Compositions and methods for the treatment of disorders related to dystrophia myotonica protein kinase

Abstract

The disclosure relates to compositions and methods for modulating, e.g., reducing or eliminating, the expression of mutated DMPK via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful in the treatment of subjects who have, have been diagnosed with having, or are at risk of having myotonic dystrophy type 1 or another DMPK-related disorder.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF DISORDERSRELATED TO DYSTROPHIA MYOTONICA PROTEIN KINASERELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 519,958, filed on August 16, 2023, the contents of which are incorporated herein by reference in their entirety.SEQUENCE LISTING

[0002] The present application is being along with a Sequence Listing in electronic format. The Sequence Listing file, entitled “14640 0094-00304 SL,” was created on June 18, 2024, and is 2,595.123 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety .FIELD OF THE DISCLOSURE

[0003] Disclosed herein are compositions and methods relating to adeno-associated virus (AAV) viral particles for the delivery of polynucleotides, e.g.. modulatory polynucleotides, for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA and their use in the treatment of myotonic dystrophy type 1 (DM1) and other disorders associated with or caused by mutated DMPK mRNA. In some embodiments, compositions disclosed herein may be used to treat a subject in need thereof, such as a human subject diagnosed with DM1 or another condition resulting from mutated DMPK mRNA expression.BACKGROUND

[0004] Dystrophia myotonica protein kinase (DMPK) (also referred to as myotonic dystrophy protein kinase) is an enzyme encoded by the DMPK gene (Ensembl Gene ID No. ENSG00000104936), which is found on chromosome 19. The DMPK gene is also known as DM15, DM1PK, DMK, MDPK, and MT- PK.

[0005] The DMPK protein is thought to be involved in cell communication and appears to play important roles in tissues such as heart, muscle, and brain.

[0006] Mutation(s) in DMPK cause myotonic dystrophy type 1 (DM1). DM1 is characterized by progressive muscle wasting and weakness. Muscle weakness is most often observed in distal muscles, and myotonia, cataracts, hypogonadism, frontal balding and electrocardiogram changes are also observed. There are an estimated 500,000 cases of DM1 worldwide.

[0007] DM1 is typically caused by trinucleotide repeat expansions in the DMPK gene. Trinucleotide repeat expansions occur in a repeated CTG segment in the 3’ UTR of DMPK. Non-diseased humans typically have 5-37 CTG repeats (SEQ ID NO: 6430). The number of CTG repeats determines the formof DM1 and the severity of disease. CTG repeats of the trinucleotide repeat expansion may be uninterrupted or may be interrupted with one or more other nucleotides.

[0008] Patients with 38-49 CTG repeats (SEQ ID NO: 6431) are typically asymptomatic.

[0009] Patients with 50-150 CTG repeats (SEQ ID NO: 6432) may manifest with mild DM1. Mild DM1 symptoms typically begin between the ages of 20 and 70 years. Mild DM1 is characterized by cataracts, myotonia, and mild muscle weakness, and patients have a normal life span.

[0010] Patients with 50 to 1000 CTG repeats (SEQ ID NO: 6433) may manifest with classic DM1. Classic DM1 symptoms typically begin in adulthood. Classic DM1 is characterized by muscle weakness and wasting, myotonia, cataracts, cardiac conduction abnormalities, and a myopathic face. Adults may be physically disabled and have a shortened lifespan.[Oil] Patients with CTG repeat lengths greater than 800 may manifest with childhood DM1. Symptoms of childhood DM1 typically begin around age 10. Childhood DM1 is characterized by learning difficulties and psychosocial problems (e.g., family problems, depression, anxiety), slurred speech, hand muscle myotonia, and heart conduction abnormalities.

[0012] Patients with CTG repeat lengths greater than 1000 may manifest with congenital DM1. Patients with congenital DM1 show symptoms before birth. Symptoms of congenital DM1 visible before birth include decreased fetal movement in the uterus, polyhydramnios, clubfoot, and ventriculomegaly. Congenital DM1 is characterized by hypotonia, and severe weakness at birth. Further symptoms of congenital DM1 include a tented appearance of the upper lip. dysarthria, intellectual disability, hypotonia, respiratory insufficiency, and early death.

[0013] In DM1 patients, the mutated DMPK gene produces an altered (mutated) mRNA. The altered mRNA is thought to trap proteins and forms foci within cells. Said foci interfere with protein production, which prevents proper cell function. Without being limited by theory', the foci may trap proteins that have a function in mRNA splicing, thereby disrupting proper (normal) mRNA splicing patterns. In muscle cells, this results in muscle weakness. DM1 particularly affects cardiac, smooth, and skeletal muscle.

[0014] There are no specific treatments for DM1, and some forms of DM1 such as congenital DM1 and childhood DM1 result in decreased lifespan. Existing treatments are directed to managing symptoms and maximizing patients’ quality of life and independence. Treatments directed to managing symptoms include anti-diabetic drugs, anti -myotonic drugs (e.g., mexiletine), and non-steroidal anti-inflammatory drugs. Thus, there remains a long-felt need to develop pharmaceutical compositions and methods for the treatment of DM1. In particular, a need exists for treatments targeting cardiac, smooth, and skeletal muscle.SUMMARY

[0015] The present disclosure addresses these challenges by providing AAV-based compositions, AAV-based compositions for use in methods for treating a DMPK-related disorder in subjects, and methods for treating a DMPK-related disorder in subjects. In some embodiments, the DMPK-related disorder is DM1. In various embodiments, disclosed herein are compositions and methods directed to AAV-based gene delivery of modulatory polynucleotides for reducing or eliminating expression of DMPK (e.g., mutated DMPK mRNA) to treat DM1. The compositions and methods are useful to reduce the effects of mutated DMPK mRNA expression, and to slow, halt or reverse muscular and other symptoms of DM1. In some embodiments, mutated DMPK mRNA expression refers to expression of DMPK mRNA comprising 50 or more CTG trinucleotide repeats (SEQ ID NO: 6434). Unless otherwise specified, DMPK, DM15. DM1PK, DMK. MDPK. and MT-PK are synonymous terms and are used interchangeably to refer to the DMPK gene. DMPK is used to refer to the transcript encoding the DMPK protein, DMPK protein refers to the protein encoded by the DMPK gene and mRNA. DM1 is used to refer to myotonic dystrophy type 1.

[0016] In some embodiments, the present disclosure provides an AAV particle comprising a nucleotide sequence encoding a modulatory' polynucleotide for reducing or eliminating expression of mutated DMPK mRNA, and an AAV capsid. In some embodiments, the modulatory polynucleotide reduces or eliminates mRNA encoding mutant DMPK (e.g., comprising aberrant CTG repeats). In some embodiments, the AAV capsid is an AAV capsid variant. In some embodiments, the AAV capsid variant is an AAV5 capsid variant.

[0017] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV5 capsid variant and a viral genome, wherein the viral genome comprises a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA. optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA; and wherein the AAV5 capsid variant comprises an amino sequence comprising the formula [N2]-[N3], wherein: (i) [N2] comprises positions Xi, X2, X3, X4, and X5. wherein: (a) position Xi is Y or T; (b) position X2is Q, T, P. or E; (c) position X3is A; (d) position X4is E or D; and (e) position X5is V or E; and (ii) [N3] comprises the amino acid sequence of VQK or VQN.

[0018] In some embodiments, [N2]-[N3] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, [N2]-[N3] is present immediately subsequent to an amino acid corresponding to position 576 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV5 capsid variant comprises [N2]-[N3] in place of an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138. In some embodiments. [N2]-[N3] comprises the amino acid sequence AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593).

[0019] In some embodiments, [N2]-[N3] comprises the amino acid sequence PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596).

[0020] In some embodiments, [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950). YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966).

[0021] In some embodiments, the AAV5 capsid variant further comprises [Nl] comprising positions XD. XE, and XF, wherein: (a) position XDof [Nl] is Q or S: (b) position XEof [Nl] is S, L. A, or T; and (c) position XFof [Nl] is S, Y, or T; wherein [Nl] immediately precedes [N2]-[N3], In some embodiments. [Nl] comprises the amino acid sequence QSS, SLS, SLY, SAT, or QTS. In some embodiments. [N1]-[N2]-[N3] comprises the amino acid sequence QSSYPAEVVQK (SEQ ID NO: 150), SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637). SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), SLSYPAEVVQK (SEQ ID NO: 642), SLSYPAEEVQK (SEQ ID NO: 643). SLSYPAEVVQN (SEQ ID NO: 644), QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646).

[0022] In some embodiments, the AAV capsid variant further comprises [NO] comprising positions XA, XB, and Xc, wherein: (a) position XAof [NO] is T; (b) position XBof [NO] is N; and (c) position Xcof [NO] is N. T, S, or K; wherein [NO] immediately precedes [Nl], In some embodiments, [NO] comprises the amino acid sequence TNN, TNS, TNT, or TNK. In some embodiments, [N0]-[Nl] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183), TNSSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650), or TNKSAT (SEQ ID NO: 651). In some embodiments, [NO]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665).

[0023] In some embodiments, the AAV capsid variant further comprises [N4] comprising positions XGand XH, wherein: (a) position X of [N4] is T, P, or N; and (b) position XHof [N4] is A or D; wherein [N4] is present immediately subsequent to [N3], In some embodiments. [N4] comprises the amino acid sequence TA, PA, TD. NA, or PA.

[0024] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV5 capsid variant and a viral genome, wherein the viral genome comprises a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA. optionally wherein the modulatorypolynucleotide comprises an RNAi agent targeting DMPK mRNA; and wherein the AAV5 capsid variant comprises an amino sequence comprising the formula [NO]-[N1]-[N2]-[N3]-[N4], wherein: (i) [NO] comprises the amino acid sequence TNN, TNS, TNT, or TNK; (ii) [Nl] comprises the amino acid sequence QSS, SLS, SLY, SAT, or QTS; (iii) [N2] comprises the amino acid sequence YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13); (iv) [N3] comprises the amino acid sequence VQK or VQN; and (v) [N4] comprises the amino acid sequence TA, PA, TD, NA, or PA, wherein [N2]-[N3] replaces an amino acid corresponding to position T577 of the amino acid sequence of SEQ ID NO: 138. In some embodiments, [NO]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence of SEQ ID NO: 1533 or any one of SEQ ID NOS: 2064-2076. In some embodiments, the AAV5 capsid variant comprises up to four different amino acids relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2076. In some embodiments, the up to four different amino acids are conservative substitutions. In some embodiments, the AAV5 capsid variant comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2076. In some embodiments, the AAV5 capsid variant comprises the amino acid sequence of SEQ ID NO: 943 or any one of SEQ ID NOs: 2064-2076. In some embodiments, the AAV5 capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 2064-2076.

[0025] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV5 capsid variant and a viral genome, wherein the viral genome comprises a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA; and wherein the AAV5 capsid variant comprises an amino sequence comprising up to four different amino acids relative to the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056. In some embodiments, the up to four different amino acids arc conservative substitutions. In some embodiments, the up to four different amino acids are present at one or more amino acids corresponding to the following positions of the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056: (i) position 1, wherein the different amino acid is T or L; (ii) position 2, wherein the different amino acid is N, L, K, A, T, or P; (iii) position 3, wherein the different amino acid is N, K, L, A, Y, or S; (iv) position 4, wherein the different amino acid is Q, L, T, S, F. Y, K, or A; (v) position 5, wherein the different amino acid is S, H, A, M, Q, T, V, or F; (vi) position 6, wherein the different ammo acid is S, P, V, A, Q, L, T, N, or M; (vii) position 7. wherein the different amino acid is Y, H, S. V, A, L, or T; (viii) position 8, wherein the different amino acid is D. P, A, Q. F, L, S. H, or M; (ix) position 9, wherein the different amino acid is F, A, L, D, or Q; (x) position 10, wherein the different amino acid is T, E, I, or S; (xi) position 11, wherein the different amino acid is V, A, N, or S; (xii) position 12. wherein the different amino acid is V, L, or P; (xiii) position 13, wherein the different amino acid is Q, E. or P; (xiv) position 14. wherein the differentamino acid is K, N, S, or L; (xv) position 15, wherein the different amino acid is T, V, M, or L; and / or (xvi) position 16, wherein the different amino acid is A, G, or R.

[0026] In some embodiments, the AAV5 capsid variant comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056. In some embodiments, the AAV5 capsid variant comprises the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056. In some embodiments, the amino acid sequence is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 570-584 of the amino acid sequence of SEQ ID NO: 138. In some embodiments, positions 7-14 of the amino acid sequence are present in place of an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

[0027] In some embodiments, the modulatory polynucleotide comprises a molecular scaffold, wherein the molecular scaffold comprises: (a) a 5’ flanking region comprising the nucleotide sequence of any one of SEQ ID NOs: 6413-6416. or a nucleotide sequence at least 95% identical thereto; (b) a loop region comprising the nucleotide sequence of any one of SEQ ID NOs: 6417-6421, or a nucleotide sequence at least 95% identical thereto; and (c) a 3’ flanking region comprising the nucleotide sequence of any one of SEQ ID NOs: 6422-6427, or a nucleotide sequence at least 95% identical thereto. In some embodiments, (a) the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6414 or SEQ ID NO: 6415, or a nucleotide sequence at least 95% identical thereto; (b) the loop region comprises the nucleotide sequence of SEQ ID NO: 6417, SEQ ID NO: 6418, or SEQ ID NO: 6421, or a nucleotide sequence at least 95% identical thereto; and (c) the 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6423, SEQ ID NO: 6424, or SEQ ID NO: 6425, or a nucleotide sequence at least 95% identical thereto.

[0028] In some embodiments, the 5’ flanking region comprises tire nucleotide sequence of SEQ ID NO: 6414, or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6417, or a nucleotide sequence at least 95% identical thereto, and the 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6423, or a nucleotide sequence at least 95% identical thereto. In some embodiments, the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6415, or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6421, or a nucleotide sequence at least 95% identical thereto, and the 3‘ flanking region comprises the nucleotide sequence of SEQ ID NO: 6425, or a nucleotide sequence at least 95% identical thereto. In some embodiments, the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6414, or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6417, or a nucleotide sequence at least 95% identical thereto, and the 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6424, or a nucleotide sequence at least 95% identical thereto. In some embodiments, the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6414. or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6418. or anucleotide sequence at least 95% identical thereto, and the 3' flanking region comprises the nucleotide sequence of SEQ ID NO: 6423, or a nucleotide sequence at least 95% identical thereto.

[0029] In some embodiments, the modulatory polynucleotide comprises siRNA or shRNA.

[0030] In some embodiments, tire modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more DMPK mRNA transcripts (e.g., one or more mutated DMPK mRNA transcripts), wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the passenger strand, the loop region, the guide strand, and the 3' flanking region. In some embodiments, the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more DMPK mRNA transcripts (e.g.. one or more mutated DMPK mRNA transcripts), wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the guide strand, the loop region, the passenger strand, and the 3' flanking region. In some embodiments, the passenger strand is 15-30 nucleotides in length. In some embodiments, the guide strand is 15-30 nucleotides in length. In some embodiments, the guide strand is 21-25 nucleotides in length and / or the passenger strand is 21-25 nucleotides in length. In some embodiments, the passenger strand is at least 70%. 80%, 90%, or 95%, or is 100%, complementary' to the guide strand. In some embodiments, the one or more DMPK mRNA transcripts comprises the nucleotide sequence of SEQ ID NO: 6428, SEQ ID NO: 6429, SEQ ID NO: 6430, SEQ ID NO: 6431, SEQ ID NO: 6432, SEQ ID NO: 6433. and / or SEQ ID NO: 6434, or a trinucleotide repeat expansion thereof.

[0031] In some embodiments, the viral genome comprises a promoter operably linked to the nucleotide sequence encoding the modulatory’ polynucleotide. In some embodiments, the viral genome further comprises an inverted terminal repeat (ITR) sequence. In some embodiments, the viral genome comprises an ITR sequence positioned 5’ relative to the nucleotide sequence encoding the modulatory’ polynucleotide. In some embodiments, the viral genome comprises an ITR sequence positioned 3’ relative to the nucleotide sequence encoding the modulatory polynucleotide. In some embodiments, the viral genome comprises an ITR sequence positioned 5 ’ relative to the nucleotide sequence encoding the modulatory polynucleotide, and an ITR sequence positioned 3‘ relative to the nucleotide sequence encoding the modulatory polynucleotide.

[0032] hi some aspects, the present disclosure provides a cell comprising an AAV particle disclosed herein, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an S19 cell), or a bacterial cell.

[0033] In some aspects, the present disclosure provides a method of making an AAV particle disclosed herein, wherein the method comprises: (i) providing a cell comprising the viral genome comprising a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA and a nucleic acid encoding the AAV5 capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV5 capsid variant; thereby making the AAV particle.

[0034] In some embodiments of a method of making the AAV particle, the viral genome comprises: (a) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% identical thereto; (b) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6415 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6421 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6425 or a nucleotide sequence at least 95% identical thereto; (c) a 5 ’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3 ’ flanking region comprising die nucleotide sequence of SEQ ID NO: 6424 or a nucleotide sequence at least 95% thereto; or (d) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6418 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% thereto; and wherein the AAV5 capsid variant comprises die amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056.

[0035] In some embodiments of a method of making the AAV particle, the viral genome comprises: (a) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% identical thereto; (b) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6415 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6421 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6425 or a nucleotide sequence at least 95% identical thereto; (c) a 5 ’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3‘ flanking region comprising die nucleotide sequence of SEQ ID NO: 6424 or a nucleotide sequence at least 95% thereto; or (d) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising die nucleotide sequence of SEQ ID NO: 6418 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% thereto; and wherein the AAV5 capsid variant comprises the amino acid sequence of SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064-2076.

[0036] In some embodiments, the method of making the AAV particle further comprises, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell. In some embodiments, the method of making the AAV particle further comprises, prior to step (i) introducing the nucleic acid encoding the AAV5 capsid variant into the cell. In some embodiments, the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an S19 cell), or a bacterial cell.

[0037] In some aspects, the present disclosure provides a pharmaceutical composition comprising an AAV particle disclosed herein and a pharmaceutically acceptable excipient.

[0038] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA to a cell, comprising administering an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the cell is in a subject. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having a DMPK-related disorder. In some embodiments, the DMPK-related disorder is myotonic dystrophy type 1 (DM1).

[0039] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA to a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having a DMPK-related disorder. In some embodiments, the DMPK-related disorder is myotonic dystrophy type 1 (DM1).

[0040] In some aspects, the present disclosure provides a method of treating a DMPK-related disorder in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder. In some embodiments, the subject has one or more mutations in the DMPK gene. In some embodiments, the one or more mutations in the DMPK gene comprises a trinucleotide repeat expansion. In some embodiments, the trinucleotide repeat expansion in the DMPK gene is 50 or more CTG repeats (SEQ ID NO: 6434). In some embodiments, the treating results in prevention of progression of the DMPK-related disorder in the subject. In some embodiments, the treating results in amelioration of at least one symptom of the DMPK- related disorder in the subject. In some embodiments, tire at least one symptom comprises cataracts, myotonia, muscle weakness and wasting, cardiac conduction abnonnalities, a myopathic face, learning difficulties, psychosocial problems including depression and / or anxiety, slurred speech, decreased fetal movement in the uterus, polyhydramnios, clubfoot, ventriculomegaly, hypotonia, a tented appearance of the upper lip, dysarthria, intellectual disability, hypotonia, respiratory insufficiency, or a combination thereof. In some embodiments, the DMPK-related disorder is myotonic dystrophy type 1 (DM1).

[0041] In some aspects, the present disclosure provides a method of treating myotonic dystrophy type 1 (DM1) in a subject, comprising administering to the subject an effective amount of apharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having DM1.

[0042] In some embodiments, the subject is a human.

[0043] In some embodiments, the pharmaceutical composition or AAV particle is delivered to a cell, tissue, or region of muscle. In some embodiments, the muscle is one or more of cardiac, smooth, and / or skeletal muscle. In some embodiments, the pharmaceutical composition or AAV particle is delivered to a cell, tissue, or region of the brain. In some embodiments, the pharmaceutical composition or AAV particle is delivered to a cell or tissue of the central nervous system (CNS) in the subject. In some embodiments, the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum. In some embodiments, the pharmaceutical composition or AAV particle is delivered to the subject via intravenous administration.

[0044] In some embodiments, the method of delivering or treating further comprises evaluating, e.g., measuring, the level of modulatory polynucleotide expression, the level of mutated DMPK mRNA expression, and / or the level of normal mRNA splicing, optionally DMPK mRNA splicing, in the subject, e.g.. in a cell, tissue, or fluid of the subject. In some embodiments, evaluating the subject’s level of modulatory polynucleotide expression, the subject’s level of mutated DMPK mRNA expression, and / or the subject’s level of normal mRNA splicing, optionally DMPK mRNA splicing, is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of modulatory’ polynucleotide expression, the subject’s level of mutated DMPK mRNA expression, and / or the subject's level of normal mRNA splicing, optionally DMPK mRNA splicing, prior to administration is compared to the subject’s level of modulatory polynucleotide expression, the subject’s level of mutated DMPK mRNA expression, and / or the subject’s level of normal mRNA splicing, optionally DMPK mRNA splicing, subsequent to administration. In some embodiments, the cell or tissue of the subject is a muscle cell or tissue. In some embodiments, the subject’s level of mutated DMPK mRNA expression subsequent to administration of the pharmaceutical composition or AAV particle is decreased relative to the subject’s level of mutated DMPK mRNA expression prior to administration of the pharmaceutical composition or AAV particle.

[0045] In some embodiments, administering die pharmaceutical composition or AAV particle to the subject results in: (i) an increase in the number and / or level of viral genomes (VG) per cell in a muscle cell or tissue of the subject relative to the number and / or level of VG per cell in a non-muscle cell or tissue of the subject; (ii) a decrease in mutated DMPK mRNA expression in a muscle cell or tissue of the subject relative to baseline and / or relative to mutated DMPK mRNA expression in a muscle cell or tissue of an individual with a DMPK-related disorder who has not been administered the pharmaceutical composition or AAV particle; and / or (iii) an increase in normal mRNA splicing, optionally DMPK mRNA splicing, in a muscle cell or tissue of the subject relative to baseline and / or relative to normalmRNA splicing, optionally DMPK mRNA splicing, in a muscle cell or tissue of an individual widr a DMPK-related disorder who has not been administered the pharmaceutical composition or AAV particle.

[0046] In some embodiments, the method of delivering or treating further comprises administering to the subject at least one additional therapeutic agent and / or therapy. In some embodiments, the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating a DMPK-related disorder, optionally wherein the at least one additional therapeutic agent and / or therapy comprises an anti-diabetic drug, an anti-myotonic drug (e.g., mexiletine), a non-steroidal antiinflammatory drug, or a combination thereof. In some embodiments, the method of delivering or treating further comprises administering an immunosuppressant to the subject. In some embodiments, the immunosuppressant comprises a corticosteroid (for example, and without limitation, prednisone, prednisolone, methylprednisolone, and / or dexamethasone), adrenocorticotropic hormone, rapamycin, mycophenolate mofetil, tacrolimus, rituximab, eculizumab hydroxychloroquine, alemtuzumab, hydroxyurea, fludarabine, and / or busulfan.

[0047] In some aspects, the present disclosure provides a use of a pharmaceutical composition or AAV particle disclosed herein for use in a method of treating a disorder disclosed herein.

[0048] In some aspects, the present disclosure provides a use of a pharmaceutical composition or AAV particle disclosed herein for use in treating a DMPK-related disorder in a subject, optionally wherein the DMPK-related disorder is myotonic dystrophy type 1. In some embodiments, the subject has. has been diagnosed with having, or is at risk of having the DMPK-related disorder, optionally wherein the DMPK-related disorder is myotonic dystrophy type 1.

