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 expression of CDKL5 proteins via delivery using an adeno-associated virus (AAV) capsid variant. The compositions and methods of the present disclosure are useful in the treatment of subjects diagnosed with, or suspected of having CDD, or another CDKL5-related disorder.

Description

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

[0001] This application claims the benefit of and priority to US Provisional Application Serial No. 63 / 499,933, filed May 3, 2023, US Provisional Application Serial No. 63 / 593,830, filed October 27, 2023, and US Provisional Application Serial No. 63 / 564,457, filed March 12, 2024, the contents of each of which are incorporated herein by reference in their entirety.SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format.The Sequence Listing file, entitled 14640_0086-00304_SL.xml, was created on March 27, 2024, and is 5,493,990 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety.FIELD

[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 (“CDKL5 protein”) and peptides (“CDKL5 peptide”) for use in the treatment of CDKL5 deficiency disorder (CDD), and other CDKL5-reIated disorders, including developmental and epileptic encephalopathy 2, and 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.BACKGROUND

[0004] Cyclin-dependent kinase-like 5 (CDKL5) is a serine / threonine protein kinase and is also known as serine / threonine kinase 9 (STK9). Other aliases for CDKL5 include EIEE2, ISSX, CFAP247, and DEE2. It is encoded by the gene CDKI.,5 (Ensembl Gene ID No.ENSG00000008086), which is located on the X chromosome.

[0005] The CDKL5 protein is an enzyme 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.

[0006] CDKL5 is responsible for phosphorylation of a number of targets. CDKL5 may target and phosphorylate the gene MECP2, which lias been characterized as important in the function of neurons and other brain cells, and in the maintenance of neuronal synapses, and is thought to be the causativeagent for Rett syndrome. CDKL5 may also target and phosphorylate CEP131, which is thought to play a role in cell proliferation. CDKL5 may also target and phosphorylate MAPI S. 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 phosphorylate AKT and mTOR, which are thought to play roles in cell proliferation, migration and development.

[0007] 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.

[0008] Mutations in CDKL5 are known to cause disease in subjects, e.g., human subjects. CDKL5 mutations lead to CDKL5 deficiency disorder (CDD). CDD is a neurodevelopmental disorder. It is characterized by nervous system symptoms including epilepsy (e.g., early -onset epilepsy), autism, deficits in cognition, limited motor skills, sleep difficulties and / or visual impairment. It is also characterized by low muscle tone and gastrointestinal reflux.

[0009] 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.

[0010] 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.

[0011] CDD is typically caused by de novo mutations in CDKL5. CDKL5 mutations in CDD patients result in a reduced amount of functional CDKL5 protein.

[0012] 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.

[0013] The current standard of care for CDD is first line treatment with an anti-epileptic drug. Anti-epileptic drugs are known in the art, and include valproate and levetiracetam. 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 lias been reported to have short durability in treating subjects with CDD. Third line treatment introduces additional anti-epileptic drags, such as topiramate, and / or alternative interventions, such as ketogenicdiet and / or vagal nerve stimulation. However, seizures in CDD are commonly refractory to known treatments.

[0014] 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.

[0015] Prior attempts at providing AAV capsids with improved properties, e.g., improved tropism suitable for delivery to the brain or CNS, have met with limited success. As such, there remains a need for effective methods of treatment using AAV capsid variants that are capable of delivering a payload of interest, e.g., CDKL5, to a target cell or tissue, e.g., a CNS cell or tissue.SUMMARY

[0016] In some embodiments, the present disclosure provides an adeno-associated vims (AAV) particle comprising: a) an AAV capsid variant comprising an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein: (i) optionally [Nl] comprises X1, X2, and X3, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises the amino acid sequence of SPH; and (iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid; and b) a viral genome comprising a cy clindependent kinase-like 5 (CDKL5 )-encoding sequence. In some embodiments, the amino acid sequence [N1]-[N2]-[N3] is in hypervariable loop IV of the AAV capsid variant. In some embodiments, 3 the AAV capsid variant is an AAV9 capsid variant. In some embodiments, [Nl] comprises XI, X2, and X3, wherein at least one of XI, X2, or X3 is G. In some embodiments, [N2]-[N3] comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0017] In some embodiments, the present disclosure provides an adeno-associated virus (AAV) particle comprising a viral genome comprising a cvclin-dependent kinase-like 5 (CDKL5)-encoding sequence and an AAV9 capsid variant comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941). In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is in hypervariable loop IV of the AAV9 capsid variant. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present immediately subsequent to an amino acid position corresponding to position 455 of SEQ ID NO: 4 or SEQ ID NO: 36.

[0018] In some embodiments, the AAV9 capsid variant comprises one, two. or all of: an N at an amino acid position corresponding to position 452, an E at an amino acid position corresponding to position 451, and / or a V at an amino acid position corresponding to position 453 of SEQ ID NO: 4. In some embodiments, the AAV9 capsid variant comprises the amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272).

[0019] In some embodiments, the AA V9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 90% identity' to SEQ ID NO: 4; (ii) a VP2 protein comprisingan amino acid sequence Slaving at least 90% identity to positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 90% identity to positions 203- 742 of SEQ ID NO: 4.

[0020] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 4; (ii) a VP2 protein comprising an amino acid sequence having at least 95% identity to positions 138-742 SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 95% identity to positions 203-742 of SEQ ID NO: 4.

[0021] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 4; (ii) a VP2 protein comprising an ammo acid sequence having at least 99% identity to positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to positions 203- 742 of SEQ ID NO: 4.

[0022] In some embodiments, the AA V9 capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 4; and / or (iii) a VPS protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 4.

[0023] In some embodiments, the AAV9 capsid variant comprises: (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to an amino acid position corresponding to position 455 of SEQ ID NO: 4; (ii) an E at an amino acid position corresponding to position 451 and a V at an amino acid position corresponding to position 453 of SEQ ID NO: 4; and (iii) no other modifications relative to wild type AAV9.

[0024] In some embodiments, the AAV9 capsid variant further comprises one, two, or all of: an E at an amino acid position corresponding to position 451, an R at an amino acid position corresponding to position 452, and / or a V at an amino acid position corresponding to position 453 of SEQ ID NO: 36. In some embodiments, the AAV9 capsid variant comprises the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589).

[0025] In some embodiments, the AAV9 capsid variant comprises: (i) a VP I protein comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 36; (ii) a VP2 protein comprising an amino acid sequence having at least 90% identity to positions 138-742 SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 90% identity to positions 203-742 of SEQ ID NO: 36.

[0026] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 36; (ii) a VP2 protein comprising an ammo acid sequence having at least 95% identity to positions 138-742 SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 95% identity to positions 203-742 of SEQ ID NO: 36.

[0027] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 36; (ii) a VP2 protein comprising an amino acid sequence having at least 99% identity’ to positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to positions 203- 742 of SEQ ID NO: 36.

[0028] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

[0029] In some embodiments, the AA V9 capsid variant comprises: (i) the amino acid sequence SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to an amino acid position corresponding to position 455 of SEQ ID NO: 36; (ii) an E at an amino acid position corresponding to position 451, an R at an amino acid position corresponding to position 452. and a V at an amino acid position corresponding to position 453 of SEQ ID NO: 36; and (iii) no other modifications relative to wild type A A V9.

[0030] In some embodiments, the present disclosure provides an AAV particle comprising an AAV capsid variant comprising an amino acid sequence having the following formula: [N1]-[N2]~ [N3], wherein the [N1]-[N2]-[N3] is present immediately subsequent to a position corresponding to the amino acid position 452 of SEQ ID NO: 982; and wherein the AAV capsid variant comprises an amino acid sequence at least 90% identical, e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97?% at least 98%. at least 99%, or 100% identical, to the amino acid sequence of SEQ ID NO: 982, e.g., to positions 203-742 of SEQ ID NO: 982.

[0031] In some embodiments, [Nl] comprises GHD. In some embodiments, [Nl] comprises the amino acid G at a position corresponding to position 453, the amino acid H at position 454, and the amino acid D at position 455 of SEQ ID NO: 138 or SEQ ID NO: 982. In some embodiments, [N3] comprises KSG.

[0032] In some embodiments, the AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity’ to SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity to positions 138-742 SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity to positions 203-742 of SEQ ID NO: 982.

[0033] In some embodiments, the AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity to SEQ ID NO: 982; (ii) a VP2 protein comprising the amnio acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity to positions 138-742 SEQID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity to positions 203-742 of SEQ ID NO: 982.

[0034] In some embodiments, the AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity to SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity to positions 138-742 SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982 or an ammo acid sequence having at least 99% identity to positions 203-742 of SEQ ID NO: 982.

[0035] In some embodiments, the AAV capsid variant comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982.

[0036] In some embodiments, the present disclosure provides an AAV particle comprising a viral genome encoding a wildtype CDKL5 protein. In some embodiments, the viral genome encodes a human CDKL5 protein. In some embodiments, the CDKL5 protein comprises the amino acid sequence of SEQ ID NO: 6413.

[0037] In some embodiments, the CDKL5-eucoding sequence comprises a nucleotide sequence that is at least 90% identical (e.g., at least 90% at least 91%, at least 92%, at least 93%, at least 94%. at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 6414. In some embodiments, the CDKL5-encoding sequence comprises a nucleotide sequence that is at least 95% identical to SEQ ID NO: 6414. In some embodiments, the CDKL5~encoding sequence comprises a nucleotide sequence that is at least 99% identical to SEQ ID NO: 6414. In some embodiments, the CDKL 5 -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.

[0038] In some embodiments, the viral genome comprises a promoter operably linked to the CDKL 5 -encoding sequence. In some embodiments, the promoter is human elongation factor 1α- subuuit (EF1α) promoter, cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken β-actin (CBA) promoter, CAG promoter, CAG derivative promoter, [3 glucuronidase (GUSB) promoter, ubiquitin C (UBC) promoter, neuron-specific enolase (NSE) promoter, platelet-derived growth factor (PDGF) promoter, platelet-derived growth factor B-chain (PDGF-p) promoter, intercellular adhesion molecule 2 (ICAM-2) promoter, synapsin (Syn) promoter, synapsin I (Synl) promoter, methyl-CpG binding protein 2 (MeCP2) promoter, Ca2+ / calmodulin-dependent protein kinase II (CaMKIl) promoter, metabotropic glutamate receptor 2 (mGluR2) promoter, neurofilament light (NFL) or heavy (NFH) promo ter, β-globin minigene n β2 promoter, preproenkephalin (PPE)promoter, enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, glial fibrillaiy acidic protein (GFAP) promoter, myelin basic protein (MBP) promoter, a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a fragment, e.g., a truncation, or a functional variant thereof.

