119, 124, 133, or 134, 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.146. The AAV particle of any one of embodiments 114-117, 119, 124, 135, or 136, 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.147. The AAV particle of any one of embodiments 114-117, 119, 124, 137, or 138, 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.148. The AAV particle of any one of embodiments 1-147. which comprises a viral genome comprising a promoter operably linked to the nucleic acid encoding the polynucleotide for inhibiting MAPT (e.g., human MAPT).149. The AAV particle of embodiment 148, wherein the promoter is a ubiquitous promoter.150. The AAV particle of embodiment 148, wherein the promoter is a cell or tissue specific promoter.151. The AAV particle of any one of embodiments 148-150 or the viral genome of embodiment 523, 525, or 526, wherein the promoter is chosen from human elongation factor la-subunit (EFla), cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken p-actin (CBA) and its derivative CAG, 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), P-globin minigene np2, 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., aMHC. cTnT, and CMV-MLC2k), a liver promoter (e.g.. hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK. C512), an Hl promoter, or a functional fragment, e.g., a truncation, or a functional variant thereof.152. The AAV particle of any one of embodiments 148, 149, 151, wherein the promoter comprises a CBA promoter or a variant thereof.153. The AAV particle of any one of embodiments 148. 150, or 151, wherein the promoter comprises a synapsin promoter or a variant thereof.154. The AAV particle of any one of embodiments 148-151, w herein the promoter comprises the nucleotide sequence of any one of the nucleotide sequences provided in Table 2; a nucleotide sequence comprising atleast 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%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the nucleotide sequences provided in Table 2.155. The AAV particle of any one of embodiments 148. 149, 151. or 152, 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: 5199.156. The AAV particle of any one of embodiments 148. 150, 151. or 153, 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: 3883.157. The AAV particle of any one of embodiments 148-156, wherein the viral genome further comprises a poly A signal sequence.158. The AAV particle of embodiment 157, 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: 4476.159. The AAV particle of any one of embodiments 148-158 or the viral genome of any one of embodiments 523 or 525-534, wherein the viral genome further comprises an inverted tenninal repeat (ITR) sequence.160. The AAV particle of embodiment 159. wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197, 5200, 5503, or 5504; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197, 5200, 5503, or 5504; 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, 5503, or 5504.161. The AAV particle of any one of embodiments 148-160, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA.162. Hie AAV particle of embodiment 161, 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 5503; 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 5503; 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 5503.163. The AAV particle of any one of embodiments 148-162, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA.164. The AAV particle of embodiment 163, wherein the ITR positioned 3’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 5504; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200 or 5504; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5504.165. The AAV particle of any one of embodiments 148-164, 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.166. The AAV particle of any one of embodiments 163-165, 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: 5200.167. The AAV particle of any one of embodiments 163-165, 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: 5503; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:5503; 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: 5503; 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: 5504; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%. 98%. or 99% identical to SEQ ID NO: 5504: 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: 5504.168. The AAV particle of any one of embodiments 148-167 or the viral genome of any one of embodiments 523 or 525-543, wherein the viral genome further comprises an enhancer, a Kozak sequence, an intron region, and / or an exon region.169. The viral genome of embodiment 168, wherein the enhancer comprises:(i) a CMVie enhancer or variant thereof; 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 4472.170. The AAV particle of embodiment 168 or 169, 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: 4471.171. The AAV particle of any one of embodiments 148-170, 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 tire CBA promoter or variant thereof.172. The AAV particle of any one of embodiments 168-171, 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 4474.173. The AAV particle of any one of embodiments 168-172, wherein the intron comprises:(i) a human beta globin intron (hBG intron) or variant thereof; 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: 4475.174. The AAV particle of any one of embodiments 148-173, which further comprises a filler sequence.175. The AAV particle of embodiment 174, 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: 3885.176. The AAV particle of any one of embodiments 148-175, 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 tire viral genome in a cell or tissue where the corresponding miRNA is expressed.177. The AAV particle of embodiment 176, wherein the encoded miR binding site modulates, e.g., reduces expression of the encoded payload in a cell or tissue of the DRG, liver, heart, hematopoietic lineage, or a combination thereof.178. The AAV particle of embodiment 176 or 177, 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) orthe at least 1-5 copies are separated by a spacer.179. The AAV particle of any one of embodiments 148-178, wherein the viral genome is self-complementary.180. The AAV particle of any one of embodiments 148-179, wherein the viral genome is single stranded.181. The AAV particle of any one of embodiments 148-180, 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).182. The AAV particle of any one of embodiments 148-181, which 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 473-503);(vi) a polyA signal sequence; and(vii) an ITR.183. The AAV particle of any one of embodiments 148-182, 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 modulator}’ polynucleotide;(vi) a polyA signal sequence; and(vii) an ITR.184. The AAV particle of any one of embodiments 148-151, 153, 154, 156-166, or 168-182, 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; ora 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 any one of SEQ ID NOs: 5632-5635 or 5661-5716, 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; ora 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: 5200.185. The AAV particle of any one of embodiments 148-151, 153, 154, 156-166, 168-182, or 184, 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; ora 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 tenmodifications, 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: 5632-5635 or 5661-5716, 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; ora 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: 5200.186. The AAV particle of any one of embodiments 148-155, 157-166, or 168-183, 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; ora nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;(ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471 a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199: a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;(iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than tenmodifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 5632-5635 or 5661-5716, 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; ora 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: 5200.187. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, or 186, 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; ora 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: 5632-5635 or 5661-5716, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;(vi) a polyA signal sequence, wherein tire 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; ora 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: 5200.188. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, or 186, 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; ora 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: 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; ora 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: 5200.189. Hie AAV particle of any one of embodiments 148-155, 157-166, 168-183, or 186, 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; ora 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 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; ora 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: 5200.190. The AAV particle of any one of embodiments 148-151, 153, 154, 156-166, 168-182, or 184, 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; ora 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; ora 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: 5200.191. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, or 186, 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; ora 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; ora 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: 5200.192. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, or 186, 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; ora 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; ora 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: 5200.193. The AAV particle of any one of embodiments 148-155, 157-166. 168-183. or 186, 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; oranucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;(ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;(iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4390, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;(vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and(vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%. 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; ora 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: 5200.194. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, or 186, 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; ora 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; ora 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: 5200.195. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, or 186, 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; ora 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 tenmodifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;(iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4393, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%. 97%. 98%. or 99% identical thereto;(vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and(vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; ora 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: 5200.196. The AAV particle of any one of embodiments 148-152-155, 157-166, 168-183, or 186. wherein the viral genome comprises in 5’ to 3’ order:(i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; ora 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; ora 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: 5200.197. The AAV particle of any one of embodiments 148-155, 157-166, or 168-183, wherein the viral genome comprises in 5’ to 3' order(i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5503: a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5503; ora 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: 5503;(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 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: 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: 5504; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5504; ora 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: 5504.198. The AAV particle of any one of embodiments 148-197, wherein the viral genome comprises the nucleotide sequence of any one of SEQ ID NOs: 5520-5631, 5856-5863, 5473-5502, 3886-3893, or 5149-5196, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 5473-5502 or 5149-5196.199. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, 186, 188, 189, 191-196, or 198, wherein the viral genome comprises the nucleotide sequence of any one of SEQ ID NOs: 5149-5196, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 5149-5196.200. The AAV particle of any one of embodiments 148-155, 157-166. 168-183. 186, or 187, wherein the viral genome comprises the nucleotide sequence of any one of SEQ ID NOs: 5520-5575 or 5856-5859, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 5520-5575 or 5856-5859.201. The AAV particle of any one of embodiments 148-155, 157-166. 168-183. 186, 188. 189, 191-196, 198. or 199, wherein the viral genome comprises the nucleotide sequence of any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, or 5185, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, or 5185.202. The AAV particle of any one of embodiments 148-155, 157-166. 168-183, 186, 188, 189, 198. 199, 201. wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 5173, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5173.203. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, 186, 187, 191, 198, 199, or 201, wherein the viral genome comprises tire nucleotide sequence of SEQ ID NO: 5195, or a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5195.204. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, 186, 187, 192, 198, 199, or 201, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 5196, or a nucleotide sequence at least 70%, 75%. 80%. 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5196.205. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, 186, 187, 192, 198, 199, or 201, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 5182, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5182.206. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, 186, 187, 194, 198, 199, or 201, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 5183, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5183.207. The AAV particle of any one of embodiments 148-155, 157-166. 168-183. 186, 187. 195, 198. 199, or 201, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 5184, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5184.208. The AAV particle of any one of embodiments 148-155, 157-166, 168-183, 186, 187, 195, 198, 199, or 201, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 5185, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5185.209. The AAV particle of any one of embodiments 148-155, 157-166. 168-183, 186, 187, or 196, wherein the viral genome comprises the nucleotide sequence of any one of SEQ ID NOs: 5473-5502, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 5473-5502.210. Hie AAV particle of any one of embodiments 148-151, 153, 154, 156-166. 168-182, 184, 190, or 198 wherein the viral genome comprises the nucleotide sequence of any one of SEQ ID NOs: 3886-3892, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 3886-3892.211. The AAV particle of any one of embodiments 148-151, 153, 154, 156-166, 168-182, 184, 190, 198, or 210, wherein tire viral genome comprises the nucleotide sequence of any one of SEQ ID NOs: 3886, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%. or 99% identical to anyone of SEQ ID NOs: 3886.212. The AAV particle of any one of embodiments 148-151, 153, 154, 156-166, 168-182, 184, or 198, wherein the viral genome comprises tire nucleotide sequence of any one of SEQ ID NOs: 5576-5631 or 5860-5863, or a nucleotide sequence at least 70%. 75%. 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 5576-5631 or 5860-5863.213. A cell comprising the AAV particle of any one of embodiments 1-212.214. The cell of embodiment 213, wherein the cell is a mammalian cell or an insect cell.215. The cell of embodiment 213 or 214, wherein the cell is a cell of a brain region or a spinal cord region (e.g., a CNS cell).216. The cell of any one of embodiments 213-215, wherein the cell is a neuron, a glial cell, or anoligodendrocyte.217. The cell of any one of embodiments 213-216, wherein the cell is a cell of the cortex, hippocampus, thalamus, or brainstem218. A method of making the AAV particle of any one of embodiments 1-212, comprising:(i) providing a host cell comprising a viral genome;(ii) incubating the host cell under conditions suitable to enclose the viral genome in an AAV capsid protein, e.g., an AAV capsid variant described herein;thereby making the AAV particle.219. The method of embodiment 218, further comprising, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the host cell.220. The method of embodiment 218 or 219, wherein the host cell comprises a second nucleic acid encoding the AAV capsid protein.221. The method of embodiment 220, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule.223. A pharmaceutical composition comprising the AAV particle of any one of embodiments 1-212, and a pharmaceutically acceptable excipient.224. A