Compositions and methods for the treatment of disorders related to CDKL5 deficiency

Abstract

The disclosure relates to compositions and methods for altering, e.g., enhancing, the level of CDKL5 protein via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful in the treatment of a CDKL5-related disorder, e.g., a CDKL5-related neurodegenerative or neuromuscular disorder.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF DISORDERSRELATED TO CDKL5 DEFICIENCYRELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 519,963, 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 0096-00304 SL,” was created on June 18, 2024, and is 2,597.723 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] Described herein are compositions and methods relating to adeno-associated virus (AAV) viral particles for the delivery of polynucleotides, e.g.. polynucleotides encoding cyclin-dependent kinase-like 5 (CDKL5) proteins and peptides for use in the treatment of a CDKL5-related disorder such as a CDK.L5 -related neurodegenerative or neuromuscular disorder (e.g., CDKL5 deficiency disorder (CDD). developmental and epileptic encephalopathy 2, or atypical Rett syndrome (collectively, CDKL5- related disorders)). In some embodiments, compositions described herein may be used to treat a subject in need thereof, such as a human subject diagnosed with a CDKL5-related disorder or other condition resulting from a deficiency in the quantity' and / or function of CDKL5 protein, or as a research tool in the study of diseases or conditions in cells or animal models of a CDKL5 -related disorder.

[0004] BACKGROUND

[0005] Cyclin-dependent kinase-like 5 (CDKL5) is a serine / threonine protein kinase. It is encoded by the gene CDKL5 (Ensembl Gene ID No. ENSG00000008086). which is located on the X chromosome.

[0006] The CDKL5 protein is an enzy me and is thought to play an important role in brain development and regulation of response to oxidative stress. CDKL5 is thought to be expressed throughout the cell, including in the nucleus and cytoplasm of soma and dendrites.

[0007] CDKL5 is responsible for phosphorylation of a number of targets. CDKL5 may target and phosphory late the gene MECP2, which has been characterized as important in tire function of neurons and other brain cells, and in the maintenance of neuronal synapses, and is thought to be the causative agent for Rett syndrome. CDKL5 may also target and phosphorylate CEP 131, which is thought to play a role in cell proliferation. CDKL5 may also target and phosphorylate MAP IS, DLG5. EB2, and / or ARHGEF. which are microtubule associated proteins, thought to play roles in neuronal division,differentiation, migration, and neurite growth. CDKL5 may also target and phosphory late AKT and mTOR, which are thought to play roles in cell proliferation, migration, and development. CDKL5 may act on targets in both the cytoplasm and in the nucleus of the cell. In the cytoplasm, CDKL5 may affect RAC1 signaling and dendritic arborization. In the nucleus, CDKL5 activity may mediate effects on gene expression, DNA methylation, mRNA splicing, and more, through targets such as MeCP2, DNM1. or SC35.

[0008] Without wishing to be bound by any particular theory, CDKL5 may be involved in the formation, growth, and migration of neurons. It may also play a role in cell division and / or transmission of chemical signals at neuronal synapses.

[0009] Mutations in CDKL5 are known to cause disease in subjects, e.g., human subjects. For example, CDKL5 mutations are one of the most common causes for genetic epilepsies, including epileptic encephalopathies. CDK5-related epilepsies are often early -onset epilepsies that manifest in infants before 3 months of age. Epilepsy may occur in three typical stages: (i) early epilepsy with focal seizures at the age of 4 weeks to 6 months, (ii) epileptic encephalopathy with infantile spasms in infancy and early childhood and (iii) tonic seizures and late myoclonic epilepsy in childhood. Movement disorders (hand-wringing stereotypy, chorea and ballisms) are also a reported feature. Developmental epileptic encephalopathies associated with CDKL5 mutations may be severe and treatment-resistant.

[0010] CDKL5 mutations have been associated with disorders such as infantile spasms (also called West syndrome). Lennox Gastaut syndrome, Rett syndrome, autism, early-onset encephalopathy, and X- linked mental retardation. CDKL5 mutations may also cause a clinical phenotype that overlaps with Rett syndrome.[OH] In addition, CDKL5 mutations may lead to CDKL5 deficiency disorder (CDD), a neurodevelopmental disorder characterized by nervous system symptoms including epilepsy (e.g., early- onset epilepsy ), low muscle tone, and developmental challenges. CDD may be characterized by autism, deficits in cognition, limited motor skills, sleep difficulties, visual impairment, and / or gastrointestinal reflux.

[0012] CDD can manifest with a broad array of clinical manifestations. Clinical manifestations of CDD comprise behavioral symptoms such as episodes of laughing or crying that occur for what appears to be no reason, hypersensitivity to touch, and disrupted sleep. Clinical manifestations also comprise facial appearance changes including microcephaly; a high, broad forehead; large, deep-set eyes; smaller- than normal space between the nose and upper lip; an upturned nose; full lips: and widely spaced teeth. Further clinical manifestations include difficulties standing and walking; small, cold feet; lack of or poor eye contact; frequent sideways glances: and cortical visual impairment or cortical blindness. Other manifestations include bruxism; limited or absent speech; difficulties eating; stereotypies; limited ability to make small, focused hand movements; gastroesophageal reflux; and constipation.

[0013] CDD has an incidence of 1 in 42000 births in the USA. and 85% of cases occur in females. Typically. CDD patients are fully reliant on caregivers for the duration of their lives.

[0014] CDD is typically caused by de novo mutations in CDKL5. CDKL5 mutations in CDD patients result in a reduced amount of functional CDKL5 protein.

[0015] Existing treatments for patients with CDD focus on alleviating symptoms such as seizures. To date, there are limited treatments available for patients with CDD, and delivery of treatments to the central nervous system (CNS) remains a significant challenge in the development of new and effective therapies. The current standard of care for CDD is first line treatment with an anti-epileptic drug. Antiepileptic drugs are known in the art and include bromide, felbamate, valproate, and levetiracetam.However, even bromide or felbamate, which yield the highest responder rates of known treatments, are still poorly effective (e.g., 20% and 33% responder rates, respectively, at 12 months). Second line treatment for refractory patients comprises first line treatment plus additional anti-epileptic drugs such as clobazam and / or lamotrigine in combination with ganaxolone. However, ganaxolone has been reported to have short durability in treating subjects with CDD. Third line treatment introduces additional antiepileptic drugs, such as topiramate, and / or alternative interventions, such as ketogenic diet and / or vagal nerve stimulation. However, seizures in CDD are commonly refractory to known treatments.

[0016] Therefore, a need remains for improved therapies and treatments that target the cause of CDD. In particular, there remains a need for pharmaceutical compositions and methods to treat CDD that can be delivered to the CNS for the treatment of CDD, and to ameliorate deficiencies of CDKL5 in subjects, e.g., human subjects.

[0017] Adeno-associated viruses (AAVs) have emerged as a widely studied and utilized viral particles for delivery of therapeutically effective polypeptides to mammalian cells. See, e.g., Tratschin et al., Mol. Cell Biol., 5(11):3251-3260 (1985) and Grimm et al., Hum. Gene Then, 10(15):2445-2450 (1999), the contents of each of which are incorporated herein by reference in their entirety.

[0018] There remains a need for effective methods of treatment using AAV capsids that are capable of delivering a pay load of interest, e.g., human CDKL5, to a target cell or tissue, e.g., a CNS cell or tissue.SUMMARY

[0019] The present disclosure addresses these challenges by providing AAV-based compositions, AAV-based compositions for use in methods for treating a CDKL5-related disorder in subjects, and methods for treating a CDKL5-related disorder in subjects. Disclosed herein are compositions and methods directed to AAV-based gene delivery of CDKL5 to ameliorate loss-of-function. Disclosed herein are compositions and methods directed to AAV-based gene delivery of CDKL5 to improve neurotransmitter release. The compositions and methods are useful to improve presynaptic vesicle release, and to slow, halt, or reverse neurodegenerative and other symptoms of CDKL5 deficiency disorder (CDD) or a CDKL5-related disorder in a subject (e.g., a subject having one or more mutations in CDKL5).

[0020] In some aspects, the present disclosure provides an AAV particle comprising an AAV capsid and a nucleotide sequence encoding a CDKL5 protein, also referred to herein as a CDKL5 -encodingsequence. In some embodiments, the nucleotide sequence encoding a CDKL5 protein is comprised in a viral genome. In some embodiments, the CDKL5 protein is a human CDKL5 protein. In some embodiments, the CDKL5 protein is a wildtype human CDKL5 protein. In some embodiments, the AAV particle comprises a viral genome encoding the CDKL5 protein (e.g., a human CDKL5 protein) and the AAV capsid is an AAV capsid variant. In some embodiments, the AAV capsid variant is an AAV5 capsid variant.

[0021] In some embodiments, the AAV capsid variant (e.g., an AAV5 capsid variant) comprises a peptide that has replaced amino acid position 577 as numbered according to SEQ ID NO: 138 . In some embodiments, the AAV capsid variant is an AAV5 capsid variant comprising a peptide comprising the amino acid sequence of VQK in loop VIII, wherein, optionally, the amino acid sequence of VQK has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) in loop VIII, or a peptide comprising one. two, or three — but no more than three — substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein, optionally, the amino acid sequence has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) in loop VIII, wherein, optionally, the peptide has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the peptide is present in a VP1 protein, a VP2 protein, and / or a VP3 protein of the AAV capsid variant. In some embodiments, the peptide is present in the VP1, VP2, and VP3 proteins of the AAV capsid variant.