[0039] 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 CDKL 5 -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 CDKL 5 -encoding sequence and an ITR sequence positioned 3 ’ relative to the CDKL5 -encoding sequence.

[0040] In some embodiments, the present disclosure provides an AAV particle comprising a viral genome comprising a cyclin-dependent kinase-like 5 ( CD KL5 )-encoding sequence and an AAV capsid variant comprising: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 4; and / or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 4.

[0041] In some embodiments, the present disclosure provides an AAV particle comprising a viral genome comprising cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence and an AAV capsid variant comprising: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

[0042] In some embodiments, tire present disclosure provides a cell comprising the AAV particle described herein. In some embodiments, the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

[0043] In some embodiments, tire present disclosure provides a method of making an AAV particle described 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 A AV particle.

[0044] In some embodiments, the viral genome of the AAV particle comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (e.g,, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and the AAV capsid variant of the AAV particle comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to SEQ ID NO: 4; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 4or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to positions 138-742 SEQ ID NO: 4; or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%. at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%. or at least 99% identity) to positions 203-742 of SEQ ID NO: 4.

[0045] In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of positions 138-742 of SEQ ID NO: 4, and / or the amino acid sequence of positions 203-742 of SEQ ID NO: 4.

[0046] In some embodiments, the viral genome of the AAV particle comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%. or at least 99% identical) thereto; and the AAV capsid variant of the AAV particle comprises (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to SEQ ID NO: 36; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g.. at least 90%, at least 91 %, at least 92%. at least 93%, at least 94%, at least 95%, at least 96%. at least 97%, at least 98%, or at least 99% identity) to positions 138-742 SEQ ID NO: 36; or (iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to positions 203-742 of SEQ ID NO: 36.

[0047] In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 36, the amino acid sequence of positions 138-742 of SEQ ID NO: 36, and / or the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

[0048] In some embodiments, the viral genome of the AAV particle comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%. at least 93%, at least 94%, at least 95%, at least 96%. at least 97%, at least 98%, or at least 99% identical) thereto; and the AAV capsid variant of the AA V particle comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, al least 93%, al least 94%, at least 95%, at least 96%, at least 97%, al least 98%, or al least 99% identity) to SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to positions 138-742 SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acidsequence of positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to positions 203-742 of SEQ ID NO: 982.

[0049] In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of positions 138-742 of SEQ ID NO: 982, and / or the amino acid sequence of positions 203-742 of SEQ ID NO: 982.

[0050] In some embodiments, the method of making further comprises, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the cell.

[0051] In some embodiments, the cell comprises a second nucleic acid molecule encoding the AAV capsid variant. In some embodiments, die method of making further comprises, prior to step (i), introducing die second nucleic acid molecule into die cell.

[0052] In some embodiments, the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an SI9 cell), or a bacterial cell.

[0053] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an AAV particle described herein and a pharmaceutically acceptable excipient,

[0054] In some embodiments, the present disclosure provides a method of delivering an AAV particle encoding an CDKL5 protein to a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or A AV particle described herein.

[0055] In some embodiments, the present disclosure provides a method of treating a subject having or diagnosed with having an CDKL5-related disorder, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle described herein.

[0056] In some embodiments, die present disclosure provides the pharmaceutical composition or the AAV particle of a pharmaceutical composition or AAV particle described herein for use in the treatment of a subject having or diagnosed with having an CDKL5-related disorder.

[0057] In some embodiments, the present disclosure provides use of the pharmaceutical composition or the AAV particle of a pharmaceutical composition or AAV particle described herein in the manufacture of a medicament for treating a subject having or diagnosed with having an CDKL5-reiated disorder.

[0058] In some embodiments, the CDKL5-related disorder is a CDKL5-related neurodegenerative or neuromuscular disorder.

[0059] In some embodiments, the CDKL5-related neurodegenerative or neuromuscular disorder isCDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, or atypical Rett syndrome.

[0060] In some embodiments, the present disclosure provides a method of treating a subject having CDD or diagnosed with having CDD, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle described herein.

[0061] In some embodiments, the subject lias one or more mutations in the CDKL5 gene.

[0062] In some embodiments, the subject has a reduced level of CDKL5 activity as compared to a reference level in a subject who does not have an CDKL5-related disorder.

[0063] 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 the disorder. In some embodiments, the treating results in a change in one or more biomarkers of the disorder. In some embodiments, the one or more biomarkers comprises neurofilament light chain or a marker of CDKL5 activity, e.g., as measured by phosphorylation levels of substrate proteins, e.g., MECP2, or as measured by mass spectrometry .

[0064] In some embodiments, the treating results in amelioration of at least one symptom of the disorder. 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 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, 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 band movements, gastroesophageal reflux, constipation, or a combination thereof,

[0065] In some embodiments, the subject is a human.

[0066] In some embodiments, the AAV particle is delivered to a cell, tissue, or region of the CNS, e.g., a region of the brain or spinal cord, e.g., the parenchyma, the cortex, substantia nigra, caudate cerebellum, striatum, corpus callosum, cerebellum, brain stern caudate-putamen, thalamus, superior colliculus, the spinal cord, or a combination thereof, and / or to neurons, or a combination thereof.

[0067] 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 an immunohistochemistry assay.

[0068] In some embodiments, evaluating the level of CDKL5 expression is performed prior to and subsequent to administration of the AAV particle, optionally wherein the le vel of CDKL5 expression prior to treatment is compared to the level of CDKL5 expression subsequent to administration.

[0069] In some embodiments, the level of CDKL5 expression is evaluated in a cell or tissue of the central nervous system (e.g., parenchyma) from the subject.

[0070] 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.

[0071] In some embodiments, the administration of pharmaceutical composition or the AAV particle results in an increase in: (i) CDKL5 activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., the cortex, striatum, thalamus, cerebellum, and / or brainstem), and / or fluid (e.g., CSF and / or serum) of the subject, relative to CDKL5 activity in the subject prior to the administration; (ii) viral genomes (VG) per cell level in a CNS tissue (e.g., the cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord) of the subject, relative to the subject’s VG per cell level in a peripheral tissue; and / or (iii) CDKL5 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., the cortex, thalamus, and / or brainstem) of the subject, as compared to CDKL5 mRN A expression in the subject prior to the administration.