method of delivering a payload (e.g., an siRNA for inhibiting MAPT expression (e.g., MAPT gene, mRNA, or protein expression)) to a cell, comprising administering an effective amount of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212.225. The method of embodiment 224, wherein the cell is a cell of a brain region or a spinal cord region.226. The method of embodiment 224 or 225, wherein the cell is a cell of the cortex, hippocampus, thalamus, or brainstem.227. The method of any one of embodiments 224-226, wherein the cell is a neuron, an astrocyte, a glial cell, or an oligodendrocyte.228. The method of any one of embodiments 224-227, wherein delivery decreases (e.g., inhibits) MAPT mRNA levels, e.g., by at least 40%, 44%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 76%, 79%, 80%, 84%, 85%, 87%, or 90%, e.g., in a cell of a brain region (e.g., cortex, hippocampus, or brain stem), e.g., as compared to a reference level (e.g., the mRNA levels in a cell that has not been delivered or prior to delivering the AAV particle or pharmaceutical composition), e.g., when measured by an assay (e.g., an assay as described in Example 7 or 10).229. The method of any one of embodiments 224-228, wherein delivery decreases (e.g., inhibits) MAPT protein levels, e.g, by at least 15%, 17%, 20%, 25%, 30%, 35%, 37%, 40%, 44%, 45%, 46%, 50%, 53%, 55%, 60%, 63%, 64%, 65%, 70%, 72%, 74%, or 75%, e.g, in a cell of a brain region (e.g, cortex, hippocampus, thalamus, or brain stem), e.g.. as compared to a reference level (e g., the protein levels in a cells that has not been delivered or prior to delivering the AAV particle or pharmaceutical composition), e.g., when measured by an assay (e.g., an assay as described in Example 7 or 10).230. The method of any one of embodiments 224-229, wherein the cell is in a subject.231. Tire method of embodiment 230, wherein the subject has or has been diagnosed with having a genetic disorder (e.g., a monogenic disorder or a polygenic disorder).232. The method of embodiment 230 or 231, wherein the subject has or has been diagnosed with having a neurological disorder (e.g., a neurodegenerative disorder).233. Tire method of any one of embodiments 230-232, wherein the subject has or has been diagnosed with having a disorder associated with tau expression, e.g., aberrant tau expression.234. The method of any one of embodiments 230-233, wherein the subject has or has been diagnosed with having a tauopathy.235. A method of treating a subject having or diagnosed with having a genetic disorder, e.g., a monogenic disorder or a polygenic disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212.236. A method of treating a subject having or diagnosed with having a neurological disorder (e.g.. a neurodegenerative disorder), comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212.237. A method of treating a subject having or diagnosed with having a disorder associated with tau expression, e.g., aberrant tau expression, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212.238. A method of treating a subject having or diagnosed with having a tauopathy, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212.239. The method of any one of embodiments 230-238, 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.240. The method of any one of embodiments 235-239, 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.240. The method of any one of embodiments 235-240, 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, biopsy sample, or aqueous cerebral spinal fluid biopsy is performed prior to, during, or after treatment with the AAV particle, modulatory polynucleotide. siRNA, or pharmaceutical composition.241. The method of any one of embodiments 224-240, wherein administration decreases, e.g., inhibits, expression of a MAPT gene, mRNA, and / or protein.242. The method of embodiments 241, wherein the MAPT gene, mRNA, and / or protein is a wild-type MAPT gene, mRNA, or protein.243. The method of embodiment 241, wherein the MAPT gene, mRNA, and / or protein is a mutated MAPT gene, mRNA, or protein (e.g., comprises at least 1 mutation).244. The method of any one of embodiments 224-243, wherein administration of the AAV particle or pharmaceutical composition results in a reduction and / or prevention of tau pathology, e.g., a decrease in a biomarker of tau pathology (e.g.,18F-flortaucipir, plasma ptau 181, or18F-PM-PBB3), e.g., as measured by a PET scan or PET scan in combination with Braak ncuropatbological staging and / or scrum biomarkcr staining, e.g., as compared to a reference (e.g., a subject that as not received the AAV particle or pharmaceutical composition).245. The method of any one of embodiments 224-244, wherein the administration decreases MAPT mRNA levels in tire subject, e.g., by at least 40%, 44%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 76%, 79%, 80%, 84%, 85%, 87%, or 90%, e.g., in a cell of a brain region (e.g., cortex, hippocampus, or brain stem), e.g., as compared to a reference level (e.g., the mRNA levels in a subject that has not received or prior to receiving the AAV particle or pharmaceutical composition), e.g., when measured by an assay (e.g., an assay as described in Example 7 or 10).246. The method of any one of embodiments 224-245, wherein the administration decreases MAPT protein levels in tire subject, e.g., by at least 15%, 17%, 20%, 25%, 30%, 35%, 37%, 40%, 44%, 45%, 46%, 50%, 53%, 55%, 60%, 63%, 64%. 65%. 70%, 72%, 74%, or 75%. e.g., in a cell of a brain region (e.g., cortex, hippocampus, thalamus, or brain stem), e.g.. as compared to a reference level (e.g., the protein levels in a subject that has not received or prior to receiving the AAV particle or pharmaceutical composition), e.g., when measured by an assay (e.g., an assay as described in Example 7 or 10).247. The method of any one of embodiments 230-246, wherein the pharmaceutical composition, the modulatory polynucleotide, or the siRNA, or AAV particle is administered to the subject intravenously, via intra-cistema magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, intramuscularly, via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.248. The method of any one of embodiments 230-247, wherein the pharmaceutical composition, the modulatory polynucleotide, the siRNA or the AAV particle is administered to the subject intravenously.249. The method of any one of embodiments 230-247, wherein the pharmaceutical composition, the modulatory polynucleotide, the siRNA, or the AAV particle is administered to the subject via intra-cistema magna injection (ICM).250. The method of any one of embodiments 230-247, wherein the pharmaceutical composition, the modulatory polynucleotide, the siRNA or the AAV particle is administered to the subject intrathecally.251. Hie pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212. for use in a method of delivering an siRNA for inhibiting MAPT expression to a cell.252. The pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212, for use in the manufacture of a medicament.253. Hie pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212. 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.254. Use of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212, in the manufacture of a medicament for delivering an siRNA for inhibiting MAPT expression to a cell.255. Use of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212, in the manufacture of a medicament.256. Use of the pharmaceutical composition of embodiment 223 or the AAV particle of any one of embodiments 1-212. 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0071] FIG.1 is a graph depicting the relative R / F activity as % over non-target control (NTC) on the Y-axis post-transfection with the modulatory polynucleotide constructs targeting MAPT indicated on the X-axis(from left to right: VOYTaumiR-102-530 (SEQ ID NO: 4380), VOYTaumiR- 102-556 (SEQ ID NO: 4381). VOYTaumiR-102-579 (SEQ ID NO: 4383), VOYTaumiR- 102-586 (SEQ ID NO: 4384), VOYTaumiR-104-530 (SEQ ID NO: 4385), VOYTaumiR- 104-556 (SEQ ID NO: 4386), VOYTaumiR- 104-579 (SEQ ID NO: 4388), VOYTaumiR- 104-586 (SEQ ID NO: 4389), VOYTaumiR-109-530 (SEQ ID NO: 4390), VOYTaumiR- 109-556 (SEQ ID NO: 4391), VOYTaumiR- 109-579 (SEQ ID NO: 4393), VOYTaumiR- 109-586 (SEQ ID NO: 4394), VOYTaumiR-114-530 (SEQ ID NO: 4395). VOYTaumiR-114-556 (SEQ ID NO: 4396), VOYTaumiR- 114-579 (SEQ ID NO: 4398), VOYTaumiR-114-586 (SEQ ID NO: 4399), VOYTaumiR-116-530 (SEQ ID NO: 4400), VOYTaumiR-116-556 (SEQ ID NO: 4401), VOYTaumiR-116-579 (SEQ ID NO: 4403), VOYTaumiR-116-586 (SEQ ID NO: 4404), VOYTaumiR- 127-530 (SEQ ID NO: 4405), VOYTaumiR- 127-556 (SEQ ID NO: 4406), VOYTaumiR-127-579 (SEQ ID NO: 4408), and VOYTaumiR-127-586 (SEQ ID NO: 4409)).