[0022] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a cyclin- dependent kinase-like 5 (CDKL5)-encoding sequence; and wherein the AAV capsid variant comprises an amino acid sequence having the formula [N2]-[N3], wherein: (i) [N2] comprises positions Xi, X2, X3, X4, and X3, wherein: (a) position Xi is Y, N, or C; (b) position X2is P, K, T, or Q; (c) position X3is A or P; (d) position X4 is E, S, or A; and (e) position X5 is V, L, or E; and (ii) [N3] comprises the amino acid sequence VQK, EQK, VKK, VHK, VQQ, or LQK; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739. or an amino acid sequence at least 95% identical thereto.

[0023] 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 AAV capsid variant is an AAV5 capsid variant comprising [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] comprises the amino acid sequence YP. YPA. YPAE (SEQ ID NO: 21), or YPAEV (SEQ ID NO: 1). In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, [N2]-[N3]comprises the amino acid sequence AEVVQK (SEQ ID NO: 36) or PAEVVQK (SEQ ID NO: 20). In some embodiments, [N2]-[N3] comprises the amino acid sequence YP AEVVQK (SEQ ID NO: 943).

[0024] In some embodiments, the AAV capsid variant further comprises [Nl] comprising positions XD, XE, and XF, wherein: (a) position XD of [Nl] is Q, T, S, A, I, L, or H; (b) position XE of [Nl] is S, G, A, or R: and (c) position XF of [Nl] is S, K, L, R, A. or T; wherein [Nl] immediately precedes [N2]- [N3], In some embodiments, [Nl] comprises the amino acid sequence QS, SS, or QSS. In some embodiments, [N1]-[N2] comprises the amino acid sequence QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] comprises the amino acid sequence SSYPAEVVQ (SEQ ID NO: 121) or QSSYP AEVVQK (SEQ ID NO: 150).

[0025] In some embodiments, the AAV capsid variant further comprises [NO] comprising positions XA. XB. and Xc. wherein: (a) position XAof [NO] is T, I, or N; (b) position XBof [NO] is N; and (c) position Xc of [NO] is N. T, S, or K; wherein [NO] immediately precedes [Nl], In some embodiments, [NO] comprises the amino acid sequence TN, NN. or TNN. In some embodiments, [NO]-[N1] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183). In some embodiments, [NO]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYP AEVVQK (SEQ ID NO: 500).

[0026] In some embodiments, 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; wherein [N4] is present immediately subsequent to [N3], In some embodiments, [N4] comprises the amino acid sequence TA.

[0027] In some embodiments, [NO]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence TNNQSSYP AEVVQKTA (SEQ ID NO: 1533). In some embodiments, [NO]-[N1]-[N2]-[N3]-[N4] 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.

[0028] In some embodiments, [NO] is present at amino acids corresponding to positions 571-573 of tire amino acid sequence of SEQ ID NO: 982; [Nl] is present at amino acids corresponding to positions 574-576 of the amino acid sequence of SEQ ID NO: 982; [N2] is present at amino acids corresponding to positions 577- 581 of the amino acid sequence of SEQ ID NO: 982; [N3] is present at amino acids corresponding to positions 582-584 of the amino acid sequence of SEQ ID NO: 982; and [N4] is present at amino acids corresponding to positions 585-586 of the amino acid sequence of SEQ ID NO: 982.

[0029] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises at least 4, 5, 6, 7. or 8 consecutive amino acids from the amino acid sequence YP AEVVQK (SEQ ID NO: 943).

[0030] In some embodiments, (i) the at least 4 consecutive amino acids comprise the amino acid sequence YPAE (SEQ ID NO: 21). optionally present at amino acids corresponding to positions 577-580 of the amino acid sequence of SEQ ID NO: 982; (ii) the at least 5 consecutive amino acids comprise theamino acid sequence YPAEV (SEQ ID NO: 1), optionally present at amino acids corresponding to positions 577-581 of the amino acid sequence of SEQ ID NO: 982; (iii) the at least 6 consecutive amino acids comprise the amino acid sequence YPAEVV (SEQ ID NO: 725), optionally present at amino acids corresponding to positions 577-582 of the amino acid sequence of SEQ ID NO: 982; or (iv) the at least 7 consecutive amino acids comprise tire amino acid sequence YPAEVVQ (SEQ ID NO: 726), optionally present at amino acids corresponding to positions 577-583 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) present at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982.

[0031] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence; and (ii) an AAV capsid variant comprising an ammo acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739. wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV capsid variant further comprises (i) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (ii) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0032] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a cyclin- dependent kinase-like 5 (CDKL5)-encoding sequence and the AAV capsid variant comprises (i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0033] In some embodiments, the AAV variant capsid comprises (i) the amino acid sequence of SEQ ID NO: 982; (ii) the amino acid sequence of SEQ ID NO: 738; and / or (iii) the amino acid sequence of SEQ ID NO: 739.

[0034] In some embodiments, the viral genome encodes a wildtype CDKL5 protein or a fragment thereof. In some embodiments, the viral genome encodes a human CDKL5 protein.

[0035] In some embodiments, the CDKL5 protein comprises the amino acid sequence of SEQ ID NO: 6413. In some embodiments, the CDKL5-encoding sequence is at least 90% identical (e.g.. at least90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or is 100% identical) to the nucleotide sequence of SEQ ID NO: 6414. In some embodiments, the CDKL5 -encoding sequence is at least 95% identical to the nucleotide sequence of SEQ ID NO: 6414. In some embodiments, the CDKL5 -encoding sequence is at least 99% identical to the nucleotide sequence of SEQ ID NO: 6414. In some embodiments, the CDKL5 -encoding sequence comprises the nucleotide sequence of SEQ ID NO: 6414. In some embodiments, the CDKL5 -encoding sequence consists of the nucleotide sequence of SEQ ID NO: 6414. In some embodiments, the viral genome comprises a promoter operably linked to the CDKL5- encoding sequence.

[0036] 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 CDKL5 -encoding sequence. In some embodiments, the viral genome comprises an ITR sequence positioned 3’ relative to the CDKL5-encoding sequence. In some embodiments, the viral genome comprises an ITR sequence positioned 5’ relative to the CDKL5 -encoding sequence, and an ITR sequence positioned 3’ relative to the CDKL5-encoding sequence.

[0037] In 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.

[0038] In some aspects, the present disclosure provides a method of making an AAV particle disclosed herein, the method comprising: (i) providing a cell comprising the viral genome comprising a CDKL5-encoding sequence and a nucleic acid encoding the AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the recombinant AAV particle.

[0039] In some embodiments of a method of making an AAV particle, the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and wherein the AAV capsid variant comprises (i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence having at least 90% identity (e.g., at least 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); or (iii) the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence having at least 90% identity (e.g., at least 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0040] In some embodiments of a method of making an AAV particle, the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 90% identical (e.g., atleast 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or die amino acid sequence of SEQ ID NO: 739.

[0041] In some embodiments of a method of making an AAV particle, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO: 739.

[0042] In some embodiments, die method of making an AAV particle comprises, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell. In some embodiments, the method of making an AAV particle comprises, prior to step (i), introducing the nucleic acid encoding the AAV 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.

[0043] In some aspects, the present disclosure provides a pharmaceutical composition comprising an AAV particle disclosed herein and a pharmaceutically acceptable excipient.

[0044] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a CDKL5 protein 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 CDKL5-related disorder. In some embodiments, the CDKL5-related disorder is a CDKL5-related neurode generative or neuromuscular disorder. In some embodiments, the subject has. has been diagnosed with having, or is at risk of having CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early-onset encephalopathy, or X- linked mental retardation.

[0045] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a CDKL5 protein 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 CDKL5-related disorder. In some embodiments, the CDKL5-related disorder is a CD KL5 -related neurodegenerative or neuromuscular disorder. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early-onset encephalopathy, or X-linked mental retardation.

[0046] In some aspects, the present disclosure provides a method of treating a CDKL5-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 CDKL5-related disorder. In some embodiments, the CDKL5-related disorder is a CDKL5-related neurodegenerative or neuromuscular disorder. In someembodiments, the CDKL5 -related neurodegenerative or neuromuscular disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett sy ndrome, autism, developmental and epileptic encephalopathy 2, early-onset encephalopathy, or X-linked mental retardation.

[0047] In some aspects, the present disclosure provides a method of treating CDKL5 deficiency disorder (CDD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having CDD.

[0048] In some embodiments, the subject has one or more mutations in the CDKL5 gene. In some embodiments, the subject has lower CDKL5 activity as compared to CDKL5 activity in an individual who does not have a CDKL5-related disorder. In some embodiments, the treating results in prevention of progression of the disorder in the subject. In some embodiments, the treating results in amelioration of at least one symptom of the disorder, as indicated by one or more biomarkers. In some embodiments, the one or more biomarkers comprises a marker of CDKL5 activity, e.g., as measured by phosphorylation levels of substrate proteins (e.g., MECP2) or as measured by mass spectrometry' . In some embodiments, the at least one symptom comprises epilepsy (e.g., early-onset epilepsy); autism; deficits in cognition; limited motor skills; sleep difficulties; visual impairment; low muscle tone; gastrointestinal reflux; behavioral symptoms (including episodes of laughing or crying that occur for what appears to be no reason, hypersensitivity to touch, and / or disrupted sleep); facial appearance changes (including microcephaly; a high, broad forehead; large, deep-set eyes; smaller-than normal space between the nose and upper lip; an upturned nose; and / or full lips and widely-spaced teeth); difficulties standing and walking; small, cold feet; lack of or poor eye contact; frequent sideways glances; cortical visual impairment or cortical blindness; bruxism; limited or absent speech; difficulties eating; stereotypies; limited ability to make small, focused hand movements; gastroesophageal reflux; constipation; or a combination thereof.