[0072] In some embodiments, the method of treating further comprises administering to the subject an additional agent suitable for treatment or prevention of an CDKL5 -related disorder. In some embodiments, the additional agent comprises one or more anti-epileptic drags (e.g., levetiracetam, phenobarbital, clobazam, topiramate), adrenocorticotropic hormone, or a combination thereof. In some embodiments, the method further comprises administering an immunosuppressant to the subject. In some embodiments, the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizmnab hydroxychloroquine.Enumerated Embodiments1. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependenl kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein:(i) optionally [Nl] comprises XI, X2, and X3, wherein at least one of XI, X2, or X3 is G;(ii) [N2] comprises the amino acid sequence of SPH; and(iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, orX6 is a basic amino acid, e.g.. a K or R.2. The AAV particle of embodiment 1, wherein X4, X5, or both of [N3] is a K.3. The AAV particle of embodiment 1 or 2, wherein X4, X5, or X6 of [N3] is an R.4. The AAV particle of any one of embodiments 1-3, wherein:(a) X4 of [N3] is: K, S, A, V, T, G, F. W, V. N, or R;(b) X5 of [N3] is: S, K, T, F, I, L, Y, H, M, or R; and / or(c) X6 of [N3] is: G, A, R, M, I, N, T, Y, D, P, V. L, E, W, N, Q, K, or S; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).5. The AAV particle of any one of embodiments 1-4, wherein [N3] comprises SK, KA, KS, AR, RM, VK, AS, SR, VK, KR. KK, KN, VR, RS, RK, KT, TS, KF, FG, KI, IG, KL. LG, TT, TY, KY, YG, KD, KP, TR, RG, VR, GA, SL. SS, FL, WK, SA, RA, LR. KW, RR, GK, TK, NK, AK, KV, KG, KH, KM, TG. SE, SV, SW, SN, HG, SQ, LW, MG, MA, or SG.6. The AAV particle of any one of embodiments 1-5, wherein [N3] is or comprises SKA, KSG, ARM, VKS, ASR, VKI, KKN, VRM, RKA, KTS, KFG, KIG, KLG, KTT, KTY, KYG, SKD, SKP, TRG, VRG, KRG, GAR, KSA, KSR, SKL, SRA, SKR, SLR, SRG, SSR, FLR, SKW, SKS, WKA, VRR, SKV, SKT, SKG, GKA, TKA, NKA, SKL, SKN, AKA, KTG, KSL, KSE, KSV, KSW, KSN, KHG, KSQ, KSK, KLW, WKG, KMG, KMA, orRSG.7. The AAV particle of any one of embodiments 1-6, wherein [N2]-[N3] comprises SPHSK (SEQ ID NO: 4701). SPHKS (SEQ ID NO: 4704), SPHAR (SEQ ID NO: 4705), SPHVK (SEQ ID NO: 4706), SPHAS (SEQ ID NO: 4707), SPHKK (SEQ ID NO: 4708), SPHVR (SEQ ID NO: 4709). SPHRK (SEQ ID NO: 4710), SPHKT (SEQ ID NO: 4711), SPIIKF (SEQ ID NO: 4712), SI-TIKI (SEQ ID NO: 4713), SPHKL (SEQ ID NO: 4714). SPHKY (SEQ ID NO: 4715), SPHTR (SEQ ID NO: 4716). SPHKR (SEQ ID NO: 4717), SPHGA (SEQ ID NO: 4718), SPHSR (SEQ ID NO: 4719), SPHSL (SEQ ID NO: 4720), SPHSS (SEQ ID NO: 4721), SPHFL (SEQ ID NO: 4722), SPHWK (SEQ ID NO: 4723), SPHGK (SEQ ID NO: 4724), SPHTK (SEQ ID NO: 4725), SPHNK (SEQ ID NO: 4726), SPHAK (SEQ ID NO: 4727), SPHKH (SEQ ID NO: 4728), SPHKM (SEQ ID NO: 4729), or SPHRS (SEQ ID NO: 4730).8. The AAV particle of any one of embodiments 1-7, wherein [N2]-[N3 ] is or comprises:(i) SPHSKA (SEQ ID NO: 941), SPHKSG (SEQ ID NO: 946), SPHARM (SEQ ID NO: 947), SPHVKS (SEQ ID NO: 948). SPHASR (SEQ ID NO: 949), SPHVKI (SEQ ID NO: 950). SPHKKN (SEQ ID NO: 954), SPHVRM (SEQ ID NO: 955), SPHRKA (SEQ ID NO: 956), SPHKFG (SEQ ID NO: 957). SPHKIG (SEQ ID NO: 958), SPHKLG (SEQ ID NO: 959), SPHKTS (SEQ ID NO: 963), SPHKTT (SEQ ID NO: 964), SPIIKTY (SEQ ID NO: 965), SPIIKYG (SEQ ID NO: 966), SPHSKD (SEQ ID NO: 967), SPHSKP (SEQ ID NO: 968), SPHTRG (SEQ ID NO: 972), SPHVRG (SEQ ID NO: 973), SPHKRG (SEQ ID NO: 974), SPHGAR (SEQ ID NO: 975), SPHKSA (SEQ ID NO: 977), SPHKSR (SEQ ID NO: 951), SPHSKL (SEQ ID NO: 960), SPHSRA (SEQ ID NO: 969), SPHSKR (SEQ ID NO: 978), SPHSLR (SEQ ID NO: 952), SPHSRG (SEQ ID NO: 961), SPHSSR (SEQ IDNO: 970). SPHFLR (SEQ ID NO: 979), SPHSKW (SEQ ID NO: 953), SPHSKS (SEQ ID NO: 962), SPHWKA (SEQ ID NO: 971), SPHVRR (SEQ ID NO: 980), SPHSKT (SEQ ID NO: 4731).SPHSKG (SEQ ID NO: 4732), SPHGKA (SEQ ID NO: 4733). SPHNKA (SEQ ID NO: 4734), SPHSKN (SEQ ID NO: 4735), SPHAKA (SEQ ID NO: 4736), SPHSKV (SEQ ID NO: 4737), SPHKTG (SEQ ID NO: 4738), SPHTKA (SEQ ID NO: 4739), SPHKSL (SEQ ID NO: 4740), SPHKSE (SEQ ID NO: 4741), SPHKSV (SEQ ID NO: 4742), SPHKSW (SEQ ID NO: 4743), SPHKSN (SEQ ID NO: 4744), SPIIKHG (SEQ ID NO: 4745), SPHKSQ (SEQ ID NO: 4746), SPHKSK (SEQ ID NO: 4747), SPHKLW (SEQ ID NO: 4748), SPHWKG (SEQ ID NO: 4749). SPHKMG (SEQ ID NO: 4750), SPHKMA (SEQ ID NO: 4751), or SPHRSG (SEQ ID NO: 976);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).9. The AAV particle of any one of embodiments 1-8, wherein the AAV capsid variant comprises an amino acid other than G at position 453 (e.g,, V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C), an amino acid other than S at position 454 (e.g., V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q), and / or an amino acid other than G at positron 455 (e.g., C, L, D, E, Y, H, V, A, N, P. or S). numbered according to any one of SEQ ID NOs: 36-59. 138, 981. or 982.10. The AAV particle of any one of embodiments 1-8, wherein the AAV capsid variant comprises die amino acid G at position 453, the amino acid S at position 454, and the amino acid G at position 455, numbered according to SEQ ID NO: 138 or 981.11 . The AAV particle of any one of embodiments 1-9, wherein the AAV capsid variant comprises the amino acid G at position 453, the amino acid H at position 454, and the amino acid D at position 455, numbered according to SEQ ID NO: 138 or 982.12. The AA V particle of any one of embodiments 1-11, wherein [N 1 ] comprises XI, X2, and X3, wherein at least one of XI, X2, or X3 is G.13. The AAV particle of any one of embodiments 1-12, wherein:(a) X1 of [N 1] is: G, V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C;(b) X2 of [Nl] is: S, V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q; and / or(c) X3 of [Nl] is: G, C, L, D, E, Y, H, V, A, N, P, or S;optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).14. The AAV particle of any one of embodiments 1-13, wherein [N1] comprises GS, SG, GH, HD, GQ, QD, VS. CS, GR, RG, QS, SH, MS, RN, TS, IS, GP, ES, SS. GN, AS, NS, LS, GG, KS. GT, PS, RS, GI, WS, DS, ID, GL, DA, DG, ME, EN, KN, KE, Al, NG, PG, TG, SV, IG, LG, AG, EG, SA, YD, HE, HG, RD, ND, PD, MG, QV. DD, HN, HP, GY, GM, GD, or HS.15. The AAV particle of any one of embodiments 1-14, wherein [Nl] is or comprises GSG, GHD, GQD, VSG, CSG, GRG, CSH, GQS, GSH, RVG, GSC, GLL, GDD, GHE, GNY, MSG, RNG, TSG, ISG, GPG, ESG, SSG, GNG, ASG, NSG, LSG, GGG, KSG, HSG, GTG, PSG, GSV, RSG, GIG, WSG, DSG, IDG, GLG, DAG, DGG, MEG, ENG, GSA, KNG, KEG, AIG, GYD, GHG, GRD, GND, GPD. GMG, GQV, GHN, GHP, or GHS.16. The AAV particle of any one of embodiments 1-15, wherein [N1]-[N2] comprises:(i) SGSPH (SEQ ID NO: 4752), HDSPH (SEQ ID NO: 4703), QDSPH (SEQ ID NO: 4753), RGSPH (SEQ ID NO: 4754). SHSPH (SEQ ID NO: 4755), QSSPH (SEQ ID NO: 4756), DDSPH (SEQ ID NO: 4757), HESPH (SEQ ID NO: 4758), NYSPH (SEQ ID NO: 4759). VGSPH (SEQ ID NO: 4760). SCSPH (SEQ ID NO: 4761), LLSPH (SEQ ID NO: 4762), NGSPH (SEQ ID NO: 4763). PGSPH (SEQ ID NO: 4764), GGSPH (SEQ ID NO: 4765), TGSPH (SEQ ID NO: 4766), SVSPH (SEQ ID NO: 4767), IGSPH (SEQ ID NO: 4768), DGSPH (SEQ ID NO: 4769), LGSPH (SEQ ID NO: 4770), AGSPH (SEQ ID NO: 4771), EGSPH (SEQ ID NO: 4772), SASPH (SEQ ID NO: 4773), YDSPH (SEQ ID NO: 4774), HGSPH (SEQ ID NO: 4775), RDSPH (SEQ ID NO: 4776), NDSPH (SEQ ID NO: 4777), PDSPH (SEQ ID NO: 4778), MGSPH (SEQ ID NO: 4779), QVSPH (SEQ ID NO: 4780), HNSPH (SEQ ID NO: 4781), HPSPH (SEQ ID NO: 4782), orHSSPH (SEQ ID NO: 4783);(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 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 ammo acid sequences in (i).17. The AAV particle of any one of embodiments 1-16, wherein [N1]-[N2] is or comprises:(i) GSGSPH (SEQ ID NO: 4695), GHDSPH (SEQ ID NO: 4784), GQDSPH (SEQ ID NO: 4785), VSGSPH (SEQ ID NO: 4786), CSGSPH (SEQ ID NO: 4787), GRGSPH (SEQ ID NO: 4788), CSHSPH (SEQ ID NO: 4789), GQSSPH (SEQ ID NO: 4790), GSHSPH (SEQ ID NO: 4791),GDDSPH (SEQ ID NO: 4792), GHESPH (SEQ ID NO: 4793), GNYSPH (SEQ ID NO: 4794), RVGSPH (SEQ ID NO: 4795), GSCSPH (SEQ ID NO: 4796), GLLSPH (SEQ ID NO: 4797), MSGSPH (SEQ ID NO: 4798), RNGSPH (SEQ ID NO: 4799), TSGSPH (SEQ ID NO: 4800), ISGSPH (SEQ ID NO: 4801), GPGSPH (SEQ ID NO: 4802). ESGSPH (SEQ ID NO: 4803), SSGSPH (SEQ ID NO: 