[0072] FIG. 2 is a graph showing the fold-change in MAPT mRNA remaining for each vectorized modulatory polynucleotide relative to the non-target control (fold change relative to NTC) on the Y -axis posttransfection with the modulatory' polynucleotide constructs targeting MAPT indicated on the X-axis (from left to right: mock, non-target control (NTC), VOYTaumiR-127-530 (SEQ ID NO: 4405), VOYTaumiR-127-556 (SEQ ID NO: 4406), VOYTaumiR-127-579 (SEQ ID NO: 4408), VOYTaumiR-127-586 (SEQ ID NO: 4409). VOYTaumiR-116-530 (SEQ ID NO: 4400), VOYTaumiR-116-556 (SEQ ID NO: 4401), VOYTaumiR-116-579 (SEQ ID NO: 4403). VOYTaumiR-116-586 (SEQ ID NO: 4404), VOYTaumiR-114-530 (SEQ ID NO: 4395), VOYTaumiR-114-556 (SEQ ID NO: 4396), VOYTaumiR-114-579 (SEQ ID NO: 4398), VOYTaumiR-114-586 (SEQ ID NO: 4399), VOYTaumiR-109-530 (SEQ ID NO: 4390), VOYTaumiR- 109-556 (SEQ ID NO: 4391), VOYTaumiR- 109-579 (SEQ ID NO: 4393), VOYTaumiR- 109-586 (SEQ ID NO: 4394), VOYTaumiR- 104-530 (SEQ ID NO: 4385), VOYTaumiR- 104-556 (SEQ ID NO: 4386). VOYTaumiR- 104-579 (SEQ ID NO: 4388), VOYTaumiR-104-586 (SEQ ID NO: 4389), VOYTaumiR-102-530 (SEQ ID NO: 4380), VOYTaumiR- 102-556 (SEQ ID NO: 4381), VOYTaumiR- 102-579 (SEQ ID NO: 4383), and VOYTaumiR- 102-586 (SEQ ID NO: 4384)).