[0049] In some aspects, the present disclosure provides a use of a pharmaceutical composition or AAV particle disclosed herein in the manufacture of a medicament for treating a DMPK-related disorder in a subject, optionally wherein the DMPK-related disorder is myotonic dystrophy type 1. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder, optionally wherein the DMPK-rclatcd disorder is myotonic dy strophy type 1.Enumerated Embodiments1. An AAV particle comprising an AAV capsid variant (e.g.. an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises the formula [N2]-[N3], wherein:(i) [N2] comprises positions Xi. X2. X3. X4. and Xs. wherein:(a) position Xi is Y, N, C, or T;(b) position X2 is P, E, K, T, or Q;(c) position X3 is A or P;(d) position X4 is E, S, D, or A; and(e) position X5 is V. L, or E; and(ii) [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.2. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises the formula [N2]-[N3], wherein:(i) [N2] comprises positions Xi, X2, X3, X4, and Xs, wherein:(a) position Xi is Y, N. or C;(b) position X2 is P. K, T. or Q;(c) position Xs is A or P;(d) position X4 is E, S, or A; and(e) position Xs is V, L, or E; and(ii) [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK. VQQ. or LQK; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.3. An AAV particle comprising an AAV capsid variant (e g., an AAV5 capsid variant) and a viral genome. wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of:(i) an [NO] comprising TNN, TNT, INN, TNS. NNN, or TNK;(ii) an [Nl] comprising QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS. QST, HSS, LSS, or QRS;(iii) an [N2] comprising YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11);(iv) an [N3] comprising VQK, EQK, VKK, VHK, VQQ, or LQK; and(v) an [N4] comprising TA, PA, or NA; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.4. The AAV particle of embodiment 1 or 2, wherein:(a) position Xi is Y or N;(b) position X2 is P, T or Q;(c) position X3 is A;(d) position X4 is E or S; and / or(e) position X5 is V or L.5. The AAV particle of any one of embodiments 1, 2, and 4, wherein [N2] comprises YP, NK. YT. YQ, NP. CP. TH, AE, PS, AA, AS, PA. PP, KA. TA, QA, TP, HA, EV. SL. EE. AV, or SH.6. The AAV particle any one of embodiments 1. 2, 4, and 5, wherein [N2] comprises YPA, YPP. NKA, YTA, YQA, YTP, NPA, CPA, THA, PAE, PPS. KAE. TAE, QAE, TPS, PAA, HAS, AEV, PSL. AEE. or AAV.7. The AAV particle of any one of embodiments 1. 2, 4, and 6, wherein [N2] comprises YPAE (SEQ ID NO: 21), YPPS (SEQ ID NO: 22), NKAE (SEQ ID NO: 23), YTAE (SEQ ID NO: 24), YQAE (SEQ ID NO: 25), YTPS (SEQ ID NO: 26), YPAA (SEQ ID NO: 27), NPAE (SEQ ID NO: 28), CPAE (SEQ ID NO: 29), THAS (SEQ ID NO: 30), PAEV (SEQ ID NO: 17), PPSL (SEQ ID NO: 31), KAEV (SEQ ID NO: 32), TAEV (SEQ ID NO: 16), PAEE (SEQ ID NO: 18), QAEV (SEQ ID NO: 15), TPSL (SEQ ID NO: 33), PAAV (SEQ ID NO: 34), or QAEE (SEQ ID NO: 35).8. The AAV particle of any one of embodiments 1-7, wherein [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CP AEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11).9. The AAV particle of any one of embodiments 1, 2, 4, and 8, wherein [N3] comprises the amino acid sequence of VQK, EQK. or VKK.10. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises VQK.11. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises EQK.12. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises VKK.13. The AAV particle of any one of embodiments 1-12, wherein [N2] is or comprises the amino acid sequence of YPAEV (SEQ ID NO: 1) and [N3] is or comprises the amino acid sequence of VQK.14. The AAV particle of any one of embodiments 1-12, wherein:(i) [N2] is or comprises the amino acid sequence of YTPSL (SEQ ID NO: 7) and [N3] is or comprises the amino acid sequence of VQK;(ii) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of VQK;(iii) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of EQK; or(iv) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of VKK.15. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-14, wherein [N2]-[N3] comprises:(i) AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).16. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-15. wherein [N2]-[N3] comprises:(i) PAEVVQK (SEQ ID NO: 20). PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48). TAEVVQK (SEQ ID NO: 49). PAEVEQK (SEQ ID NO: 50). PAEEVQK (SEQ ID NO: 51),QAEVVQK (SEQ ID NO: 52), TPSLVQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61), or QAEEVQK (SEQ ID NO: 62);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).17. The AAV particle of any one of embodiments 1-16, wherein [N2]-[N3] is or comprises:(i) YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948). YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSLVKK (SEQ ID NO: 954), YPAEVVKK (SEQ ID NO: 955). YPAEVVHK (SEQ ID NO: 956), YPAAVVQK (SEQ ID NO: 957), NPAEVVQK (SEQ ID NO: 958), YPAEVVQQ (SEQ ID NO: 959), CPAEVVQK (SEQ ID NO: 960). YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).18. The AAV particle of any one of embodiments 1-17, which further comprises one, two, three or all of an amino acid other than Q at position 574 (e.g.. T, S, A. I. L, or H), an amino acid other than S at position 575 (e.g., G, A, or R), and / or an amino acid other than S at position 576 (e.g.. K, L, R, A, or T), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.19. The AAV particle of any one of embodiments 1-17, which further comprises:(i) a Q at position 574. an S at position 575. and / or an S at position 576. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982:(ii) a T at position 574, an S at position 575, and / or a L at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(iii) an S at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(iv) a Q at position 574, an S at position 575, and / or an R at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(v) a Q at position 574. an S at position 575. and / or a K at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(vi) an A at position 574. a G at position 575, and / or an A at position 576. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(vii) an I at position 574. a G at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(viii) a Q at position 574. an A at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(ix) an A at position 574, an S at position 575, and / or an S at position 576. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(x) an L at position 574, a G at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(xi) a Q at position 574, an S at position 575, and / or a T at position 576. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(xii) an H at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(xiii) an L at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or(xiv) a Q at position 574, an R at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the ammo acid sequence of SEQ ID NO: 138 or 982.20. The AAV particle of any one of embodiments 1-19, which further comprises [Nl], wherein [Nl] comprises positions XD, XE, and XF, wherein:(a) position XDis Q, T. S, A, I, L. or H;(b) position XEis S, G, A, or R: and(c) position XFis S, K, L, R, A. or T; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).21. The AAV particle of embodiment 20. wherein [Nl] comprises SK, SL, SS, SR, GA. GS. AS. ST. RS.QS. TS. AG, IG. QA, LG, HS. LS, or QR.22. The AAV particle of any one of embodiments 3, 20, and 21, wherein [Nl] is or comprises QSS, QSK, TSL, SSS. QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS.23. The AAV particle of any one of embodiments 20-22, wherein [N1]-[N2] comprises:(i) SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64), SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68). GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70). STNKA (SEQ ID NO: 71), SSYTA (SEQ ID NO: 72), SSYQA (SEQ ID NO: 73). SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77), or SSTHA (SEQ ID NO: 78);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. or 4 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).24. The AAV particle of any one of embodiments 20-23, wherein [N1]-[N2] comprises:(i) SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81), SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84). GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).25. The AAV particle of embodiment 3 or any one of embodiments 20-24, wherein [N1]-[N2] is or comprises:(i) QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98). SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101). AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103). QASYPAEV (SEQ ID NO: 104),ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), HSSYPAAV (SEQ ID NO: 115), QSSNPAEV (SEQ ID NO: 116), QSSYTAEV (SEQ ID NO: 117), TSLCPAEV (SEQ ID NO: 118), QRSYTAEV (SEQ ID NO: 119), or QSSYQAEE (SEQ ID NO: 120);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).26. The AAV particle of any one of embodiments 20-25, wherein [N1]-[N2]-[N3] comprises:(i) SSYPAEVVQ (SEQ ID NO: 121), SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125), GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127), ASYPAEVVQ (SEQ ID NO: 128), STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO: 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVVQ (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134), SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140), SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145), RSYTAEVVQ (SEQ ID NO: 146), SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).27. The AAV particle of embodiment 3 or any one of embodiments 20-26, wherein [N1]-[N2]-[N3] is or comprises:(i) QSSYPAEVVQK (SEQ ID NO: 150). QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153). QSRYPAEVVQK (SEQ IDNO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169). QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173). HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175). SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178). QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i): or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).28. The AAV particle of any one of embodiments 1-27, which further comprises [NO], wherein [NO] comprises positions XA, XB, and Xc, wherein:(a) position XAis T, I, or N;(b) position XBis N;(c) position Xcis N, T, S, or K; and optionally, wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of tire aforesaid amino acids in (a)-(c).29. The AAV particle of embodiment 28, wherein [NO] comprises TN, IN, NN, NT, NS. or NK.30. The AAV particle of embodiment 3, 28. or 29. wherein [NO] is or comprises TNN, TNT. INN, TNS, NNN. or TNK.31. The AAV particle of embodiment 3 or any one of embodiments 28-30, wherein [N0]-[Nl] is or comprises:(i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187). TNNAGA (SEQ ID NO: 188), TNNIGS(SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190). TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, or 5 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).32. The AAV particle of embodiment 3 or any one of embodiments 28-31, wherein [NO]-[N1]-[N2]-[N3] is or comprises:(i) TNNQSSYPAEVVQK (SEQ ID NO: 500). TNNQSKYPAEVVQK (SEQ ID NO: 503). TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513). TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524). TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSS YQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), TNNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 551), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557). TNNQSSYTAEVVKK (SEQ ID NO: 558). TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562), or TNKQASYPAEVVQK (SEQ ID NO: 563);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7. 8. 9, 10. 11. 12, or 13 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).33. The AAV particle of embodiment 3 or 32. wherein [NO]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500).34. The AAV particle of embodiment 3 or 32. wherein [NO]-[N1]-[N2]-[N3] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503). TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), or INNQSSYPAEVVQK (SEQ ID NO: 543).35. The AAV particle of any one of embodiments 1-34, which further comprises [N4], wherein [N4] comprises positions X(; and XH. wherein:(a) position XGis T, P, or N; and(b) position Xu is A; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b).36. The AAV particle of embodiment 35, wherein [N4] is or comprises TA, PA. or NA.37. The AAV particle of any one of embodiments 3, 35, and 36, wherein [N3]-[N4] is or comprises:(i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. or 4 amino acids, e.g., consecutive amino acids, thereof:(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).38. The AAV particle of embodiment 3 or any one of embodiments 35-37, wherein [NO]-[N1]-[N2]- [N3]-[N4] is or comprises:(i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310). TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214). TNNQSKYPAEVEQKTA (SEQ ID NO: 1254). TNNTSLYPAEEVQKTA (SEQ ID NO: 1583). TNTASSYQAEVVQKTA (SEQ ID NO: 1584). TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342). TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453). TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598). TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601). TNNQSSYTAEVVQKNA (SEQ ID NO: 1 02). TNNTSLCPAEVVQKTA (SEQ ID NO: 1603). TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), TNNQRSYTAEVVQKTA (SEQ ID NO: 1604), TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), , TNKQASYPAEVVQKTA (SEQ ID NO: 1587);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).39. The AAV particle of embodiment 3 or any one of embodiments 35-38, wherein [NO]-[N1]-[N2]- [N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).40. The AAV particle of embodiment 3 or any one of embodiments 35-38, wherein [N0]-[N 1]-[N2]- [N31-[N41 is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021). TNNTSLYPAEVVQKTA (SEQ ID NO: 1232). TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300). TNNQSRYPAEVVQKTA (SEQ ID NO:1327), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024).41. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises the fonnula [B]-[C] (SEQ ID NO: 6435), wherein(i) [B] comprises positions Xi, X2, and X3, wherein:(a) position Xi is Q, T, S, A, I, L, or H;(b) position X2 is S, G, or A; and(c) position X3 is S, K, L, R, or A; and(ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943): wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.42. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of:(i) an [A], wherein [A] comprises the amino acid sequence of TNN. TNT, INN, NNN, TNS, or TNK;(ii) a [B], wherein [B] comprises the amino acid sequence of QSS, TSL. SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS;(iii) a [C], wherein [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); and(iv) a [D], wherein [D] comprises the amino acid sequence of TA or PA; and wherein, optionally, [C] replaces position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; and wherein, further optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.43. The AAV particle of embodiment 41, wherein:(a) position Xi is Q, T. S, A, or H;(b) position X2 is S or G; and(c) position X3 is S, K. L, or R.44. The AAV particle of embodiment 41 or 43, wherein [B] comprises QS. TS. SS, AG. IG. QA. AS, LG. HS, SK, SL, SR, GA, or GS.45. The AAV particle of any one of embodiments 41-44, wherein [B] is or comprises QSS. TSL, SSS, QSR, QSK, AGA, IGS, QAS. ASS, LGS, or HSS.46. The AAV particle of embodiment 41 or any one of embodiments 43-45, wherein [B]-[C] comprises:(i) SSYPAEVVQK (SEQ ID NO: 572), SKYPAEVVQK (SEQ ID NO: 573), SLYPAEVVQK (SEQ ID NO: 574), SRYPAEVVQK (SEQ ID NO: 575), GAYPAEVVQK (SEQ ID NO: 576), GSYPAEVVQK (SEQ ID NO: 580), or ASYPAEVVQK (SEQ ID NO: 582);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).47. The AAV particle of any one of embodiments 41-46, wherein [B]-[C] is or comprises:(i) QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154). AGAYPAEVVQK (SEQ ID NO: 156). IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), or HSSYPAEVVQK (SEQ ID NO: 162);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).48. The AAV particle of any one of embodiments 41-47, wherein [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150).49. The AAV particle of any one of embodiments embodiment 41-47, wherein [B]-[C] is or comprises AGAYPAEVVQK (SEQ ID NO: 156), TSLYPAEVVQK (SEQ ID NO: 152), QSKYPAEVVQK (SEQ ID NO: 151), or QSRYPAEVVQK (SEQ ID NO: 154).50. The AAV particle of any one of embodiments 1-49, which further comprises one or both of an amino acid other than T at position 571 (e.g., I or N). and / or an amino acid other than N at position 573 (e.g., T, S, or K), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.51. The AAV particle of any one of embodiments 1-49, which further comprises:(i) a T at position 571, an N at position 572. and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(ii) a T at position 571, an N at position 572, and / or a T at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(iii) an I at position 571, an N at position 572, and / or an N at position 573. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(iv) a T at position 571. an N at position 572, and / or an S at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(v) an N at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or(vi) a T at position 571, an N at position 572, and / or a K at position 573, relative to a reference sequence numbered according to the ammo acid sequence of SEQ ID NO: 138 or 982.52. The AAV particle of any one of embodiments 41- 1, which further comprises [A], wherein [A] comprises positions XA, XB, and Xc, wherein:(a) position XA is T, I, or N;(b) position XB is N; and(c) position Xc is N, T, S, or K; and optionally wherein the AAV capsid variant comprises an ammo acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).53. The AAV particle of embodiment 52, wherein [A] comprises TN. IN. NN, NT, NS, or NK.54. The AAV particle of any one of embodiments 42, 52, and 53. wherein [A] is or comprises TNN, TNT. INN, NNN, TNS, or TNK.55. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B] is or comprises:(i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNHSS (SEQ ID NO: 194), INNQSS (SEQ ID NO: 196), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199). or TNKQAS (SEQ ID NO: 201):(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, or 5 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).56. The AAV particle of embodiment 42 or any one of embodiments 52-55, wherein [A]-[B]-[C] is or comprises:(i) TNNQSSYPAEVVQK (SEQ ID NO: 500). TNNQSKYPAEVVQK (SEQ ID NO: 503). TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGS YPAEVVQK (SEQ ID NO: 523), TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNQSSYPAEVVQK (SEQ ID NO: 543), NNNQSRYPAEVVQK (SEQ ID NO: 552). TNSTSLYPAEVVQK (SEQ ID NO: 556), or TNKQASYPAEVVQK (SEQ ID NO: 563);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).57. The AAV particle of embodiment 42 or any one of embodiments 52-54. wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500).58. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B]-[C] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNQSRYPAEVVQK (SEQ ID NO: 510), or INNQSSYPAEVVQK (SEQ ID NO: 543).59. The AAV particle of any one of embodiments 1-58, which further comprises:(i) an amino acid other than T at position 578 (e.g., P or N), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138: or(ii) an amino acid other than T at position 585 (e.g., P or N), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.60. The AAV particle of any one of embodiments 1-58, which further comprises:(i) a T at position 578 and / or an A at position 579. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or a T at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982;(ii) a P at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or a P at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982; or(iii) an N at position 578 and / or an A at position 579. relative to a reference sequence numbered according to die amino acid sequence of SEQ ID NO: 138; or an N at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982.61. The AAV particle of any one of embodiments 41-60, which further comprises [D], wherein [D] comprises positions X4 and X5, wherein:(a) position X4 is T or N; and(b) position X5 is A.62. The AAV particle of embodiment 42 or 61, wherein [D] is or comprises TA or PA.63. The AAV particle of any one of embodiments 42, 61, and 62, wherein [C]-[D] is or comprises:(i) YPAEVVQKTA (SEQ ID NO: 584) or YPAEVVQKPA (SEQ ID NO: 586);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).64. The AAV particle of embodiment 42 or any one of embodiments 61-63. wherein [A]-[B]-[C]-[D] is or comprises:(i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194). TNTASSYPAEVVQKTA (SEQ ID NO: 1575). TNNLGSYPAEVVQKTA (SEQ ID NO: 1027). TNNHSSYPAEVVQKTA (SEQ ID NO: 1310). TNNSSSYPAEVVQKPA (SEQ ID NO: 1142). 1NNQSSYPAEVVQKTA (SEQ ID NO: 1024), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601). TNSTSLYPAEVVQKTA (SEQ ID NO: 1605). or TNKQASYPAEVVQKTA (SEQ ID NO: 1587);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4. 5. 6, 7, 8, 9. 10, 11, 12. 13. 14, or 15 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).65. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).66. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024).67. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises an amino sequence comprising the fonnula [N2]- [N3], wherein:(i) [N2] comprises positions Xi. X2. Xs. X4. and X5. wherein:(a) position Xi is Y or T;(b) position X2 is Q, T. P, or E;(c) position X3 is A;(d) position X4 is E or D; and(e) position X5 is V or E; and(ii) [N3] comprises the amino acid sequence of VQK or VQN; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.68. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises one. two, three, four, or all of:(i) an [NO] comprising TNN, TNS, TNT, or TNK;(ii) an [Nl] comprising QSS, SLS. SLY. SAT, or QTS;(iii) an [N2] comprising YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5). TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13);(iv) an [N3] comprising VQK or VQN; and(v) an [N4] comprising TA. PA. TD, NA, or PA; wherein, optionally, the modulator}' polynucleotide comprises an RNAi agent targeting DMPK mRNA.69. The AAV particle of embodiment 1 or 67, wherein [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV, AE, or AD.70. The AAV particle of any one of embodiments 1, 67, and 69, wherein [N2] comprises YPA, YQA, YTA, TEA, QAE, TAE, PAE, EAE, PAD, AEV, AEE, or ADV.71. The AAV particle of any one of embodiments 1, 67, 69, and 70, wherein [N2] comprises YPAE (SEQ ID NO: 21), YQAE (SEQ ID NO: 25), YTAE (SEQ ID NO: 24), TEAE (SEQ ID NO: 587), YPAD (SEQ ID NO: 588), QAEV (SEQ ID NO: 15). TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), EAEV (SEQ ID NO: 590), or PADV (SEQ ID NO: 19).72. The AAV particle of embodiment 1 or any one of embodiments 67-71, wherein [N2] is or comprises YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13).73. The AAV particle of embodiment 1 or any one of embodiments 67-72, wherein [N3] comprises the amino acid sequence of VQK.74. The AAV particle of embodiment 1 or 67 or any one of embodiments 69-73, wherein [N2]-[N3] comprises:(i) AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, or 5 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).75. The AAV particle of embodiment 1 or 67 or any one of embodiments 69-74. wherein [N2]-[N3] comprises:(i) PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), P AEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or P ADVVQK (SEQ ID NO: 596);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).76. The AAV particle of embodiment 1 or any one of embodiments 57-75, wherein [N2]-[N3] is or comprises:(i) YP AEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YT AEVVQK (SEQ ID NO: 948). YP AEEVQK (SEQ ID NO: 950), YP AEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965). or YP ADVVQK (SEQ ID NO: 966);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).77. The AAV particle of embodiment 1 or any one of embodiments 67-76, wherein [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943).78. The AAV particle of any one of embodiments 1-77, wherein [N2J-IN3 J replaces position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.79. The AAV particle of embodiment 1 or any one of embodiments 67-78. which further comprises one, two. three or all of an amino acid other than Q at position 574 (e.g.. S), an amino acid other than S at position 575 (e.g., L, A, or T), and / or an amino acid other than S at position 576 (e.g., Y or T), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.80. The AAV particle of embodiment 1 or any one of embodiments 67-78, which further comprises:(i) a Q at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(ii) an S at position 574, an L at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the ammo acid sequence of SEQ ID NO: 138 or 982;(iii) an S at position 574, an L at position 575, and / or a Y at position 576, relative to a reference sequence numbered according to the ammo acid sequence of SEQ ID NO: 138 or 982;(iv) an S at position 574, an A at position 575, and / or a T at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or(v) a Q at position 574. a T at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.81. The AAV particle of embodiment 1 or any one of embodiments 67-80, which further comprises [Nl], wherein [Nl] comprises positions XD, XE. and XF. wherein:(a) position XDis Q or S;(b) position XEis S, L. A, or T; and(c) position XFis S, Y. or T; andoptionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).82. The AAV particle of embodiment 81, wherein [Nl] comprises QS, SL, SA, QT, LS, LY, AT, TS, or SS.83. The AAV particle of any one of embodiments 68, 81, and 82. wherein [Nl] is or comprises QSS, SLS, SLY, SAT, or QTS.84. The AAV particle of any one of embodiments 81-83, wherein [N1]-[N2] comprises:(i) SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597). LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603). or TSTEA (SEQ ID NO: 605);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).85. The AAV particle of any one of embodiments 81-84, wherein [N1]-[N2] comprises:(i) SSYPAE (SEQ ID NO: 79), LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), ATYPAE (SEQ ID NO: 613), LSYPAE (SEQ ID NO: 616), TSTEAE (SEQ ID NO: 619), or LSYPAD (SEQ ID NO: 621);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).86. The AAV particle of embodiment 68 or any one of embodiments 81-85. wherein [N1]-[N2] is or comprises:(i) QSSYPAEV (SEQ ID NO: 96), SLSYQAEV (SEQ ID NO: 622), SLSYTAEV (SEQ ID NO: 623), SLYYPAEV (SEQ ID NO: 624). SATYPAEV (SEQ ID NO: 625). SLSYPAEV (SEQ ID NO:629), SLSYPAEE (SEQ ID NO: 632), QTSTEAEV (SEQ ID NO: 633), or SLSYPADV (SEQ ID NO: 634);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).87. The AAV particle of embodiment 68 or any one of embodiments 81-86. wherein [N 1 ]-[N2]-[N3] is or comprises:(i) QSSYPAEVVQK (SEQ ID NO: 150). SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), SLSYPAEVVQK (SEQ ID NO: 642), SLSYPAEEVQK (SEQ ID NO: 643). SLSYPAEVVQN (SEQ ID NO: 644). QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4. 5, 6, 7, 8, 9. 10, 11, or 12 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, tw o. or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).88. The AAV particle of embodiment 68 or any one of embodiments 81-87, wherein [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150).89. The AAV particle of embodiment 1 or any one of embodiments 67-88, which further comprises [NO], wherein [NO] comprises positions XA, XB, and Xc. wherein:(a) position XAis T;(b) position XBis N; and(c) position Xcis N, T. S, or K; and optionally wherein the AAV capsid comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).90. The AAV particle of embodiment 89. wherein [NO]:(i) comprises TN, NS, NT. NN. or NK; and / or(ii) is or comprises TNS, TNT, TNN, or TNK.91. The AAV particle of any one of embodiments 68, 89, and 90. wherein [NO]-[N1] is or comprises:(i) TNNQSS (SEQ ID NO: 183), TNSSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650), or TNKSAT (SEQ ID NO: 651);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, or 5 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).92. The AAV particle of embodiment 68 or any one of embodiments 89-91, wherein [NO]-[N1]-[N2]- [N3] is or comprises:(i) TNNQSSYPAEVVQK (SEQ ID NO: 500). TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).93. The AAV particle of embodiment 68 or any one of embodiments 89-92. wherein [N0]-[Nl]-[N2]- [N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500).94. The AAV particle of embodiment 1 or any one of embodiments 67-93, which further comprises [N4], wherein [N4] comprises positions XGand XH. wherein:(a) position XGis T, P. or N ; and(b) position XHis A or D; andoptionally wherein the AAV capsid variant comprise an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b).95. The AAV particle of embodiment 94, wherein [N4] is or comprises TA, TD, PA, or NA.96. The AAV particle of embodiment 68, 94, and 95, wherein [N3]-[N4] is or comprises:(i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565). VKKTA (SEQ ID NO: 566). VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. or 4 amino acids, e.g.. consecutive amino acids, thereof:(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).97. The AAV particle of embodiment 68 or any one of embodiments 94-96, wherein [NO]-[N1]-[N2]- [N3]-[N4] is or comprises:(i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLSYQAEVVQKTA (SEQ ID NO: 2064). TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), TNNQTSTEAEVVQKTA (SEQ ID NO: 2074), TNKSATYPAEVVQKTA (SEQ ID NO: 2075), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).98. The AAV particle of embodiment 68 or any one of embodiments 94-97. wherein [NO]-[N1]-[N2]- [N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).99. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises the formula [K1]-[K2], wherein:(i) [KI] comprises LSY or LYY; and(ii) [K2] comprises positions Xi, X2, X3, and X4, wherein:(a) position Xi is Q, T, or P;(b) position X2 is A;(c) position X3 is E or D; and(d) position X4 is V or E; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.100. An AAV particle comprising an AAV capsid variant (e.g.. an AAV5 capsid variant) and a viral genome. wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of:(i) an [KO], which comprises TNNS (SEQ ID NO: 14);(ii) an [KI], which comprises LSY or LYY;(iii) an [K2], which comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18). or PADV (SEQ ID NO: 19);(iv) an [K3], which comprise VQK or VQN; and(v) an [K4], which comprises TA, TD, NA, or PA; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.101. The AAV particle of embodiment 99 or 100, wherein [KI] comprises LSY.102. The AAV particle of embodiment 99 or 101, wherein [K2] comprises QA, TA, PA. EV, EE, DV, AE. or AD.103. The AAV particle of any one of embodiments 99, 101, and 102. wherein [K2] comprises QAE, TAE. PAE, PAD, AEV, AEE, or ADV.104. The AAV particle of any one of embodiments 99-103, wherein [K2] is or comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19).105. The AAV particle of embodiment 99 or any one of embodiments 101-104, wherein [K1]-[K2] comprises LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), or LSYPA (SEQ ID NO: 603).106. The AAV particle of embodiment 99 or any one of embodiments 101-105. wherein [K1]-[K2] comprises:(i) LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), LSYPAE (SEQ ID NO: 616), or LSYPAD (SEQ ID NO: 621);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4. or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).107. The AAV particle of any one of embodiments 99-106, wherein [K1]-[K2] is or comprises:(i) LSYQAEV (SEQ ID NO: 667), LSYTAEV (SEQ ID NO: 668), LYYPAEV (SEQ ID NO: 669), LSYPAEV (SEQ ID NO: 671), LSYPAEE (SEQ ID NO: 673), or LSYPADV (SEQ ID NO: 674);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).108. The AAV particle of any one of embodiments 99-107, which further comprises an amino acid other than Q at position 574 (e.g., S). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.109. The AAV particle of any one of embodiments 99-108, which further comprises S at position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.110. The AAV particle of any one of embodiments 99-109, which further comprises [KO], wherein [KO] is or comprises TNNS (SEQ ID NO: 14); an amino acid sequence comprising any portion of an amino acid sequence, e.g., any 2 or 3 amino acids, e.g.. consecutive amino acids, thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of TNNS (SEQ ID NO: 14); or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of TNNS (SEQ ID NO: 14).111. The AAV particle of embodiment 110. wherein [K0]-[Kl] comprises:(i) TNSSLS (SEQ ID NO: 647) or TNSSLY (SEQ ID NO: 648);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4. or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).112. The AAV particle of any one of embodiments 100, 110, and 111, wherein [K0]-[Kl] is or comprises:(i) TNSSLSY (SEQ ID NO: 676) or TNSSLYY (SEQ ID NO: 678);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).113. The AAV particle of any one of embodiments 110-112, wherein [KO]-[K1]-[K2] comprises:(i) TNSSLSYQA (SEQ ID NO: 679). TNSSLSYTA (SEQ ID NO: 681), TNSSLYYPA (SEQ ID NO: 682). or TNSSLSYPA (SEQ ID NO: 683);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7. or 8 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).114. The AAV particle of any one of embodiments 110-113, wherein [KO]-[K1]-[K2] comprises:(i) TNSSLSYQAE (SEQ ID NO: 684), TNSSLSYTAE (SEQ ID NO: 685), TNSSLYYPAE (SEQ ID NO: 686), TNSSLSYPAE (SEQ ID NO: 687), or TNSSLSYPAD (SEQ ID NO: 689);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7. 8. or 9 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).115. The AAV particle of embodiment 100 or any one of embodiments 110-114, wherein [KO]-[K1]- [K2] is or comprises:(i) TNSSLSYQAEV (SEQ ID NO: 692), TNSSLSYTAEV (SEQ ID NO: 693), TNSSLYYPAEV (SEQ ID NO: 696). TNSSLSYPAEV (SEQ ID NO: 697). TNSSLSYPAEE (SEQ ID NO: 698), or TNSSLSYPADV (SEQ ID NO: 699);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).116. The AAV particle of any one of embodiments 99-115, which further comprises [K3], wherein [K3] comprises positions XA, XB, and Xc, wherein:(a) position XAis V;(b) position XBis Q; and(c) position Xcis K or N ; and optionally wherein the AAV capsid comprises an amino acid modification, e.g.. a conservative substitution, of any of the aforesaid amino acids in (a)-(c).117. The AAV particle of embodiment 116, wherein [K3]:(i) comprises VQ, QK, or QN;(ii) is or comprises VQK or VQN.118. The AAV particle of embodiment 100, 116, or 117, wherein [K2]-[K3] is or comprises:(i) QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), PAEVVQN (SEQ ID NO: 594), or PADVVQK (SEQ ID NO: 596);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).119. The AAV particle of embodiment 100 or any one of embodiments 116-118, wherein [K1]-[K2]- [K3] is or comprises:(i) LSYQAEVVQK (SEQ ID NO: 700). LSYTAEVVQK (SEQ ID NO: 701), LYYPAEVVQK (SEQ ID NO: 702), LSYPAEVVQK (SEQ ID NO: 703). LSYPAEEVQK (SEQ ID NO: 704), LSYPAEVVQN (SEQ ID NO: 706), or LSYPADVVQK (SEQ ID NO: 708);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).120. The AAV particle of embodiment 100 or any one of embodiments 116-119, wherein [K0]-[Kl]- [K2]-[K3] is or comprises:(i) TNSSLSYQAEVVQK (SEQ ID NO: 652). TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660). or TNSSLSYPADVVQK (SEQ ID NO: 665);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7. 8. 9, 10. 11. 12, or 13 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).121. The AAV particle of any one of embodiments 99-120, which further comprises [K4], wherein [K4] comprises positions XDand XE, wherein:(a) position XDis T, P, or N; and(b) position XEis A or D; and optionally wherein the AAV capsid variant comprise an amino acid modification, e.g.. a conservative substitution, of any of the aforesaid amino acids in (a) or (b).122. The AAV particle of embodiment 100 or 121, wherein [K4] is or comprises TA, TD, PA, or NA.123. The AAV particle of embodiment 100, 121. or 122, wherein [K3]-[K4] is or comprises:(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).124. The AAV particle of embodiments 100 or any one of embodiments 121-123, wherein [K0]-[Kl]- [K2]-[K3]-[K4] is or comprises:(i) TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068). TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7. 8. 9, 10. 11, 12, 13, 14. or 15 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).125. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises | B|-|C| (SEQ ID NO: 6436), wherein:(i) [B] comprises positions Xi, X2, and X3, wherein:(a) position Xi is Q or S;(b) position X2 is S, L, or A; and(c) position X3 is S, Y, or T; and(ii) |C | comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.126. An AAV particle comprising an AAV capsid variant (e.g.. an AAV5 capsid variant) and a viral genome. wherein the viral genome comprises a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and wherein the AAV capsid variant comprises one, two, three, four, or all of:(i) an [A] comprising TNN. TNS, TNT, or TNK;(ii) a [B] comprising QSS, SLY, SAT, or SLS;(iii) a [C] comprising YPAEVVQK (SEQ ID NO: 943); and(iv) a [D] comprising TA, TD, NA, or PA; wherein, optionally, [C] replaces position 577 relative to reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; wherein, further optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.127. The AAV particle of embodiment 125, comprising wherein [B] comprises QS, SL, SA, LY. AT, LS, or SS.128. The AAV particle of any one of embodiments 125-127, comprising wherein [B] is or comprises QSS, SLY, SAT, or SLS.129. The AAV particle of any one of embodiments 125, 127. and 128, wherein [B]-[C] comprises:(i) SSYPAEVVQK (SEQ ID NO: 572), LYYPAEVVQK (SEQ ID NO: 702), ATYPAEVVQK (SEQ ID NO: 718), or LSYPAEVVQK (SEQ ID NO: 703);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7, 8. or 9 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).130. The AAV particle of any one of embodiments 125-129, wherein [B]-[C] is or comprises:(i) QSSYPAEVVQK (SEQ ID NO: 150), SLYYPAEVVQK (SEQ ID NO: 639). SATYPAEVVQK (SEQ ID NO: 641), or SLSYPAEVVQK (SEQ ID NO: 642):(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4. 5, 6, 7, 8, 9. or 10 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).131. The AAV particle of embodiment 126 or 130, wherein [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150).132. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-131, which further comprises an amino acid other than N at position 573 (e.g., T. S, or K), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.133. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-131, which further comprises:(i) a T at position 571, an N at position 572. and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138;(ii) a T at position 571, an N at position 572, and / or a T at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138;(iii) a T at position 571, an N at position 572, and / or a S at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or(iv) a T at position 571, an N at position 572, and / or a K at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.134. The AAV particle of any one of embodiments 125-133, which further comprises [A], wherein [A] comprises positions XA, XB, and Xc, wherein:(a) position XAis T;(b) position XBis N; and(c) position Xcis N, T. S, or K; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).135. The AAV particle of embodiment 126 or 134. wherein [A]:(i) comprises TN, NS, NT, NK, or NN;(ii) is or comprises TNN, TNS, TNT, or TNK.136. The AAV particle of any one of embodiments 126, 134, and 135, wherein [A]-[B] is or comprises:(i) TNNQSS (SEQ ID NO: 183), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNSSLS (SEQ ID NO: 647), or TNKSAT (SEQ ID NO: 651);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).137. The AAV particle of embodiment 126 or any one of embodiments 134-136, wherein [A]-[B]-[C] is or comprises:(i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLYYPAEVVQK (SEQ ID NO: 655). TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), or TNKSATYPAEVVQK (SEQ ID NO: 663);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3. 