4804), GNGSPH (SEQ ID NO: 4805). ASGSPH (SEQ ID NO: 4806), NSGSPH (SEQ ID NO: 4807), LSGSPH (SEQ ID NO: 4808), GGGSPII (SEQ ID NO: 4809), KSGSPH (SEQ ID NO: 4810), HSGSPH (SEQ ID NO: 4811), GTGSPH (SEQ ID NO: 4812), PSGSPH (SEQ ID NO: 4813). GSVSPH (SEQ ID NO: 4814), RSGSPH (SEQ ID NO: 4815), GIGSPH (SEQ ID NO: 4816), WSGSPH (SEQ ID NO: 4817), DSGSPH (SEQ ID NO: 4818), IDGSPH (SEQ ID NO: 4819), GLGSPH (SEQ ID NO: 4820), DAGSPH (SEQ ID NO: 4821), DGGSPH (SEQ ID NO: 4822), MEGSPH (SEQ ID NO: 4823), ENGSPH (SEQ ID NO: 4824), GSASPH (SEQ ID NO: 4825), KNGSPH (SEQ ID NO: 4826), KEGSPH (SEQ ID NO: 4827), AIGSPH (SEQ ID NO: 4828). GYDSPH (SEQ ID NO: 4829), GHGSPH (SEQ ID NO: 4830), GRDSPH (SEQ ID NO: 4831). GNDSPH (SEQ ID NO: 4832), GPDSPH (SEQ ID NO: 4833), GMGSPH (SEQ ID NO: 4834). GQVSPH (SEQ ID NO: 4835), GHNSPH (SEQ ID NO: 4836), GHPSPH (SEQ ID NO: 4837), or GHSSPH (SEQ ID NO: 4838);(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 relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).18. The AAV particle of any one of embodiments 1-17, wherein [N1]-[N2]-[N3] comprises:(i) SGSPHSK (SEQ ID NO: 4839), HDSPHKS (SEQ ID NO: 4840), SGSPHAR (SEQ ID NO: 4841), SGSPHVK (SEQ ID NO: 4842), QDSPHKS (SEQ ID NO: 4843), SGSPHKK (SEQ ID NO: 4844), SGSPHVR (SEQ ID NO: 4845), SGSPHAS (SEQ ID NO: 4846), SGSPHRK (SEQ ID NO: 4847), SGSPHKT (SEQ ID NO: 4848), SHSPHKS (SEQ ID NO: 4849), QSSPHRS (SEQ ID NO: 4850), RGSPHAS (SEQ ID NO: 4851), RGSPHSK (SEQ ID NO: 4852), SGSPHKF (SEQ ID NO: 4853), SGSPHKI (SEQ ID NO: 4854), SGSPHKL (SEQ ID NO: 4855), SGSPHKY (SEQ ID NO: 4856), SGSPHTR (SEQ ID NO: 4857), SHSPHKR (SEQ ID NO: 4858), SGSPHGA (SEQ ID NO: 4859), HDSPHKR (SEQ ID NO: 4860), DDSPHKS (SEQ ID NO: 4861), HESPHKS (SEQ ID NO: 4862), NYSPHKI (SEQ ID NO: 4863), SGSPHSR (SEQ ID NO: 4864), SGSPHSL (SEQ ID NO: 4865), SGSPHSS (SEQ ID NO: 4866). VGSPIISK (SEQ ID NO: 4867), SCSPHRK (SEQ ID NO: 4868), SGSPHFL (SEQ ID NO: 4869), LLSPHWK (SEQ ID NO: 4870), NGSPHSK (SEQ ID NO: 4871), PGSPHSK (SEQ ID NO: 4872), GGSPHSK (SEQ ID NO: 4873), TGSPHSK (SEQ ID NO: 4874), SVSPHGK (SEQ ID NO: 4875), SGSPHTK (SEQ ID NO: 4876), IGSPHSK (SEQ IDNO: 4877), DGSPHSK (SEQ ID NO: 4878), SGSPHNK (SEQ ID NO: 4879), LGSPHSK (SEQ ID NO: 4880), AGSPHSK (SEQ ID NO: 4881), EGSPHSK (SEQ ID NO: 4882), SASPHSK (SEQ ID NO: 4883), SGSPHAK (SEQ ID NO: 4884), HDSPHKI (SEQ ID NO: 4885), YDSPHKS (SEQ ID NO: 4886), HDSPHKT (SEQ ID NO: 4887), RGSPHKR (SEQ ID NO: 4888), HGSPHSK (SEQ ID NO: 4889), RDSPHKS (SEQ ID NO: 4890), NDSPHK.S (SEQ ID NO: 4891), QDSPHKI (SEQ ID NO: 4892), PDSPHK I (SEQ ID NO: 4893), PDSPHKS (SEQ ID NO: 4894), MGSPHSK (SEQ ID NO: 4895), IIDSPHKH (SEQ ID NO: 4896), QVSPHKS (SEQ ID NO: 4897), HNSPHKS (SEQ ID NO: 4898), NGSPHKR (SEQ ID NO: 4899), HDSPHKY (SEQ ID NO: 4900), NDSPHKI (SEQ ID NO: 4901), IIDSPHKL (SEQ ID NO: 4902). HPSPHWK (SEQ ID NO: 4903), HDSPIIKM (SEQ ID NO: 4904), or HSSPHRS (SEQ ID NO: 4905);(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 relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).19. The AAV particle of any one of embodiments 1-18, wherein [N1]-[N2]-[N3] is or comprises:(i) GSGSPHSKA (SEQ ID NO: 4697). GHDSPHKSG (SEQ ID NO: 4698), GSGSPHARM (SEQ ID NO: 4906), GSGSPHVKS (SEQ ID NO: 4907), GQDSPHKSG (SEQ ID NO: 4908), GSGSPHASR (SEQ ID NO: 4909), GSGSPHVKI (SEQ ID NO: 4910), GSGSP HKKN (SEQ ID NO: 4911), GSGSPHVRM (SEQ ID NO: 4912), VSGSPHSKA (SEQ ID NO: 4913), CSGSPHSKA (SEQ ID NO: 4914), GSGSPHRKA (SEQ ID NO: 4915), CSGSPHKTS (SEQ ID NO: 4916), CSHSPHKSG (SEQ ID NO: 4917), GQSSPHRSG (SEQ ID NO: 4918), GRGSPHASR (SEQ ID NO: 4919), GRGSPHSKA (SEQ ID NO: 4920), GSGSPHKFG (SEQ ID NO: 4921), GSGSPHKIG (SEQ ID NO: 4922), GSGSPHKLG (SEQ ID NO: 4923), GSGSPHKTS (SEQ ID NO: 4924), GSGSPHKTT (SEQ ID NO: 4925), GSGSPHKTY (SEQ ID NO: 4926), GSGSPHKYG (SEQ ID NO: 4927), GSGSPHSKD (SEQ ID NO: 4928), GSGSPHSKP (SEQ ID NO: 4929), GSGSPHTRG (SEQ ID NO: 4930), GSGSPHVRG (SEQ ID NO: 4931), GSHSPHKRG (SEQ ID NO: 4932), GSHSPHKSG (SEQ ID NO: 4933), VSGSPHASR (SEQ ID NO: 4934), VSGSPHGAR (SEQ ID NO: 4935), VSGSPHKFG (SEQ ID NO: 4936), GHDSPHKRG (SEQ ID NO: 4937), GDDSPHKSG (SEQ ID NO: 4938), GHESPHKSA (SEQ ID NO: 4939), GHDSPIIKSA (SEQ ID NO: 4940), GNYSPHKIG (SEQ ID NO: 4941). GHDSPHKSR (SEQ ID NO: 4942), GSGSPIISKL (SEQ ID NO: 4943), GSGSPHSRA (SEQ ID NO: 4944), GSGSI-TISKR (SEQ ID NO: 4945), GSGSPHSLR (SEQ ID NO: 4946), GSGSPHSRG (SEQ ID NO: 4947), GSGSPHSSR (SEQ ID NO: 4948), RVGSPHSKA (SEQ ID NO: 4949), GSGSPHRKA (SEQ ID NO: 4950), GSGSPHFLR (SEQ ID NO: 4951), GSGSPHSKW (SEQ ID NO: 4952), GSGSPHSKS (SEQ ID NO: 4953), GLLSPHWKA (SEQID NO: 4954), GSGSPHVRR (SEQ ID NO: 4955), GSGSPHSKV (SEQ ID NO: 4956), MSGSPHSKA (SEQ ID NO: 4957). RNGSPHSKA (SEQ ID NO: 4958), TSGSPHSKA (SEQ ID NO: 4959), TSGSPHSKA (SEQ ID NO: 4960), GPGSPHSKA (SEQ ID NO: 4961), GSGSPHSKT (SEQ ID NO: 4962), ESGSPHSK A (SEQ ID NO: 4963), SSGSPHSKA (SEQ ID NO: 4964), GNGSPHSKA (SEQ ID NO: 4965). ASGSPHSKA (SEQ ID NO: 4966), NSGSPHSKA (SEQ ID NO: 4967), TSGSPHSKA (SEQ ID NO: 4968), GGGSPHSKA (SEQ ID NO: 4969), KSGSPHSKA (SEQ ID NO: 4970), GGGSPHSKS (SEQ ID NO: 4971), GSGSPHSKG (SEQ ID NO: 4972). HSGSPHSKA (SEQ ID NO: 4973), GTGSPHSKA (SEQ ID NO: 4974), PSGSPHSKA (SEQ ID NO: 4975), GSVSPHGKA (SEQ ID NO: 4976). RSGSPHSKA (SEQ ID NO: 4977), GSGSPHTKA (SEQ ID NO: 4978), GIGSPHSKA (SEQ ID NO: 4979), WSGSPHSKA (SEQ ID NO: 4980), DSGSPHSKA (SEQ ID NO: 4981), IDGSPHSKA (SEQ ID NO: 4982), GSGSPHNKA (SEQ ID NO: 4983), GLGSPHSKS (SEQ ID NO: 4984), DAGSPHSKA (SEQ ID NO: 4985), DGGSPHSKA (SEQ ID NO: 4986), MEGSPHSKA (SEQ ID NO: 4987), ENGSPHSKA (SEQ ID NO: 4988).GSASPHSKA (SEQ ID NO: 4989), GNGSPHSKS (SEQ ID NO: 4990), KNGSPHSKA (SEQ ID NO: 4991), KEGSPHSKA (SEQ ID NO: 4992), AIGSPHSKA (SEQ ID NO: 4993), GSGSPHSKN (SEQ ID NO: 4994), GSGSPHAKA (SEQ ID NO: 4995), GHDSPHKIG (SEQ ID NO: 4996), GYDSPHKSG (SEQ ID NO: 4997), GHESPHKSG (SEQ ID NO: 4998), GHDSPHK.TG (SEQ ID NO: 4999). GRGSPHKRG (SEQ ID NO: 5000), GQDSPHKSG (SEQ ID NO: 4908), GHDSPHKSL (SEQ ID NO: 5001), GHGSPHSKA (SEQ ID NO: 5002), GHDSPHKSE (SEQ ID NO: 5003), VSGSPHSKA (SEQ ID NO: 4913), GRDSPHKSG (SEQ ID NO: 5004), GNDSPHKSV (SEQ ID NO: 5005), GQDSPHKIG (SEQ ID NO: 5006), GHDSPHKSV (SEQ ID NO: 5007), GPDSPI IKIG (SEQ ID NO: 5008), GPDSPHKSG (SEQ ID NO: 5009), GHDSPHKSW (SEQ ID NO: 5010), GHDSPHKSN (SEQ ID NO: 5011), GMGSPHSKT (SEQ ID NO: 5012), GHDSPHKHG (SEQ ID NO: 5013), GQVSPHKSG (SEQ ID NO: 5014), GDDSPHKS V (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016), GNGSPHKRG (SEQ ID NO: 5017), GHDSPHKYG (SEQ ID NO: 5018), GHDSPHKSQ (SEQ ID NO: 5019), GNDSPHKIG (SEQ ID NO: 5020), GHDSPHKSK (SEQ ID NO: 5021), GHDSPHKLW (SEQ ID NO: 5022), GHPSPHWKG (SEQ ID NO: 5023), GHDSPHKMG (SEQ ID NO: 5024), GHDSPHKMA (SEQ ID NO: 5025), or GHSSPHRSG (SEQ ID NO: 502.6);(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 relative to any of the amino acid sequences in (i); or(iv) an ammo acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).20. The AAV particle of any one of embodiments 1-19, wherein [N3] comprises SK, KA, KS, or SG.21. The AAV particle of any one of embodiments 1-20, wherein [N3] is or comprises SKA, KSG, or KYG.22. The AA V particle of any one of embodiments 1 -21 , wherein [N2.]