[0073] FIG. 3 is a graph showing the fold-change in MAPT mRNA remaining for each vectorized modulatory polynucleotide relative to the non-target control (fold change relative to NTC) on the Y-axis posttransfecti...

Claims

We claim:

1. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide that targets human MAPT, wherein the AAV capsid variant comprises:(i) three, four, or all of the amino acid R at position 584, the amino acid T at position 586, the amino acid L at position 588, the amino acid Q at position 589, and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and(ii) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV;wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to tire amino acid sequence of positions 203-736 of SEQ ID NO: 138.

2. Tire AAV particle of claim 1, wherein the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present immediately subsequent to amino acid 453, numbered according to SEQ ID NO: 982 or 6412.

3. The AAV particle of claim 1 or 2, wherein the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present at amino acids 454-459, numbered according to SEQ ID NO: 982 or 6412.

4. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide that targets human MAPT, wherein the AAV capsid variant comprises:(i) three, four, or all of the amino acid R at position 584, the amino acid T at position 586. the amino acid L at position 588. the amino acid Q at position 589. and / or the amino acid L at position 590, numbered according to SEQ ID NO: 138; and(ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV;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.

5. The AAV particle of claim 4, wherein the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present immediately subsequent to amino acid 455, numbered according to SEQ ID NO: 981.

6. Tire AAV particle of claim 4 or 5, wherein the amino acid sequence SPHSKA (SEQ ID NO: 941) is present at amino acids 456-461, numbered according to SEQ ID NO: 981 or 6411.

7. The AAV particle of any one of claims 4-6, wherein the AAV capsid variant further comprises:(a) the amino acid E at position 451, numbered according to SEQ ID NO: 981;(b) the amino acid V at position 453, numbered according to SEQ ID NO: 981; and / or(c) the amino acid R at position 452, numbered according to SEQ ID NO: 981.

8. The AAV particle of any one of claims 1-7, wherein the AAV capsid variant comprises:(i) the amino acid R at position 590, T at position 592, L at position 594, Q at position 595, and L at position 596, numbered according to SEQ ID NO: 981, 982. 6411, or 6412; or(ii) the amino acid R at position 584, T at position 586, L at position 588, Q at position 589. and L at position 590, numbered according to SEQ ID NO: 138 or 6414.

9. Tire AAV particle of any one of claims 1-3 or 8, wherein the AAV capsid variant comprises:(i) an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 6412:(ii) an amino acid sequence at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6412; and / or(iii) an amino acid sequence at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 6412.

10. The AAV particle of any one of claims 1-3, 8, or 9, wherein the AAV capsid variant comprises:(i) the amino acid sequence of amino acids 203-742 of SEQ ID NO: 6412;(ii) the amino acid sequence of amino acids 138-742 of SEQ ID NO: 6412; and / or(iii) the amino acid sequence of SEQ ID NO: 6412.

11. Tire AAV particle of any one of claims 1-3, or 8-10, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 6416, or nucleotide sequence at least 90%, 92%, 95%, 97%, 98%, or 99% identical thereto.

12. The AAV particle of any one of claims 4-8, wherein the AAV capsid variant comprises:(i) an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 6411;(ii) an amino acid sequence at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 6411: and / or(iii) an amino acid sequence at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 6411.

13. The AAV particle of any one of claims 4-8 or 12, wherein the AAV capsid variant comprises:(i) the amino acid sequence of amino acids 203-742 of SEQ ID NO: 6411;(ii) the amino acid sequence of amino acids 138-742 of SEQ ID NO: 6411; and / or(iii) the amino acid sequence of SEQ ID NO: 6411.

14. The AAV particle of any one of claims 4-8, 12, or 13, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 6415, or nucleotide at least 90%, 92%, 95%, 97%, 98%, or 99% identical thereto.

15. The AAV particle of any one of claims 1-14, wherein hypervariable loop IV comprises amino acids 449-460, numbered according to SEQ ID NO: 138.

16. The AAV particle of any one of claims 1-15, wherein the AAV capsid variant:(i) has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138(ii) transduces a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)), optionally wherein the level of transduction is at least 5, 10, 15, 20, 25, 30. 35.40, 45, 50, 55, 60, or 65-fold greater as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 2;(iii) is enriched at least about 3, 4, 5, 6, 7, 8, 9, or 10-fold, in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1;(iv) is capable of transducing the brain of at least two to three species, e.g., a non-human primate and / or rodent (e.g., Macaca fascicularis. Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c mice, C57B1 / 6 mice, and / or CD-I outbred mice), when measured by an assay as described in Example 2;(v) delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2), optionally wherein the brain region is a putamen. caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN);(vi) delivers an increased level of viral genomes to a brain region, optionally wherein the level of viral genomes is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50-fold, as compared to areference 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), optionally wherein the a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN);(vii) is enriched at least about 5, 10, 15, 20, 25, 30, or 35 -fold, in the spinal cord compared to a reference sequence of SEQ ID NO:

138. e g., when measured by an assay as described in Example 2, optionally wherein the region of the spinal cord is a thoracic spinal cord region, cervical spinal cord region, lumbar spinal cord region;(viii) shows preferential transduction in a brain region relative to the transduction in tire dorsal root ganglia (DRG) and / or tire liver;(xi) is capable of transducing neuronal cells and non-neuronal cells, e g., glial cells (e.g., astrocytes); (ix) is capable of transducing at least 20%, 25%, 30%, 40%, 50%. 55%. 60%. 65%, 70%, 75%, 80%, or 85% of cells in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, cerebellar cortex, cerebellum, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)), e.g., when measured by an assay as described in Example 2;(x) is capable of transducing at least 10%, 15%, 20%, 25%, 30%, 40%, 50%, 55%, 60%, or 65% of neurons (e.g., NeuN+ neurons) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex);(xi) is capable of transducing at least 70%, 75%, 80%, 85%, 90%, or 95% of astrocytes (e.g., Sox9+ astrocytes) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g., when measured by an assay as described in Example 2;(xii) is capable of transducing at least 90% or 95% of neurons, e.g., motor neurons (e.g., ChAT+ neurons) in the spinal cord (e.g., the cervical spinal cord, the thoracic spinal cord, or the lumbar spinal cord), e.g., when measured by an assay as described in Example 2; and / or(xiii) is capable of transducing at least 90%, 95%, or 98% of astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., the cervical spinal cord, the thoracic spinal cord, or the lumbar spinal cord), e.g., when measured by an assay as described in Example 2.

17. The AAV particle of any one of claims 1-16, wherein the encoded polynucleotide comprises a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein the antisense strand sequence is fully or partially complementary' to human MAPT.

18. The AAV particle of claim 17, 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 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 5A, 9A, or 9B;wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.

19. The AAV particle of claim 17 or 18, 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 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: 4906, 4926, 4946, 4966, 4986, 5006, or 5853;(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 tire 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(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 tire 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;(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;(xiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of any one of SEQ ID NOs: 5638. 5740. 5766, 5784, 5812, or 5839;(xiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5644, 5744, 5768, 5788, 5816, or 5841;(xv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of any one of SEQ ID NOs: 5652. 5748. 5770, 5792, 5820, or 5843;(xvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5658, 5752, 5774, 5796, 5824, or 5845;(xvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5721, 5756, 5776, 5800, 5829, or 5847;(xviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of any one of SEQ ID NOs: 5727. 5760. 5778, 5804, 5833, 5849;(xix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5733, 5764, 5780, 5808, 5837, or 5851;(xx) 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 tire nucleotide sequence of SEQ ID NO: 5853; or(xxi) 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: 5855.

20. The AAV particle of any one of claims 17-19, 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 tire 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 tire 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 tire 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 tire 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 tire 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 tire 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 tire 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 tire 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;(1) 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 tire 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 tire nucleotide sequence of SEQ ID NO: 5144;(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.

21. The AAV particle of any one of claims 17-20, 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 tire 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 tire 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;(1) 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.

22. The AAV particle of any one of claims 17-21, wherein:(i) tire 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.

23. The AAV particle of any one of claims 17-19, wherein:(i) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5638;(ii) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5740;(iii) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5766;(iv) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5784;(v) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5812;(vi) the antisense sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5839;(vii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5644;(viii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5744;(ix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5768;(x) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5788;(xi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5816;(xii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5841;(xiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5652;(xiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5748;(xv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5770;(xvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5792;(xvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5820;(xviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5843;(xix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5658;(xx) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5752;(xxi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5774;(xxii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5796:(xxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5824;(xxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5845:(xxv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5721;(xxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5756:(xxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5776;(xxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5800;(xxix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5829;(xxx) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5847;(xxxi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5727;(xxxii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5760;(xxxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5778:(xxxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5804;(xxxv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5833:(xxxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5849;(xxxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5733:(xxxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5764;(xxxix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5780;(xl) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5808;(xli) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5837;(xlii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5851;(xliii) 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: 5853; or(xliv) 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: 5855.

24. The AAV particle of any one of claims 17-19 or 23, wherein:(i) the antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5638;(ii) the antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5740;(iii) the antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5766;(iv) the antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5784;(v) the antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5812;(vi) the antisense sequence comprises the nucleotide sequence of SEQ ID NO: 5641; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5839;(vii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5644;(viii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5744;(ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5768;(x) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5788;(xi) the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5816;(xii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5649 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5841;(xiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5652;(xiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5748;(xv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5770;(xvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5792:(xvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5820;(xviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5655 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5843;(xix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5658:(xx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5752;(xxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5774;(xxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5796:(xxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5824;(xxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5718 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5845;(xxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5721;(xxvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5756;(xxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and tire sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5776;(xxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5800;(xxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5829;(xxx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5724 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5847;(xxxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5727;(xxxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5760;(xxxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5778;(xxxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5804;(xxxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5833;(xxxvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5730 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5849;(xxxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5733;(xxxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5764;(xxxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5780;(xl) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5808;(xli) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5837;(xlii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5736 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5851;(xliii) 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: 5853; or(xliv) 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: 5855.