4, 5, 6, 7. 8. 9, 10. 11. 12, or 13 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).138. The AAV particle of embodiment 126 or any one of embodiments 134-137, wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500).139. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-138, which further comprises one or both of an amino acid other than T at position 578 (e.g., P or N) and / or an amino acid other than A at position 579 (e.g., D), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.140. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-138. which further comprises:(i) a T at position 578 and / or an A at position 579, relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138;(ii) a T at position 578 and / or a D at position 579, relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138;(iii) a P at position 578 and / or an A at position 579, relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138; or(iv) an N at position 578 and / or an A at position 579. relative to a reference sequence numbered according to die amino acid sequence of SEQ ID NO: 138.141. The AAV particle of any one of embodiments 125-140, which further comprises [D], wherein [D] comprises positions X4 and X5, wherein:(a) position X4 is T, N. or P; and(b) position X5 is A or D; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b).142. The AAV particle of embodiment 141, wherein [D] is or comprises TA, TD, NA, or PA.143. The AAV particle of embodiment 126, 141, or 142, wherein [C]-[D] is or comprises:(i) YPAEVVQKTA (SEQ ID NO: 584), YPAEVVQKTD (SEQ ID NO: 719), YPAEVVQKNA (SEQ ID NO: 724), or YPAEVVQKPA (SEQ ID NO: 586);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).144. The AAV particle of embodiment 126 or any one of embodiments 141-143, wherein [A]-[B]-[C]- [D] is or comprises:(i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070). TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNKSATYPAEVVQKTA (SEQ ID NO: 2075);(ii) (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g.. any 2, 3. 4. 5, 6, 7, 8. 9. 10, 11, 12, 13, 14. or 15 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).145. The AAV particle of embodiment 126 or any one of embodiments 141-144, wherein [A]-[B]-[C]- [D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).146. The AAV particle of any one of the embodiments 1-40, 59, 60, 67-98, 139, and 140, wherein [N2]- [N3] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982.147. The AAV particle of any one of embodiments 2, 15-40, 59, 60, 68, 79-98, 139, 137, and 146 wherein [NO], [Nl], and / or [N4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138. or positions 571-599, numbered according to SEQ ID NO: 982.148. The AAV particle of any one of embodiments 2, 15-40. 59, 60, 68, 79-98, 139. 140, 146, and 147. wherein [N0]-[Nl]-[N2]-[N3]-[N4] is present in loop VIII. optionally wherein loop VIII comprisespositions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982.149. The AAV particle of any one of embodiments 1-40. 59, 60, 67-98, 139, 140, and 146-148, wherein [N2] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.150. The AAV particle of any one of embodiments 1-40. 59, 60, 67-98. 139, 140, and 146-149, wherein [N2] replaces position 577 (e.g., T577). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.151. The AAV particle of any one of embodiments 1-40. 59. 60, 67-98. 139, 140, and 146-150, wherein [N2] is present immediately subsequent to position 576. and wherein [N2] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.152. The AAV particle of any one of 1-40, 59. 60, 67-98. 139, 140, and 146-151, wherein [N2] corresponds to positions 577-581 (e.g., Y577, P578, A579, E580. V581) of SEQ ID NO: 982.153. The AAV particle of any one of embodiments 1-152, wherein the capsid variant comprises an amino acid other than T at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.154. The AAV particle of any one of embodiments 1-153, wherein the capsid variant comprises a Y at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.155. The AAV particle of any one of embodiments 1-40. 59, 60, 67-98, 139, 140, and 146-154, wherein Xi of [N2] is present at position 577 (e.g., T577), and positions X2-X5 of [N2] are present immediately subsequent to position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.156. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-155, wherein Xi of [N2] corresponds to position 577 (e.g., Y577), X2 of [N2] corresponds to position 578 (e.g., P588), X3 of [N2] corresponds to position 579 (e.g., A579), X4 of [N2] corresponds to position 580 (e.g., E580). and X5 of [N2] corresponds to position 581 (e.g., V581) of SEQ ID NO: 982.157. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-156, wherein [N2]-[N3] is present immediately subsequent to position 576, relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138 or 982.158. The AAV particle of any one of embodiments 1-40. 59, 60, 67-98, 139, 140, and 146-157, wherein [N2]-[N3] replaces position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.159. The AAV particle of any one of embodiments 1-40. 59, 60, 67-98. 139, 140, and 146-158, wherein [N2]-[N3] is present immediately subsequent to position 576, and wherein [N2]-[N3] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.160. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-159, wherein [N2]-[N3] corresponds to positions 577-584 (e.g., Y577, P578, A579. E580. V581, V582, Q583, K584) of SEQ ID NO: 982.161. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139. 140, and 146-160. wherein [N2]-[N3]-[N4] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.162. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-161, wherein [N2]-[N3]-[N4] replaces positions 577-579 (e.g., T577, T578, and A579). relative to a reference sequence numbered according to the ammo acid sequence of SEQ ID NO: 138.163. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-162, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 576, and wherein [N2]-[N3]-[N4] replaces positions 577-579 (e.g., T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.164. The AAV particle of any one of embodiments 1-40. 59, 60, 67-98. 139, 140, and 146-163, wherein [N2]-[N3]-[N4] corresponds to positions 577-586 (e.g., Y577, P578, A579, E580. V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982.165. The AAV particle of any one of embodiments 3, 18-40. 59, 60, 68, 79-98, 139. 140, and 146-164. wherein [Nl] is present immediately subsequent to position 573. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.166. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-165, wherein [Nl] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.167. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-166, wherein [Nl] is present immediately subsequent to position 573, and wherein [Nl] replaces positions 574-576 (e.g., Q574. S575. and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.168. The AAV particle of any one of embodiments 3, 18-40. 59, 60, 68, 79-98, 139. 140, and 146-167. wherein [N l] replaces positions 574-576 (e.g., Q574, S575, and S576). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.169. The AAV particle of any one of embodiments 3, 18-40, 59, 60. 68. 79-98, 139, 140. and 146-168, wherein [Nl ] is present immediately subsequent to position 573, and wherein [Nl] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.170. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68. 79-98, 139, 140. and 146-169, wherein [Nl] corresponds to positions 574-576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982.171. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-170, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the ammo acid sequence of SEQ ID NO: 138 or 982.172. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-171, wherein [N1]-[N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.173. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139. 140, and 146-171, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 573, and wherein [Nl]- [N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.174. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-173, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 574-586 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982.175. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-174 wherein [NO] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.176. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139. 140, and 146-175, wherein [NO] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.177. The AAV particle of any one of embodiments 3, 18-40. 59, 60, 68, 79-98, 139. 140, and 146-176. wherein [NO] is present immediately subsequent to position 570, and wherein [NO] replaces positions 571-573 (e.g., T571, N572. and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.178. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68. 79-98, 139, 140. and 146-177 wherein [NO] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.179. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68. 79-98, 139, 140, and 146-178, wherein [NO] replaces positions 571-573 (e.g., T571, N572, and N573). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.180. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-179, wherein [NO] is present immediately subsequent to position 570, and wherein [NO] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.181. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-181, wherein [NO] corresponds to positions 571-573 (e.g., T571, N572, and N573) of SEQ ID NO: 982.182. The AAV particle of any one of embodiments 3, 18-40. 59, 60, 68, 79-98, 139. 140, and 146-181, wherein [NO]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.183. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-182, wherein [NO]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.184. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-183, wherein [N0]-[Nl]-[N2]-[N3]-[N4] is present immediately subsequent to position 570, and wherein [NO]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577. T578. and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.185. The AAV particle of any one of embodiments 3, 18-40. 59, 60, 68, 79-98, 139. 140, and 146-184. wherein [N0]-[Nl]-[N2]-[N3]-[N4] corresponds to positions 571-586 (e.g.. T571. N572. N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586), of SEQ ID NO: 982.186. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139. 140, and 146-185. wherein [N4] is present immediately subsequent to position 584, numbered according to SEQ ID NO: 982.187. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-186. wherein [N4] replaces position 578 and 579, numbered according to SEQ ID NO: 138; or positions 585 and 586 numbered according to SEQ ID NO: 982.188. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-187, wherein [N4] is present immediately subsequent to position 584 and replaces positions 585 and 586 numbered according to SEQ ID NO: 982.189. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-188, wherein:(i) XA of [NO] is present at position 571, XB of [NO] is present at position 572, and Xc of [NO] is present at position 573, numbered according to SEQ ID NO: 982;(ii) XDof [Nl] is present at position 574, XEof [Nl] is present at position 575, and XFof [Nl] is present at position 576, numbered according to SEQ ID NO: 982;(iii) Xi of [N2] is present at position 577, X2 of [N2] is present at position 578, X3 of [N2] is present at position 579. X4 of [N2] is present at position 580, and X5 of [N2] is present at position 581, numbered according to SEQ ID NO: 982;(iv) [N3] is present at positions 582-584, numbered according to SEQ ID NO: 982; and / or(v) Xaof [N4] is present at position 585 and XHof [N4] is present at position 586, numbered according to SEQ ID NO: 982.190. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-189, wherein:(i) [NO] is present at positions 571-573, numbered according to SEQ ID NO: 982;(ii) [Nl] is present at positions 574-576, numbered according to SEQ ID NO: 982;(iii) [N2] is present at positions 577-581, numbered according to SEQ ID NO: 982;(iv) [N3] is present at positions 582-584, numbered according to SEQ ID NO: 982;(v) [N4] is present at positions 585-586. numbered according to SEQ ID NO: 982;(vi) [N2]-[N3] is present at positions 577-584. numbered according to SEQ ID NO: 982; and / or(vii) [NO]-[N1]-[N2]-[N3]-[N4] is present at positions 571-586, numbered according to SEQ IDNO: 982.191. The AAV particle of any one of embodiments 1-40. 59. 60, 67-98. 139, 140, and 146-190, wherein [N3] is present immediately subsequent to [N2],192. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139. 140, and 146-191. wherein [N4] is present immediately subsequent to [N3],193. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139. 140, and 146-192. wherein the capsid variant comprises from N-terminus to C-terminus [N2]-[N3],194. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-193, wherein the capsid variant comprises from N-terminus to C-terminus [N1]-[N2]-[N3],195. The AAV particle of any one of embodiments 3, 18, 19, 28-40, 59, 60, 68, 89-98, 139, 140, and 146-194, wherein the capsid variant comprises from N-tcnninus to C -terminus [NO]-[N1]-[N2]-[N3],196. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-195, wherein the capsid variant comprises from N-terminus to C-terminus [N1]-[N2]-[N3]-[N4],197. The AAV particle of any one of embodiments 3, 18, 19. 28-40, 59, 60, 68, 89-98, 139, 140, and 146-196, wherein the capsid variant comprises from N-terminus to C-terminus [NO]-[N1]-[N2]-[N3]- [N4],198. The AAV particle of any one of embodiments 41-66 or any one of embodiments 125-145, wherein [B]-[C] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982.199. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198, wherein [A] and / or [D] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982.200. The AAV particle of any one of embodiments 42. 52-66, 126, 134-145, 198, and 199. wherein [A]- [B]-[C]-[D] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982.201. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-200, wherein [B] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.202. The AAV particle of any one of embodiments 41-66, 125-145. and 198-201, wherein [B] replaces positions 574-576 (e.g.. Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.203. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145. or any one of embodiments 198-202, wherein [B] is present immediately subsequent to position 573, and wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138.204. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-203, wherein [B] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.205. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-204, wherein [B] replaces positions 574-576 (e.g.. Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.206. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-205, wherein [B] is present immediately subsequent to position 573, and wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.207. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-206, wherein [B] corresponds to positions 574-576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982.208. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-207, wherein [B]-[C] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.209. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-208, wherein [B]-[C] replaces positions 574-577 (e.g.. Q574, S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.210. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-209. wherein [B]-[C] is present immediately subsequent to position 573, and wherein [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.211. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145. or any one of embodiments 198-210, wherein [B]-[C] corresponds to positions 574-584 (e.g., Q574. S575, S576, Y577. P578. A579, E580, V581, V582, Q583, K584) of SEQ ID NO: 982.212. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-211, wherein [B]-[C]-[D] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.213. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-212, wherein [B]-[C]-[D] replaces positions 574-579 (e.g.. Q574, S575, S576, T577, T578. and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.214. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-213, wherein [B]-[C]-[D] is present immediately subsequent to position 573, and wherein [B]-[C1-[D] replaces positions 574-579 (e.g., Q574, S575. S576. T577. T578. and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.215. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-214, wherein [B]-[C]-[D] corresponds to positions 574-586 (e.g.. Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982.216. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-215, wherein [C] is present immediately subsequent to position 76, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.217. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-216, wherein [C] replaces position 577 (e.g., T577). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.218. The AAV particle of any one of embodiments 41-66. any one of embodiments 125-145, or any one of embodiments 198-217, wherein [C] is present immediately subsequent to position 576, and wherein [C] replaces 577 (e.g., T577). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.219. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145. or any one of embodiments 198-218, wherein [C] corresponds to positions 577-584 (e.g., Y577. P578, A579, E580, V581. V582, Q583, K584) of SEQ ID NO: 982.220. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-219, wherein [A] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.221. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-220, wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.222. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-221, wherein [A] is present immediately subsequent to position 570. and wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.223. The AAV particle of any one of embodiments 42, 52-66, 126. 134-145, and 198-222. wherein [A] is present immediately subsequent to position 570. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.224. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-223, wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.225. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-224, wherein [A] is present immediately subsequent to position 570. and wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.226. The AAV particle of any one of embodiments 42, 52-66, 126. 134-145, and 198-225. wherein [A] corresponds to positions 571-573 (e.g., T571, N572. and N573) of SEQ ID NO: 982. T1. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-226, wherein [D] is present immediately subsequent to position 584, numbered according to SEQ ID NO: 982.228. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145. and 198-227, wherein [D] replaces positions 578 and 579 numbered according to SEQ ID NO: 138; or positions 585 and 586, numbered according to SEQ ID NO: 982.229. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-228, wherein [D] is present immediately subsequent to position 584 and replaces positions 585 and 586, numbered according to SEQ ID NO: 982.230. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-229, wherein [A]- [B]-[C]-[D] is present immediately subsequent to position 570, relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138 or 982.231. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-230, wherein [A]- [B]-[C]-[D] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.232. The AAV particle of any one of embodiments 42, 52-66, 126. 134-145, and 198-231. wherein [A]- [B]-[C]-[D] is present immediately subsequent to position 570. and wherein [ A]- [B]-[C1 -[D] replaces positions 571-579 (e.g., T571, N572, N573. Q574, S575, S576, T577, T578, and A579). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.233. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-232, wherein [A]- [B]-[C]-[D] corresponds to positions 571-586 (e.g., T571, N572, N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982.234. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-233, wherein:(i) XAof [A] is present at position 571 , XBof [A] is present at position 572, and Xcof [A] is present at position 573, numbered according to SEQ ID NO: 982;(ii) Xi of [BJ is present at position 574, X2 of [BJ is present at position 575. and X3 of [BJ is present at position 576. numbered according to SEQ ID NO: 982;(iii) [C] is present at positions 577-584, numbered according to SEQ ID NO: 982; and / or(iv) X4 of [D] is present at position 585 and position X5 of [D] is present at position 86. numbered according to SEQ ID NO: 982.235. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-234, wherein:(i) [A] is present at positions 571-573, numbered according to SEQ ID NO: 982;(ii) [B] is present at positions 574-576, numbered according to SEQ ID NO: 982;(iii) [C] is present at positions 577-584, numbered according to SEQ ID NO: 982;(iv) [D] is present at positions 585-586, numbered according to SEQ ID NO: 982; and / or(v) [A]-[B]-[C]-[D] is present at positions 571-586, numbered according to SEQ ID NO: 982.236. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-235, wherein [C] is present immediately subsequent to [B],237. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-236 wherein [D] is present immediately subsequent to [Cl .238. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-237, wherein the capsid variant comprises from N-terminus to C-terminus [B]-[C] .239. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145. and 198-238, wherein the AAV capsid variant comprises from N-terminus to C-terminus [A]-[B]-[C],240. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-239, wherein the AAV capsid variant comprises from N-terminus to C-terminus [B]-[C]-[D],241. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-240, wherein the AAV capsid variant comprises from N-terminus to C-terminus [A]-[B]-[C]-[D],242. The AAV particle of any one of the embodiments 99-124, wherein [K1]-[K2] is present in loop VIII.243. The AAV particle of any one of embodiments 92-124 or embodiment 242, wherein [KO], [K3], and / or [K4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982.244. The AAV particle of any one of embodiments 92-124 embodiment 242, or embodiment 243, wherein [KO]-[K1]-[K2]-[K3]-[K4] is present in loop VIII. optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599. numbered according to SEQ ID NO: 982.245. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-244, wherein [KI] is present immediately subsequent to position 574, relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138.246. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-245, wherein [KI] replaces positions 575-577 (e.g., S575. S576. and T577), relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138.247. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-246, wherein [KI] is present immediately subsequent to position 574, and wherein [KI] replaces positions 575-577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.248. The AAV particle of any one of embodiments 100, 116-124, and 242-247, wherein [K1]-[K2]-[K3] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.249. The AAV particle of any one of embodiments 100, 116-124, and 242-248, wherein [K1]-[K2]-[K3] replaces positions 575-577 (e.g., S575, S576, and T577). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.250. The AAV particle of any one of embodiments 100, 116-124, and 242-249, wherein [K1]-[K2]-[K3] is present immediately subsequent to position 574, and wherein [K1]-[K2]-[K3] replaces positions 575- 577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.251. The AAV particle of any one of embodiments 100, 121-124, and 242-250, wherein [K1]-[K2]-[K3]- [K4] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.252. The AAV particle of any one of embodiments 100, 121-124, and 242-251, wherein [K1]-[K2]-[K3]- [K4] replaces positions 575-579 (e.g., S575, S576, T577, T578, and A579). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.253. The AAV particle of any one of embodiments 100, 121-124, and 242-252, wherein [K1]-[K2]-[K3]- [K4] is present immediately subsequent to position 574, and wherein [K1]-[K2]-[K3]-[K4] replaces positions 575-579 (e.g.. S575. S576. T577, T578, and A579). relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.254. The AAV particle of any one of embodiments 100, 110-124. and 242-253, wherein [K0] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.255. The AAV particle of any one of embodiments 100, 110-124, and 242-254, wherein [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574), relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138.256. The AAV particle of any one of embodiments 100, 110-124, and 242-255, wherein [K0] is present immediately subsequent to position 570, and wherein [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.257. The AAV particle of any one of embodiments 100, 121-124, and 242-256, wherein [KO]-[K1]-[K2]- [K3]-[K4] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.258. The AAV particle of any one of embodiments 100, 121-124, and 242-257. wherein [KO]-[K1]-[K2]- [K3]-[K4] replaces positions 571-579 (e.g.. T571. N572. N573, Q574, S575, S576, T577, T578. andA579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.259. The AAV particle of any one of embodiments 100, 121-124, and 242-258, wherein [KO]-[K1]-[K2]- [K3]-[K4] is present immediately subsequent to position 570, and wherein [KO]-[K1]-[K2]-[K3]-[K4] replaces positions 571-579 (e.g., T571, N572, N573. Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.260. The AAV particle of any one of embodiments 100, 116-124, and 242-259, wherein [K3] is present immediately subsequent [K2] .261. The AAV particle of any one of embodiments 100, 121-124, and 242-260. wherein [K4J is present immediately subsequent [K3] .262. The AAV particle of any one of embodiments 100, 121-124. and 242-261, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2],263. The AAV particle of any one of embodiments 100, 116-124. and 242-262, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2]-[K3],264. The AAV particle of any one of embodiments 100, 116-124. and 242-263, wherein the AAV capsid variant comprises from N-terminus to C-terminus [KO]-[K1]-[K2]-[K3],265. The AAV particle of any one of embodiments 100, 121-124, and 242-264, wherein the AAV capsid variant comprises from N-tcrminus to C-terminus [K1]-[K2]-[K3]-[K4],266. The AAV particle of any one of embodiments 100, 121-124, and 242-265, wherein the AAV capsid variant comprises from N-terminus to C -terminus [KO]-[K1]-[K2]-[K3]-[K4],267. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising:(a) any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25;(b) an amino acid sequence comprising at least 3, 4, 5, 6. 7, 8, 9, 10, 11. 12. 13, 14, or 15 consecutive amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25;(c) an amino acid sequence comprising one, tw o, or three but no more than four different amino acids, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25; or(d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 20-25; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.268. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising:(a) the amino acid sequence of any one of SEQ ID NOs: 943. 1021. 1024. 1027. 1112. 1142. 1214. 1232. 1254. 1300. 1310. 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587. 1590, 1591-1593, 1598-1608, and 1610-1624;(b) an amino acid sequence comprising at least 3. 4, 5, 6, 7. 8. 9. 10. 11, 12, 13, 14. or 15 consecutive amino acids from any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575. 1578. 1583-1587, 1590, 1591- 1593, 1598-1608, and 1610-1624;(c) an amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578. 1583- 1587, 1590, 1591-1593, 1598-1608, and 1610-1624; or(d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, and 1610-1624; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.269. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and an AAV capsid variant (e g., an AAV5 capsid variant) comprising:(a) the amino acid sequence of SEQ ID NO: 943 or SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064-2080 (optionally any one of SEQ ID NOs: 2064-2076);(b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from SEQ ID NO: 943 or SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064- 2080 (optionally any one of SEQ ID NOs: 2064-2076);(c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of SEQ ID NO: 943 or SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064-2080 (optionally any one of SEQ ID NOs: 2064-2076); or(d) an amino sequence comprising one, two. or three but no more than four modifications, e.g.. substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NO: 943 or SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064-2080 (optionally any one of SEQ ID NOs: 2064-2076); wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.270. An AAV particle comprising a viral genome comprising a nucleic acid sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA; and an AAV capsid variant (e g., an AAV5 capsid variant) comprising:(a) the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591;(b) an amino acid sequence comprising at least 3, 4, 5, 6, 7. 8, 9, 10. 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533. 1538. 1585. 1590, and 1591;(c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300. 1327, 1533, 1538, 1585, 1590, and 1591; or(d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.271. The AAV particle of any one of embodiments 267-270, wherein the AAV capsid variant comprises at least 3, 4, 5. 6, or 7 consecutive amino acids from SEQ ID NO: 943 or of any one of SEQ ID NOs: 946-966.272. The AAV particle of embodiment 271. wherein the at least 3 consecutive amino acids comprise YPA.273. The AAV particle of embodiment 271, wherein the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21).274. The AAV particle of embodiment 271, wherein the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1).275. The AAV particle of embodiment 271. wherein the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725).276. The AAV particle of embodiment 271. wherein the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726).277. The AAV particle of embodiment 271. wherein the amino acid sequence comprises YPAEVVQK (SEQ ID NO: 943).278. The AAV particle of any one of embodiments 267, 268, and 270. wherein the AAV capsid variant comprises:(i) YTP;(ii) YTPS (SEQ ID NO: 26);(iii) YTPSL (SEQ ID NO: 7);(iv) YTPSLV (SEQ ID NO: 727);(v) YTPSL VQ (SEQ ID NO: 728); and / or(vi) YTPSL VQK (SEQ ID NO: 952).279. The AAV capsid variant of any one of embodiments 267, 268. and 270, wherein:(i) the at least 3 consecutive amino acids comprise YPP;(ii) the at least 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22);(iii) the at least 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2);(iv) the at least 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729);(v) the at least 7 consecutive amino acids comprise YPPSLVQ (SEQ ID NO: 732); and / or(vi) the amino acid sequence comprises YPPSLVQK (SEQ ID NO: 946).280. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein:(i) the at least 3 consecutive amino acids comprise YPP;(ii) the at least 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22);(iii) the at least 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2);(iv) the at least 6 consecutive amino acids comprise YPPSLE (SEQ ID NO: 733);(v) the at least 7 consecutive amino acids comprise YPPSLEQ (SEQ ID NO: 734); and / or(vi) the amino acid sequence comprises YPPSLEQK (SEQ ID NO: 953).281. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein:(i) the at least 3 consecutive amino acids comprise YPP;(ii) the at least 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22);(iii) the at least 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2);(iv) the at least 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729);(v) the at least 7 consecutive amino acids comprise YPPSL VK (SEQ ID NO: 735); and / or(vi) the amino acid sequence comprises YPPSLVKK (SEQ ID NO: 954).282. The AAV particle of any one of embodiments 267-277. wherein the AAV capsid variant comprises an amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).283. The AAV particle of any one of embodiments 267, 268, 270. and 278-281, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327. 1533, 1538, 1585, 1590, and 1591.284. The AAV particle of any one of embodiments 267, 268, 270, and 378-281, wherein the AAV capsid variant comprises an amino acid sequence comprising one, Evo, or three but no more than four different amino acids, relative to the amino acid sequence of any of SEQ ID NOs: 946, 952, 953, and 954.285. The AAV particle of any one of embodiments 267-277 or embodiment 282, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).286. The AAV particle of any one of embodiments 267, 268. 270, 278-281, and 283, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591.287. The AAV particle of any one of embodiments 267, 268. 270, 278-281. and 284, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two. or three but no more than fourmodifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 946, 952, 953, and 954.288. The AAV particle of any prior embodiment, e.g., any one of embodiments 267-277, 282, and 285, wherein the AAV capsid variant comprises an amino acid sequence encoded b :(i) a nucleotide sequence comprising SEQ ID NO: 944 or a nucleotide sequence that comprises at least one, two. three, four, five. six. seven, eight, nine, or ten modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; or(ii) a nucleotide sequence comprising at least one, two, three, four, five. six. or seven, eight, nine, or ten, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944.289. The AAV particle of any one of embodiments I l-lTI . 282, 285, and 289. w herein the AAV capsid variant is encoded by:(i) a nucleotide sequence comprising at least one. two, three, four, five, six, or seven modifications, e.g.. substitutions, but no more than ten modifications, e.g.. substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; or(ii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944.290. The AAV particle of embodiment 267, wherein the capsid variant comprises:(a) the amino acid sequence of any one of SEQ ID NOs: 2024-2063 (optionally any one of SEQ ID NOs: 2024-2056) or SEQ ID NO: 2078;(b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 2024-2063 (optionally any one of SEQ ID NOs: 2024-2056) or SEQ ID NO: 2078;(c) an amino acid sequence comprising one, tw o, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063 (optionally any one of SEQ ID NOs: 2024-2056) or SEQ ID NO: 2078; or(d) an amino sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063 (optionally any one of SEQ ID NOs: 2024-2056) or SEQ ID NO: 2078.291. The AAV particle of embodiment 267 or 290, wherein the different amino acids of the amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to the aminoacid sequence of any one of SEQ ID NOs: 2024-2063 (optionally any one of SEQ ID NOs: 2024-2056) or SEQ ID NO: 2078, are present at one or more of the following positions:(i) position 1, wherein the different amino acid is T or L;(ii) position 2, wherein the different amino acid is N. L, K, A, T, or P;(iii) position 3, wherein the different amino acid is N, K, L, A, Y. or S;(iv) position 4. wherein the different amino acid is Q, L, T, S, F, Y, K, or A;(v) position 5, wherein the different amino acid is S, H, A, M, Q, T, V, or F;(vi) position 6. wherein the different amino acid is S, P, V, A, Q, L. T, N, or M;(vii) position 7, wherein the different amino acid is Y, H. S, V, A, L, or T;(viii) position 8, wherein the different amino acid is D. P, A, Q, F, L, S. H, or M;(ix) position 9. wherein the different amino acid is F, A, L. D, or Q:(x) position 10, wherein the different amino acid is T, E. I, or S;(xi) position 11, wherein the different amino acid is V. A, N. or S;(xii) position 12, wherein the different amino acid is V, L, or P;(xiii) position 13. wherein the different amino acid is Q, E, or P;(xiv) position 14. wherein the different amino acid is K, N, S. or L;(xv) position 15, wherein the different amino acid is T, V, M. or L; and / or(xvi) position 16. wherein the different amino acid is A, G, or R.292. The AAV particle of embodiment 267, wherein the capsid variant comprises:(a) the amino acid sequence of any one of SEQ ID NOs: 1632-2023;(b) an amino acid sequence comprising at least 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1632-2023;(c) an amino acid sequence comprising one, tw o. or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-2023; or(d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-2023.293. The AAV particle of embodiment 268 or 292, wherein the different amino acids of the amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-2023. are present at one or more of the following positions:(i) position 1, wherein the different amino acid is T, G. N, S, E. L, Y. V, or I;(ii) position 2, wherein the different amino acid is D. N, K. E, V, G, R, L. H, F, P. T, A, S. I. orY;(iii) position 3, wherein the different amino acid is Y, N, K, T, W, Q, M, V, C, A, L, F, H, G, R,S, or P;(iv) position 4, wherein the different amino acid is H, Q, P, E, R, K, A, S, V, L, T, D, I, G, M, or N;(v) position 5, wherein the different amino acid is R, S, K, N. H, G, W, A, P, V, Q, Y, L, or F;(vi) position 6. wherein the different amino acid is G, S, F, R, W, H, I, C, M, A, Y, K, N, Q, V.P, E, D, T, or L;(vii) position 7, wherein the different amino acid is D, Y. S, I, H, F. P, K, R. G, L, Q, A, M, T, N, V, W. C, or E:(viii) position 8, wherein the different amino acid is P, L. Q, T. W, V. G, K. I. Y, N, H, R, D. S, M, A. F, or E;(ix) position 9. wherein the different amino acid is A, R, T. Q, S, M, L, E. K, V. G, D. N, H, F. P, or I;(x) position 10, wherein the different amino acid is K, E, Q, H, V, G, R, S, P, I, N, M, A, L, D, or T;(xi) position 11, wherein the different amino acid is V, A. E, N. R, L, M, T, Q. S, K, C. G, D. Y, P, H, F, or I;(xii) position 12, wherein the different amino acid is V. P, L, S, T, N, A. G, K. R, I, H, E. Q, or M;(xiii) position 13, wherein the different amino acid is Q, K, N, A, H, R, T, V, E, I, P, G, S, or L;(xiv) position 14. wherein the different amino acid is K, E, I, Y, Q, R, G, D, L, N, or S;(xv) position 15, wherein the different amino acid is S, T, N, Q. I. P, E, G. K, M, or H; and / or(xvi) position 16, wherein the different amino acid is A, D, L, Y, Q. or T.294. The AAV particle of any one of embodiments 267-293, wherein the amino acid sequence is present in loop VIII of the AAV capsid variant.295. The AAV particle of any one of embodiments 267-294, wherein the amino acid sequence is present immediately subsequent to position 570, 571, 572. 573, 574, 575, or 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.296. The AAV particle of any one of embodiments 267-295, wherein the amino acid sequence replaces one, two, three, four, five or all of positions 571, 572, 573. 