-[N3] comprises SPHSK (SEQID NO: 4701), SPHKS (SEQ ID NO: 4704), or SPHKY (SEQ ID NO: 4715).23. The AAV particle of any one of embodiments 1-22, wherein [N2]-[N3] is or comprises SPHSKA (SEQ ID NO: 941).24. The AAV particle of any one of embodiments 1-22, wherein [N2]-[N3] is or comprises SPHKSG (SEQ ID NO: 946).25. The AAV particle of any one of embodiments 1-22, wherein [N2]-[N3] is or comprises SPHKYG (SEQ ID NO: 966).2.6. The AAV particle of any one of embodiments 1-2.5, wherein [N1] comprises GS, SG, GH, or HD.27. The AAV particle of any one of embodiments 1-2.6, wherein [N 1] is or comprises GSG.2.8. The AAV particle of any one of embodiments 1-26, wherein [N1] is or comprises GHD.29. The AAV particle of any one of embodiments 1-23 or 26-27, wherein [N1]-[N2]-[N3] comprisesSGSPHSK (SEQ ID NO: 4839).30. The AAV particle of any one of embodiments 1 -22, 24, 26, or 28, wherein [N1]-[N2]-[N3] comprises HDSPHKS (SEQ ID NO: 4840).31 . The AA V particle of any one of embodiments 1 -22. or 25-27, wherein [N1]-[N2]-[N3] comprises SGSPHK.YG (SEQ ID NO: 5027).32. The AAV particle of any one of embodiments 1-8, 10, 12-23, 26-27, or 29, wherein [N1]-[N2]- [N3] is or comprises GSGSPHSKA (SEQ ID NO: 4697).33. The AAV particle of any one of embodiments 1-9, 11-22, 24, 26, 28, or 30, wherein [N1]-[N2]- [N3] is or comprises GHDSPHKSG (SEQ ID NO: 4698).34. The AAV particle of any one of embodiments 1-8, 10, 12-22, 25-27, or 31, wherein [N1]-[N2]-[N3] is or comprises GSGSPHKYG (SEQ ID NO: 4927).35. The AAV particle of any one of embodiments 1-34, wherein [N1]-[N2]-[N3] replaces positions 453-455, numbered according to SEQ ID NO: 138,36. The AAV particle of any one of embodiments 1-35, wherein the AAV capsid variant comprises an amino acid other than Q al position 456 (e.g., W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F), an amino acid other than N al position 457 (e.g., Y, C, K, T, H, R. D, V, S, P, G, W, E, F, A, I. M, Q, or L), an amino acid other than Q at position 458 (e.g., G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y), and / or an amino acid other than Q at position 459 (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V), numbered according to SEQ ID NO: 138.37. The AAV particle of any one of embodiments 1-36, wherein the AAV capsid variant comprises an amino acid other than Q at position 462 (e.g., W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F), an amino acid other than N at position 463 (e.g., Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, I, M, Q, or L), an amino acid other than Q at position 464 (e.g. , G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y). and / or an amino acid other than Q at position 465 (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T. D, or V), numbered according to SEQ ID NO: 981, 982, 36. 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57.38. The AAV particle of any one of embodiments 1-37, wherein the AAV capsid variant comprises:(a) the amino acid Q al position 456, the amino acid N at position 457, the amino acid Q at position 458, and / or the amino acid Q at position 459, numbered according to SEQ ID NO: 138: or(b) the amino acid Q at position 462, the amino acid N at position 463, the amino acid Q at position 464, and / or the amino acid Q at position 465, numbered according to SEQ ID NO: 981, 982, 36, 37, 39. 40, 42-46, 48, 49, 50, 52, 53. 56, or 57.39. The AA V particle of any one of embodiments 1 -38, wherein the AAV capsid variant further comprises [N4], wherein [N4] comprises X7 X8 X9 X10, and wherein:(a) X7 is: Q, W, K, R. G, L, V, S, P, H, K, I, M, A, E, or F:(b) X8 is: N, Y, C, K, T, H, R, D. V, S. P, G, W, E, F, A, I, M, Q, or L:(c) X9 is: Q. G, K, H, R, T, L, D, A, P, I, F, V, M. W, Y, S, E, N, or Y; and(d) X10 is: Q. H, L, R, W, K, A, P, E. M, I, S, G, N. Y, C, V, T, D, or V; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(d).40. The AAV particle of embodiment 39, wherein:(a) X7 of [N4] is Q orR;(b) X8 of [N4] is N or R;(c) X9 of [N4] is Q or R; and(d) X10 of [N4] is Q, L, orR,41. The AAV particle of embodiment 39 or 40, wherein [N4] is or comprises:(i) QNQQ (SEQ ID NO: 5028), WNQQ (SEQ ID NO: 5029), QYYV (SEQ ID NO: 5030), RRQQ (SEQ ID NO: 5031), GCGQ (SEQ ID NO: 5032), LRQQ (SEQ ID NO: 5033), RNQQ (SEQ ID NO: 5034), VNQQ (SEQ ID NO: 5035), FRLQ (SEQ ID NO: 5036), FNQQ (SEQ ID NO: 5037), LLQQ (SEQ ID NO: 5038), SNQQ (SEQ ID NO: 5039), RLQQ (SEQ ID NO: 5040), LNQQ (SEQ ID NO: 5041), QRKL (SEQ ID NO: 5042), LRRQ (SEQ ID NO: 5043), QRLR (SEQ ID NO: 5044), QRRL (SEQ ID NO: 5045), RRLQ (SEQ ID NO: 5046), RLRQ (SEQ ID NO: 5047), SKRQ (SEQ ID NO: 5048), QLYR (SEQ ID NO: 5049), QLTV (SEQ ID NO: 5050), QNKQ (SEQ ID NO: 5051), KNQQ (SEQ ID NO: 5052), QKQQ (SEQ ID NO: 5053), QTQQ (SEQ ID NO: 5054), QNHQ (SEQ ID NO: 5055), QHQQ (SEQ ID NO: 5056), QNQH (SEQ ID NO: 5057), QHRQ (SEQ ID NO: 5058), LTQQ (SEQ ID NO: 5059). QNQW (SEQ ID NO: 5060), QNTH (SEQ ID NO: 5061), RRRQ (SEQ ID NO: 5062), QYQQ (SEQ ID NO: 5063), QNDQ (SEQ ID NO: 5064), QNRH (SEQ ID NO: 5065), RDQQ (SEQ ID NO: 5066), PNLQ (SEQ ID NO: 5067), HVRQ (SEQ ID NO: 5068). PNQH (SEQ ID NO: 5069), HNQQ (SEQ ID NO: 5070), QSQQ (SEQ ID NO: 5071), QPAK (SEQ ID NO: 5072), QNLA (SEQ ID NO: 5073), QNQL (SEQ ID NO: 5074), QGQQ (SEQ ID NO: 5075), LNRQ (SEQ ID NO: 5076), QNPP (SEQ ID NO: 5077), QNLQ (SEQ ID NO: 5078), QDQE (SEQ ID NO: 5079), QDQQ (SEQ ID NO: 5080), HWQQ (SEQ ID NO: 5081), PNQQ (SEQ ID NO: 5082), PEQQ (SEQ ID NO: 5083), QRTM (SEQ ID NO: 5084), LHQH (SEQ ID NO: 5085), QHRI (SEQ ID NO: 5086), QY1H (SEQ ID NO: 5087), QKFE (SEQ ID NO: 5088), QFPS (SEQ ID NO: 5089), QNPL (SEQ ID NO: 5090), QAIK (SEQ ID NO: 5091), QNRQ (SEQ ID NO: 5092), QYQH (SEQ ID NO: 5093), QNPQ (SEQ ID NO: 5094), QHQL (SEQ ID NO: 5095), QSPP (SEQ ID NO: 5096), QAKL (SEQ ID NO: 5097), KSQQ (SEQ ID NO: 5098), QDRP (SEQ ID NO: 5099), QNLG (SEQ ID NO: 5100), QAFH (SEQ ID NO: 5101), QNAQ (SEQ ID NO: 5102), HNQL (SEQ ID NO: 5103), QKLN (SEQ ID NO: 5104), QNVQ (SEQ ID NO: 5105), QAQQ (SEQ ID NO: 5106), QTPP (SEQ ID NO: 5107), QPPA (SEQ ID NO: 5108). QERP (SEQ ID NO: 5109), QDLQ (SEQ ID NO: 5110), QAMH (SEQ ID NO: 5111), QHPS (SEQ ID NO: 5112). PGLQ (SEQ ID NO: 5113). QGIR (SEQ ID NO: 5114), QAPA (SEQ ID NO: 5115), QIPP (SEQ ID NO: 5116), QTQL (SEQ ID NO: 5117), QAPS (SEQ ID NO: 5118), QNTY (SEQ ID NO: 5119), QDKQ (SEQ ID NO: 5120), QNHL (SEQ ID NO: 5121), QIGM (SEQ ID NO: 5122), LNKQ (SEQ ID NO: 5123), PNQL (SEQ ID NO: 5124), QLQQ (SEQ ID NO: 5125), QRMS (SEQ ID NO: 5126), QGIL (SEQ ID NO: 5127), QDRQ (SEQ ID NO: 5128), RDWQ (SEQ ID NO: 5129), QERS (SEQ ID NO: 5130), QNYQ (SEQ ID NO: 5131), QRTC (SEQID NO: 5132), QIGH (SEQ ID NO: 5133), QGAI (SEQ ID NO: 5134), QVPP (SEQ ID NO: 5135), QVQQ (SEQ ID NO: 5136), LMRQ (SEQ ID NO: 5137), QYSV (SEQ ID NO: 5138), QAIT (SEQ ID NO: 5139), QKTL (SEQ ID NO: 5140), QLHH (SEQ ID NO: 5141), QN1I (SEQ ID NO: 5142), QGHH (SEQ ID NO: 5143), QSKV (SEQ ID NO: 5144), QLPS (SEQ ID NO: 5145), IGKQ (SEQ ID NO: 5146), QAIH (SEQ ID NO: 5147), QHGL (SEQ ID NO: 5148), QFMC (SEQ ID NO: 5149), QNQM (SEQ ID NO: 5150), QHLQ (SEQ ID NO: 5151), QPAR (SEQ ID NO: 5152), QSLQ (SEQ ID NO: 5153), QSQL (SEQ ID NO: 5154), HSQQ (SEQ ID NO: 5155), QMPS (SEQ ID NO: 5156), QGSL (SEQ ID NO: 5157), QVPA (SEQ ID NO: 5158). HYQQ (SEQ ID NO: 5159), QVPS (SEQ ID NO: 5160), RGEQ (SEQ ID NO: 5161). PGQQ (SEQ ID NO: 5162), LEQQ (SEQ ID NO: 5163), QNQS (SEQ ID NO: 5164), QKVI (SEQ ID NO: 5165), QNND (SEQ ID NO: 5166), QSVH (SEQ ID NO: 5167), QPLG (SEQ ID NO: 5168), HNQE (SEQ ID NO: 5169), QIQQ (SEQ ID NO: 5170), QVRN (SEQ ID NO: 5171), PSNQ (SEQ ID NO: 5172), QVGH (SEQ ID NO: 5173), QRD1 (SEQ ID NO: 5174), QMPN (SEQ ID NO: 5175), RGLQ (SEQ ID NO: 5176). PSLQ (SEQ ID NO: 5177), QRDQ (SEQ ID NO: 5178). QAKG (SEQ ID NO: 5179), QSAH (SEQ ID NO: 5180). QSTM (SEQ ID NO: 5181), QREM (SEQ ID NO: 5182), QYRA (SEQ ID NO: 5183), QRQQ (SEQ ID NO: 5184), QWQQ (SEQ ID NO: 5185), QRMN (SEQ ID NO: 5186), GDSQ (SEQ ID NO: 5187). QKIS (SEQ ID NO: 5188), PSMQ (SEQ ID NO: 5189), SPRQ (SEQ ID NO: 5190), MEQQ (SEQ ID NO: 5191), QYQN (SEQ ID NO: 5192), QIRQ (SEQ ID NO: 5193), QSVQ (SEQ ID NO: 5194), RSQQ (SEQ ID NO: 5195). QNK.L (SEQ ID NO: 5196), QIQH (SEQ ID NO: 5197), PRQQ (SEQ ID NO: 5198), HTQQ (SEQ ID NO: 5199), QRQH (SEQ ID NO: 5200), RNQE (SEQ ID NO: 5201), QSKQ (SEQ ID NO: 5202), QNQP (SEQ ID NO: 5203), QSPQ (SEQ ID NO: 5204), QTRQ (SEQ ID NO: 5205). QNLH (SEQ ID NO: 5206), QNQE (SEQ ID NO: 5207), LNQP (SEQ ID NO: 5208), QNQD (SEQ ID NO: 5209), QNLL (SEQ ID NO: 5210), QLVI (SEQ ID NO: 5211), RTQE (SEQ ID NO: 5212), QTHQ (SEQ ID NO: 5213), QDQH (SEQ ID NO: 5214), QSQH (SEQ ID NO: 5215), VRQQ (SEQ ID NO: 5216), AWQQ (SEQ ID NO: 5217), QSVP (SEQ ID NO: 5218), QNIQ (SEQ ID NO: 5219), LDQQ (SEQ ID NO: 5220), PDQQ (SEQ ID NO: 5221), ESQQ (SEQ ID NO: 5222), QRQL (SEQ ID NO: 5223), QI1V (SEQ ID NO: 5224), QKQS (SEQ ID NO: 5225), QSHQ (SEQ ID NO: 5226), QFVV (SEQ ID NO: 5227), QSQP (SEQ ID NO: 5228), QNEQ (SEQ ID NO: 5229), INQQ (SEQ ID NO: 5230), RNRQ (SEQ ID NO: 5231), RDQK (SEQ ID NO: 5232), QWKR (SEQ ID NO: 5233), ENRQ (SEQ ID NO: 5234), QTQP (SEQ ID NO: 5235), QKQL (SEQ ID NO: 5236), RNQE (SEQ ID NO: 5237), ISIQ (SEQ ID NO: 5238), QTVC (SEQ ID NO: 5239), QQIM (SEQ ID NO: 5240), LNI-IQ (SEQ ID NO: 5241), QNQA (SEQ ID NO: 5242), QMIPI (SEQ ID NO: 5243). RNIIQ (SEQ ID NO: 5244), or QK M N (SEQ ID NO: 5245);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, or 3 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).42. The