[0049] In some embodiments, the subject is a human.

[0050] In some embodiments, the AAV particle or the pharmaceutical composition is delivered to a cell, tissue, or region of the central nervous system (CNS) and / or the peripheral nervous system (PNS) in the subject. In some embodiments, the cell, tissue, or region of the CNS and / or the PNS is a cell (e g., a neuron), tissue, or region of the neocortex, spinal cord, dorsal root ganglion, globus pallidus. putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei). In some embodiments, the AAV particle or the pharmacal composition is delivered to the subject via intravenous administration.

[0051] In some embodiments, the method of delivering or treating further comprises evaluating, e.g.. measuring, the level of CDKL5 expression, e.g., CDKL5 gene expression, CDKL5 mRNA expression, and / or CDKL5 protein expression, in the subject, e.g.. in a cell, tissue, or fluid of the subject. In some embodiments, the level of CDKL5 protein expression is measured by an ELISA, a Western blot, or animmunohistochemistry assay. In some embodiments, evaluating the level of CDKL5 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject's level of CDKL5 expression prior to administration is compared to the subject's level of CDKL5 expression subsequent to administration.

[0052] hi some embodiments, the method of delivering or treating further comprises evaluating the level of CDKL5 expression in a cell or tissue of the CNS and / or the PNS. In some embodiments, the cell or tissue of the CNS and / or PNS is a cell (e.g., a neuron) or tissue of the neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei).

[0053] In some embodiments, the subject’s level of CDKL5 protein expression subsequent to administration is increased relative to the subject’s level of CDKL5 protein expression prior to administration.

[0054] In some embodiments, the method of treating or delivering further comprises evaluating, e.g.. measuring, the level of CDKL5 activity in the subject, e.g., in a cell or tissue of the subject.

[0055] In some embodiments, administering the pharmaceutical composition or AAV particle to the subject results in an increase in: (i) the level of CDKL5 activity in a cell, tissue (e g., a cell or tissue of the CNS and / or the PNS, e.g.. neocortex, spinal cord, dorsal root ganglion, globus pallidus. putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g.. Purkinje cell layer and deep cerebellar nuclei), and / or neurons, and / or fluid (e.g.. CSF and / or serum) of the subject relative to baseline and / or relative to CDKL5 activity in a cell, tissue, or fluid of an individual with a CDKL5-related disorder who has not been administered the pharmaceutical composition or AAV particle; (ii) the number and / or level of viral genomes (VG) per cell level in a tissue of the CNS and / or the PNS, e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei), and / or neurons of the subject, relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or (iii) the level of CDKL5 protein or CDKL5 gene expression in a cell or tissue (e.g., a cell or tissue of the CNS and / or the PNS, e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen. caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei), and / or neurons of the subject relative to baseline and / or CDKL5 protein or CDKL5 gene expression in a cell or tissue of an individual with a CDKL5 -related disorder who has not been administered the pharmaceutical composition or AAV particle.

[0056] In some embodiments, the method of delivering or treating further comprises administering to the subject at least one additional 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 CDKL5 -related disorder. In some embodiments, the at least one additional therapeutic agent and / or therapy comprisesone or more anti-epileptic drugs (e.g., valproate, levetiracetam, clobazam, lamotrigine, ganaxolone, topiramate, bromide, felbamate, phenobarbital, or a combination thereof).

[0057] 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), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

[0058] In some aspects, the present disclosure provides a pharmaceutical composition or AAV particle disclosed herein for use in a method of treating a disorder disclosed herein.

[0059] In some aspects, the present disclosure provides a pharmaceutical composition or AAV particle disclosed herein for use in the treatment of a CDKL5 -related disorder; optionally wherein the CDKL5-related disorder is CDK.L5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2. infantile spasms (e.g., West syndrome). Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation. In some embodiments, the subject has. has been diagnosed with having, or is at risk of having the CDKL5-related disorder, optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD). developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.