574, 575, and / or 576 (e.g., positions T571, N572, N573, Q574, S575, S576, T577, T578, and / or A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.297. The AAV particle of any one of embodiments 267-296, wherein the amino acid sequence is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.298. The AAV particle of any one of embodiments 267-297, wherein the AAV capsid variant comprises an amino acid residue other than T at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.299. The AAV particle of any one of embodiments 267-298, wherein the AAV capsid variant comprises the amino acid Y at position 577. relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.300. The AAV particle of any one of embodiments 267-299. wherein the AAV capsid variant comprises the substitution T577Y, numbered according to SEQ ID NO: 138.300. The AAV particle of any one of embodiments 267-299, wherein the AAV capsid variant comprises the substitution T577Y. numbered according to SEQ ID NO: 138.301. The AAV particle of embodiment 298 or 299. wherein the amino acid sequence is or comprises YPAEVVQK (SEQ ID NO: 943). and starts at position 577, relative to a reference sequence numbered according to tire amino acid sequence of SEQ ID NO: 138 or 982.302. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-301, wherein the AAV capsid variant comprises an amino acid other than T at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered relative to SEQ ID NO: 138.303. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-302, wherein the AAV capsid variant comprises the amino acid Y at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20). which is present immediately subsequent to position 577, numbered relative to SEQ ID NO: 138.304. The AAV particle of any one of embodiments 267-277. 282, 285, 288. 289, and 294-303, wherein the AAV capsid variant comprises the amino acid Y at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20). which is present immediately subsequent to position 577 (e.g., at positions 578-584), numbered relative to SEQ ID NO: 982.305. The AAV particle of any one of embodiments 267-277 , 282, 285, 288, 289, and 294-304, wherein die AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the amino acid sequence replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.306. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-305, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). wherein the amino acid sequence:(i) is present immediately subsequent to position 576; and(ii) replaces position 577 (e.g., T577). wherein in (i) and (ii) are numbered relative to SEQ ID NO: 138.307. The AAV particle of any one of embodiments 267-277. 282, 285, 288. 289, and 294-306. wherein the AAV capsid variant further comprises an amino acid other than T at position 571 (e.g., I), numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982.308. The AAV particle of any one of embodiments 267-277 , Tl. 275, 278, 289. and 294-307, wherein the AAV capsid variant further comprises I at position 571. numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982.309. The AAV particle of any one of embodiments 1 ' 1- 11 , 282, 285, 288, 289, and 294-308, wherein the AAV capsid variant further comprises one, two, or all of an amino acid other than Q at position 574 (e.g., A or T), S at position 575 (e.g., G), and / or S (e.g., A, L, K, or R) at position 576, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982.310. The AAV particle of any one of embodiments I l- ll , 282, 285, 288, 289, and 294-309, wherein die AAV capsid variant further comprises:(i) A at position 574, G at position 575, and A at position 576, numbered relative to SEQ ID NO: 138 or 982; or(ii) T at position 574 and L at position 576, numbered relative to SEQ ID NO: 138 or 982.311. The AAV particle of any one of embodiments Ifyl- Tl, 282, 285, 288. 289, and 294-309, wherein the AAV capsid variant further comprises:(i) K at position 576. numbered relative to SEQ ID NO: 138 or 982; or(ii) R at position 576, numbered relative to SEQ ID NO: 138 or 982.312. The AAV particle of any one of embodiments 267-277 , 282, 285, 288, 289, and 294-310, wherein die capsid variant comprises:(i) A at position 574, G at position 575, A at position 576, and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and(ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982.313. The AAV particle of any one of embodiments 267-277, 282, 285, 288. 289, and 294-310, wherein the AAV capsid variant comprises:(i) T at position 574. L at position 576, and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and(ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982.314. The AAV particle of any one of embodiments 267-277, 282. 285, 288, 289. 294-309, and 311. wherein the AAV capsid variant comprises:(i) K at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and(ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982.315. The AAV particle of any one of embodiments T l- ll , 282, 285, 288, 289, 295-309, and 311, wherein the AAV capsid variant comprises:(i) R at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and(ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982.316. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-308, wherein the AAV capsid variant comprises:(i) I at position 571 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and(ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982.317. The AAV particle of any one of embodiments 267, 268. 270, 278, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence TPSLVQK (SEQ ID NO: 53), which is present immediately subsequent to position 577. all numbered according to SEQ ID NO: 138 or 982.318. The AAV particle of any one of embodiments 267, 268, 270, 279, 283, 284, 286, and 287, wherein die AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLVQK (SEQ ID NO: 47), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982.319. The AAV particle of any one of embodiments 267, 268. 270, 280, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLEQK (SEQ ID NO: 54), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982.320. The AAV particle of any one of embodiments 267, 268. 270, 281. 283, 284, 286. and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLVKK (SEQ ID NO: 55), which is present immediately subsequent to position 577. all numbered according to SEQ ID NO: 138 or 982.321. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant further comprises a modification, e.g.. an insertion, substitution (e.g., conservative substitution), and / or deletion, in loop I, II. IV. and / or VI.322. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NO: 138.323. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three, but no more than 30, 20 or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 138.324. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence with at least 80% (e.g., at least about 85. 90, 95, 96, 97, 98, or 99%) sequence identity to SEQ ID NO: 138.[Embodiments 325-327 are intentionally absent.]328. The AAV particle of any one of the embodiments provided herein, wherein the capsid variant comprises a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof.329. The AAV particle of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, and 321-328, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 137-731, e.g., a VP2, of SEQ ID NO: 982, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.330. The AAV particle of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, and 321-329, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 193-731. e.g., a VP3, of SEQ ID NO: 982, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96. 97, 98, or 99%) sequence identity thereto.331. The AAV particle of any one of embodiments 1-321, wherein the AAV capsid variant comprises a sequence with at least 80% (e.g.. at least about 85. 90. 95, 96, 97, 98. or 99%) sequence identity to the amino acid sequence corresponding to positions 137-724, e.g., a VP2, of SEQ ID NO: 138.332. The AAV particle of any one of embodiments 1-321, wherein the AAV capsid variant comprises a sequence with at least 80% (e.g., at least about 85, 90, 95, 96. 97, 98, or 99%) sequence identity to the amino acid sequence corresponding to positions 193-724, e.g., a VP3. of SEQ ID NO: 138.333. The AAV particle of any one of embodiments I l- ll , 282. 285, 288, 289, 294-306, and 321-328, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, 6, or 7 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein:(i) the at least 3 consecutive amino acids comprise YPA;(ii) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21);(iii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1);(iv) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725); or(v) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726); wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 739.334. The AAV particle of any one of embodiments 267-277 , 282, 285, 288. 289, 294-306, 321-328, and 333, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3. 4, 5, or 6, or 7 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). wherein:(i) the at least 3 consecutive amino acids comprise YPA;(ii) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21);(iii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1);(iv) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725); or(v) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137- 731 of SEQ ID NO: 982: (c) a VP3 protein comprising the amino acid sequence of positions 193-731 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98. or 99%) sequence identity to any of the amino acid sequences in (a)-(c).335. The AAV particle of any one of embodiments 267-277. 282, 285, 288. 289, 294-306. 321-328, and 334, wherein the AAV capsid variant comprises one, two, or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises:(a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982;(b) a VP2 protein comprising the amino acid sequence of positions 137-731 of SEQ ID NO: 982;(c) a VP3 protein comprising the amino acid sequence of positions 193-731 of SEQ ID NO: 982; or(d) an amino acid sequence with at least 90% (e.g.. at least about 95, 96. 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c).336. The AAV particle of any one of embodiments I l- ll , 282. 285, 288, 289, 294-306, 321-328, and 333-335, comprising one, two, or three but no more than four different ammo acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739; or an amino acid sequence at least 90%, 95%, 96%, 97%, 98%. or 99% sequence identity to the amino acid sequence of SEQ ID NO: 739.337. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-336, comprising one or two, but no more than three substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 982.338. The AAV particle of any one of embodiments 1-98, 125-241, 'Lfil-L' Tl, 282, 285, 288, 289, 294-306, 321-328, and 333-337. wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence with at least 80% (e.g., at least about 85. 90, 95, 96, 97. 98, or 99%) sequence identity thereto.339. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-338, wherein the capsid variant comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 95% identity thereto.340. The AAV particle of any one of embodiments 1-98, 125-241, 267-277 , 282, 285, 288, 289, 294-306, 321-328, and 333-339, wherein the capsid variant comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 98% identity thereto.341. The AAV particle of any one of embodiments 1-98, 125-241, ISl-L' TI, 282, 285. 288, 289, 294-306, 321-328, or 333-340, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NO: 982.342. The AAV particle of any one of embodiments 1-98, 125-241, 1 -1T1. 282, 285, 288. 289, 294-306. 321-328. and 333-341, wherein the capsid variant comprises an amino acid sequence comprising at least one. two or three, but not more than 30, 20 or 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 982.343. The AAV particle of any one of embodiments 1-98, 125-241, 267-277. 282, 285, 288. 289, 294-306. 321-328, and 333-342, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.344. The AAV particle of any one of the embodiments provided herein, wherein the nucleotide sequence encoding the AAV capsid variant is codon-optimized.[Embodiments 345-349 are intentionally absent.]350. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which 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: 138.351. The AAV particle of any one of embodiments 1-66, 139, 140. 146-241, 267, 268, 270-289, and 294-344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cordcell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.352. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which 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: 139.353. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which transduces a brain region, e.g., a temporal cortex, perirhinal cortex, globus pallidus, putamen. caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum, optionally wherein the level of transduction is at least 1.5, 2.2, 2.4. 2.5. 2.6. 2.7, 3.0, 3.2, 3.5, 3.7, 4.0, 4.2, 4.5. 4.7. 4.9. 5. 10. 15, 20, 25. 30. 35-fold greater as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 2.354. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241. 267, 268, 270-289, and 294-353, which is enriched at least about 2, 3, 4, 5. 6. 7, 8, 9, 10, 12, 15. 17, 20, 25, 30. 35, 40, 45, 50, 55. 60, or 65-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 1.355. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294-354, which is enriched at least about 10, 12, 15, 17, 20, 25, 30, 35, 40, 45, 50, 55, 60, 61, 62, 63, 64, or 65-fold in die brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1.356. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294-355, which is enriched in die brain of at least two to three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), e.g., as compared to a reference sequence of SEQ ID NO: 138.357. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294-356, which is enriched at least about 2, 3, 4. 5, 6, 7, 8, 9. 10, 12, 15, 17. 20, 25, 30, 35, 40, 45-fold in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Examples 1. 2, 4, and 5.358. The AAV particle of embodiment 356 or 357, wherein the at least tw o to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, rat, and / or mouse (e.g., BALB / c mice).359. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294-358, which is enriched at least about 5, 10, 15, 20, 25, 30, 35, 40. 45, 50, 55, 60, 65, 70, 75, 80, 85. 90, 100, 125, 150, 175, 200, or 225-fold, in the brain compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4.360. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294-359, which delivers an increased level of a pay load to a brain region, optionally wherein the level of the payload is increased by at least 20, 25, 30, or 35-fold, as compared to a reference sequence of SEQ ID NO: 139, e.g.. when measured by an assay, e.g.. a qRT-PCR or a qPCR assay (e.g., as described in Example 2).361. The AAV particle of any one of embodiments 1-66, 139. 140, 146-241. 267, 268, 270-289, and 294-360, which delivers an increased number and / or level of viral genomes to a brain region, optionally wherein the number and / or level of viral genomes is increased by at least 1.5, 2.2, 2.4, 2.5, 2.6, 2.7. 3.0. 3.2, 3.5, 3.7, 4.0. 4.2. 4.5. 4.7, 4.9, or 5-fold as compared to a reference sequence of SEQ ID NO: 139, e.g.. when measured by an assay, e.g.. a qRT-PCR or a qPCR assay (e.g., as described in Example 2).362. The AAV particle of any one of embodiments 350-361, wherein tire brain region is a temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, cerebellum, or a combination thereof.363. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 362, which is enriched at least about 3, 3.5, 4.0, 4.5, 5, 5.0, 6.0, or 6.5-fold in a spinal cord region compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay as described in Example 2.364. The AAV particle of any one of embodiments 363, wherein the spinal cord region is a cervical region, a lumbar region, a thoracic region, or a combination thereof.365. The AAV particle of any one of the embodiments provided herein, which shows preferential transduction in a brain region relative to transduction in the dorsal root ganglia (DRG).366. The AAV particle of any one of embodiments 1-66, 139, 140. 146-241, 267. 268, 270-289, and 294- 365, which is capable of transducing neuronal cells.367. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268. 270-289, and 294-366, which is capable of transducing non-neuronal cells, e.g., glial cells (e.g., oligodendrocytes).368. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294-367, which shows preferential transduction in a brain region relative to transduction in the liver.369. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285. 288, 289, 294-306, and 321-349, which has an increased tropism for a heart cell or heart tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.370. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285. 288, 289, 294-306, 321-349, and 369, which has an increased tropism for a heart cell or tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 139.371. The AAV particle of any one of embodiments 67-267. 269, 271-277. 282, 285, 288. 289, 294-306. 321-349, 369, and 370. which delivers an increased level of a payload to a heart region, optionally wherein the level of the payload is increased by at least 1.5, 2, or 2.5-fold, as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., an IHC assay or a RT-ddPCR assay (e.g., as described in Example 2).372. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369-371, which has an increased tropism for a heart cell or tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising tire amino acid sequence of SEQ ID NO: 982.373. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369-372, which is enriched at least about 4, 5, 10, 15. 20, 25, 30, 35, 40, 45, or 50-fold in the heart compared to a reference sequence of SEQ ID NO: 982, e.g.. when measured by an assay as described in Example 4.374. The AAV particle of any one of embodiments 267, 290. 291, 321-328. 331, 332, and 344. which has an increased tropism for a muscle cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.- TI -375. The AAV particle of any one of embodiments 267, 290, 291, 321-328, 331, 332, 344, and 374, which is enriched at least about 2, 3, 4, 5, 10, 15, 20, 25, 30, or 35-fold in the muscle compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4.376. The AAV particle of embodiment 374 or 375, wherein the muscle cell or tissue is a cardiac muscle (e.g., a heart ventricle or a heart atrium, or both), a quadriceps muscle, or both.377. The AAV particle of any one of embodiments 267, 292. 293, 321-328. 331, 332, and 344. which has an increased tropism for a liver cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.378. The AAV particle of any one of embodiments 267, 292. 293, 321-328. 331, 332, 344. and 377, which is enriched at least about 10. 15, 20, 25, 30. 35. 40, 45, 50. 55. 60, 65, 70, 75. 80. 85, 90, 95. 100, 110, 115, 120, 130, 140, 150, 160, 170, 180, 185, or 190-fold in the liver compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4.379. The AAV particle of any one of embodiments 1-378, wherein the AAV particle comprises a viral genome comprising 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).380. The AAV particle of any one of the embodiments provided herein, wherein the AAV particle 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 Rep 52 protein).381. The AAV particle of embodiment 379 or 380, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene.[Embodiments 382-445 are intentionally absent.]446. A cell, e.g.. ahost cell, comprising the AAV particle of any one of embodiments 1-381.447. The cell of embodiment 446, wherein the cell is a mammalian cell or an insect cell.448. The cell of embodiment 446 or 447, wherein the cell is a muscle, heart, and / or brain cell.449. The cell of any one of embodiments 446-448, wherein the cell is a skeletal muscle, smooth muscle, or cardiac muscle cell.450. A method of making an AAV particle of any one of the embodiments disclosed herein, comprising:(i) providing a host cell comprising a viral genome comprising a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of DMPK mRNA and a nucleic acid encoding an AAV capsid variant: and(ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle.451. The method of embodiment 450, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the host cell.452. The method of embodiment 450 or 451. further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell.[Embodiment 453 is intentionally absent ]454. A pharmaceutical composition comprising the AAV particle of any one of embodiments 1-381, and a pharmaceutically acceptable excipient.455. A method of delivering to a subject a modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA, comprising administering an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, thereby delivering the modulatory' polynucleotide.456. The method of embodiment 455, wherein the modulatory polynucleotide is delivered to a cell or tissue of the muscle, heart, and / or brain.457. The method of embodiment 456, wherein the cell or tissue is a muscle cell or tissue.458. The method of embodiment 456 or embodiment 457, wherein the cell or tissue is a skeletal muscle cell or tissue or a cardiac muscle cell or tissue.459. The method of embodiment 456 or embodiment 457, wherein the cell or tissue is a smooth muscle cell or tissue.460. The method of any one of embodiments 455-459, wherein the subject is a human.461. The method of embodiment 460, wherein the subject has, has been diagnosed with having, or is at risk of having a genetic disorder.462. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having a muscular disorder or a neuromuscular disorder, such as a muscular dystrophy.463. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having a DMPK-related disorder.464. The method of any one of embodiments 460-463. wherein the subject has, has been diagnosed with having, or is at risk of having myotonic dystrophy type 1 (DM1).465. A method of treating a DMPK-related disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or tire AAV particle of any one of embodiments 1-381. optionally wherein the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder.466. A method of treating a muscular dystrophy in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381. optionally wherein the subject has, has been diagnosed with having, or is at risk of having the muscular dystrophy.467. A method of treating a muscular disorder or a neuromuscular disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, optionally wherein the subject has, has been diagnosed with having, or is at risk of having the muscular disorder or the neuromuscular disorder.468. The method of any one of embodiments 465-467. wherein the genetic disorder, muscular dystrophy, muscular disorder, or neuromuscular disorder is DM1.469. The method of any one of embodiments 465-468. wherein the treatment comprises prevention of progression of the disease or disorder in the subject.470. The method of any one of embodiments 460-469. wherein the subject is a human.471. The method of any one of embodiments 465-470, wherein the AAV particle is administered to the subject intravenously, via intra-cisterna magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly.472. The method of any one of embodiments 465-471, wherein the AAV particle is administered to the subject via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.473. The method of any one of embodiments 465-471. wherein the AAV particle is administered to the subject intravenously.474. The method of any one of embodiments 455-473. wherein the subject has aberrant expression or activity of DMPK. e.g., of a DMPK gene. DMPK mRNA. and / or DMPK protein.475. The method of any one of embodiments 455-474, wherein the subject has mutated DMPK mRNA.476. The method of any one of embodiments 465-474, wherein administration of the AAV particle results in amelioration of at least one symptom of the DMPK-related disorder in the subject.477. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in a method of delivering a payload to a cell or tissue.478. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in a method of treating a genetic disorder, a muscular dystrophy, a muscular disorder, or a neuromuscular disorder.479. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in the manufacture of a medicament.480. Use of the pharmacal composition of embodiment 454 or the AAV particle of any one of embodiments 1-381 in the manufacture of a medicament.481. Use of the pharmacal composition of embodiment 454 or the AAV particle of any one of embodiments 1-381 in the manufacture of a medicament for treating a genetic disorder, a muscular dystrophy, a muscular disorder, or a neuromuscular disorder.482. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the viral genome comprises a modulatory polynucleotide comprising a molecular scaffold, wherein the molecular scaffold comprises:(a) a 5’ flanking region, optionally comprising any one of SEQ ID NOs: 6413-6416;(b) a loop region, optionally comprising any one of SEQ ID NOs: 6417-6421; and(c) a 3’ flanking region, optionally comprising any one of SEQ ID NOs: 6422-6427.483. The AAV particle of embodiment 482. wherein:(a) the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414 or SEQ ID NO: 6415;(b) the loop region of tire molecular scaffold comprises SEQ ID NO: 6417, SEQ ID NO: 6418. or SEQ ID NO: 6421; and(c) the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423, SEQ ID NO: 6424, or SEQ ID NO: 6425.484. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414, the loop region of the molecular scaffold comprises SEQ ID NO: 6417. and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423.485. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6415, the loop region of the molecular scaffold comprises SEQ ID NO: 6421, and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6425.486. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414, the loop region of the molecular scaffold comprises SEQ ID NO: 6417, and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6424.487. The AAV particle of embodiment 482 or embodiment 483, wherein the 5’ flanking region of the molecular scaffold comprises SEQ ID NO: 6414, the loop region of the molecular scaffold comprises SEQ ID NO: 6418, and the 3’ flanking region of the molecular scaffold comprises SEQ ID NO: 6423.488. The AAV particle of any one of embodiments 482-488, wherein the modulatory polynucleotide comprises siRNA.489. The AAV particle of embodiment 488. wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more DMPK mRNA transcripts, and wherein the passenger strand and the guidestrand are located, respectively , on a 5’ arm and a 3’ arm of a stem loop structure, wherein the passenger strand is located between the 5 ' flanking region and the loop region and the guide strand is located between the loop region and the 3’ flanking region.490. The AAV particle of embodiment 488, wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more DMPK mRNA transcripts, and wherein the guide strand and the passenger strand are located, respectively, on a 5’ ann and a 3’ arm of a stem loop structure, wherein the guide strand is located between the 5 ’ flanking region and the loop region and the passenger strand is located between the loop region and the 3 ’ flanking region.491. The AAV particle of embodiment 489 or embodiment 490, wherein the passenger strand is 15-30 nucleotides in length.492. The AAV particle of any one of embodiments 489-491, wherein the guide strand is 15-30 nucleotides in length.493. The AAV particle of embodiment 492, wherein the guide strand is 21-25 nucleotides in length.494. The AAV particle of any one of claims 489-493, wherein the passenger strand is at least 70% complementary to the guide strand.495. The AAV particle of any one of embodiments 489-494, wherein the one or more DMPK mRNA transcripts comprises SEQ ID NO: 6428 and / or SEQ ID NO: 6429, or a trinucleotide repeat expansion thereof.496. The AAV particle of any one of embodiments 482-495, wherein die viral genome comprises a promoter operably linked to the sequence encoding the modulatory polynucleotide.497. The AAV particle of any one of embodiments 482-496, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.498. The AAV particle of embodiment 497. wherein the viral genome comprises an ITR sequence positioned 5’ relative to the sequence encoding the modulatory polynucleotide.499. The AAV particle of embodiment 497 or embodiment 498, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the sequence encoding the modulatory polynucleotide.500. The AAV particle of any of embodiments 497-499, wherein the viral genome comprises an ITR sequence positioned 5‘ relative to the sequence encoding the modulatory polynucleotide, and an ITR sequence positioned 3‘ relative to the sequence encoding the modulatory polynucleotide.501. The AAV particle of any one of embodiments 482-500, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) present at positions 577-584 numbered according to SEQ ID NO: 982.502. The AAV particle of any one of embodiments 482-501. wherein the AAV capsid variant comprises a VP1 protein comprising an amino acid sequence at least 95% identical to SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at positions 577-584 numbered according to SEQ ID NO: 982.503. The AAV particle of embodiment 502, wherein the AAV capsid variant further comprises(i) a VP2 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 738, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or(ii) a VP3 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 739, wherein the VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).504. The AAV particle of any one of embodiments 482-503, wherein the AAV capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 99% identity’ to SEQ ID NO: 982, wherein the VP1 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943);(ii) a VP2 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 738, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or(iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 739, wherein the VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943), wherein, optionally, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA.505. The AAV particle of any one of embodiments 482-504, wherein the AAV variant capsid comprises:(i) a VP1 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 982;(ii) a VP2 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 738; and / or(iii) a VP3 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 739.506. A cell comprising the AAV particle of any one of embodiments 482-505, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an SI9 cell), or a bacterial cell.507. A method of making the AAV particle of any one of embodiments 482-505, wherein the method comprises:(i) providing a cell comprising a viral genome comprising a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of DMPK mRNA and a nucleic acid encoding an AAV capsid variant: and(ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle.508. The method of embodiment 507, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.509. The method of embodiment 507 or embodiment 508, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the cell.510. The method of any one of embodiments 507-509, further comprising, prior to step (i). introducing the nucleic acid encoding the AAV capsid variant into the cell.511. The method of any one of embodiments 507-510, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an SI9 cell), or a bacterial cell.512. A pharmaceutical composition comprising the AAV particle of any one of embodiments 482-505 and a pharmaceutically acceptable excipient.513. A method of delivering a modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482- 505, thereby delivering the modulatory polynucleotide.514. The method of embodiment 513, wherein the subject has, has been diagnosed with having, or is at risk of having a disease associated with a DMPK-related disorder.515. The method of claim 514. wherein the disease is myotonic dystrophy type 1 (DM1).516. A method of treating a DMPK-related disorder in a subject, comprising administering to the subject an effective amount of die pharmaceutical composition of embodiment 512 or die AAV particle of any one of embodiments 482-505, diereby treating the DMPK-related disorder.517. The method of embodiment 516, wherein the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder.518. The method of embodiment 516 or embodiment 517, wherein the subject has one or more mutations in the DMPK gene.519. The method of embodiment 518, wherein the one or more mutations in the DMPK gene comprises a trinucleotide repeat expansion.520. The method of claim 519, wherein the trinucleotide repeat expansion in the DMPK gene is 50 or more CTG repeats (SEQ ID NO: 6434).521. The method of any one of embodiments 516-520, wherein the administration results in prevention of progression of the DMPK-related disorder in the subject.522. The method of any one of embodiments 516-521, wherein administration results in amelioration of at least one symptom of the DMPK-related disorder in the subject.523. The method of embodiment 522, wherein the at least one symptom comprises cataracts, myotonia, muscle weakness and wasting, cardiac conduction abnormalities, a myopathic face, learning difficulties, psychosocial problems including depression and / or anxiety, slurred speech, decreased fetal movement in die uterus, polyhydramnios, clubfoot, ventriculomegaly, hypotonia, a tented appearance of the upper lip, dysarthria, intellectual disability, hypotonia, respiratory insufficiency, or a combination thereof.524. The method of any one of embodiments 513-524. further comprising administering at least one additional therapeutic agent and / or therapy, optionally comprising an agent and / or therapy for treating the DMPK-related disorder and / or an immunosuppressant.525. The method of embodiment 524. wherein the at least one additional therapeutic agent and / or therapy for treating the DMPK-related disorder comprises an anti-diabetic drug, an anti-myotonic drug (e.g., mexiletine). a non-steroidal anti-inflammatory drug, or a combination thereof and / or the immunosuppressant comprises a corticosteroid (for example, and without limitation, prednisone.prednisolone, methylprednisolone, and / or dexamethasone), adrenocorticotropic hormone, rapamycin, mycophenolate mofetil, tacrolimus, rituximab, eculizumab hydroxychloroquine, alemtuzumab, hydroxyurea, fludarabine, and / or busulfan.526. The method of any one of embodiments 516-525, wherein the DMPK-related disorder is DM1.527. A method of treating myotonic dystrophy type 1 (DM1) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505, thereby treating DM1.528. The method of embodiment 527, wherein the subject has, has been diagnosed with having, or is at risk of having DM 1.529. The method of any one of embodiments 513-528, wherein the subject is a human subject.530. The method of any one of embodiments 513-529, wherein the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the muscle, heart, and / or brain.531. The method of embodiment 530, wherein the cell or tissue is muscle cell or tissue, i.e., of skeletal muscle, smooth muscle, and / or cardiac muscle.532. The method of any one of embodiments 513-531, further comprising evaluating, e.g., measuring, (i) the level of modulatory polynucleotide expression, (ii) the level of DMPK expression, e.g., DMPK gene, DMPK mRNA, and / or DMPK protein expression, and / or (iii) the level of normal mRNA splicing in the subject, e.g., in a cell, tissue, or fluid, of the subject, optionally wherein the mRNA splicing is DMPK mRNA splicing.533. The method of embodiment 532. wherein the level of DMPK protein is measured by an ELISA, a Western blot, or an immunohistochemistry assay.534. The method of embodiment 532 or embodiment 533, wherein evaluating the subject’s level of modulatory polynucleotide expression, level of DMPK expression, and / or level of nonnal mRNA splicing (e.g., DMPK mRNA splicing) is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of modulatory polynucleotide expression, level of DMPK expression, and / or level of normal mRNA splicing (e.g., DMPK mRNA splicing) prior to administration is compared to the subject’s level of modulatorypolynucleotide expression, level of DMPK expression, and / or level of normal mRNA splicing (e.g., DMPK mRNA splicing) subsequent to administration.535. The method of any one of embodiments 532-534, wherein subject’s level of DMPK mRNA and / or protein expression (e.g., mutated DMPK mRNA expression) subsequent to administration is decreased relative to the subject’s level of DMPK mRNA and / or protein expression (e.g., mutated DMPK mRNA expression) prior to administration.536. The method of any one of embodiments 532-535. further comprising evaluating, e.g.. measuring, the level of modulatory polynucleotide activity and / or DMPK activity and / or mRNA splicing in the subject, e.g., in a cell or tissue of the subject.537. The method of any one of embodiments 513-536. wherein the administration results in:(i) an increase in the number and / or level of viral genomes (VG) per cell in a muscle cell or tissue of the subject relative to the number and / or level of VG per cell in a non-muscle cell or tissue of the subject;(ii) a decrease in mutated DMPK mRNA expression in a muscle cell or tissue of the subject relative to baseline and / or relative to mutated DMPK mRNA expression in a muscle cell or tissue of an individual with a DMPK-related disorder who has not been administered the pharmaceutical composition or AAV particle; and / or(iii) an increase in normal mRNA splicing, optionally DMPK mRNA splicing, in a muscle cell or tissue of the subject relative to baseline and / or relative to normal mRNA splicing, optionally DMPK mRNA splicing, in a muscle cell or tissue of an individual with a DMPK-related disorder who has not been administered the pharmaceutical composition or AAV particle.538. The method of any one of embodiments 513-537, further comprising administering to the subject at least one additional therapeutic agent and / or therapy.539. The method of embodiment 538. wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy for treating the DMPK-related disorder, optionally wherein the at least one additional therapeutic agent and / or therapy comprises anti-diabetic drug, an anti-myotonic drug (e.g.. mexiletine), a non-steroidal anti-inflammatory drug, or a combination thereof.540. The method of embodiment 538. wherein the at least one additional therapeutic agent and / or therapy comprises an immunosuppressant, optionally wherein the immunosuppressant is a corticosteroid (for example, and without limitation, prednisone, prednisolone, methylprednisolone, and / or dexamethasone),adrenocorticotropic hormone, rapamycin, mycophenolate mofetil, tacrolimus, rituximab, eculizumab hydroxychloroquine, alemtuzumab, hydroxyurea, fludarabine, and / or busulfan.541. The method of any one of embodiments 513-539, further comprising administering an immunosuppressant to the subject, optionally wherein the immunosuppressant is a corticosteroid (for example, and without limitation, prednisone, prednisolone, methylprednisolone, and / or dexamethasone), adrenocorticotropic hormone, rapamycin, mycophenolate mofetil, tacrolimus, rituximab, eculizumab hydroxychloroquine, alemtuzumab. hydroxyurea, fludarabine, and / or busulfan.542. The pharmacal composition of embodiment 512 or the AAV particle of any one of embodiments 482-505 for use in a method of treating a disorder according to any one of claims 517-538.543. The pharmacal composition of embodiment 512 or the AAV particle of any one of embodiments 482-505 for use in treating a DMPK-related disorder, optionally wherein the DMPK- related disorder is DM1.544. The pharmaceutical composition or the AAV particle for use of embodiment 542 or embodiment 543. wherein the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder, optionally wherein the DMPK-related disorder is DM1.545. Use of the pharmaceutical composition of embodiment 512 or the AAV particle of any one of embodiments 482-505 in the manufacture of a medicament for treatment of a DMPK-related disorder in a subject, optionally wherein the DMPK-related disorder is DM1.546. The use of claim 545, wherein the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder, optionally wherein the DMPK-related disorder is DM1.