AA V particle of any one of embodiments 39-41, wherein [N1]-[N2]-[N3]-[N4] is or comprises:(i) the amino acid sequence of any of SEQ ID NOs: 1800-2241;(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any2, 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 relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).43. The AAV particle of any one of embodiments 39-42, wherein [N1]-[N2]-[N3]-[N4] is or comprises GSGSPHSKAQNQQ (SEQ ID NO: 1801).44. The AAV particle of any one of embodiments 39-42, wherein |N1]-[N2]-[N3]-[N4] is or comprises GHDSPH KSGQNQQ (SEQ ID NO: 1800).45. The AAV particle of any one of embodiments 39-42, wherein [NT]-[N2]-[N3]-[N4] is or comprises GSGSPHK YGQNQQT (SEQ ID NO: 910).46. The AAV particle of any one of embodiments 1-45, wherein the AAV capsid variant comprises an amino acid other than T at position 450 (e.g., S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G), an amino acid other than I at position 451 (e.g., M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L), and / or an amino acid other than N at position 452 (e.g., M, E, G, Y, W, T, 1, Q, F, V, A, L, 1, P, K, R, H, S, D, or S), numbered according to any one of SEQ ID NOs: 36-59, 138, 981, or 982.47. The AA V particle of any one of embodiments 1 -46, wherein the AAV capsid variant comprises the amino acid T at position 450, the amino acid I at position 451, and / or the amino acid N at position 452, numbered according to any one of SEQ ID NOs: 138, 981, or 982.48. The AAV particle of any one of embodiments 1-47, wherein the AAV capsid variant further comprises [NO], wherein [NO] comprises XAXB. and Xc, and wherein:(a) XAis: T, S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G;(b) XBis: 1, M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L; and(c) Xcis: N, M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S: andoptionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c).49. The AA V particle of embodiment 48, wherein [NO] is or comprises TIN, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW. ANN, IPE, ADM, IEY, ADY, IET, MEW, CEY. RIN, MEI, LEY, ADW, IEI, DIM, FEQ. MEE, CDQ, LPE, IEN, MES, AEI, VEY, IIN, TSN, IEV, MEM, AEV, MDA, VEW, AEQ, LEW, MEL. MET, MEA, IES, MEV, CEI, ATN, MDG, QEV, ADQ, NMN, IEM, ISN, TGN, QQQ, H DW , IEG, TH, TFP, TEK, EIN, TVN, TFN, SIN, TER, TSY, ELH, AIN. SVN, TDN, TFH , TVH, TEN. TSS, TID, TCN, NIN. TEH, AEM, AIK. TDK, TFK. SDQ. TEI, NTN, IET, SIK, TEL, TEA, TAN, TIY, TFS, TES, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, NAD, TIT, NCV, T1R, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV, SDI, NSI, NSL, EW, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, N Al, AEN, AET, ETA, NNL, or any dipeptide thereof.50. The AAV particle of embodiment 48 or 49, wherein [NO]-[N1]-[N2]-[N3]-[N4] is or comprises:(i) the amino acid sequence of any one of SEQ ID NOs: 2242-2886;(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g,, consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).51. The AAV particle of any one of embodiments 48-50, wherein [NO]-[N1]-[N2]-[N3]-[N4] is or comprises T1NGSGSPHSKAQNQQ (SEQ ID NO: 2242).52. The AAV particle of any one of embodiments 48-50. wherein [NO]-[N1]-[N2]-[N3]-[N4] is or comprises TINGHDSPHKSGQNQQ (SEQ ID NO: 2243).53. The AA V particle of any one of embodiments 48-52, wherein [NO]-[N1]-[N2]-[N3]-[N4] is or comprises TINGSGSPHKYGQNQQT (SEQ ID NO: 5246).54. The AAV particle of any one of embodiments 1-53, wherein [N1]-[N2]-[N3] is present in loop IV.55. The AAV particle of any one of embodiments 48-54, wherein [NO] and [N4] are present in loop IV.56. The AAV particle of any one of embodiments 48-55, wherein [NO] is present immediately subsequent to position 449, numbered according to SEQ ID NO: 138.57. The AA V particle of any one of embodiments 48-56, wherein [NO] is present immediately subsequent to position 449, numbered according to any one of SEQ ID NOs: 36-59, 981, or 982,58. The AAV particle of any one of embodiments 48-57. wherein [NO] replaces positions 450, 451. and 452 (e.g., T450, 1451, and N452), numbered according to SEQ ID NO: 138.59. The AAV particle of any one of embodiments 48-58, wherein [NO] replaces positrons 450-452 (e.g., T450, 1451, and N452), numbered according to any one of SEQ ID NOs: 36-59, 981, or 982.60. The AAV particle of any one of embodiments 48-59, wherein [NO] corresponds to positions 450- 452 of any one of SEQ ID NOs: 36-59, 138, 981 or 982.61. The AAV particle of any one of embodiments 48-60, wherein [NO] is present immediately subsequent to position 449 and wherein [NO] replaces positions 450-452 (e.g., T450, 1451, and N452), numbered according to SEQ ID NO: 138.62. The AAV particle of any one of embodiments 48-61, wherein [NO] is present immediately subsequent to position 449 and wherein [NO] replaces positions 450-452 (e.g.. T450, 1451, and N452 ), numbered according to any one of SEQ ID NOs: 36-59, 981, or 982.63. The AAV particle of any one of embodiments 1-62, wherein [N1] is present immediately subsequent to position 452, numbered according to the amino acid sequence of SEQ ID NO: 138.64. The AAV particle of any one of embodiments 1-63, wherein [N1] is present immediately subsequent to position 452, numbered according to SEQ ID NO: 981 or 982.65. The AAV particle of any one of embodiments 1-61, wherein [N1] replaces positions 453-455(e.g,, G453, S454, and G455), numbered according to SEQ ID NO: 138.66. The AAV particle of any one of embodiments 1-64, wherein [N1] replaces positions 453 (e.g.,G453), numbered according to SEQ ID NO: 138.67. The AAV particle of any one of embodiments 1-65, wherein [N1] replaces positions 453-455 (e.g., G453, S454, and G455), numbered according to SEQ ID NO: 981.68. The AAV particle of any one of embodiments 1-65 or 67, wherein [Nl] replaces positions 453- 455, numbered according to SEQ ID NO: 982.69. The AA V particle of any one of embodiments 1 -65, 67, or 68, wherein [N 1] is present immediately subsequent to position 452 and wherein [N1 ] replaces positions 453-455 (e.g., G453. S454, and G455), numbered according to SEQ ID NO: 138.70. The AAV particle of any one of embodiments 1-64 or 66, wherein [Nl] is present immediately subsequent to position 452 and wherein [N1] replaces positions 453 (e.g., G453), numbered according to SEQ ID NO: 138.71. The AAV particle of any one of embodiments 1-64, 66 or 70, wherein [Nl] is present immediately subsequent to position 452 and wherein [N1] replaces positions 453-455, numbered according to SEQ ID NO: 4, 36, 981, or 982.72. The AAV particle of any one of embodiments 1-71, wherein [N1] corresponds to positions 453-455, numbered according to any one of SEQ ID NOs: 4, 36-59, 981, or 982.73. The AAV particle of any one of embodiments 1-72, wherein the AAV capsid variant comprises an amino acid other than S at position 454 and / or an amino acid oilier than G at position 455, numbered according to SEQ ID NO: 138, 981, or 982.74. The AAV particle of any one of embodiments 1-73, wherein the AAV capsid variant comprises the amino acid H at position 454 and the amino acid D at position 455, numbered according to SEQ ID NO: 138 or 982.75. The AAV particle of any one of embodiments 1 -74, wherein the AAV capsid variant comprises a substitution at position 454 (e.g., S454H) and / or a substitution at position 455 (e.g., G455D), numbered according to SEQ ID NO: 138.76. The AAV particle of any one of embodiments 1-75, wherein the AAV capsid vanant comprises the amino acid II at position 454 and the ammo acid D at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455. numbered according to SEQ ID NO: 138.77. The AAV particle of any one of embodiments 1 -76, wherein the AAV capsid variant comprises the amino acid H at position 454 and the amino acid D at position 455, numbered according to SEQ ID NO: 982.78. The AA V particle of any one of embodiments 1 -77, wherein the AAV capsid variant comprises the amino acid H at position 454 and the amino acid D at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455. numbered according to SEQ ID NO: 982.79. The AAV particle of any one of embodiments 1-72, wherein the AAV capsid variant comprises the amino acid S at position 454 and the amino acid G at position 455, numbered according to SEQ ID NO: 138.80. The AAV particle of