[0060] 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 the treatment of a CDKL5 -related disorder; optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation. In some embodiments, die subject has, has been diagnosed with having, or is at risk of having the CDKL5-related disorder, optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lemiox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.Enumerated Embodiments1. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises an amino sequence comprising the following formula:[N2]-[N3], wherein:(i) [N2] comprises positions Xi, X2, X3, X4, and X5, wherein:(a) position Xi is Y, N. C, or T:(b) position X2 is P. E, K. T, or Q;(c) position Xs 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.2. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g.. encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises an amino sequence comprising the following fonnula:[N2]-[N3], wherein:(i) [N2] comprises positions Xi, X2, X3, X4, and X5, wherein:(a) position Xi is Y, N. or C;(b) position X2 is P. K, T. or Q;(c) position X3 is A or P;(d) position X4 is E, S, or A; and(e) position X5 is V, L, or E; and(ii) [N3J comprises the amino acid sequence of VQK, EQK, VKK, VHK. VQQ. or LQK.3. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, tw o. 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 [N41 comprising TA, PA, or NA.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 Xs 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 YQ AEE (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) [N2J 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), T AEVVQK (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, 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).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 amino 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 XD is Q, T, S, A, I, L, or H;(b) position XE is S, G, A, or R; and(c) position XF is 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 [N 1 ]-[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 ID NO: 154). QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEWQK (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 (SEQID 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 XDis 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 the 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), 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);(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 1NNQSSYPAEVVQK (SEQ ID NO: 543).35. The AAV particle of any one of embodiments 1-34, which further comprises [N4], wherein [N4] comprises positions XGand XH. wherein:(a) position XGis T, P, or N; and(b) position XHis 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: 1602). 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 [N0]-[N 1]-[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]- [N3]-[N4] 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. Aii AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant). wherein the AAV capsid variant comprises an amino sequence comprising the following formula: [B]-[C] (SEQ ID NO: 6420). 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 X is S, K. L, R, or A; and(ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).42. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, tw o, 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 [Df wherein | ID | comprises the amino acid sequence of TA or PA; and optionally wherein [CJ replaces position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.43. 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).Q ASYPAEVVQK (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 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 amino acid sequence of SEQ ID NO: 138 or 982.52. The AAV particle of any one of embodiments 41-51, which further comprises [A], wherein [A] comprises positions XA, XB, and Xc, wherein:(a) position XAis T, I, or N;(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 die 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), 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);(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 orN), 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 the 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 X i and Xs. wherein:(a) position X4 is T or N; and(b) position Xs 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), 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);(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 a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV 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 X2 is Q, T, P. or E;(c) position Xs 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.68. An AAV particle comprising a viral genome encoding a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant). 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.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), AEE VQK (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). PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), 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).76. The AAV particle of embodiment 1 or any one of embodiments 57-75, wherein [N2]-[N3] is or comprises:(i) 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);(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 [N2]-[N3] 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 ammo 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 amino 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 amino 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 XE is S, L, A. or T; and(c) position XFis S, Y, 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).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 [N1]-[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, 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).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 [NO]-[N1]-[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; 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).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 a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), 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 Xs is E or D; and(d) position X4 is V or E.100. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, two, three, four, or all of:(i) an [K0], 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.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 [K2J 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 [K0], wherein [K0] 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 [K0]-[Kl]- [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 [KO]-[K1]- [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:(i) 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);(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 any one of embodiments 100 or any one of embodiments 121-123, wherein [KO]-[K1]-[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 a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises [B]-[C] (SEQ ID NO: 6421), 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 Xs is S. Y, or T; and(ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943).126. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, tw o. 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; andoptionally wherein [C] replaces position 577 relative to reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.127. 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 XB is 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 [AJ -[BJ -[CJ 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 the ammo 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). TNS SLY YPAEVVQKTA (SEQ ID NO: 2066). TNTS AT YPAEVVQKTA (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 positions571-592 (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 [NO]-[N1]-[N2]-[N3]-[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: 982.149. 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 amino 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 [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: 982.169. 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 amino 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 [NO]-[N1]-[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 [NO]-[N1]-[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) XAof [NO] is present at position 571, XBof [NO] is present at position 572. and Xcof [NO] is present at position 573, numbered according to SEQ ID NO: 982;(ii) XDof [Nl] is present at position 574, X|. of [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 78, X3 of [N2] is present at position 579, X4 of [N2] is present at position 580, and Xs 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) XGof [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 ID NO: 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-terminus 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-tenninus to C -terminus [N0]-[Nl]-[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 73, 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: 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 73, 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 ammo 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]-[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: 138.215. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-214, wherein [BJ -|CJ-IDJ 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 576, 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, A 79, 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 tire 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: 982.227. 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, XDof [A] is present at position 572, and Xcof [A] is present at position 573. numbered according to SEQ ID NO: 982;(ii) Xi of [B] is present at position 574, X2 of [B] is present at position 575, and X3 of [B] 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 Xs of [D] is present at position 586, 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 [C] .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 the 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 the 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 tire 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 ammo 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 [KO] 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, and A579), 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 [K4] 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-tenninus to C-tenninus [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-tenninus [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-tenninus [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-terminus 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-tenninus to C -terminus [KO]-[K1]-[K2]-[K3]-[K4],267. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) 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, 14, or 23-28;(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, 14, or 23-28;(c) 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 provided in Tables 1, 2A, 2B, 14, or 23-28; 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, 14, or 23-28.268. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) 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 ofany 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 1610-1624.269. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising:(a) the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080;(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 NOs: 943 or any one of SEQ ID NOs: 2064-2080;(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 NOs: 943 or any one of SEQ ID NOs: 2064-2080; 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 NOs: 943 or any one of SEQ ID NOs: 2064-2080.270. An AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)- encoding sequence (e.g., encoding a human CDKL5 protein) 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, 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: 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 1591.271. 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) YTPSLVQK (SEQ ID NO: 952).279. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein:(i) the 3 consecutive amino acids comprise YPP;(ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22);(iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2);(iv) the 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729);(v) the 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 3 consecutive amino acids comprise YPP;(ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22);(iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2);(iv) the 6 consecutive amino acids comprise YPPSLE (SEQ ID NO: 733);(v) the 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 3 consecutive amino acids comprise YPP;(ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22);(iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2);(iv) the 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729);(v) the 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, two, 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 ammo 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: 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 by:(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 267-277, 282. 285, and 289, wherein 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;(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;(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; 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: 2024-2063.291. 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 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;(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, 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; 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, or Y;(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, orN;(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 ammo 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: 138.301. 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 the 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 T l- ll , 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 die 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 the 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 die AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein die ammo 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. 272, 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 267-277, 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 T l- ll , 282, 285, 288, 289, and 294-309, wherein the 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 267-277, 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 the 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 die 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 267-277, 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 T l- ll , 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 the 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 die 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 267-277, 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, or 6 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 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 ofSEQ 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 tire 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 267-277, 282. 285, 288, 289. 294-306, 321-328. and 333-335. 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), 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 T l- ll , 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, 267-277, 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, 'Lfil-L' Tl, 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, 267-277, 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, 267-277, 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, 1 -1T1. 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 cord cell, 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 cordcell, 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 the 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 tire 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 two to three species are Macaca fascicularis. Chlorocebus sabaeus, CalUthrixjacchus, 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 the 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 pay load 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 die 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: 982.375. 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 heart 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 382-443 are intentionally absent.]444. A cell, e.g., ahost cell, comprising the AAV particle of any one of embodiments 1-381.445. The cell of embodiment 444, wherein the cell is a mammalian cell or an insect cell.446. The cell of embodiment 444 or embodiment 445, wherein the cell is a muscle cell (e.g., a cell of the heart, diaphragm, or quadriceps).447. The cell of embodiment 444 or embodiment 445. wherein the cell is a cell of the CNS and / or the PNS.- TI -448. The cell of embodiment 447, wherein the cell is a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, oligodendrocyte.449. The cell of any embodiment 447 or embodiment 448, wherein the cell is a cell of the neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei).450. A method of making an AAV particle of any one of the embodiments disclosed herein, comprising(i) providing a cell comprising a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence 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.453. The method of embodiment 452, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule.454. A pharmaceutical composition comprising the AAV particle of any one of embodiments 1-381, and a pharmaceutically acceptable excipient.455. A mediod of delivering a CDKL5 protein to a subject, comprising administering an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381.456. The method of embodiment 455. wherein the CDKL5 protein is delivered to a cell or tissue of the CNS (i.e., a cell or tissue of a brain or spinal cord region) and / or the PNS.457. The method of embodiment 456, wherein the cell or tissue of the CNS and / or the PNS is a cell (e.g, a neuron) or tissue of the neocortex, spinal cord, dorsal root ganglion, globus pallidus. putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei).[Embodiment 458 is intentionally absent.]459. The method of embodiment 455 or 456, wherein the cell or tissue of the CNS comprises a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, or an oligodendroc te.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 neurological (e.g.. a neurodegenerative disorder) or a neuromuscular disorder.463. The method of embodiment 460 or 461. wherein the subject has, has been diagnosed with having, or is at risk of having a CDKL5-related disorder.464. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early-onset encephalopathy, or X- linked mental retardation.465. A method of treating a CDKL5-related disorder in a subject, comprising administering to the subject an effective amount of die 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 CDKL5 -related disorder.466. A method of treating a neurological disorder, e.g., a neurodegenerative 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 die neurological disorder.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, neurological disorder, neurodegenerative disorder, muscular disorder, or neuromuscular disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early-onset encephalopathy, or X-linked mental retardation.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 465-471, wherein the AAV particle is administered to the subject via intra-cistcrna magna injection (ICM).475. The method of any one of embodiments 465-471, wherein the AAV particle is administered to the subject intraarterially.476. The method of any one of embodiments 465-474. wherein administration of the AAV particle results in an increased presence, level, and / or activity of a CDKL5 gene, mRNA, protein, or a combination thereof.477. The pharmacal 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 neurological disorder, a neurodegenerative disorder, a muscular disorder, a neuromuscular disorder, or a neuro-oncological disorder.479. The pharmacal 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 neurological disorder, a neurodegenerative disorder, a muscular disorder, a neuromuscular disorder, or a neuro- oncological disorder.482. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the encoded CDKL5 protein comprises an amino acid sequence of SEQ ID NO: 6413, or an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%, or 99% identical) to SEQ ID NO: 6413, wherein, optionally, the encoded CDKL5 protein is a human CDKL5 protein.483. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the CDKL5 -encoding sequence comprises a nucleotide sequence that is at least 80% identical (e.g., at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 6414.484. The AAV particle, pharmacal composition, cell, method, or use of any one of the embodiments provided herein, wherein the CDKL5 -encoding sequence comprises a nucleotide sequence that is at least 90% (e.g.. at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the nucleotide sequence of SEQ ID NO: 6414.485. The AAV particle of embodiment 483 or embodiment 484, wherein the CDKL5 -encoding sequence comprises a nucleotide sequence at least 95% identical to SEQ ID NO: 6414.486. The AAV particle of any one of embodiments 483-485. wherein the CDKL5 -encoding sequence comprises the nucleotide sequence of SEQ ID NO: 6414.487. The AAV particle of any one of embodiments 483-486, wherein the CDKL5 -encoding sequence consists of the nucleotide sequence of SEQ ID NO: 6414.488. The AAV particle of any one of embodiments 482-487, wherein the AAV capsid variant comprises at least 4, 5, 6. 7, or 8 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). and wherein the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 739.489. The AAV particle of embodiment 488. wherein:(i) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21), optionally wherein YPAE (SEQ ID NO: 21) is present at positions 577-580 numbered according to SEQ ID NO: 982;(ii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1). optionally wherein YPAEV (SEQ ID NO: 1) is present at positions 577-581 numbered according to SEQ ID NO: 982;(iii) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725). optionally wherein YPAEVV (SEQ ID NO: 725) is present at positions 577-582 numbered according to SEQ ID NO: 982; or(iv) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726), optionally wherein YPAEVVQ (SEQ ID NO: 726) is present at positions 577-583 numbered according to SEQ ID NO: 982.490. The AAV particle of embodiment 488 or 489, 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: 982.491. The AAV particle of any one of embodiments 488-490, wherein the AAV capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 95% identity to SEQ IDNO: 982; or(ii) a VP2 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 738.492. The AAV particle of any one of embodiments 488-491, wherein the AAV capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 99% identity to SEQ IDNO: 982;(ii) a VP2 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 738; or(iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 739.493. The AAV particle of any one of embodiments 488-492, wherein the AAV capsid variant 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; or(iii) a VP3 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 739; or wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 984 or a sequence at least 90% identical thereto.494. The AAV particle of any one of the embodiments provided herein, wherein the viral genome further comprises a promoter operably linked to the CDKL5 -encoding sequence.[Embodiments 496-513 are intentionally absent.]514. The AAV particle of any one of embodiments 494-513, wherein the viral genome further comprises at least one inverted terminal repeat (ITR) region, optionally wherein the at least one ITR region is an AAV2 ITR.515. The AAV particle of embodiment 514, wherein the viral genome comprises a 5’ ITR region and a 3’ ITR region, optionally wherein the 5’ ITR region and the 3’ ITR region is each an AAV2 ITR.[Embodiments 516-522 are intentionally absent.]523. The AAV particle of any one of embodiments 494-522, wherein the encoded CDKL5 protein is a wildtype CDKL5 protein, optionally wherein the encoded CDKL5 protein is a human CDKL5 protein.524. The AAV particle of embodiment 523, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to the nucleotide sequence of SEQ ID NO: 6414.[Embodiments 525-527 are intentionally absent.]528. The AAV particle of any one of embodiments 494-527. wherein the viral genome is single-stranded.529. The AAV particle of any one of embodiments 494-527, wherein the viral genome is self- complementary.530. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises:(i) a promoter; and(ii) a CDKL5 -encoding sequence comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence that is at least 80% identical (e.g.. at least 80%, 85%, 90%. 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%. or 99% identical) to SEQ ID NO: 6414.531. The AAV particle of embodiment 530. wherein the viral genome further comprises a 5’ inverted terminal repeat (ITR) region and / or a 3’ 1TR region.[Embodiments 532-696 are intentionally absent.]697. An AAV particle comprising an AAV capsid variant and a viral genome, wherein the capsid variant comprises:(a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence that is at least 90% identical (e.g., at least 90%. 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%. or 99% identical) thereto, wherein the VP1 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943);(b) a VP2 protein comprising the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or(c) a VP3 protein comprising the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence that is at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto, wherein tire VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and wherein the viral genome comprises: the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence that is at least 90% identical (e.g.. at least 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to the nucleotide sequence of SEQ ID NO: 6414.698. The AAV particle of embodiment 697. wherein:(a) the VP1 protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 982;(b) a VP2 protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 738; and / or(c) a VP3 protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 739.699. The AAV particle of embodiment 698, wherein:(a) the VP1 protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 982;(b) a VP2 protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 738; and / or(c) a VP3 protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 739.700. The AAV particle of any one of embodiments 697-699, wherein:(a) the VP1 protein comprises the amino acid sequence of SEQ ID NO: 982;(b) the VP2 protein comprises the amino acid sequence of SEQ ID NO: 738; and / or(c) the VP3 protein comprises the amino acid sequence of SEQ ID NO: 739.701. The AAV particle of embodiment 701, wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 984 or a nucleotide sequence that is at least 90% identical thereto.702. The AAV particle of embodiment 701, wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 984.703. The AAV particle of any one of embodiments 482-702, further comprising a nucleic acid encoding a Rep protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein.704. A vector encoding the AAV particle of any one of embodiments 660-703.705. A cell comprising the AAV particle of any one of embodiments 660-703 or the vector of embodiment 704.706. The cell of embodiment 705, which is a mammalian cell (e.g.. an HEK293 cell), an insect cell (e.g., an SI9 cell), or a bacterial cell.707. A method of making an AAV particle of any one of embodiments 482-706, wherein the method comprises:(i) providing a cell comprising a viral genome comprising a CDKL5 -encoding sequence 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.708. The method of embodiment 707, wherein: the viral genome comprises a nucleotide sequence of SEQ ID NO: 6414, or a nucleotide sequence at least 90% identical to SEQ ID NO: 6414; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.709. The method of embodiment 708, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the cell.710. The method of embodiment 708 or embodiment 709, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell.711. The method of any one of embodiments 707-710, wherein the cell comprises a mammalian cell, an insect cell, or a bacterial cell.712. The method of embodiment 711, wherein the cell is an HEK293 cell or an S19 cell.713. A pharmaceutical composition comprising the AAV particle of any one of embodiments 485-703 and a pharmaceutically acceptable excipient.714. A method of delivering a CDKL5 protein to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 482-704, thereby delivering the CDKL5 protein.715. The method of embodiment 714, wherein the subject has, has been diagnosed with having, or is at risk of having a CDKL5-related disorder, optionally wherein the disorder is a CDKL5-related neurodegenerative or neuromuscular disorder.716. The method of embodiment 715, wherein CDKL5-related disorder is CDKL5 deficiency disorder (CDD). developmental and epileptic encephalopathy 2, infantile spasms (e.g.. West syndrome), LennoxGastaut syndrome, Rett syndrome, aty pical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early-onset encephalopathy, or X-linked mental retardation.717. A method of treating a CDKL5 -related disorder in a subject, comprising administering an effective amount of the pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 485-703. thereby treating the CDKL5-related disorder, optionally wherein the subject has, has been diagnosed with having, or is at risk of having a CDKL5 -related disorder, further optionally wherein the CDKL5-related disorder is a CDKL5-related neurodegenerative or neuromuscular disorder.718. The method of embodiment 717, wherein the subject has, has been diagnosed with having, or is at risk of having CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, or atypical Rett syndrome.719. A method of treating CDKL5 deficiency disorder (CDD) in a subject, comprising administering an effective amount of the pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 485-703. thereby treating CDD.720. The method of embodiment 719, wherein the subject has, has been diagnosed with having, or is at risk of having CDD.721. The method of any one of embodiments 714-720, wherein the subject has a reduced level of CDKL5 protein or gene expression as compared to a healthy individual.722. The method of any one of embodiments 714-721, wherein the subject has one or more mutations in the CDKL5 gene.723. The method of any one of embodiments 714-722, wherein the subject has lower CDKL5 activity as compared to CDKL5 activity in an individual who does not have a CDKL5 -related disorder.724. The method of any one of embodiments 717-723. wherein the treatment results in prevention of progression of the CDKL5-related disorder (e g., CDD) in the subject.725. The method of any one of embodiments 717-724. wherein the treatment results in amelioration of at least one symptom of the CDKL5-related disorder, as indicated by one or more biomarkers.726. The method of embodiment 725, wherein the one or more biomarkers comprises a marker of CDKL5 activity, e.g., as measured by phosphorylation levels of substrate proteins (e.g., MECP2) or as measured by mass spectrometry'.727. The method of embodiment 725, wherein the at least one symptom comprises epilepsy (e.g., early- onset epilepsy); autism; deficits in cognition; limited motor skills; sleep difficulties; visual impairment: low muscle tone; gastrointestinal reflux; behavioral symptoms (including episodes of laughing or crying that occur for what appears to be no reason, hypersensitivity to touch, and / or disrupted sleep); facial appearance changes (including microcephaly; a high, broad forehead; large, deep-set eyes: smaller-than normal space between the nose and upper lip; an upturned nose; and / or full lips and widely-spaced teeth); difficulties standing and walking: small, cold feet; lack of or poor eye contact; frequent sideways glances; cortical visual impairment or cortical blindness; bruxism; limited or absent speech; difficulties eating; stereotypies; limited ability to make small, focused hand movements; gastroesophageal reflux; constipation; or a combination thereof.728. The method of any one of embodiments 714-727, wherein the subject is a human subject.729. The method of any one of embodiments 714-728, wherein the subject is a juvenile, e.g., between 6 years of age to 20 years of age.730. The method of any one of embodiments 714-729, wherein the subject is an adult, e.g., above 20 years of age.731. The method of any one of embodiments 714-730, wherein the AAV particle is administered to the subject intravenously, intracerebrally (IC), via intrathalamic (ITH) administration, intramuscularly, intrathecally, intracerebroventricularly, via intraparenchymal administration, via focused ultrasound (FUS), e.g., coupled with tire intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration, or via intra-cistema magna injection (ICM).732. The method of any one of embodiments 714-730. wherein the AAV particle is administered to a cell, tissue, or region of the CNS and / or the PNS.733. The method of embodiment 732, wherein the AAV particle is administered to at least two tissues, or regions of the CNS and / or the PNS, e.g., by bilateral administration.734. The method of embodiment 732. wherein the cell, tissue, or region of and / or the PNS is a cell (e.g., a neuron), tissue, or region of the neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e g., Purkinje cell layer and deep cerebellar nuclei).735. The method of any one of embodiments 714-730. wherein the AAV particle is administered to the cerebral spinal fluid, the serum, or a combination thereof.736. The method of any one of embodiments 714-735. further comprising evaluating (e.g.. measuring the level of CDKL5 gene, CDKL5 mRNA, and / or CDKL5 protein expression) in the subject (e.g.. in a cell, tissue, or fluid of the subject), optionally wherein the level of CDKL5 protein is measured by an assay described herein.737. The method of embodiment 736, wherein the level of CDKL5 protein expression is measured by an enzyme-linked immunosorbent assay (ELISA), a Western blot, or an immunohistochemistry assay.738. The method of embodiment 736 or embodiment 737, comprising evaluating the level of CDKL5 expression in a cell or tissue of the CNS and / or the PNS (e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei) and / or neurons).739. The method of any one of embodiments 717-738, wherein the treatment results in an increase in:(i) the level of CDKL5 activity’ in a cell, tissue (e.g., a cell or tissue of the CNS and / or the PNS, e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei), and / or neurons, and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or relative to CDKL5 activity in a cell, tissue, or fluid of an individual with a CDKL5-related disorder who has not been administered the pharmaceutical composition or AAV particle;(ii) the number and / or level of viral genomes (VG) per cell in a cell or tissue of the CNS and / or the PNS (e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei), and / or neurons) of the subject, relative to the number and / or level of VG per cell level in a peripheral tissue of the subject: and / or(iii) the level of CDKL5 protein or CDKL5 gene expression in a cell or tissue of the CNS and / or the PNS (e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei), and / or neurons of the subject relative to baseline and / or CDKL5 protein or CDKL5gene expression in a cell or tissue of an individual with a CDKL5-related disorder who has not been administered the pharmaceutical composition or AAV particle.740. The method of any one of embodiments 714-739, further comprising administering to the subject at least one additional therapeutic agent and / or therapy.741. The method of embodiment 740. wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy for treating the CDKL5-related disorder (e.g., CDKL5 deficiency disorder (CDD). developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2. early-onset encephalopathy, or X-linked mental retardation), optionally wherein the at least one additional therapeutic agent and / or therapy comprises one or more anti-epileptic drugs (e.g., valproate, levetiracetam, clobazam, lamotrigine, ganaxolone. topiramate, bromate, felbamate, phenobarbital, or a combination thereof).742. The method of embodiment 740, 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), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.743. The pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 485-703 for use in the treatment of a CDKL5-related disorder, optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy , or X-linked mental retardation.744. Use of an effective amount of the pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 485-703 in the manufacture of a medicament for the treatment of a CDKL5-related disorder, optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g.. West syndrome), Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early-onset encephalopathy, or X-linked mental retardation.745. The pharmacal composition or use of embodiment 743 or embodiment 744, wherein the subject has. has been diagnosed with having, or is at risk of having the CDKL5-related disorder, optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epilepticencephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut sy ndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.