[0050] The details of various aspects or embodiments of the present disclosure are set forth below. Other features, objects, and advantages of the disclosure will be apparent from tire description and the claims. In the description, the singular fonns also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art in the field of this disclosure. In the case of conflict, the present description will control.BRIEF DESCRIPTION OF THE DRAWINGS

[0051] FIGs. 1A-1D show immunohistochemistry images from various CNS and peripheral tissues isolated from NHPs (cynomolgus macaques) at 28 days post intravenous administration of AAV particles comprising the TTN-002 capsid variant (top panels) or AAV9 control capsid (bottom panels) and a self-complementary genome encoding a cynomolgus monkey frataxin protein fused to an HA tag driven by a chicken beta actin (CBA) heterologous promoter. FIG. 1A shows, from left to right, the cerebellum (Purkinje cell layer), spinal cord (cervical), cortex (temporal), and the brainstem. FIG. IB shows, from left to right, the globus pallidus, the hippocampus, the thalamus, the putamen, and the dentate. FIG. 1C shows, from left to right, the whole brain (level H), the whole brain (level K), and the cerebellum. FIG. ID shows, from left to right, the spinal cord (thoracic), the DRG (thoracic), the liver, and the heart.DETAILED DESCRIPTIONOverview

[0052] Disclosed herein, inter alia, arc compositions comprising an AAV capsid variant comprising a sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA. In some embodiments, the present disclosure provides a method for delivering the AAV capsid variant comprising tire sequence encoding the modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA to a cell or tissue in a subject. In some embodiments, the present disclosure provides a method for treating myotonic dystrophy type 1 (DM1) or another disorder associated with mutated DMPK mRNA expression (i.e., another DMPK-related disorder). In various embodiments, AAV capsid variants disclosed herein have enhanced tropism for a cell or tissue, for example a cell or tissue of the muscle, heart, and / or brain. In some embodiments, the AAV capsid variants described herein have enhanced tropism for a cell or tissue of the heart. In some embodiments, the AAV capsid variants described herein have enhanced tropism for a cell or tissue of muscle. In some embodiments, the AAV capsid variants described herein have enhanced tropism for a cell or tissue of cardiac muscle. In some embodiments, the AAV capsid variants described herein have enhanced tropism for a cell or tissue of skeletal muscle. In some embodiments, the AAV capsid variants described herein have enhanced tropism for a cell or tissue of smooth muscle. In some embodiments, the AAV capsid variants described herein have enhanced tropism for more than one tissue (e g., heart and brain).