any one of embodiments 1-72 or 79. wherein the AAV capsid variant comprises the amino acid S at position 454 and the amino acid G at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455, numbered according to SEQ ID NO: 138.81. The A AV particle of any one of embodiments 1-72, 79, or 80, wherein the AAV capsid variant comprises the amino acid S at position 454 and tire amino acid G al position 455, numbered according to SEQ ID NO: 981.82. The AAV particle of any one of embodiments 1-72 or 79-81, wherein the AAV capsid variant comprises the amino acid S at position 454 and the amino acid G at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately subsequent to position 455, numbered according to SEQ ID NO: 981.83. The AAV particle of any one of embodiments 1-82, wherein [N2 J is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.84. The AA V particle of any one of embodiments 1 -83, wherein [N2] corresponds to positions 456- 458 (e.g., S456. P457, H458) of SEQ ID NO: 981 or 982.85. The AAV particle of any one of embodiments 1-83, wherein [N2] corresponds to positions 456- 458 (e.g., S456, P457, H458) of any one of SEQ ID NOs: 4 or 36-59.86. The AAV particle of any one of embodiments 1-85, wherein [N2]-[N3] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.87. The AA V particle of any one of embodiments 1-86, wherein [N2] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 4, 36, 981, or 982.88. The AAV particle of any one of embodiments 1-87, wherein [N2]-[N3] is present immediately subsequent to position 455. numbered according to SEQ ID NO: 4, 36, 981, or 982.89. The AAV particle of any one of embodiments 1-88, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, S459, K460, A461) of SEQ ID NO: 981.90. The AAV particle of any one of embodiments 1-88, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, K459, S460, G461) of SEQ ID NO: 982.91. The AAV particle of any one of embodiments 1-90, wherein [N2] is present immediately subsequent to [N1].92. The AAV particle of any one of embodiments 1-64, 66, 70, or 71, wherein [N3] is present immediately subsequent to [N2] and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138.93. The AAV particle of any one of embodiments 1-1-64, 66, 70, 71, or 92, w herein |N3 ] is present immediately subsequent to [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138.94. The AAV particle of any one of embodiments 39-93, wherein [N4] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.95. The AA V particle of any one of embodiments 39-94, wherein [N4] replaces positions 456-459(e.g,, Q456, N457, Q458, and Q459), numbered according to SEQ ID NO: 138.96. The AAV particle of any one of embodiments 39-95. wherein [N4] corresponds to positions 462- 465 (e.g., Q462, N463. Q464, Q465) of SEQ ID NO: 4, 36, 981, or 982.97. The AAV particle of any one of embodiments 39-96, wherein [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459), numbered according to SEQ ID NO: 138.98. The AAV particle of any one of embodiments 39-97, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 456-459(e.g,, Q456, N457, Q458, and Q459), numbered according to SEQ ID NO: 138.99. The AA V particle of any one of embodiments 39-98, wherein [N2]-[N3]-[N4] corresponds to positions 456-465 (e.g., S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465) of SEQ ID NO: 981.100. The AAV particle of any one of embodiments 39-98, wherein [N2]-[N3]-[N4] corresponds to positions 456-465 (e.g., S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465) of SEQ IDNO: 982.101. The AAV particle of any one of embodiments 39-98, wherein [N2]-[N3]-[N4] corresponds to positions 456-465 of any one of SEQ ID NOs: 4 or 36-59.102. The AAV particle of any one of embodiments 39-101, wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459), numbered according to SEQ ID NO: 138.103. The AAV particle of any one of embodiments 39-102, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 452, and wherein [N1]-[N2]-[N3]-[N4] replaces positrons 453- 459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459), numbered according to SEQ ID NO:138.104. The AAV particle of any one of embodiments 39-99, 102, or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461 , Q462, N463, Q464, Q465) of SEQ ID NO: 981.105. The AAV particle of any one of embodiments 39-98, 100, 102, or 103, wherein [N1]-[N2]-[N3]~[N4] corresponds to positions 453-465 (e.g., G453, H454, D455, S456, P457, H458, K459, S460,G461, Q462, N463, Q464, Q465) of SEQ ID NO: 982.106. The AAV particle of any one of embodiments 39-98, 102. or 103, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-465 of any one of SEQ ID NOs: 4 or 36-59.107. The AAV particle of any one of embodiments 1-99 or 102-104, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461) of SEQ ID NO: 981.108. The AAV particle of any one of embodiments 1-98, 100, 102, 103, or 105, wherein [N1]-[N2]- [N3] corresponds to positions 453-461 (e.g., G453, H454, D455, S456, P457, H458, K459, S460,G461) of SEQ ID NO: 982.109. The AAV particle of any one of embodiments 39-98, 102. 103, or 106, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 of any one of SEQ ID NOs: 36-59.110. The AAV particle of any one of embodiments 48-109, wherein [N0]-[NT]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, 1451 , N452, G453, S454, G455, Q456, N457, Q458, and Q459), numbered according to SEQ ID NO: 138.1 11. The AAV particle of any one of embodiments 48-110, wherein [NO]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 449, and wherein [N0]-[Nl]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, 1451, N452, G453, S454, G455, Q456. N457, Q458, and Q459), numbered according to SEQ ID NO: 138.112. The AAV particle of any one of embodiments 48-99. 102-104, or 106, wherein [NO]-[N1]-[N2]- [N3]-[N4] corresponds to positions 450-465 (e.g., T450, 1451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465) of SEQ ID NO: 981.113. The AAV particle of any one of embodiments 48-98, 100, 102, 103, 105, or 108, wherein [N0]- [N1]-[N2]-[N3]-[N4] corresponds to positions 450-465 (e.g., T450, 1451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463. Q464, Q465) of SEQ ID NO: 982.114. The AAV particle of any one of embodiments 48-98, 102, 103, 106, or 109. wherein [N0]-[Nl]-[N2]-[N3]-[N4] corresponds to positions 450-465 of any one of SEQ ID NOs: 36-59.115. The AAV particle of any one of embodiments 39-114, wherein [N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465). numbered according to SEQ ID NO: 4, 36. 981, or 982.116. The AAV particle of any one of embodiments 39-115, wherein [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465), numbered according to SEQ ID NO: 4, 36, 981, or 982.117. The AAV particle of any one of embodiments 39-116, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 462-465(e.g,, Q462, N463, Q464, and Q465), numbered according to SEQ ID NO: 4, 36, 981, or 982.118. The AAV particle of any one of embodiments 1-117, wherein [N3] is present immediately subsequent to [N2],119. The AAV particle of any one of embodiments 1-118, wherein the AAV capsid variant comprises, from N-terminus to C-tenninus, [N2]-[N3].120. The AAV particle of any one of embodiments 1-119, wherein the AAV capsid variant comprises, from N-terminus to C-terminus, [N1]-[N2]-[N3],121. The AAV particle of any one of embodiments 48-120, wherein tbe AAV capsid variant comprises, from N-tenninus to C-tenninus, [N0]-[N1]-[N2]-[N3].122. The AAV particle of any one of embodiments 39-121, wherein the AAV capsid variant comprises, from N-terminus to C-terminus, [N1]-[N2]-[N3]-[N4].123. The AAV particle of any one of embodiments 48-122, wherein the AAV capsid variant comprises, from N-terminus to C-terminus, [N0]-[Nl]-[N2j-[N3]-[N4],124. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid other T at position 460 (e.g., N, 1, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G orS), numbered according to SEQ ID NO: 138.125. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino acid N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G or S at position 460, numbered according to SEQ ID NO: 138.126. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid other T at position 466 (e.g., N, I, C, H, R. L, D, Y, A. M, Q, I, E, K, P, G or S), numbered according to any one of SEQ ID NOs: 36-59. 