[0061] 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 the 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

[0062] 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 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 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

[0063] Described herein, inter alia, are compositions comprising an AAV capsid variant comprising a sequence encoding a CDKL5 protein, e.g., a human CDKL5 protein. In some embodiments, the present disclosure provides a method of delivering the AAV capsid variant comprising the sequence encoding the CDKL5 protein to a cell or tissue in a subject. In some embodiments, the present disclosure provides a method for delivering the AAV capsid variant, thereby providing a CDKL5 protein, e.g., a human CDKL5 protein to a cell or tissue in a subject. The AAV capsid variants described herein have enhanced CNS tropism compared to other cells or tissues in the body, e.g., liver and / or the DRG.

[0064] 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.Engineered adeno-associated virus (AAV) capsids with improved brain tropism represent an attractive solution to the limitations of CNS delivery. AAV-derived vectors are promising tools for clinical gene transfer because of their non-pathogenic nature, their low immunogenic profile, low rate of integrationinto 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.

[0065] 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 with or engineered to target a particular tissue and express or deliver CDKL5. The genome of the virus may encode a CDKL5 protein, and the viral particle comprising said genome may be delivered to a target cell, tissue, or organism. In some embodiments, the genome encodes a human CDKL5 protein, e.g., a wildtype human CDKL5 protein. In some embodiments, the target cell is a CNS cell. In some embodiments, the target tissue is a CNS tissue. In some embodiments, the target CNS tissue is brain tissue.

[0066] Gene therapy presents an alternative approach for treating a CDKL5-related disorder such as a CDKL5-related neurodegenerative or neuromuscular disorder (e.g., CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2. or atypical Rett syndrome). 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, an AAV particle described herein can be used to administer and / or deliver a gene encoding CDKL5 protein (e.g., human CDKL5 protein) preferentially to the CNS (e.g., the brain or the spinal cord).

[0067] Provided herein are compositions and methods which may provide for improved features compared to prior AAV-mediated enzyme replacement approaches, including (i) increased biodistribution throughout the CNS (e.g., the cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord), (ii) elevated CDKL5 expression in multiple brain regions (e.g., cortex, thalamus, and brain stem); and (iii) preferential biodistribution in the CNS over the liver and / or DRG, of the subject.

[0068] Also provided herein are AAV capsid variants (e.g., AAV5 capsid variants) with improved properties compared to wildtype AAV5 and / or wildtype AAV9, such as (i) increased penetrance through the blood brain barrier following intravenous administration, (ii) wider distribution throughout the multiple brain regions, e.g., temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus. Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum, (iii) elevated CDKL5 expression in multiple brain regions, (iv) wider distribution in one or more peripheral tissues, e.g.. the heart, muscle, and / or liver, and / or (v) elevated CDKL5 expression in one or more peripheral tissues. In some embodiments, the AAV capsids described herein enhance the delivery of a CDKL5 to multiple regions of the brain including, for example, the CNS and / or the PNS. Exemplary' regions may comprise the neocortex, spinal cord, dorsal root ganglion.globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei) and / or neurons. In some embodiments, the AAV capsids described herein enhance the delivery' of CDKL5 to the forebrain. In some embodiments, the AAV capsids described herein enhance the delivery' of a CDKL5 to the spinal cord. In some embodiments, the AAV capsid variants with enhanced brain tropism described herein are capable of significantly increasing CDKL5 mRNA expression in the brain. In some embodiments, the AAV capsid variants are capable of significantly increasing CDKL5 mRNA expression in the forebrain.

[0069] Thus, the compositions and methods described herein can be used in the treatment of a CDKL5-related disorder such as a CDKL5-related neurodegenerative or neuromuscular disorder (e.g., CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome). Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation. In some embodiments, the CDKL5-related disorder is CDKL5 deficiency disorder (CDD). developmental and epileptic encephalopathy 2, or atypical Rett syndrome. In some embodiments, the disclosure provides an AAV particle comprising one of the AAV capsid variants disclosed herein and an AAV viral genome comprising a nucleotide sequence comprising a promoter and a sequence encoding a CDKL5 protein for use in treating a CDKL5-related disorder such as a CDKL5-related neurodegenerative or neuromuscular disorder (e.g., CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy' 2. infantile spasms (e.g., West syndrome). Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation; optionally, CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, or atypical Rett syndrome).I. CompositionsAdeno-associated viral (AA V) vectors

[0070] 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-ty pe 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) 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, VP 1 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 the 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.

[0071] 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.

[0072] 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).

[0073] Typically, AAV particles for CDKL5 delivery may be recombinant viral vectors which are replication defective as they lack sequences encoding functional Rep and Cap proteins 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 CDKL5 protein.

[0074] In some embodiments, the AAV particles of the present disclosure may be introduced into mammalian cells.

[0075] 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.

[0076] In other embodiments, AAV particles of the present disclosure may be used to deliver CDKL5 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.

[0077] 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.

[0078] 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,die 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 tenn "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).

[0079] The AAV particles and payloads 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 type, tissue, or organ. As a non-limiting example, the AAV particle may have enhanced tropism for cells and tissues of the central or peripheral nervous systems (CNS and PNS, respectively). In some embodiments, an AAV particle of the disclosure may. in addition, or alternatively, have decreased tropism for a cell-type, tissue or organ.

[0080] 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.

[0081] 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 the 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.

[0082] 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 strandedDNA. 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.

[0083] 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).

[0084] 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 CNS cell-type, region, or tissue.Capsid Peptides

[0085] 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 wildfype AAV capsid) for enhanced or improved transduction of a target tissue (e.g., cells of the CNS or PNS). 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.

[0086] 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 a temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, cerebellum, cervical spinal cord, thoracic spinal cord, or lumbar spinal cord.

[0087] 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.

[0088] 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.

[0089] 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 the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0090] In 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.

[0091] 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 heart muscle (e.g., a heart atrium or a heart ventricle) or a quadriceps. In some embodiments, the peptide may increase distribution of an AAV particle to a muscle cell, region, or tissue after intravenous administration.

[0092] In some embodiments, a peptide may comprise a sequence as set forth in Table 1 (e.g., comprising the amino acid sequence ofany 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 Tables 14 or 23-28.Table 1. Exemplary Peptide SequencesTable 2A. Exemplary Peptide SequencesTable 2B. Exemplary Peptide Sequences

[0093] 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 Xs and [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 X5of [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 X5. In some embodiments, the amino acid sequence of [N3] comprises VQK. In some embodiments, the amino acid sequence of [N3] consists of VQK.

[0094] In some embodiments, a peptide described herein comprises an amino acid sequence having die formula [N2]-[N3], wherein [N2] comprises positions Xi, X2, X3, X4, and X, and [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, [N3] comprises the 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 X2of [N2] is P, K, T, or Q. In some embodiments, position X2of [N2] is P, T, or Q. In some embodiments, position X3of [N2] is A or P. In some embodiments, position X3of [N2] is A. In some embodiments, position X4of [N2] is E, S, or A. In some embodiments, position Xs of [N2] is V, L, or E. In some embodiments, position Xs 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 IDNO: 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 amino 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), 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). 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), YPPSLVKK (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 ID NO: 960), YT AEVVKK (SEQ ID NO: 961), YP AEVLQK (SEQ ID NO: 962), or YQ AEEVQK (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, 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, [N2]-[N3] is YP AEVVQK (SEQ ID NO: 943). In some embodiments. [N2]-[N3] comprises the amino acid sequence YP AEVVQK (SEQ ID NO: 943).

[0095] 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] isS, G, A, or R. In some embodiments, position XF of [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, 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, 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), SSYPAA VVQ (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: 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); 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, 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, the ammo acid sequence of [N1]-[N2]-[N3] is QSSYPAEVVQK (SEQ ID NO: 150).

[0096] 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 XBof [NO] is N. In some embodiments, position Xc 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, [N0]-[Nl] 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.. 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] 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), 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), 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, 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, 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).

[0097] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N4], w4iich 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 acidsequences (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 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, [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), TNNIGSYPAEV VQKTA (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), 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: 1602), 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), 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, 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 TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0098] In some embodiments, a peptide described herein comprises the formula [N2]-[N3], wherein [N2] comprises positions Xi. X2, X3, X4, and Xs and [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 X2 of [N2] is Q, T, P. or E. In someembodiments, 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 X5 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), AEEVQK (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), YP AEEVQK (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., conser ative 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, [N2]-[N3] is YP AEVVQK (SEQ ID NO: 943).

[0099] 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 or S. In some embodiments, position XEof [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. [N1]-[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 tire 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).

[0100] 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 X, ■ 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, [N0]-[Nl] 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 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, [N0]-[N 1 ]-[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).

[0101] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2J-[N3], further comprises [N4J . which comprises positions XGand XH. In some embodiments, position XGof [N4] is T. P, or N. In some embodiments, position XH of [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 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), 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 acidsequences. In some embodiments, [NO]-[N1]-[N2]-[N3]-[N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0102] 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-tenninus to C-tenninus, [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],

[0103] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [B]-[CJ. wherein [B] comprises positions X 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 X, 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 X2 of [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. hr some embodiments, [B] comprises S at position X2. In 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 (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); 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).

[0104] 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. Insome embodiments, position XBof [A] is N. In some embodiments, position Xcof [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), TNTASSYPAEVVQK (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, 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, 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).

[0105] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [D], wherein [D] comprises position X4and X5. In some embodiments, position X4of [D] is T or N. In some embodiments, position X5 of [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 TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSL YPAEVVQKTA (SEQ ID NO: 1232), TNNSSS YPAEVVQKTA (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), 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 the 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).