[0053] AAVs have proven to be useful as a biological tool due to their relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. AAV- derived vectors are promising tools for clinical gene transfer because of their non-pathogenic nature, their low immunogenic profile, low rate of integration into the host genome, and long-term transgene expression in non-dividing cells. However, the transduction efficiency of naturally occurring AAVs in certain organs is too low for clinical applications, and capsid neutralization by pre-existing neutralizing antibodies may prevent treatment of a large proportion of patients. For these reasons, considerable efforts have been devoted to obtaining capsid variants with enhanced properties. Of many approaches tested so far, significant advances have resulted from directed evolution of AAV capsids using in vitro or in vivo selection of capsid variants created by capsid sequence randomization using either error-prone PCR, shuffling of various parent serotypes, or insertion of fully randomized short peptides at defined positions.

[0054] The genome of the virus may be modified to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded witir or engineered to target a particular tissue and express or deliver a desired pay load. The genome of the virus may encode a modulatory polynucleotide, e.g., a modulatory polynucleotide for reducing or eliminating expression of DMPK mRNA, and the viral particle comprising said genome may be delivered to a target cell, tissue, or organism. In some embodiments, the target cell or tissue is in the muscle, heart, and / or brain. In some embodiments, the target cell is a muscle cell, i.e., a skeletal muscle, smooth muscle, and / or cardiac muscle cell. In some embodiments, the target tissue is a muscle tissue, i.e., a skeletal muscle, smooth muscle, and / or cardiac muscle tissue.

[0055] Gene therapy presents an alternative approach for DM1 and related diseases sharing singlegene etiology. AAVs are commonly used in gene therapy approaches as a result of a number of advantageous features. Without wishing to be bound by theory, it is believed in some embodiments, that an AAV particle described herein can be used to administer and / or deliver a modulatory polynucleotide, in order to achieve sustained, high concentrations, allowing for longer lasting efficacy, fewer dose treatments, broad biodistribution, and / or more consistent levels of the modulatory polynucleotide, relative to a non- AAV therapy.

[0056] Provided herein are AAV capsid variants (e g., AAV5 capsid variants), as well as compositions and methods comprising said AAV capsid variants, which may provide with improved properties or features compared to prior AAV-mediated enzyme replacement approaches and / or compared to wildtype AAV5 and / or wildtype AAV9, including (i) increased biodistribution throughout muscle and / or heart tissue, (ii) elevated modulatory polynucleotide expression in muscle and / or heart tissue; and (iii) preferential biodistribution in muscle and / or heart tissue over other tissues or cells such as the liver and / or DRG.

[0057] In some embodiments, the AAV capsid variants with enhanced muscle and / or heart tropism described herein arc capable of significantly increasing modulatory polynucleotide expression in muscle and / or heart cells or tissues affected by mutated DMPK mRNA expression. In some embodiments, the AAV capsid variants with enhanced muscle and / or heart tropism described herein are capable of significantly reducing or eliminating expression of DMPK mRNA in muscle and / or heart.

[0058] Thus, the compositions and methods described herein can be used in the treatment of DMPK- related disorders, i.e., disorders associated with or caused by mutated DMPK mRNA expression, such as DM1. In some embodiments, the disclosure provides an AAV particle comprising an AAV capsid variant disclosed herein and an AAV viral genome comprising a nucleotide sequence comprising a promoter and a sequence encoding a modulatory polynucleotide for use in treating a DMPK-related disorder. In some embodiments, the modulatory polynucleotide reduces or eliminates expression of mutated DMPK mRNA. In some embodiments, the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA. In some embodiments, the DMPK-related disorder is DM1.I. CompositionsAdeno-associated viral (AA V) vectors

[0059] AAVs have a genome of about 5,000 nucleotides in length and contains two open reading frames encoding the proteins responsible for replication (Rep) and the structural protein of the capsid (Cap). The open reading frames are flanked by two Inverted Terminal Repeat (ITR) sequences, which serve as the origin of replication of the viral genome. The wild-type AAV viral genome comprises nucleotide sequences for two open reading frames, one for the four non-structural Rep proteins (Rep78. Rep68, Rep52. Rep40, encoded by Rep genes) and one for the three capsid, or structural, proteins (VP1 , VP2, VP3. encoded by capsid genes or Cap genes). The Rep proteins are important for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid. Alternative splicing and alternate initiation codons and promoters result in the generation of four different Rep proteins from a single open reading frame and the generation of three capsid proteins from a single open reading frame. Though it varies by AAV seroty pe, as a non-limiting example, for AAV5 (SEQ ID NO: 138 and 137) VP1 refers to amino acids 1-724. VP2 refers to amino acids 137-724, and VP3 refers to amino acids 193-724. In some embodiments, e.g., for the amino acid sequence of SEQ ID NO: 982, VP1 comprises amino acids 1-731, VP2 comprises amino acids 137-731, and VP3 comprises amino acids 193-731. In other words, VP1 is the full-length capsid protein sequence, while VP2 and VP3 are shorter components of the whole. As a result, changes in the sequence in the VP3 region, are also changes to VP1 and VP2, however, the percent difference as compared to the parent sequence will be greatest for VP3 since it is the shortest sequence of tire three. Though described here in relation to the amino acid sequence, the nucleic acid sequence encoding these proteins can be similarly described.Together, the three capsid proteins assemble to create the AAV capsid. While not wishing to be bound by theory', the AAV capsid typically comprises a molar ratio of 1 : 1: 10 of VP1 :VP2:VP3.

[0060] The AAV particle typically requires a co-helper e.g.. adenovirus) to undergo productive infection in cells. In the absence of such helper functions, the AAV virions essentially enter host cells but do not integrate into the cells’ genome.

[0061] AAV particles have been investigated for delivery of gene therapeutics because of several unique features. Non-limiting examples of the features include (i) the ability to infect both dividing and non-dividing cells; (ii) a broad host range for infectivity, including human cells; (iii) wild-type AAV has not been associated with any disease and has not been shown to replicate in infected cells; (iv) the lack of cell-mediated immune response against the vector, and (v) the non-integrative nature in a host chromosome thereby reducing potential for long-term genetic alterations. Moreover, infection with AAV particles has minimal influence on changing the pattern of cellular gene expression (Stilwell and Samulski et al., Biotechniques, 2003, 34, 148, the contents of which are herein incorporated by reference in their entirety).

[0062] Typically , AAV particles for delivery of a modulatory polynucleotide may be recombinant viral vectors which are replication defective as they lack sequences encoding functional Rep and Capproteins within the viral genome. In some cases, the replication defective AAV particles may lack most or all coding sequences and essentially only contain one or two AAV ITR sequences and a nucleic acid sequence encoding a modulatory poly nucleotide (e.g., a modulatory' polynucleotide for reducing or eliminating DMPK).

[0063] hi some embodiments, the AAV particles of the present disclosure may be introduced into mammalian cells.

[0064] AAV particles may be modified to enhance the efficiency of delivery. Such modified AAV particles of the present disclosure can be packaged efficiently and can be used to successfully infect the target cells at high frequency and with minimal toxicity.

[0065] In other embodiments, AAV particles of the present disclosure may be used to deliver a modulatory polynucleotide to the central nervous system (see, e.g.. U.S. Pat. No. 6,180,613; the contents of which are herein incorporated by reference in their entirety) or to specific tissues of the CNS.

[0066] It is understood that the compositions described herein may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0067] In some embodiments. AAV capsid variants disclosed herein comprise one or more modifications (e.g.. one or more substitutions) in the loop VIII region of AAV5. In some embodiments, the AAV5 loop VIII region comprises amino acid positions 571-579, e.g.. position 577, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV5 loop VIII region (e.g., positions 571-579, e.g.. position 577) protrudes above the 3-fold axis of symmetry, e.g., is a surface-exposed location in the AAV5 capsid, e.g.. as described in Govindasamy et al. “Structural Insights into Adeno-Associated Virus Serotype 5,’’ Journal of Virology, 2013, 87(20): 11187-11199 (the contents of which are hereby incorporated by reference in their entirety ). In some embodiments, the term “loop-’ (e.g., as used in loop VIII) is used interchangeably herein with the term "variable region" (e.g., variable region VIII), or “VR” (e.g., VR-VIII). In some embodiments, loop VIII (e.g., VR-VIII) comprises positions 571-599 (e.g., amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)), numbered according to SEQ ID NO: 982. In some embodiments, loop VIII or variable region VIII (VR-VIII) is as described in Govindasamy et al. (supra) (the contents of which are hereby incorporated by reference in their entirety ).

[0068] The AAV particles and pay loads of the disclosure may be delivered to one or more target cells, tissues, organs, or organisms. In some embodiments, the AAV particles of the disclosure demonstrate enhanced tropism for a target cell ty pe, tissue, or organ. As a non-limiting example, the AAV particle may have enhanced tropism for cells and tissues of the muscle, heart, and / or brain. In some embodiments, the AAV particles of the disclosure demonstrate enhanced tropism for skeletal muscle. In some embodiments, the AAV particles of the disclosure demonstrate enhanced tropism for smooth muscle. In some embodiments, the AAV particles of the disclosure demonstrate enhanced tropism for cardiac muscle. In some embodiments, an AAV particle of the disclosure may, in addition, or alternatively, have decreased tropism for a cell-type, tissue, or organ.

[0069] In some embodiments, AAV are used as a biological tool due to a relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. The genome of the virus may be manipulated to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload.

[0070] In some embodiments, the AAV is a recombinant AAV. In some embodiments, the wild-type AAV viral genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length. In some embodiments, inverted terminal repeats (ITRs) cap die viral genome at both the 5’ and the 3’ end, providing origins of replication for the viral genome. In some embodiments, an AAV viral genome comprises two ITR sequences. In some embodiments, the ITRs have a characteristic T- shaped hairpin structure defined by a self-complementary region (145nt in wild-type AAV) at the 5’ and 3’ ends of the ssDNA which form an energetically stable double stranded region. In some embodiments, the double stranded hairpin structures comprise multiple functions including, but not limited to, acting as an origin for DNA replication by functioning as primers for the endogenous DNA polymerase complex of the host viral replication cell.

[0071] AAV particles of the present disclosure may be produced recombinantly and may be based on adeno-associated virus (AAV) reference sequences. In addition to single-stranded AAV viral genomes (e.g., ssAAVs), the present disclosure also provides for self-complementary AAV (scAAVs) viral genomes. scAAV viral genomes contain DNA strands which anneal together to form double-stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the transduced cell. In some embodiments, the AAV particle of the present disclosure is an scAAV. In some embodiments, the AAV particle of the present disclosure is an ssAAV.

[0072] Methods for producing and / or modifying AAV particles are disclosed in the art such as pseudotyped AAV particles (PCT Patent Publication Nos. W0200028004; W0200123001;W02004112727; W02005005610; and W02005072364, the content of each of which is incorporated herein by reference in its entirety).

[0073] As described herein, the AAV particles of the disclosure comprising an AAV capsid variant and a viral genome have enhanced tropism for a cell-type or a tissue, e.g.. a muscle cell-type, region, or tissue.Capsid Peptides

[0074] Disclosed herein are AAV particles comprising an AAV capsid variant comprising a peptide (e.g., inserted into a wildtype AAV capsid and / or in substitution of an amino acid or peptide in a wildtype AAV capsid) for enhanced or improved transduction of a target tissue (e.g.. muscle, heart.and / or brain cells). In some embodiments, the nucleic acid encoding the peptide is an isolated nucleic acid. In some embodiments, the nucleic acid encoding the peptide is a recombinant nucleic acid.

[0075] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of the CNS. The cell of the CNS may be, but is not limited to, neurons (e.g.. excitatory, inhibitory, motor, sensory, autonomic, sympathetic, parasympathetic, Purkinje, Betz, etc.), glial cells (e.g., microglia, astrocytes, oligodendrocytes) and / or supporting cells of the brain such as immune cells (e.g., T cells). The tissue of the CNS may be, but is not limited to, the cortex (e.g., frontal, parietal, occipital, temporal), thalamus, hypothalamus, striatum, putamen. caudate nucleus, hippocampus, entorhinal cortex, basal ganglia, or deep cerebellar nuclei. In some embodiments, the tissue of the CNS is spinal cord, temporal cortex, perirhinal cortex, globus pallidus. putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum.

[0076] In some embodiments, the peptide may modulate distribution of an AAV particle to a cell, region, or tissue of the CNS. In some embodiments, the peptide may decrease distribution of an AAV particle to the DRG.

[0077] In some embodiments, the peptide may increase distribution of an AAV particle to the CNS (e.g., the cortex) after intravenous administration. In some embodiments, the peptide may increase distribution of an AAV particle to the CNS (e.g.. the cortex) following focused ultrasound (FUS), e g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0078] In some embodiments, the peptide may modulate distribution of an AAV particle to the PNS (e.g., DRG) after intravenous administration. In some embodiments, the peptide may increase distribution of an AAV particle to non-DRG cells of the PNS following focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration. In some embodiments, the peptide may decrease distribution of an AAV particle to the DRG following focused ultrasound (FUS), e.g., coupled with die intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0079] hi some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of a heart, e.g., a heart atrium or a heart ventricle. In some embodiments, the peptide may increase distribution of an AAV particle to a heart cell, region, or tissue after intravenous administration.

[0080] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of a muscle. In some embodiments, the muscle is a cardiac muscle (e.g., a heart atrium or a heart ventricle) or a quadriceps. In some embodiments, the muscle is a skeletal muscle. In some embodiments, the muscle is a smooth muscle. In some embodiments, the peptide may increase distribution of an AAV particle to a muscle cell, region, or tissue after intravenous administration.

[0081] In some embodiments, a peptide may comprise a sequence as set forth in Table 1 (e.g., comprising the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590-1593, 1598-1624, or 2064-2079). In some embodiments, a peptide may comprise a sequence as set forth in Table 2A or 2B. In some embodiments, the peptide may comprise a sequence set forth in Table 11 or 20-25.

[0082] In some embodiments, a peptide has at least 90% identity (e.g., has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identity, or has 100% identity) to a sequence as set forth in SEQ ID NO: 1533, any one of SEQ ID NOs: 2024-2056, any one of SEQ ID NOs: 2064-2076. or SEQ ID NO: 2078. In some embodiments, a peptide may comprise a sequence as set forth in SEQ ID NO: 1533. any one of SEQ ID NOs: 2024-2056, any one of SEQ ID NOs: 2064-2076, or SEQ ID NO: 2078. In some embodiments, a peptide has at least 90% identity (e.g., has at least 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, 98%. or 99% identity, or has 100% identity) to a sequence as set forth in SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064-2076. In some embodiments, a peptide may comprise a sequence as set forth in SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064-2076. In some embodiments, a peptide has at least 90% identity (e.g.. has at least 90%, 91%. 92%, 93%, 94%, 95%. 96%, 97%, 98%, or 99% identity, or has 100% identity) to a sequence as set forth in SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056. In some embodiments, a peptide may comprise a sequence as set forth in SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056. In some embodiments, a peptide has at least 90% identity (e.g., has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%, or 99% identity, or has 100% identity) to a sequence as set forth in any one of SEQ ID NOs: 2024-2056. In some embodiments, a peptide may comprise a sequence as set forth in any one of SEQ ID NOs: 2024-2056. In some embodiments, a peptide has at least 90% identity (e.g., has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, or has 100% identity) to a sequence as set forth in any one of SEQ ID NOs: 2064-2076. In some embodiments, a peptide may comprise a sequence as set forth in any one of SEQ ID NOs: 2064-2076. In some embodiments, a peptide has at least 90% identity (e.g., has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, or has 100% identity) to a sequence as set forth in SEQ ID NO: 2078. In some embodiments, a peptide may comprise a sequence as set forth in SEQ ID NO: 2078.Table 1. Exemplary Peptide SequencesTable 2A. Exemplary Peptide SequencesTable 2B. Exemplary Peptide Sequences

[0083] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions X X2, X3, X4, and X5and [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ. or LQK. In some embodiments, position Xi of [N2] is Y, N, C, or T. In some embodiments, position X2of [N2] is P, E, K, T, or Q. In some embodiments, position X3of [N2] is A or P. In some embodiments, position X4of [N2] is E, S, D, or A. In some embodiments, position Xs of [N2] is V, L, or E. In some embodiments, [N2] comprises Y at position Xi. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X3. In some embodiments, the amino acid sequence of [N3] comprises VQK. In some embodiments, the amino acid sequence of [N3] consists of VQK.

[0084] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions Xi, X2. X3, X4, and X5and [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ. or LQK. In some embodiments, [N3] comprisesdie amino acid sequence of VQK, EQK, or VKK. In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, [N3] consists of the amino acid sequence VQK. In some embodiments, position Xi of [N2] is Y, N, or C. In some embodiments, position Xi of [N2] is Y or N. In some embodiments, position X2 of [N2] is P, K, T, or Q. In some embodiments, position X2 of [N2] is P, T, or Q. In some embodiments, position X3 of [N2] is A or P. In some embodiments, position X3 of [N2] is A. In some embodiments, position X4of [N2] is E, S, or A. In some embodiments, position X5of [N2] is V, L, or E. In some embodiments, position X? of [N2] is V or L. In some embodiments, [N2] comprises Y at position Xi. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments. [N2] comprises V at position X5. In some embodiments. [N2] comprises YPA, YPP, NKA. YTA. YQA. YTP. NPA, CPA, THA, PAE, PPS. KAE. TAE. QAE. TPS, PAA, HAS, AEV, PSL, AEE, or AAV. In some embodiments. [N2] comprises YPAE (SEQ ID NO: 21). YPPS (SEQ ID NO: 22), NKAE (SEQ ID NO: 23). YTAE (SEQ ID NO: 24), YQAE (SEQ ID NO: 25). YTPS (SEQ ID NO: 26), YPAA (SEQ ID NO: 27), NPAE (SEQ ID NO: 28), CPAE (SEQ ID NO: 29), THAS (SEQ ID NO: 30). PAEV (SEQ ID NO: 17), PPSL (SEQ ID NO: 31), KAEV (SEQ ID NO: 32). TAEV (SEQ ID NO: 16). PAEE (SEQ ID NO: 18), QAEV (SEQ ID NO: 15). TPSL (SEQ ID NO: 33). PAAV (SEQ ID NO: 34), or QAEE (SEQ ID NO: 35). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4). YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6). YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8). NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11). In some embodiments, [N2] comprises the ammo acid sequence of YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises the amino acid sequence of AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46). In some embodiments, [N2]-[N3] comprises the amino acid sequence PAEVVQK (SEQ ID NO: 20), PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48), TAEVVQK (SEQ ID NO: 49), PAEVEQK (SEQ ID NO: 50), PAEEVQK (SEQ ID NO: 51), QAEVVQK (SEQ ID NO: 52), TPSL VQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61). or QAEEVQK (SEQ ID NO: 62). In some embodiments, [N2]-[N3] is or comprises YP AEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947). YTAEVVQK (SEQ ID NO: 948), YP AEVEQK (SEQ ID NO: 949), YP AEEVQK (SEQ ID NO: 950). YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSL VKK (SEQ ID NO: 954). YP AEVVKK (SEQ ID NO: 955), YP AEVVHK (SEQ ID NO: 956). YP AAVVQK (SEQ ID NO: 957). NP AEVVQK (SEQ ID NO: 958), YP AEVVQQ (SEQ ID NO: 959). CPAEVVQK (SEQ IDNO: 960), YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, tw o. or three but no more than four modifications, e.g., substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the aforesaid ammo acid sequences; or an amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943). In some embodiments. [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0085] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [N2]-[N3], further comprises [Nl], which comprises positions XD. XE. and XF. In some embodiments, position XDof [Nl] is Q. T, S, A. I. L, or H. In some embodiments, position XEof [Nl] is S, G, A. or R. In some embodiments, position XEof [Nl] is S, K. L, R. A, or T. In some embodiments. [Nl] comprises SK, SL, SS. SR. GA, GS, AS, ST, RS, QS. TS. AG. IG. QA, LG, HS, LS, or QR. In some embodiments, [Nl] is or comprises QSS. QSK. TSL, SSS, QSR, AGA, IGS. QAS, ASS, LGS, QST, HSS, LSS, or QRS. In some embodiments, the amino acid sequence of [Nl] is QSS. In some embodiments, [N1]-[N2] comprises SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64). SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68), GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70), STNKA (SEQ ID NO: 71). SSYTA (SEQ ID NO: 72). SSYQA (SEQ ID NO: 73), SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77). or SSTHA (SEQ ID NO: 78). In some embodiments, [N1]-[N2] comprises SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81), SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84), GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95). In some embodiments, [N1]-[N2] is or comprises QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97). TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104). ASSYPAEV (SEQ ID NO: 105). LGSYPAEV (SEQ ID NO: 106). QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), HSSYPAAV (SEQ ID NO: 115). QSSNPAEV (SEQ ID NO: 116). QSSYTAEV (SEQ ID NO: 117). TSLCPAEV (SEQ ID NO: 118), QRSYTAEV (SEQ ID NO: 119). or QSSYQAEE (SEQ ID NO: 120); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4. 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one. two, or three butno more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [N1]-[N2] is QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] comprises SSYPAEVVQ (SEQ ID NO: 121), SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125). GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127). ASYPAEVVQ (SEQ ID NO: 128). STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO: 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVVQ (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134). SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140). SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145). RSYTAEVVQ (SEQ ID NO: 146). SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149). In some embodiments, [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152). SSSYPAEVVQK (SEQ ID NO: 153). QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157). QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160). QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 1 8), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170). LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [N1]-[N2]-[N3] is QSSYPAEVVQK (SEQ ID NO: 150).