25. The AAV particle of any one of claims 17-19, 23 or 24, wherein:(i) tire nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5637;(ii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5739;(iii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5765;(iv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5783;(v) the nucleotide sequence encoding the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5811;(vi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5640 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5838;(vii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5643;(viii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5743;(ix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5767;(x) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5787;(xi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5815;(xii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5648 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5840;(xiii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5651;(xiv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5747;(xv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5769;(xvi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5791;(xvii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5819;(xviii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5654 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5842;(xix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5657;(xx) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5751;(xxi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5773;(xxii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5795;(xxiii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5823;(xxiv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5717 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5844;(xxv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5720;(xxvi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5755;(xxvii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5775;(xxviii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5799;(xxix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5827;(xxx) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5723 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5846;(xxxi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5726;(xxxii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5759;(xxxiii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5777;(xxxiv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5803;(xxxv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5832;(xxxvi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5729 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5848;(xxxvii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5732;(xxxviii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5763;(xxxix) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5779;(xl) tire nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5807;(xli) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5836;(xlii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5735 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5850;(xliii) 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: 5852; or(xliv) 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: 5854.

26. An AAV particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412; 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.

27. An AAV particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6411; 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.

28. The AAV particle of any one of claims 17-27, 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; and / or(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 tire sense strand sequence and / or at the 3’ end of the antisense strand sequence, of 1 or 2 nucleotides.

29. The AAV particle of any one of claims 17-28, wherein:(iii) the sense strand and the antisense strand comprise one mismatch; and / or(iv) the antisense strand and the target sequence comprise one mismatch.

30. The AAV particle of any one of claims 1-29, wherein the polynucleotide for inhibiting MAPT (e.g., human MAPT) further comprises a modulatory polynucleotide, wherein the modulatory polynucleotide comprises the siRNA.

31. The AAV particle of claim 30. wherein the modulatory polynucleotide further comprises one, two, three or all of:(i) a 5 ’ flanking region;(ii) a loop region; and(iii) a 3’ flanking region.

32. The AAV particle of claim 31. wherein:(A) (i) the 5' flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4878- 4886; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886;(ii) the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4887-4896; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; or a nucleotide sequencecomprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; and / or(iii) the 3’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4897-4904; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904; and / or(B) (i) the nucleotide sequence encoding the 5’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395;(ii) the nucleotide sequence encoding the loop region comprises tire 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.

33. The AAV particle of any one of claims 30-32, wherein the modulatory polynucleotide comprises:(A) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879. a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprisingone, 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 nucleotidesequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879;(ii) 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;(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;(E) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4884, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4884, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotidesrelative to the nucleotide sequence of SEQ ID NO: 4884; 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: 4884;(ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4893, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4893, 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: 4893; 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: 4893; and(iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4903, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4903, 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: 4903, or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4903; or(F) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4882, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4882, 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: 4882; 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: 4882;(ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4893, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4893, 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: 4893; 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: 4893; 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, or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4898.

34. The AAV particle of any one of claims 31-33, 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.

35. The AAV particle of any one of claims 30-34, wherein the modulatory polynucleotide comprises in 5' to 3’ order:(A) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880: a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880:(ii) the sense strand sequence comprising the nucleotide 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 comprising the nucleotide 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 comprising the nucleotide 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 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 comprising the nucleotide 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 comprising the nucleotide sequence of SEQ ID NO: 4922;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one. two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891;(iv) the antisense strand sequence comprising the nucleotide 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 comprising the nucleotide 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 comprising the nucleotide sequence of SEQ ID NO: 4908; and (v) a 3’ flanking region comprising the nucleotide sequence 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 comprising the nucleotide 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 comprising the nucleotide sequence of SEQ ID NO: 4912; and (v) a 3’ flanking region comprising the nucleotide sequence 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 nucleotidesrelative 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 comprising the nucleotide 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 comprising the nucleotide sequence of SEQ ID NO: 4920; and (v) a 3’ flanking region comprising the nucleotide sequence 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 comprising the nucleotide 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 comprising the nucleotide sequence of SEQ ID NO: 4924; and (v) a 3’ flanking region comprising the nucleotide sequence 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.

36. The AAV particle of any one of claims 30-35, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises in 5 ’ to 3 ' order:(A) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4355: a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355:(ii) the sense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4905;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366;(iv) the antisense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4907; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375: a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375:(B) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4355: a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355:(ii) the sense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4917;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366;(iv) the antisense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4919; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375;(C) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355;(ii) the sense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4921;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one. two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366;(iv) the antisense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4923; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375: a nucleotide sequence comprising one, two, three, four, five, six. or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375: or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375;(D) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354;(ii) the sense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4965;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363;(iv) the antisense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4907; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373:(E) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354;(ii) the sense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4969;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363:(iv) the antisense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4911; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six. or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373;(F) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotidesrelative 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 comprising the nucleotide sequence of SEQ ID NO: 4977;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363. a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363;(iv) the antisense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4919; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373. a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373; or(G) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354. a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354;(ii) the sense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4981;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363;(iv) the antisense strand sequence comprising the nucleotide sequence of SEQ ID NO: 4923; and (v) a 3’ flanking region comprising the nucleotide sequence 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.

37. The AAV particle of any one of claims 30-36, 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, 4407, 5661-5716, or 5632-5635, or nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.

38. An AAV particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412; 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.

39. An AAV particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6411; 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.

40. An AAV particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412 or 6411; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, 4409, 4390, 4391, 4393, 4394, 4380-4389, 4392, 4395-4404, 4406, 4407. 5661-5716 or 5632-5635.

41. The AAV particle of any one of claims 1-40, which comprises a viral genome comprising a promoter operably linked to the nucleic acid encoding the polynucleotide for inhibiting human MAPT.