[0106] 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 some embodiments, [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]-[C] is QSSYPAEVVQK (SEQ ID NO: 150).

[0107] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [A], which comprises positions XA, XB, and Xc. In some embodiments, position XA of [A] is T. 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, 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, L 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, [A]-[B] is TNNQSS (SEQ ID NO: 183). In some embodiments. [A]-[B]-[C] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0108] In some embodiments, a peptide comprising the formula [B]-[C], further comprises [D], wherein [D] comprises position X4and X5. In some embodiments, position X i of [D] is T, N, or P. In some embodiments, position X, 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).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); 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 die aforesaid amino acid sequences. In some embodiments, [A]-[B]-[C]-[D] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0109] 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 [CJ . In some embodiments, the peptide comprises from N-terminus to C-terminus. [B]-[C] . In some embodiments, the peptide comprises from N-terminus to C-terminus. [B]-[C]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [A]-[B]-[C]. In some embodiments, the peptide comprises from N-terminus to C-terminus, [B]-[C]-[D], In some embodiments, die peptide comprises from N-terminus to C-terminus. [A]-[B]-[C]-[D],

[0110] In 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 X4of [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.

[0111] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [K1]-[K2]. further comprises [K0], which comprises TNNS (SEQ ID NO: 14). In some- I ll -embodiments, [KO]-[K1] 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. [KOJ- [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.

[0112] In some embodiments, peptide comprising the amino acid sequence comprising the formula of [K1]-[K2], further comprises [K3], 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 Xcof [K3] is K orN. 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), 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, 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, [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 aminoacids) 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 tire 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. two. or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences.

[0113] 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 XDof [K4] is T, P, or N. In some embodiments, position XEof [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.

[0114] In some embodiments, [K2] is present immediately subsequent to [KI], In some embodiments, [KI] is present immediately subsequent to [KO], 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-tenninus to C-tenninus, [K1]-[K2], In some embodiments, the peptide comprises from N-tenninus 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],

[0115] 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 the sequences provided in Tables 1, 2A, 2B, 14. and 23-28. 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 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 2064-2080. 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.

[0116] 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 some embodiments, the 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).

[0117] In some embodiments, a peptide described herein comprises 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 the amino acid sequence of any one of the sequences provided in Tables 1, 2A, 2B, 14, and 23-28. 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, 14, and 23-28. 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 aminoacid 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: 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.

[0118] 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, 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 YPAEVVQK (SEQ ID NO: 943).

[0119] In some embodiments, the 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; (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....

Claims

CLAIMS1. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence; and wherein the AAV capsid variant comprises an amino acid sequence having the formula [N2]-[N3], wherein:(i) [N2] comprises positions Xi. X2, X3, X4, and X5, wherein:(a) position Xi is Y, N, or C;(b) position X2is P. K, T, or Q;(c) position X3is A or P;(d) position X4is E, S, or A; and(e) position X5is V, L, or E; and(ii) [N3] comprises the amino acid sequence VQK. EQK, VKK, VHK, VQQ, or LQK; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% identical thereto.

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 [N2]-[N3] 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 AAV capsid variant is an AAV5 capsid variant comprising IN2J-[N3J 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] comprises the amino acid sequence YP, YPA, YPAE (SEQ ID NO: 21). or YPAEV (SEQ ID NO: 1).

6. The AAV particle of any one of claims 1-5, wherein [N3] comprises the amino acid sequence VQK.

7. The AAV particle of any one of claims 1-6, wherein [N2]-[N3] comprises the amino acid sequence AEVVQK (SEQ ID NO: 36) or PAEVVQK (SEQ ID NO: 20).

8. The AAV particle of any one of claims 1-7, wherein [N2]-[N3] comprises the amino acid sequence YP AEVVQK (SEQ ID NO: 943).

9. The AAV particle of any one of claims 1-8, wherein the AAV capsid variant further comprises [Nl] comprising positions XD, XE, and XF, wherein:(a) position XD of [Nl] is Q, T, S. A, I, L, or H;(b) position XE of [Nl] is S, G, A, or R; and(c) position XF of [Nl] is S, K, L, R, A, or T; wherein [Nl] immediately precedes [N2]-[N3],10. The AAV particle of claim 9, wherein [Nl] comprises the amino acid sequence QS, SS, or QSS.

11. The AAV particle of claim 9 or claim 10, wherein [N1]-[N2] comprises the amino acid sequence QSSYPAEV (SEQ ID NO: 96).

12. The AAV particle of any one of claims 9-11, wherein [N1]-[N2]-[N3] comprises the amino acid sequence SSYPAEVVQ (SEQ ID NO: 121) or QSSYPAEVVQK (SEQ ID NO: 150).

13. The AAV particle of any one of claims 9-12. wherein the AAV capsid variant further comprises [NO] comprising positions XA, XB, and Xc, wherein:(a) position XAof [NO] is T, I, or N;(b) position XBof [NO] is N; and(c) position Xcof [NO] is N, T, S, or K; wherein [NO] immediately precedes [Nl],14. The AAV particle of claim 13, wherein [NO] comprises the amino acid sequence TN, NN, or TNN.

15. The AAV particle of claim 13 or claim 14, wherein [NO]-[N1] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183).

16. The AAV particle of any one of claims 13-15, wherein [NO]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYPAEVVQK (SEQ ID NO: 500).

17. The AAV particle of any one of claims 13-16, 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; wherein [N4] is present immediately subsequent to [N3J.

18. The AAV particle of claim 17, wherein [N4] comprises the amino acid sequence TA.

19. The AAV particle of claim 17 or claim 18, wherein [NO]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

20. The AAV particle of any one of claims 16-18, wherein [NO]-[N1]-[N2]-[N3]-[N4] 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.

21. The AAV particle of claim 20, wherein:(i) [NO] is present at amino acids corresponding to positions 571-573 of the amino acid sequence of SEQ ID NO: 982:(ii) [N1J is present at amino acids corresponding to positions 574-576 of the amino acid sequence of SEQ ID NO: 982;(iii) [N2] is present at amino acids corresponding to positions 577- 581 of the amino acid sequence of SEQ ID NO: 982;(iv) [N3] is present at amino acids corresponding to positions 582-584 of the amino acid sequence of SEQ ID NO: 982; and(v) [N4] is present at amino acids corresponding to positions 585-586 of the amino acid sequence of SEQ ID NO: 982.

22. An adeno-associated virus (AAV) particle comprising:(i) a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence; and(ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises at least 4, 5, 6, 7, or 8 consecutive amino acids from the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

23. The AAV particle of claim 22, wherein:(i) the at least 4 consecutive amino acids comprise the amino acid sequence YPAE (SEQ ID NO: 21). optionally present at amino acids corresponding to positions 577-580 of the amino acid sequence of SEQ ID NO: 982;(ii) the at least 5 consecutive amino acids comprise the amino acid sequence YPAEV (SEQ ID NO: 1), optionally present at amino acids corresponding to positions 577-581 of the amino acid sequence of SEQ ID NO: 982;(iii) the at least 6 consecutive amino acids comprise the amino acid sequence YPAEVV (SEQ ID NO: 725). optionally present at amino acids corresponding to positions 577-582 of the amino acid sequence of SEQ ID NO: 982; or(iv) the at least 7 consecutive amino acids comprise the amino acid sequence YPAEVVQ (SEQ ID NO: 726), optionally present at amino acids corresponding to positions 577-583 of die amino acid sequence of SEQ ID NO: 982.

24. The AAV particle of claim 22 or 23, wherein die AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) present at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982.

25. An adeno-associated virus (AAV) particle comprising:(i) a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence; and(ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982.

26. The AAV particle of claim 25, wherein the AAV capsid variant further comprises(i) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or(ii) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

27. An adcno-associatcd virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence and die AAV capsid variant comprises(i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943):(ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943): and / or(iii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

28. The AAV particle of any one of claims 1-27, wherein the AAV variant capsid comprises(i) the amino acid sequence of SEQ ID NO: 982;(ii) the amino acid sequence of SEQ ID NO: 738; and / or(iii) the amino acid sequence of SEQ ID NO: 739.

29. The AAV particle of any one of claims 1-28, wherein the viral genome encodes a wildtype CDKL5 protein or a fragment thereof.

30. The AAV particle of any one of claims 1-29, wherein the viral genome encodes a human CDK.L5 protein.

31. The AAV particle of claim 29 or claim 30, wherein the CDKL5 protein comprises the amino acid sequence of SEQ ID NO: 6413.

32. The AAV particle of any one of claims 1-31. wherein the CDKL5 -encoding sequence is at least 90% identical (e.g., at least 90%. 91%, 92%, 93%, 94%. 95%. 96%, 97%, 98%. or 99%. or is 100% identical) to the nucleotide sequence of SEQ ID NO: 6414.

33. The AAV particle of claim 32, wherein the CDKL5-encoding sequence is at least 95% identical to the nucleotide sequence of SEQ ID NO: 6414.

34. The AAV particle of claim 33, wherein the CDKL5-encoding sequence is at least 99% identical to die nucleotide sequence of SEQ ID NO: 6414.

35. The AAV particle of claim 34, wherein the CDKL5-cncoding sequence comprises the nucleotide sequence of SEQ ID NO: 6414.

36. The AAV particle of claim 35, wherein the CDKL5-encoding sequence consists of the nucleotide sequence of SEQ ID NO: 6414.