[0086] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [NO], wherein [NO] comprises positions XA, XB. and Xc. In some embodiments, position XAof [NO] is T. I. or N. In some embodiments, positions XB of [NO] is N. In someembodiments, position X, ■ of [NO] is N, T, S, or K. In some embodiments, [NO] comprises TN, IN, NN, NT, NS, or NK. In some embodiments, [NO] is or comprises TNN, TNT, INN, TNS, NNN, or TNK. In some embodiments, the amino acid sequence of [NO] is TNN. In some embodiments, [NO]-[N1] is or comprises TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201): an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4, or 5 amino acids, e.g.. consecutive amino acids) thereof: an amino acid sequence comprising one. two, or three but no more than four modifications, e.g., substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences: or an amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments. [N0]-[Nl] is TNNQSS (SEQ ID NO: 183). In some embodiments, [NO]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGS YPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524). TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542). INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 551), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557), TNNQSSYTAEVVKK (SEQ ID NO: 558). TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562) or TNKQASYPAEVVQK (SEQ ID NO: 563); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g.. any 2, 3, 4, 5. 6. 7, 8. 9, 10. 11. 12, or 13 amino acids, e.g.. consecutive amino acids) thereof; an amino acid sequence comprising one. two, or three but no more than four modifications, e.g., substitutions (e.g.. conservativesubstitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, tw o. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [NO]-[N1]-[N2]-[N3] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0087] hi some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N4], which comprises positions XGand XH. In some embodiments, position XGof [N4] is T, P, or N. In some embodiments, position XGof [N4] is T. In some embodiments, position XH of [N4] is A. In some embodiments. [N4] is or comprises TA, PA, or NA. In some embodiments, [N4] is TA. In some embodiments, [N3]-[N4] is or comprises VQKTA (SEQ ID NO: 564). EQKTA (SEQ ID NO: 565). VKKTA (SEQ ID NO: 566). VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568). VQQTA (SEQ ID NO: 569). VQKNA (SEQ ID NO: 570). or LQKTA (SEQ ID NO: 571); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g.. any 2. 3. or 4 amino acids, e.g.. consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, tw o. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N3]-[N4] is VQKTA (SEQ ID NO: 564). In some embodiments, [NO]-[N1]-[N2]-[N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSKYPAEVVQKTA (SEQ ID NO: 1327). TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583), TNTASSYQAEVVQKTA (SEQ ID NO: 1584), TNNQSSYTPSL VQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592). TNNQSSYPPSL VQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599). TNNSSSYPAEVVQQTA (SEQ ID NO: 1419). NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEV VQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605). TNNQRSYTAEV VQKTA (SEQ ID NO: 1604). TNNQSSYTAEVVKKTA (SEQ ID NO: 1606). TNNHSSYPAEVLQKTA (SEQ ID NO: 1607).TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, tw o. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [NO]-[N1]-[N2]-[N3]- [N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0088] In some embodiments, a peptide described herein comprises the formula [N2]-[N3], wherein [N2] comprises positions Xi. X2, X3, X4, and X5and [N3] comprises the amino acid sequence of VQK or VQN. In some embodiments. [N3] comprises the amino acid sequence VQK. In some embodiments, position Xi of [N2] is Y or T. In some embodiments, position X2of [N2] is Q, T, P. or E. In some embodiments, position X3of [N2] is A. In some embodiments, position X4of [N2] is E or D. In some embodiments, position X4of [N2] is E or D. In some embodiments, position Xs of [N2] is V or E. In some embodiments, [N2] comprises Y at position Xi. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X5. In some embodiments, [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV. AE, or AD. In some embodiments, [N2] comprises YPA, YQA, YTA, TEA, QAE, TAE, PAE. EAE. PAD, AEV, AEE, or ADV. In some embodiments, [N2] comprises YPAE (SEQ ID NO: 21), YQAE (SEQ ID NO: 25), YTAE (SEQ ID NO: 24), TEAE (SEQ ID NO: 587), YPAD (SEQ ID NO: 588), QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), EAEV (SEQ ID NO: 590), or PADV (SEQ ID NO: 19). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13). In some embodiments, [N2] is YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises AEVVQK (SEQ ID NO: 36), AEE VQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593). In some embodiments, [N2]-[N3] comprises PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49). PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596). In some embodiments, [N2]-[N3] is or comprises YP AEVVQK (SEQ ID NO: 943), YQ AEVVQK (SEQ ID NO: 951), YT AEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YP AEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2. 3. 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one. tw o. or three but no more than four different amino acids,relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943).

[0089] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [N2]-[N3], further comprises [Nl], which comprises positions XD, XE, and XF. In some embodiments, position XD of [Nl] is Q or S. In some embodiments, position XE of [Nl] is S, L, A, or T. In some embodiments, position XFof [Nl] is S, Y, or T. In some embodiments, [Nl] comprises QS, SL, SA. QT, LS, LY, AT, TS, or SS. In some embodiments, [Nl] is or comprises QSS, SLS. SLY, SAT, or QTS. In some embodiments, [Nl] is QSS. In some embodiments, [N1]-[N2] comprises SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603). or TSTEA (SEQ ID NO: 605). In some embodiments. [Nl ]-[N2] comprises SSYPAE (SEQ ID NO: 79). LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), ATYPAE (SEQ ID NO: 613), LSYPAE (SEQ ID NO: 616). TSTEAE (SEQ ID NO: 619), or LSYPAD (SEQ ID NO: 621). In some embodiments. [N1]-[N2] is or comprises QSSYPAEV (SEQ ID NO: 96), SLSYQAEV (SEQ ID NO: 622), SLSYTAEV (SEQ ID NO: 623), SLYYPAEV (SEQ ID NO: 624), SATYPAEV (SEQ ID NO: 625), SLSYPAEV (SEQ ID NO: 629), SLSYPAEE (SEQ ID NO: 632). QTSTEAEV (SEQ ID NO: 633). or SLSYPADV (SEQ ID NO: 634); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g.. substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N1]-[N2] is QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641). SLSYPAEVVQK (SEQ ID NO: 642), SLSYPAEEVQK (SEQ ID NO: 643), SLSYPAEVVQN (SEQ ID NO: 644), QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2. 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N1]-[N2]-[N3] is QSSYPAEVVQK (SEQ ID NO: 150).

[0090] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [NO], wherein [NO] comprises positions XA, XB. and Xc. In some embodiments, position XAof [NO] is T. In some embodiments, positions XBof [NO] is N. In some embodiments, position Xc of [NO] is N. T, S, or K. In some embodiments, [NO] comprises TN, NS, NT,NN, or NK. In some embodiments, [NO] is or comprises TNS, TNT, TNN, or TNK. In some embodiment, [NO] is TNN. In some embodiments, [NO]-[N1] is or comprises TNNQSS (SEQ ID NO: 183), TNSSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650), or TNKSAT (SEQ ID NO: 651); an amino acid sequence comprising any portion oT any of the aforesaid amino acid sequences (e.g., any 2. 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments. [NO]-[N1] is TNNQSS (SEQ ID NO: 183). In some embodiments, [NO]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLSYQAEVVQK (SEQ ID NO: 652). TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656). TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4, 5, 6, 7, 8, 9. 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [NO]-[N1]-[N2]-[N3] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0091] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N4], which comprises positions Xoand XH. In some embodiments, position Xu of [N4] is T, P, or N. In some embodiments, position XHof [N4] is A or D. In some embodiments, [N4] is or comprises TA, TD, PA, or NA. In some embodiments, [N4] is TA. In some embodiments, [N3]-[N4] is or comprises VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of die aforesaid amino acid sequences. In some embodiments, [N3]-[N4] is VQKTA (SEQ ID NO: 564). In some embodiments, [NO]-[N1]-[N2]-[N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLSYQAEVVQKTA (SEQ ID NO: 2064). TNSSLSYTAEVVQKTA (SEQ ID NO: 2065).TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), TNNQTSTEAEVVQKTA (SEQ ID NO: 2074). TNKSATYPAEVVQKTA (SEQ ID NO: 2075), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2. 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of die aforesaid amino acid sequences. In some embodiments, |N0]-|N 1 ] -|N2]-|N3]-|N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0092] In some embodiments, [Nl] is present immediately subsequent to [NO], In some embodiments, [N2] is present immediately subsequent to [Nl], In some embodiments, [N3] is present immediately subsequent to [N2], In some embodiments, [N4] is present immediately subsequent to [N3] . In some embodiments, the peptide comprises from N-terminus to C-terminus, [N2]-[N3], In some embodiments, the peptide comprises from N-terminus to C-terminus, [N1]-[N2]-[N3], In some embodiments, the peptide comprises from N-terminus to C-terminus, [N1]-[N2]-[N3]-[N4], In some embodiments, the peptide comprises from N-terminus to C-terminus, [NO]-[N1]-[N2]-[N3], In some embodiments, the peptide comprises from N-terminus to C-terminus, [NO]-[N1]-[N2]-[N3]-[N4],

[0093] In some embodiments, a peptide described herein comprises an amino acid sequence having die formula [B]-[C], wherein [B] comprises positions Xi, X2, and X3, and [C] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). In some embodiments, position Xi of [B] Xi is Q, T, S, A, I, L, or H. In some embodiments, position Xi of [B] Xi is Q, T, S, A, or H. In some embodiments, position X2of [B] is S, G, or A. In some embodiments, position X2of [B] is S or G. In some embodiments, position X3of [B] is S, K, L, R, or A. In some embodiments, position X3of [B] is S, K, L, or R. In some embodiments, [B] comprises Q at position Xi . In some embodiments. [B] comprises S at position X2. hi some embodiments, [B] comprises S at position X3. In some embodiments, [B] comprises QS, TS, SS, AG, IG. QA, AS, LG, HS, SK, SL, SR, GA, or GS. In some embodiments, [B] is or comprises QSS, TSL, SSS, QSR. QSK. AGA, IGS, QAS, ASS, LGS, or HSS. In some embodiments, the amino acid sequence of [B] is QSS. In some embodiments, [B]-[C] comprises SSYPAEVVQK (SEQ ID NO: 572), SKYPAEVVQK (SEQ ID NO: 573), SLYPAEVVQK (SEQ ID NO: 574), SRYPAEVVQK (SEQ ID NO: 575). GAYPAEVVQK (SEQ ID NO: 576). GSYPAEVVQK (SEQ ID NO: 580). or ASYPAEVVQK (SEQ ID NO: 582). In some embodiments. [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154). AGAYPAEVVQK (SEQID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), or HSSYPAEVVQK (SEQ ID NO: 162); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [B]-[C] is QSSYPAEVVQK (SEQ ID NO: 150).

[0094] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [A], which comprises positions XA, XB, and Xc. In some embodiments, position XAof [A] is T. I. or N. In some embodiments, position XB of [A] is N. In some embodiments, position Xc of [A] is N. T. S, or K. In some embodiments. [A] comprises TN, IN. NN, NT, NS, or NK. In some embodiments, [A] is or comprises TNN, TNT, INN, NNN, TNS, or TNK. In some embodiments, [A] is TNN. In some embodiments, [A]-[B] is or comprises TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184). TNNTSL (SEQ ID NO: 185). TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187). TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190). TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192). TNNHSS (SEQ ID NO: 194), INNQSS (SEQ ID NO: 196), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), or TNKQAS (SEQ ID NO: 201); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one. two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517). TNT ASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNHSSYPAEVVQK (SEQ ID NO: 525), INNQSSYPAEVVQK (SEQ ID NO: 543), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNSTSLYPAEVVQK (SEQ ID NO: 556), or TNKQASYPAEVVQK (SEQ ID NO: 563): an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g.. any 2, 3, 4, 5. 6. 7, 8. 9, 10. 11. 12, or 13 amino acids, e.g.. consecutive amino acids) thereof; an amino acid sequence comprising one. two, or three but no more than four modifications, e.g., substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an aminoacid sequence comprising one, tw o. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0095] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [D], wherein [D] comprises position X4 and X5. In some embodiments, position X4 of [D] is T or N. In some embodiments, position X5of [D] is A. In some embodiments, [D] is or comprises TA or PA. In some embodiments, the amino acid sequence of [D] is TA. In some embodiments, [C]-[D] is or comprises YPAEVVQKTA (SEQ ID NO: 584) or YPAEVVQKPA (SEQ ID NO: 586); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4. 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [C]-[D] is YPAEVVQKTA (SEQ ID NO: 584). In some embodiments, [A]-[B]-[C]-[D] is or comprises TNNQSS YPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232). TNNSSS YPAEVVQKTA (SEQ ID NO: 1539). TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGS YPAEVVQKTA (SEQ ID NO: 1112). TNNQASYPAEVVQKTA (SEQ ID NO: 1194). TNTASSYPAEVVQKTA (SEQ ID NO: 1575). TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310).TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605). or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8. 9, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of tire aforesaid amino acid sequences. In some embodiments, [C]-[D] is YPAEVVQKTA (SEQ ID NO: 584). In some embodiments, [A]-[B]-[C]-[D] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0096] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [B]-[C], wherein [B] comprises positions Xi, X2, and X3. and [C] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). In some embodiments, position Xi of [B] is Q or S. In some embodiments, position X2of [B] is S. L, or A. In some embodiments, position X3of [B] is S, Y, or T. In some embodiments, [B] comprises Q at position Xi . In some embodiments. [B] comprises S at position X2. In some embodiments. [B] comprises S at position X3. In some embodiments. [B] comprises QS. SL. SA. LY, AT, LS, or SS. In some embodiments, [B] is or comprises QSS, SLY, SAT, or SLS. In someembodiments, [B] is QSS. In some embodiments, [B]-[C] comprises SSYPAEVVQK (SEQ ID NO: 572), LYYPAEVVQK (SEQ ID NO: 702), ATYPAEVVQK (SEQ ID NO: 718), or LSYPAEVVQK (SEQ ID NO: 703). In some embodiments, [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641). or SLSYPAEVVQK (SEQ ID NO: 642); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one. two, or three but no more than four modifications, e g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [B] -[Cl is QSSYPAEVVQK (SEQ ID NO: 150).

[0097] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [A], which comprises positions XA. XB. and Xc. In some embodiments, position XAof [A] is T. In some embodiments, position XBof [A] is N. In some embodiments, position Xc of [A] is N, T, S. or K. In some embodiments, [A] comprises TN, NS, NT. NK. or NN. In some embodiments, [A] is or comprises TNN, TNS, TNT, or TNK. In some embodiments, the amino acid sequence of [A] is TNN. In some embodiments, [A]-[B] is or comprises TNNQSS (SEQ ID NO: 183), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649). TNSSLS (SEQ ID NO: 647), or TNKSAT (SEQ ID NO: 651); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one. two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), or TNKSATYPAEVVQK (SEQ ID NO: 663); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10. 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments, [A]-[B]-[C] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0098] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [D], wherein [D] comprises position X4 and X5. In some embodiments, position X4 of [D] is T. N, or P. In some embodiments, position X5 of [D] is A or D. In some embodiments, [D] is or comprises TA. TD,NA, or PA. In some embodiments, the amino acid sequence of [D] is TA. In some embodiments, [C]-[D] is or comprises YPAEVVQKTA (SEQ ID NO: 584), YPAEVVQKTD (SEQ ID NO: 719), YPAEVVQKNA (SEQ ID NO: 724), or YPAEVVQKPA (SEQ ID NO: 586); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4. 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [C]-[D] is YPAEVVQKTA (SEQ ID NO: 584). In some embodiments. [A]-[B]-[C]-[D] is or comprises TNNQSS YPAEVVQKTA (SEQ ID NO: 1533), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066). TNTSATYPAEVVQKTA (SEQ ID NO: 2067).TN SSLS YPAEVVQKTA (SEQ ID NO: 2068), TN SSLS YPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072). TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNKSATYPAEVVQKTA (SEQ ID NO: 2075); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4. 5, 6, 7, 8. 9. 11, 12, 13, 14. or 15 amino acids, e.g.. consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [A]-[B]-[C]-[D] is TNNQSS YPAEVVQKTA (SEQ ID NO: 1533).

[0099] In some embodiments, [B] is present immediately subsequent to [A], In some embodiments, [C] is present immediately subsequent to [B], In some embodiments, [D] is present immediately subsequent to [C], In some embodiments, the peptide comprises from N-terminus to C-tenninus, [B]-[C], In some embodiments, the peptide comprises from N-terminus to C-terminus, [B]-[C], In some embodiments, the peptide comprises from N-tcrminus to C-tcrminus, [A]-[B]-[C], In some embodiments, the peptide comprises from N-terminus to C-tenninus, [B]-[C]-[D], In some embodiments, the peptide comprises from N-terminus to C-terminus, [A]-[B]-[C]-[D],

[0100] hi some embodiments, a peptide described herein comprises the formula [K1]-[K2], wherein, [KI] comprises LSY or LYY, and [K2] comprises positions Xi, X2, X3, and X4. In some embodiments, [KI] comprises LSY. In some embodiments, position Xi of [K2] is Q, T or P. In some embodiments, position X2of [K2] is A, in some embodiments, position X3of [K2] is E or D. In some embodiments, position X4 of [K2] is V or E. In some embodiments, [K2] comprises QA, TA, PA, EV, EE, DV, AE. or AD. In some embodiments, [K2] comprises QAE. TAE, PAE, PAD, AEV, AEE, or ADV. In some embodiments. [K2] is or comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19). In some embodiments, [K1]-[K2] comprises LSYQA (SEQ ID NO: 597). LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), or LSYPA (SEQ ID NO: 603). In some embodiments, [K1]-[K2] comprises LSYQAE (SEQ ID NO: 607),LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), LSYPAE (SEQ ID NO: 616), or LSYPAD (SEQ ID NO: 621). In some embodiments, [K1]-[K2] is or comprises LSYQAEV (SEQ ID NO: 667), LSYTAEV (SEQ ID NO: 668), LYYPAEV (SEQ ID NO: 669), LSYPAEV (SEQ ID NO: 671), LSYPAEE (SEQ ID NO: 673), or LSYPADV (SEQ ID NO: 674); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2. 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0101] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [K1]-[K2], further comprises [KO], which comprises TNNS (SEQ ID NO: 14). In some embodiments. [KOJ-[K1 J comprises TNSSLS (SEQ ID NO: 647) or TNSSLY (SEQ ID NO: 648). In some embodiments, [KO]-[K1] is or comprises TNSSLSY (SEQ ID NO: 676) or TNSSLYY (SEQ ID NO: 678); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4. 5. or 6 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g.. substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [KO]-[K1]-[K2] comprises TNSSLSYQA (SEQ ID NO: 679), TNSSLSYTA (SEQ ID NO: 681). TNSSLYYPA (SEQ ID NO: 682), or TNSSLSYPA (SEQ ID NO: 683). In some embodiments, [KO]-[K1]-[K2] comprises TNSSLSYQAE (SEQ ID NO: 684), TNSSLSYTAE (SEQ ID NO: 685), TNSSLYYPAE (SEQ ID NO: 686). TNSSLSYPAE (SEQ ID NO: 687), or TNSSLSYPAD (SEQ ID NO: 689). In some embodiments, [K0]- [K1]-[K2] is or comprises TNSSLSYQAEV (SEQ ID NO: 692), TNSSLSYTAEV (SEQ ID NO: 693), TNSSLYYPAEV (SEQ ID NO: 696), TNSSLSYPAEV (SEQ ID NO: 697), TNSSLSYPAEE (SEQ ID NO: 698), or TNSSLSYPADV (SEQ ID NO: 699); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0102] In some embodiments, peptide comprising the amino acid sequence comprising the formula of [K1]-[K2], further comprises [K.3], wherein [K3] comprises positions XA, XB, and Xc. In some embodiments, position XAof [K3] is V. In some embodiments, position XBof [K3] is Q. In some embodiments, position Xc of [K3] is K or N. In some embodiments, [K3] comprises VQ, QK, or QN. In some embodiments, [K3] is or comprises VQK or VQN. In some embodiments. K2]-[K3] is or comprises QAEVVQK (SEQ ID NO: 52). TAEVVQK (SEQ ID NO: 49). PAEVVQK (SEQ ID NO: 20).- I ll -PAEEVQK (SEQ ID NO: 51) ,PAEVVQN (SEQ ID NO: 594), or PADVVQK (SEQ ID NO: 596); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, tw o. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [K1]-[K2]-[K3] is or comprises LSYQAEVVQK (SEQ ID NO: 700), LSYTAEVVQK (SEQ ID NO: 701), LYYPAEVVQK (SEQ ID NO: 702), LSYPAEVVQK (SEQ ID NO: 703), LSYPAEEVQK (SEQ ID NO: 704), LSYPAEVVQN (SEQ ID NO: 706), or LSYPADVVQK (SEQ ID NO: 708); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3. 4, 5, 6, 7, 8. or 9 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [KO]-[K1]-[K2]-[K3] is or comprises TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), or TNSSLSYPADVVQK (SEQ ID NO: 665); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2. 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two. or three but no more than four modifications, e.g.. substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, tw o. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0103] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [K1]-[K2], further comprises [K4], wherein [K4] comprises positions XD and XE. In some embodiments, position XD of [K4] is T, P, or N. In some embodiments, position XE of [K4] is A or D. In some embodiments, [K4] is or comprises TA, TD, PA. or NA. In some embodiments, [K3]-[K4] is or comprises VQKTA (SEQ ID NO: 564), VQKTD (SEQ ID NO: 714), VQNTA (SEQ ID NO: 715), VQKNA (SEQ ID NO: 570). or VQKPA (SEQ ID NO: 567); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2. 3, or 4 amino acids, e.g.. consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments. [NO]-[N1]-[N2]-[N3]-[N4] is or comprises TNSSLSYQAEVVQKTA (SEQ ID NO:2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of die aforesaid amino acid sequences.

[0104] In some embodiments, [K2J is present immediately subsequent to [K1J. In some embodiments. [KI] is present immediately subsequent to [K0], In some embodiments. [K3] is present immediately subsequent to [K2], In some embodiments, [K4] is present immediately subsequent to [K3], In some embodiments, the peptide comprises from N-terminus to C-terminus, [K1]-[K2], In some embodiments, the peptide comprises from N-terminus to C-terminus, [KO]-[K1]-[K2]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [K1]-[K2]-[K3], In some embodiments, the peptide comprises from N-terminus to C-terminus, [KO]-[K1]-[K2]-[K3], In some embodiments, the peptide comprises from N-terminus to C-terminus, [K1]-[K2]-[K3]-[K4], In some embodiments, the peptide comprises from N-terminus to C-terminus, [KO]-[K1]-[K2]-[K3]-[K4],

[0105] In some embodiments, a peptide described herein comprises an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10. 11, 12, 13, 14, or 15 consecutive amino acids from any one of die sequences provided in Tables 1, 2A, 2B, 11, and 20-25. In some embodiments, the peptide comprises an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID Nos: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254. 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583- 1587, 1590, 1591-1593, 1598-1608, and 1610-1624. In some embodiments, the peptide comprises an ammo acid sequence comprising at least3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 943 or 2064-2080. In some embodiments, the peptide comprises an amino acid sequence comprising at least 3,4. 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 943 or 2064-2076. In some embodiments, the peptide comprises an amino acid sequence comprising at least 3, 4. 5, 6, 7, 8, 9. 10, 11, 12, 13. 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 2064- 2080. In some embodiments, the peptide comprises at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID Nos: 943 or any one of SEQ ID NOs: 946-966.