42. The AAV particle of claim 41, wherein the promoter:(i) is a ubiquitous promoter;(ii) is a cell or tissue specific promoter;(iii) is chosen from human elongation factor la-subunit (EFla), cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken -actin (CBA) and its derivative CAG, glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived grow th factor (PDGF), platelet-derived growth factor B-chain (PDGF- ), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpGbinding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), P-globin minigene np2, 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., aMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK. C512) or a functional fragment, e.g., a truncation, or a functional variant thereof:(iii) is a CBA promoter or variant thereof;(iv) a sy napsin 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.

43. The AAV particle of claim 41 or 42. 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 tire modulatory polynucleotide or siRNA;(ii) a poly adenylation (poly A) 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.

44. The AAV particle of any one of claims 41-43, wherein:(i) the ITR positioned 5 ' relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197 or 5503; a nucleotide sequence comprising at 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 5503; or a nucleotide sequence with at least 80%, 85%, 90%. 95%.96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197 or 5503;(ii) the ITR positioned 3’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 5504; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200 or 5504; or a nucleotide sequence with at least 80%, 85%, 90%. 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5200 or 5504;(iii) the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 4476;(iv) the enhancer comprises a CMVie enhancer or variant thereof;(v) the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471 or 4472; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471 or 4472; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4471 or 4472; and / or (vi) the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g.. substitutions, insertions, or deletions, relative to SEQ ID NO: 4475: or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4475.

45. The AAV particle of any one of claims 41-44, wherein the viral genome is self-complementary or single stranded.

46. The AAV particle of any one of claims 41-45. 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; ora 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, 5027-5050, 5661-5716, or 5632-5635, ornucleotide 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; ora 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; ora nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;(ii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 3883; at least one, two. three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 3883; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3883;(iii) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than tenmodifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(iv) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409, 5027-5050, 5661-5716, or 5632-5635, 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; ora 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; ora 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, 5027-5050, 5661-5716, or 5632-5635, ornucleotide 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; ora 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.

47. The AAV particle of any one of claims 41-46, 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; ora 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 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; ora 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; ora 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; ora nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200:(C) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; ora 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; ora 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; ora 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: 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; ora 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; ora nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;(ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%. 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;(iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%. 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4390, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;(vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and(vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; ora 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; ora 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 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; ora 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; ora nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;(ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%. 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;(iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475: a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4393, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%. 97%. 98%. or 99% identical thereto;(vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and(vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; ora 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;(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; ora 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; ora 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(I) (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; ora 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 tenmodifications, 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: 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: 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; ora 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.

48. The AAV particle of any one of claims 41-47. 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, 5473-5502, 5520-5631, 5856-5863, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 5520-5631 or 5856-5863.

49. An adeno-associated virus (AAV) particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412: and(ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, 5184, or 5864.

50. An adeno-associated virus (AAV) particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6411; and(ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, 5184, or 5864.

51. An adeno-associated virus (AAV) particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 6412 or 6411; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194, 3886-3893, 5473-5502, 5520-5631, or 5856-5863.

52. A cell comprising the AAV particle of any one of claims 1-51, 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.

53. A method of making the AAV particle of any one of claims 1-51, comprising:(i) providing a host cell comprising a AAV viral genome;(ii) incubating the host cell under conditions suitable to enclose the viral genome in an AAV capsid protein;thereby making the AAV particle.

54. A pharmaceutical composition comprising the AAV particle of any one of claims 1-51, and a pharmaceutically acceptable excipient.

55. 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 54 or the AAV particle of any one of claims 1-51, thereby delivering the siRNA for inhibiting MAPT expression to the cell.

56. The method of claim 55, wherein the cell is:(a) a mammalian cell or an insect cell;(b) a cell of a brain region or a spinal cord region (e.g., a CNS cell);(c) a cell of the brain or the spinal cord (e.g., a cell of a putamen, caudate, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, Lateral Geniculate Nucleus (LGN), cervical spinal cord, lumbar spinal cord, and / or thoracic spinal cord);(d) a neuron or an astrocyte; and / or(e) in a subject.

57. The method of claim 56, 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.

58. 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 54 or the AAV particle of any one of claims 1-51.

59. The method of claim 57 or 58, 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.

60. The method of claim 58 or 59, 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.

61. The method of any one of claims 58-60. 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 tire blood test, imaging test, biopsy sample, or aqueous cerebral spinal fluid biopsy is performed prior to, during, or after treatment with the AAV particle, or pharmaceutical composition.

62. The method of any one of claims 56-61, wherein the pharmaceutical composition or AAV particle are administered to the subject:(i) intravenously, via intra-cistcma magna injection (I CM), intracerebrally, intrathecal ly. 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.

63. The pharmaceutical composition of claim 54 or the AAV particle of any one of claims 1-51, for use in a method of delivering an siRNA for inhibiting MAPT expression to a cell.

64. The pharmaceutical composition of claim 54 or the AAV particle of any one of claims 1-51, 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.

65. Use of the pharmaceutical composition of claim 54 or the AAV particle of any one of claims 1-51, in the manufacture of a medicament for delivering an siRNA for inhibiting MAPT expression to a cell.

66. Use of the pharmaceutical composition of claim 54 or the AAV particle of any one of claims 1-51, 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.

Images