37. The AAV particle of any one of claims 1-36, wherein the viral genome comprises a promoter operably linked to the CDKL5-encoding sequence.

38. The AAV particle of any one of claims 1-37, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.

39. The AAV particle of claim 38, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the CDKL5 -encoding sequence.

40. The AAV particle of claim 38 or claim 39, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the CDKL5-encoding sequence.

41. The AAV particle of any of claims 38-40, wherein the viral genome comprises an ITR sequence positioned 5’ relative to the CDKL5-encoding sequence, and an ITR sequence positioned 3’ relative to the CDKL5 -encoding sequence.

42. A cell comprising the AAV particle of any one of claims 1-41, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g.. an SP cell), or a bacterial cell.

43. A method of making the AAV particle of any one of claims 1-41, the method comprising:(i) providing a cell comprising the viral genome comprising a CDKL5 -encoding sequence and a nucleic acid encoding the AAV capsid variant; and(ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the recombinant AAV particle.

44. The method of claim 43, wherein the viral genome comprises(a) the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%. or 99% identical) thereto; and wherein the AAV capsid variant comprises(i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%. or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943);(ii) the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence having at least 90% identity (e.g., at least 90%. 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%. or 99% identity) thereto. wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); or(iii) the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%. 93%. 94%, 95%, 96%. 97%. 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

45. The method of claim 43, wherein the viral genome comprises(a) the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; andwherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO: 739.

46. The method of claim 43, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO:

738. and / or the amino acid sequence of SEQ ID NO: 739.

47. The method of any one of claims 43-46. further comprising, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell.

48. The method of any one of claims 43-47. further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell.

49. The method of any one of claims 43-48, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g.. an S® cell), or a bacterial cell.

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

51. A method of delivering an AAV particle encoding a CDKL5 protein to a cell, comprising administering an effective amount of the pharmaceutical composition of claim 50 or the AAV particle of any one of claims 1-41.

52. The method of claim 51, wherein the cell is in a subject, optionally wherein the subject has, has been diagnosed with having, or is at risk of having a CDKL5 -related disorder, further optionally wherein the CDKL5-related disorder is a CDKL5-related neurodegenerative or neuromuscular disorder.

53. The method of claim 52, wherein the subject has, has been diagnosed with having, or is at risk of having CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.

54. A method of treating a CDKL5-related disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 50 or the AAV particle of any one of claims 1-41.

55. The method of claim 54, wherein the subject has, has been diagnosed with having, or is at risk of having the CDKL5-related disorder.

56. The method of claim 55, wherein the CDKL5-related disorder is a CDKL5-related neurodegenerative or neuromuscular disorder.

57. The method of claim 56, wherein the CD KL5 -related neurodegenerative or neuromuscular disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome). Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.

58. A method of treating CDKL5 deficiency disorder (CDD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 50 or the AAV particle of any one of claims 1-41.

59. The method of claim 58, wherein the subject has. has been diagnosed with having, or is at risk of having CDD.

60. The method of any one of claims 54-59, wherein the subject has one or more mutations in the CDKL5 gene.

61. The method of any one of claims 54-60, wherein the subject has lower CDKL5 activity as compared to CDKL5 activity in an individual who does not have a CDKL5-related disorder.

62. The method of any one of claims 54-61, wherein the treating results in prevention of progression of die disorder in the subject.

63. The method of any one of claims 54-62, wherein the treating results in amelioration of at least one symptom of the disorder, as indicated by one or more biomarkers.

64. The method of claim 63, wherein the one or more biomarkers comprises a marker of CDKL5 activity, e.g., as measured by phosphorylation levels of substrate proteins (e.g., MECP2) or as measured by mass spectrometry.

65. The method of claim 63, wherein the at least one symptom comprises epilepsy (e.g.. early -onset epilepsy); autism; deficits in cognition; limited motor skills; sleep difficulties; visual impairment; lowmuscle tone; gastrointestinal reflux; behavioral symptoms (including episodes of laughing or cry ing that occur for what appears to be no reason, hypersensitivity to touch, and / or disrupted sleep); facial appearance changes (including microcephaly; a high, broad forehead; large, deep-set eyes; smaller-than normal space between the nose and upper lip; an upturned nose; and / or full lips and widely-spaced teeth); difficulties standing and walking: small, cold feet; lack of or poor eye contact; frequent sideways glances; cortical visual impairment or cortical blindness; bruxism; limited or absent speech; difficulties eating; stereotypies; limited ability to make small, focused hand movements: gastroesophageal reflux; constipation; or a combination thereof.

66. The method of any one of claims 52-65. wherein the subject is a human.

67. The method of any one of claims 52-66. wherein the AAV particle or the pharmaceutical composition is delivered to a cell, tissue, or region of the central nervous system (CNS) and / or the peripheral nervous system (PNS) in the subject.

68. The method of any one of claims 52-67, wherein the cell, tissue, or region of the CNS and / or the PNS is a cell (e.g., a neuron), tissue, or region of the neocortex, spinal cord, dorsal root ganglion, globus pallidus. putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g.. Purkinje cell layer and deep cerebellar nuclei).

69. The method of any one of claims 52-68, wherein the AAV particle or the pharmaceutical composition is delivered to the subject via intravenous administration.

70. The method of any one of claims 52-69, further comprising evaluating, e.g., measuring, the level of CDKL5 expression, e.g., CDKL5 gene expression, CDKL5 mRNA expression, and / or CDKL5 protein expression, in the subject, e.g., in a cell, tissue, or fluid of the subject.

71. The method of claim 70, wherein the level of CDKL5 protein expression is measured by an ELISA, a Western blot, or an immunohistochemistry assay.

72. The method of claim 70 or claim 71, wherein the evaluating the level of CDKL5 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of CDKL5 expression prior to administration is compared to the subject’s level of CDKL5 expression subsequent to administration.

73. The method of any one of claims 70-72. comprising evaluating the level of CDKL5 expression in a cell or tissue of the CNS and / or the PNS.

74. The method of claim 73, wherein the cell or tissue of the CNS and / or PNS is a cell (e.g, a neuron) or tissue of the neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei).

75. The method of any one of claims 70-74, wherein the subject’s level of CDKL5 protein expression subsequent to administration is increased relative to the subject’s level of CDKL5 protein expression prior to administration.

76. The method of any one of claims 52-75. further comprising evaluating, e.g.. measuring, the level of CDK.L5 activity in the subject, e.g.. in a cell or tissue of the subject.

77. The method of any one of claims 52-76, wherein administering the pharmaceutical composition or AAV particle to the subject results in an increase in:(i) the level of CDKL5 activity in a cell, tissue (e.g., a cell or tissue of the CNS and / or the PNS. e.g.. neocortex, spinal cord, dorsal root ganglion, globus pallidus. putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g.. Purkinje cell layer and deep cerebellar nuclei), and / or neurons, and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or relative to CDKL5 activity in a cell, tissue, or fluid of an individual with a CDKL5-related disorder who has not been administered the pharmaceutical composition or AAV particle;(ii) the number and / or level of viral genomes (VG) per cell level in a tissue of the CNS and / or the PNS, e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei), and / or neurons of the subject, relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or(iii) the level of CDKL5 protein or CDKL5 gene expression in a cell or tissue (e.g., a cell or tissue of the CNS and / or the PNS, e.g., neocortex, spinal cord, dorsal root ganglion, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, retina, brainstem, and / or cerebellum (e.g., Purkinje cell layer and deep cerebellar nuclei), and / or neurons of the subject relative to baseline and / or CDKL5 protein or CDKL5 gene expression in a cell or tissue of an individual with a CDKL5 -related disorder who has not been administered the pharmaceutical composition or AAV particle.

78. The method of any one of claims 52-77. further comprising administering to the subject at least one additional agent and / or therapy.

79. The method of claim 78, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating a CDKL5 -related disorder.

80. The method of claim 79, wherein the at least one additional therapeutic agent and / or therapy comprises one or more anti-epileptic drugs (e.g., valproate, levetiracetam, clobazam, lamotrigine, ganaxolone, topiramate, bromide, felbamate, phenobarbital, or a combination thereof).

81. The method of any one of claims 52-80. further comprising administering an immunosuppressant to the subject.

82. The method of claim 81, wherein the immunosuppressant comprises a corticosteroid (for example, and without limitation, prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil. tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

83. The pharmaceutical composition of claim 50 or the AAV particle of any one of claims 1-41 for use in a method of treating a disorder according to any one of claims 54-82.

84. The pharmaceutical composition of claim 50 or the AAV particle of any one of claims 1-41, for use in the treatment of a CDKL5-related disorder; optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD). developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2. early -onset encephalopathy, or X-linked mental retardation.

85. The pharmaceutical composition or AAV particle for use of claim 84, wherein the subject has, has been diagnosed with having, or is at risk of having the CDKL5-rclatcd disorder, optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.

86. Use of the pharmaceutical composition of claim 50 or the AAV particle of any one of claims 1-41 in the manufacture of a medicament for the treatment of a CDKL5 -related disorder; optionally wherein the CDKL5-related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome. Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.

87. The use of claim 86, wherein the subject has, has been diagnosed with having, or is at risk of having the CDKL5 -related disorder, optionally wherein the CDKL5 -related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, infantile spasms (e.g., West syndrome), Lennox Gastaut syndrome, Rett syndrome, atypical Rett syndrome, autism, developmental and epileptic encephalopathy 2, early -onset encephalopathy, or X-linked mental retardation.

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