[0106] In some embodiments, the at least 3 consecutive amino acids comprise YPA. In some embodiments, the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21). In some embodiments, the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1). In someembodiments, die at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725). In some embodiments, die at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726). In some embodiments, the amino acid sequence comprises YPAEVVQK (SEQ ID NO: 943). In some embodiments, the amino acid sequence consists of YPAEVVQK (SEQ ID NO: 943).

[0107] hi some embodiments, a peptide described herein comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of the sequences provided in Tables 1, 2A, 2B, 11, and 20-25. In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of the sequences provided in Tables 1, 2A, 2B, 11, and 20-25. In some embodiments, the peptide comprises an amino acid sequence comprising one. two, or three but no more than four modifications, e.g.. substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583- 1587, 1590, 1591-1593, 1598-1608. and 1610-1624. In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583- 1587, 1590. 1591-1593, 1598-1608, and 1610-1624. In some embodiments, the peptide comprises an amino acid sequence comprising one, two. or three but no more than four modifications, e.g.. substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943 and 2064-2080. In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080.

[0108] In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943 and 2064-2076. In some embodiments, the peptide comprises an amino acid sequence comprising one, tw o. or three but no more than four different amino acids relative to the amino acid sequence of SEQ ID Nos: 943 or any one of SEQ ID NOs: 2064-2076. In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g.. conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 2064-2076. In some embodiments, the peptide comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 2064-2076.

[0109] In some embodiments, the peptide comprises an amino acid sequence comprising one, two. or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions.or deletions, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). In some embodiments, die peptide comprises an amino acid sequence comprising one, two, or three but no more dian four different amino acids relative to die ammo acid sequence of YPAEVVQK (SEQ ID NO: 943).

[0110] In some embodiments, die peptide comprises an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID Nos: 2024-2063. In some embodiments, the peptide comprises an amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID Nos: 2024- 2063. In some embodiments, the different amino acids of the amino acid sequence comprising one. two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID Nos: 2024-2063, are present at one or more of the following positions: (i) position 1, wherein the different amino acid is T or L; (ii) position 2, wherein the different amino acid is N. L, K, A. T, or P; (iii) position 3, wherein the different amino acid is N, K. L, A. Y, or S; (iv) position 4. wherein the different amino acid is Q, L, T, S, F, Y, K, or A; (v) position 5, wherein the different amino acid is S, H, A, M, Q, T. V, or F; (vi) position 6, wherein the different amino acid is S, P, V. A, Q. L, T, N. or M; (vii) position 7, wherein the different amino acid is Y. H, S, V, A, L. or T; (viii) position 8, wherein the different amino acid is D, P. A, Q, F. L, S, H. or M; (ix) position 9, wherein the different amino acid is F, A, L, D, or Q; (x) position 10. wherein the different amino acid is T. E, I, or S: (xi) position 11, wherein the different amino acid is V. A, N. or S...

Claims

CLAIMS1. An adeno-associated virus (AAV) particle comprising an AAV5 capsid variant and a viral genome, wherein the viral genome comprises a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA; and wherein the AAV5 capsid variant comprises an amino sequence comprising the formula [N2]- [N3], wherein:(i) [N2] comprises positions Xi, X2, Xs, X4, and X5. wherein:(a) position Xi is Y or T;(b) position X2 is Q, T. P, or E;(c) position X is A;(d) position X4 is E or D; and(e) position Xs is V or E; and(ii) [N3] comprises the amino acid sequence of VQK or VQN.

2. The AAV particle of claim 1, wherein [N2]-[N3] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO: 982.

3. The AAV particle of claim 1 or claim 2, wherein | N21-| N31 is present immediately subsequent to an amino acid corresponding to position 576 of the amino acid sequence of SEQ ID NO: 982.

4. The AAV particle of any one of claims 1-3, wherein the AAV5 capsid variant comprises [N2]-[N3] in place of an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

5. The AAV particle of any one of claims 1-4, wherein [N2]-[N3] comprises the amino acid sequence AEVVQK (SEQ ID NO: 36). AEEVQK (SEQ ID NO: 39). AEVVQN (SEQ ID NO: 591). or ADVVQK (SEQ ID NO: 593).

6. The AAV particle of any one of claims 1-5, wherein [N2]-[N3] comprises the amino acid sequence PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595). or PADVVQK (SEQ ID NO: 596).

7. The AAV particle of any one of claims 1-6, wherein [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966).

8. The AAV particle of any one of claims 1-7. wherein the AAV5 capsid variant further comprises [Nl] comprising positions XD. XE. and XF, wherein:(a) position XDof [Nl] is Q or S;(b) position XEof [Nl] is S, L, A. or T; and(c) position XFof [Nl] is S, Y, or T; wherein [Nl] immediately precedes [N2]-[N3] .

9. The AAV particle of claim 8, wherein [Nl] comprises the amino acid sequence QSS. SLS, SLY, SAT. or QTS.

10. The AAV particle of claim 8 or claim 9, wherein [N1]-[N2]-[N3] comprises the amino acid sequence QSSYPAEVVQK (SEQ ID NO: 150), SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637), SLYYPAEVVQK (SEQ ID NO: 639). SATYPAEVVQK (SEQ ID NO: 641), SLSYPAEVVQK (SEQ ID NO: 642). SLSYPAEEVQK (SEQ ID NO: 643), SLSYPAEVVQN (SEQ ID NO: 644), QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646).

11. The AAV particle of any one of claims 8-10. wherein the AAV capsid variant further comprises [NO] comprising positions XA, XB, and Xc, wherein:(a) position XAof [NO] is T;(b) position XBof [NO] is N; and(c) position Xc of [NO] is N, T, S, or K; wherein [NO] immediately precedes [Nl],12. The AAV particle of claim 11, wherein [NO] comprises the amino acid sequence TNN, TNS, TNT, or TNK.

13. The AAV particle of claim 11 or claim 12, wherein [NO]-[N1] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183), TNSSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650). or TNKSAT (SEQ ID NO: 651).

14. The AAV particle of any one of claims 11-13. wherein [NO]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYPAEVVQK (SEQ ID NO: 500). TNSSLSYQAEVVQK (SEQ ID NO: 652),TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665).

15. The AAV particle of any one of claims 11-14, wherein the AAV capsid variant further comprises [N4] comprising positions XGand XH, wherein:(a) position XGof [N4] is T, P, or N; and(b) position XHof [N4] is A or D: wherein [N4] is present immediately subsequent to [N3],16. The AAV particle of claim 15, wherein [N4] comprises the amino acid sequence TA, PA, TD, NA. or PA.

17. An adeno-associated virus (AAV) particle comprising an AAV5 capsid variant and a viral genome, wherein the viral genome comprises a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA; and wherein the AAV5 capsid variant comprises an amino sequence comprising the formula [N0]- [N1]-[N2]-[N3]-[N4], wherein:(i) [NO] comprises the amino acid sequence TNN, TNS, TNT, or TNK;(ii) [Nl] comprises the amino acid sequence QSS, SLS, SLY, SAT, or QTS;(iii) [N2] comprises the amino acid sequence YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13);(iv) [N3] comprises tire amino acid sequence VQK or VQN; and(v) [N4] comprises the amino acid sequence TA, PA, TD, NA, or PA. wherein [N2]-[N3] replaces an amino acid corresponding to position T577 of the amino acid sequence of SEQ ID NO: 138.

18. The AAV particle of claim 17, wherein [NO]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence of SEQ ID NO: 1533 or any one of SEQ ID NOS: 2064-2076.

19. The AAV particle of claim 17, wherein the AAV5 capsid variant comprises up to four different amino acids relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064- 2076.

20. The AAV particle of claim 19, wherein the up to four different amino acids are conservative substitutions.

21. The AAV particle of any one of claims 17-20, wherein the AAV5 capsid variant comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2076.

22. The AAV particle of claim 21, wherein the AAV5 capsid variant comprises the amino acid sequence of SEQ ID NO: 943 or any one of SEQ ID NOs: 2064-2076.

23. The AAV particle of claim 22. wherein the AAV5 capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 2064-2076.

24. An adeno-associated vims (AAV) particle comprising an AAV5 capsid variant and a viral genome, wherein the viral genome comprises a nucleotide sequence encoding a modulatory polynucleotide for reducing or eliminating expression of mutated dystrophia myotonica protein kinase (DMPK) mRNA, optionally wherein the modulatory polynucleotide comprises an RNAi agent targeting DMPK mRNA; and wherein the AAV5 capsid variant comprises an ammo sequence comprising up to four different amino acids relative to the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024- 2056.

25. The AAV particle of claim 24, wherein the up to four different amino acids are conservative substitutions.

26. The AAV particle of claim 24, wherein the up to four different amino acids are present at one or more amino acids corresponding to the following positions of the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056:(i) position 1, wherein the different amino acid is T or L;(ii) position 2, wherein the different amino acid is N. L, K, A, T, or P;(iii) position 3, wherein the different amino acid is N, K. L, A, Y. or S;(iv) position 4. wherein the different amino acid is Q, L, T. S, F, Y. K, or A;(v) position 5. wherein the different amino acid is S. H, A, M, Q. T, V, or F;(vi) position 6. wherein the different amino acid is S, P, V. A, Q. L. T, N. or M;(vii) position 7, wherein the different amino acid is Y, H, S, V, A, L, or T;(viii) position 8, wherein the different amino acid is D, P, A, Q, F, L, S, H, or M;(ix) position 9, wherein the different amino acid is F, A, L, D, or Q;(x) position 10, wherein the different amino acid is T, E, I, or S;(xi) position 11, wherein the different amino acid is V, A, N, or S;(xii) position 12, wherein the different amino acid is V, L, or P;(xiii) position 13, wherein the different amino acid is Q, E, or P;(xiv) position 14, wherein the different amino acid is K, N. S, or L;(xv) position 15. wherein the different amino acid is T. V, M, or L; and / or(xvi) position 16, wherein the different amino acid is A, G. or R.

27. The AAV particle of claim 24, wherein the AAV5 capsid variant comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056.

28. The AAV particle of claim 24, wherein the AAV5 capsid variant comprises the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056.

29. The AAV particle of any one of claims 24-28, wherein the amino acid sequence is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 570-584 of the amino acid sequence of SEQ ID NO: 138.

30. The AAV particle of any one of claims 24-29, wherein positions 7-14 of the amino acid sequence are present in place of an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

31. The AAV particle of any one of claims 1-30, wherein the modulatory polynucleotide comprises a molecular scaffold, wherein the molecular scaffold comprises:(a) a 5’ flanking region comprising the nucleotide sequence of any one of SEQ ID NOs: 6413- 6416, or a nucleotide sequence at least 95% identical thereto;(b) a loop region comprising the nucleotide sequence of any one of SEQ ID NOs: 6417-6421. or a nucleotide sequence at least 95% identical thereto; and(c) a 3’ flanking region comprising the nucleotide sequence of any one of SEQ ID NOs: 6422- 6427, or a nucleotide sequence at least 95% identical thereto.

32. The AAV particle of claim 31, wherein:(a) the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6414 or SEQ ID NO: 6415. or a nucleotide sequence at least 95% identical thereto;(b) the loop region comprises the nucleotide sequence of SEQ ID NO: 6417, SEQ ID NO: 6418, or SEQ ID NO: 6421, or a nucleotide sequence at least 95% identical thereto; and(c) the 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6423, SEQ ID NO: 6424, or SEQ ID NO: 6425, or a nucleotide sequence at least 95% identical thereto.

33. The AAV particle of claim 32, wherein the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6414, or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6417, or a nucleotide sequence at least 95% identical thereto, and the 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6423, or a nucleotide sequence at least 95% identical thereto.

34. The AAV particle of claim 32, wherein the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6415, or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6421, or a nucleotide sequence at least 95% identical thereto, and the 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6425, or a nucleotide sequence at least 95% identical thereto.

35. The AAV particle of claim 32, wherein the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6414. or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6417, or a nucleotide sequence at least 95% identical thereto, and the 3’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6424, or a nucleotide sequence at least 95% identical thereto.

36. The AAV particle of claim 32, wherein the 5’ flanking region comprises the nucleotide sequence of SEQ ID NO: 6414, or a nucleotide sequence at least 95% identical thereto, the loop region comprises the nucleotide sequence of SEQ ID NO: 6418, or a nucleotide sequence at least 95% identical thereto, and die 3‘ flanking region comprises the nucleotide sequence of SEQ ID NO: 6423, or a nucleotide sequence at least 95% identical thereto.

37. The AAV particle of any one of claims 1-36, wherein the modulatory polynucleotide comprises siRNA or shRNA.

38. The AAV particle of claim 37, wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more DMPK mRNA transcripts (e.g., one or more mutated DMPK mRNA transcripts), wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the passenger strand, the loop region, the guide strand, and the 3' flanking region.

39. The AAV particle of claim 37, wherein the modulatory polynucleotide further comprises a passenger strand and a guide strand, wherein the guide strand binds to and reduces or eliminates expression of one or more DMPK mRNA transcripts (e.g., one or more mutated DMPK mRNA transcripts), wherein the modulatory polynucleotide comprises from 5' to 3': the 5' flanking region, the guide strand, the loop region, the passenger strand, and the 3' flanking region.

40. The AAV particle of claim 38 or claim 39, wherein the passenger strand is 15-30 nucleotides in length.

41. The AAV particle of any one of claims 38-40. wherein the guide strand is 15-30 nucleotides in length.

42. The AAV particle of claim 41, wherein the guide strand is 21-25 nucleotides in length and / or the passenger strand is 21-25 nucleotides in length.

43. The AAV particle of any one of claims 38-42, wherein the passenger strand is at least 70%. 80%, 90%, or 95%, or is 100%, complementary to the guide strand.

44. The AAV particle of any one of claims 38-43, wherein the one or more DMPK mRNA transcripts comprises the nucleotide sequence of SEQ ID NO: 6428. SEQ ID NO: 6429, SEQ ID NO: 6430, SEQ ID NO: 6431. SEQ ID NO: 6432, SEQ ID NO: 6433, and / or SEQ ID NO: 6434, or a trinucleotide repeat expansion thereof.

45. The AAV particle of any one of claims 1-44, wherein the viral genome comprises a promoter operably linked to the nucleotide sequence encoding the modulatory polynucleotide.

46. The AAV particle of any one of claims 1-45, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.

47. The AAV particle of claim 46, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleotide sequence encoding the modulatory polynucleotide.

48. The AAV particle of claim 46 or claim 47, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the nucleotide sequence encoding the modulatory polynucleotide.

49. The AAV particle of any of claims 46-48, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the nucleotide sequence encoding the modulatory polynucleotide, and an ITR sequence positioned 3‘ relative to the nucleotide sequence encoding the modulatory polynucleotide.

50. A cell comprising the AAV particle of any one of claims 1-49, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

51. A method of making the AAV particle of any one of claims 1-49, wherein the method comprises:(i) providing a cell comprising the viral genome comprising a nucleotide sequence encoding a modulatory poly nucleotide for reducing or eliminating expression of mutated DMPK mRNA and a nucleic acid encoding the AAV5 capsid variant; and(ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV5 capsid variant; thereby making the AAV particle.

52. The method of claim 51, wherein the viral genome comprises:(a) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% identical thereto;(b) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6415 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6421 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6425 or a nucleotide sequence at least 95% identical thereto;(c) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6424 or a nucleotide sequence at least 95% thereto; or(d) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6418 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% thereto; and wherein the AAV5 capsid variant comprises the amino acid sequence of SEQ ID NO: 2078 or any one of SEQ ID NOs: 2024-2056.

53. The method of claim 51, wherein the viral genome comprises:(a) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ IDNO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% identical thereto;(b) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6415 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6421 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6425 or a nucleotide sequence at least 95% identical thereto;(c) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6417 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6424 or a nucleotide sequence at least 95% thereto; or(d) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 95% identical thereto, a loop region comprising the nucleotide sequence of SEQ ID NO: 6418 or a nucleotide sequence at least 95% identical thereto, and a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 6423 or a nucleotide sequence at least 95% thereto; and wherein the AAV5 capsid variant comprises the amino acid sequence of SEQ ID NO: 1533 or any one of SEQ ID NOs: 2064-2076.

54. The method of any one of claims 51-53, further comprising, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell.

55. The method of any one of claims 51-54, further comprising, prior to step (i) introducing the nucleic acid encoding the AAV5 capsid variant into the cell.

56. The method of any one of claims 51-55, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an S19 cell), or a bacterial cell.

57. A pharmaceutical composition comprising the AAV particle of any one of claims 1-49 and a pharmaceutically acceptable excipient.

58. A method of delivering an AAV particle encoding a modulatory polynucleotide for reducing or eliminating expression of mutated DMPK mRNA to a cell, comprising administering an effective amount of the pharmaceutical composition of claim 57 or the AAV particle of any one of claims 1-49.

59. The method of claim 58, wherein the cell is in a subject, optionally wherein subject has, has been diagnosed with having, or is at risk of having a DMPK-related disorder.

60. The method of claim 59, wherein the DMPK-related disorder is myotonic dystrophy type 1 (DM1).

61. A method of treating a DMPK-related disorder in a subject, comprising administering to the subject an effective amount of die pharmaceutical composition of claim 57 or the AAV particle of any one of claims 1-49.

62. The method of claim 61, wherein the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder.

63. The method of claim 61 or claim 62, wherein the subject has one or more mutations in the DMPK gene.

64. The method of claim 63, wherein the one or more mutations in the DMPK gene comprises a trinucleotide repeat expansion.

65. The method of claim 64, wherein the trinucleotide repeat expansion in the DMPK gene is 50 or more CTG repeats (SEQ ID NO: 6434).

66. The method of any one of claims 61-65, wherein the treating results in prevention of progression of die DMPK-related disorder in the subject.

67. The method of any one of claims 61-66, wherein the treating results in amelioration of at least one symptom of the DMPK-related disorder in the subject.

68. The method of claim 67, wherein the at least one symptom comprises cataracts, myotonia, muscle weakness and wasting, cardiac conduction abnormalities, a myopathic face, learning difficulties, psychosocial problems including depression and / or anxiety, slurred speech, decreased fetal movement in the uterus, polyhydramnios, clubfoot, ventriculomegaly, hypotonia, a tented appearance of the upper lip, dysarthria, intellectual disability, hypotonia, respiratory insufficiency, or a combination thereof.

69. The method of any one of claims 61-68. wherein the DMPK-related disorder is myotonic dystrophy type 1 (DM1).

70. A method of treating myotonic dystrophy type 1 (DM1) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 57 or the AAV particle of any one of claims 1-49.

71. The method of claim 70, wherein the subject has, has been diagnosed with having, or is at risk of having DM1.

72. The method of any one of claims 59-71, wherein the subject is a human.

73. The method of any one of claims 59-72, wherein the pharmaceutical composition or AAV particle is delivered to a cell, tissue, or region of muscle.

74. The method of claim 73, wherein the muscle is one or more of cardiac, smooth, and / or skeletal muscle.

75. The method of any one of claims 59-72. wherein the pharmaceutical composition or AAV particle is delivered to a cell, tissue, or region of the brain.

76. The method of any one of claims 59-72, wherein the pharmaceutical composition or AAV particle is delivered to a cell or tissue of the central nervous system (CNS) in the subject.

77. The method of claim 75 or claim 76. wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus. Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum.

78. The method of any one of claims 59-77, wherein the pharmaceutical composition or AAV particle is delivered to the subject via intravenous administration.

79. The method of any one of claims 59-78, further comprising evaluating, e.g., measuring, the level of modulatory polynucleotide expression, the level of mutated DMPK mRNA expression, and / or the level of normal mRNA splicing, optionally DMPK mRNA splicing, in the subject, e.g., in a cell, tissue, or fluid of the subject.

80. The method of claim 79, wherein evaluating the subject’s level of modulatory polynucleotide expression, the subject’s level of mutated DMPK mRNA expression, and / or the subject’s level of normal mRNA splicing, optionally DMPK mRNA splicing, is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of modulatory polynucleotide expression, the subject’s level of mutated DMPK mRNA expression, and / or the subject’s level of normal mRNA splicing, optionally DMPK mRNA splicing, prior to administration is compared to the subject’s level of modulatory polynucleotide expression, the subject’slevel of mutated DMPK mRNA expression, and / or the subject's level of normal mRNA splicing, optionally DMPK mRNA splicing, subsequent to administration.

81. The method of claim 79 or claim 80, wherein the cell or tissue of the subject is a muscle cell or tissue.

82. The method of any one of claims 59-81, wherein the subject's level of mutated DMPK mRNA expression subsequent to administration of the pharmaceutical composition or AAV particle is decreased relative to the subject’s level of mutated DMPK mRNA expression prior to administration of the pharmaceutical composition or AAV particle.

83. The method of any one of claims 59-81. wherein administering the pharmaceutical composition or AAV particle to the subject results in:(i) an increase in the number and / or level of viral genomes (VG) per cell in a muscle cell or tissue of the subject relative to the number and / or level of VG per cell in a non-muscle cell or tissue of the subject;(ii) a decrease in mutated DMPK mRNA expression in a muscle cell or tissue of the subject relative to baseline and / or relative to mutated DMPK mRNA expression in a muscle cell or tissue of an individual with a DMPK-related disorder who has not been administered the pharmaceutical composition or AAV particle; and / or(iii) an increase in normal mRNA splicing, optionally DMPK mRNA splicing, in a muscle cell or tissue of the subject relative to baseline and / or relative to normal mRNA splicing, optionally DMPK mRNA splicing, in a muscle cell or tissue of an individual with a DMPK-related disorder who has not been administered the pharmaceutical composition or AAV particle.

84. The method of any one of claims 59-83, further comprising administering to the subject at least one additional therapeutic agent and / or therapy.

85. The method of claim 84, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating a DMPK-related disorder, optionally wherein the at least one additional therapeutic agent and / or therapy comprises an anti-diabetic drug, an anti-myotonic drug (e.g.. mexiletine). a non-steroidal anti-inflammatory drug, or a combination thereof.

86. The method of any one of claims 59-85. further comprising administering an immunosuppressant to the subject.

87. The method of claim 86, wherein the immunosuppressant comprises a corticosteroid (for example, and without limitation, prednisone, prednisolone, methylprednisolone, and / or dexamethasone).adrenocorticotropic hormone, rapamycin, mycophenolate mofetil, tacrolimus, rituximab, eculizumab hydroxychloroquine, alemtuzumab, hydroxyurea, fludarabine, and / or busulfan.

88. The pharmaceutical composition of claim 57 or the AAV particle of any one of claims 1-49 for use in a method of treating a disorder according to any one of claims 61-87.

89. The pharmaceutical composition of claim 57 or the AAV particle of any one of claims 1-49 for use in treating a DMPK-related disorder in a subject, optionally wherein the DMPK-related disorder is myotonic dystrophy type 1.

90. The pharmaceutical composition or AAV particle for use of claim 89. wherein the subject has, has been diagnosed with having, or is at risk of having the DMPK-related disorder, optionally wherein the DMPK-related disorder is myotonic dystrophy type 1.

91. Use of the pharmaceutical composition of claim 57 or the AAV particle of any one of claims 1-49 in the manufacture of a medicament for treating a DMPK-related disorder in a subject, optionally wherein the DMPK-related disorder is myotonic dystrophy type 1.

92. The use of claim 91, wherein the subject has. has been diagnosed with having, or is at risk of having the DMPK-related disorder, optionally wherein the DMPK-related disorder is myotonic dystrophy type 1.- n -

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