981, or 982.127. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino acid N, I. C, H, R, L, D, Y, A, M, Q, I, E, K. P, G or S at position 466, numbered according to any one of SEQ ID NOs: 36-59, 981 or 982.12.8. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid other K at position 449 (e.g,, an E, an N, or a T), numbered according to anyone of SEQ ID NOs: 36-59, 138, 981, or 982.129. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises the amino E, N, or T at position 449, numbered according to any one of SEQ ID NOs: 36- 59, 138, 981 or 982.130. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises [A] [B] (SEQ ID NO: 4694), wherein:(i) [A] comprises the amino acid sequence of GSGSPH (SEQ ID NO: 4695); and(ii) [B] comprises X1 X2 X3 X4 X5 X6 X7, wherein:(a) X1 is: S, C, F, or V;(b) X2 is: K. L, R. I, E, Y, V. or S;(c) X3 is: A, R, L, G. I, Y, S, F . or W;(d) X4 is: W, Q, R, G, L, V, S, orF;(e) X5 is: N, Y, R, C, K, orL;(f) X6 is: Q, G, K, R, T, L, or Y; and(g) X7 is: Q, L, R, or V: optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any- of the aforesaid amino acids in (a)-(g).131. The AAV particle of embodiment 130, wherein(a) X1 is S;(b) X2 is K orL;(c) X3 is: A, R, or L;(d) X4 is: Q or R;(e) X5 is: N or R;(f) X6 is: Q or R; and(g) X7 is: Q, L, or R.132. The AAV particle of embodiment 130 or 131, wherein [B] comprises:(i) SLLWNQQ (SEQ ID NO: 5247), SKAQYYV (SEQ ID NO: 5248), SKLRRQQ (SEQ ID NO: 5249), STWQNQQ (SEQ ID NO: 5250), SKAGCGQ (SEQ ID NO: 5251), SRAQNQQ (SEQ ID NO: 5252), SKRLRQQ (SEQ ID NO: 5253), SLRRNQQ (SEQ ID NO: 5254). SRGRNQQ (SEQ ID NO: 5255), SEIVNQQ (SEQ ID NO: 5256), SSRRNQQ (SEQ ID NO: 52.57), CLLQNQQ (SEQ ID NO: 5258), SKAFRLQ (SEQ ID NO: 5259), CLAQNQQ (SEQ ID NO: 5260), FLRQNQQ (SEQ ID NO: 5261), SLRFNQQ (SEQ ID NO: 5262), SYLRNQQ (SEQ ID NO: 5263), CSLQNQQ (SEQ ID NO: 5264), VLWQNQQ (SEQ ID NO: 5265), SKWLLQQ (SEQ ID NO: 5266), SLWSNQQ (SEQ ID NO: 5267), SKRRLQQ (SEQ ID NO: 5268), SVYLNQQ (SEQ ID NO: 5269), SLWLNQQ (SEQ ID NO: 5270), SKAQRKL (SEQ ID NO: 5271), SKALRRQ (SEQ ID NO: 5272), SKAQRLR (SEQ ID NO: 5273), SKAQNQQ (SEQ ID NO: 5274), SKAQRRL (SEQ ID NO: 5275), SKARRQQ (SEQ ID NO: 5276), SKARRLQ (SEQ ID NO: 5277), SKSRRQQ (SEQ ID NO: 5278), SKARLRQ (SEQ ID NO: 5279), SKASKRQ (SEQ ID NO: 5280), VRRQNQQ (SEQ ID NO: 5281), SKAQLYR (SEQ ID NO: 5282), SLFRNQQ (SEQ ID NO: 5283), SKAQLTV (SEQ ID NO: 5284);(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 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).133. The AAV particle of any one of embodiments 130-132, wherein [A][B] comprises:(i) GSGSPHSLLWNQQ (SEQ ID NO: 5285), GSGSPHSKAQYYV (SEQ ID NO: 2060), GSGSPHSKLRRQQ (SEQ ID NO: 2061), GSGSPHSIWQNQQ (SEQ ID NO: 5286), GSGSPHSKAGCGQ (SEQ ID NO: 2062), GSGSPHSRAQNQQ (SEQ ID NO: 2063), GSGSPHSKRLRQQ (SEQ ID NO: 2064), GSGSPHSLRRNQQ (SEQ ID NO: 2065), GSGSPHSRGRNQQ (SEQ ID NO: 2066), GSGSPHSEIVNQQ (SEQ ID NO: 5287), GSGSPHSSRRNQQ (SEQ ID NO: 2067), GSGSPHCLLQNQQ (SEQ ID NO: 5288), GSGSPHSKAFRLQ (SEQ ID NO: 2068), GSGSPHCLAQNQQ (SEQ ID NO: 5289), GSGSPHFLRQNQQ (SEQ ID NO: 2070), GSGSPHSLRFNQQ (SEQ ID NO: 2071), GSGSPHSYLRNQQ (SEQ ID NO: 5290), GSGSPHCSLQNQQ (SEQ ID NO: 5291), GSGSPII VLWQNQQ (SEQ ID NO: 5292), GSGSPHSKWLLQQ (SEQ ID NO: 2.072), GSGSPHSLWSNQQ (SEQ ID NO: 52.93), GSGSPI- ISKRRLQQ (SEQ ID NO: 2073), GSGSPHSVYLNQQ (SEQ ID NO: 5294), GSGSPHSLWLNQQ (SEQ ID NO: 5295), GSGSPHSKAQRKL (SEQ ID NO: 2074), GSGSPHSKALRRQ (SEQ ID NO: 2075), GSGSPHSKAQRLR (SEQ ID NO: 2076), GSGSPHSKAQNQQ (SEQ ID NO: 1801), GSGSPHSKAQRRL (SEQ ID NO: 2077), GSGSPHSKARRQQ (SEQ ID NO: 2078),GSGSPHSKARRLQ (SEQ ID NO: 2079), GSGSPHSKSRRQQ (SEQ ID NO: 2080), GSGSPHSKARLRQ (SEQ ID NO: 2082), GSGSPHSKASKRQ (SEQ ID NO: 2083), GSGSPHVRRQNQQ (SEQ ID NO: 2084), GSGSPHSKAQLYR (SEQ ID NO: 2085), GSGSPH SLFRNQQ (SEQ ID NO: 5296), GSGSPHSKAQLTV (SEQ ID NO: 2086);.(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 relative to any of the amino acid sequences in (i); or(iv) an ammo 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)134. The AAV particle of any one of embodiments 130-133, wherein the AAV capsid variant further comprises one, two, or all of an amino acid other than T at position 450 (e.g., S, Y, or G), an amino acid other than 1 at position 451 (e.g., M or L), and / or an amino acid other than N at position 452 (e.g., S), numbered according to SEQ ID NO: 138.135. The AAV particle of any one of embodiments 130-134, wherein the AAV capsid variant further comprises an S at position 450 and an M at position 451 , numbered according to SEQ ID NO: 138.136. The AA V particle of any one of embodiments 130-134, wherein the AAV capsid variant further comprises a Y at position 450. an L at position 451, and an S at position 452, numbered according to SEQ ID NO: 138.137. The AAV particle of any one of embodiments 130-134, wherein the AAV capsid variant further comprises a G at position 450, anL at position 451, and an S at position 452, numbered according to SEQ ID NO: 138.138. The AAV particle of any one of embodiments 130-137, wherein [A] [B] is present in loop IV.139. The AAV particle of any one of embodiments 130-138, wherein [A] is present immediately subsequent to position 452, numbered according to SEQ ID NO: 138.140. The AAV particle of any one of embodiments 130-139, wherein [A] replaces positions 453-455 (e.g., G453, S454. G455). numbered according to SEQ ID NO: 138.141. The AAV particle of any one of embodiments 130-140, wherein [A] is present immediately subsequent to position 452, and wherein [A] replaces positions 453-455 (e.g., G453, S454, G455), numbered according to SEQ ID NO: 138.142. The AAV particle of any one of embodiments 130-141, wherein [B] is present immediately subsequent to [A],143. The AAV particle of any one of embodiments 130-142, wherein [B] replaces positions 456-459 (e.g., Q456, N457, Q458, Q459), numbered according to SEQ ID NO: 138.144. The AAV particle of any one of embodiments 130-143, wherein [A][B] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, Q459), numbered according to SEQ ID NO: 138.145. The AAV particle of any one of embodiments 130-144, wherein [A] [B] is present immediately subsequent to position 452, and wherein [A][B] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, Q459), numbered according to SEQ ID NO: 138.146. The AAV particle of any one of embodiments 130-145, wherein the AzAV capsid variant comprises, from N-terminus to C -terminus, [A] [B] .147. An adeno-associated virus ( AA V) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises [A] [B] (SEQ ID NO: 4699), wherein:(i) [A] comprises XI X2 X3 X4 X5 X6, wherein(a) XI is T, M, A, C, 1, R, L, D, F, V, Q, N, or H;(b) X2 is I, P, E, N, D, S, A, T, M, or Q;(c) X3 is N, E, G, Y, W, M, T, I, K, Q, F, S, V, A, or L;(d) X4 is G. D, R, or E;(e) X5 is H, Q. N, or D;(f) X6 is D or R; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g.. a conservative substitution, of any of the aforesaid amino acids m (a)-(f); and(ii) [B] comprises SPHKSG (SEQ ID NO: 946).148. The AAV particle of embodiment 147, wherein(a) X1 is: T, M, A, or I;(b) X2 is: E, I orD;(c) X3 is: N. Q, Y, I, M, or V ;(d) X4 is G;(e) X5 is H; and(f) X6 is D,149. The AAV particle of embodiment 147 or 148, wherein [A] comprises:(i) TINGHD (SEQ ID NO: 5297), MPEGIID (SEQ ID NO: 5298), MEGGHD (SEQ ID NO: 5299), MEYGIID (SEQ ID NO: 5300), A EW GHD (SEQ ID NO: 5301), CEWGHD (SEQ ID NO: 5302), ANNGQD (SEQ ID NO: 5303), IPEGHD (SEQ ID NO: 5304), ADMGHD (SEQ ID NO: 5305), 1EYGHD (SEQ ID NO: 5306), ADYGHD (SEQ ID NO: 5307), 1ETGHD (SEQ ID NO: 5308), MEWGHD (SEQ ID NO: 5309), CEYGHD (SEQ ID NO: 5310), RINGED (SEQ ID NO: 5311), MEIGHD (SEQ ID NO: 5312), LEYGHD (SEQ ID NO: 5313). ADWGHD (SEQ ID NO: 5314), IEIGHD (SEQ ID NO: 5315), TIKDND (SEQ ID NO: 5316), DIJMGHD (SEQ ID NO: 5317), FEQGHD (SEQ ID NO: 5318), MEFGHD (SEQ ID NO: 5319), CDQGHD (SEQ ID NO: 5320), LPEGHD (SEQ ID NO: 5321), IENGHD (SEQ ID NO: 5322), MESGHD (SEQ ID NO: 5323), AEIGHD (SEQ ID NO: 5324), VEYGHD (SEQ ID NO: 532.5), TSNGDD (SEQ ID NO: 5326). IEVGHD (SEQ ID NO: 5327), MEMGHD (SEQ ID NO: 5328), AEVGHD (SEQ ID NO: 5329), MDAGHD (SEQ ID NO: 5330), VEWGHD (SEQ ID NO: 5331), AEQGHD (SEQ ID NO: 5332), LEWGIID (SEQ ID NO: 5333), MELGHD (SEQ ID NO: 5334), METGHD (SEQ ID NO: 5335), MEAGHD (SEQ ID NO: 5336), TINRQR (SEQ ID NO: 5337). IESGIID (SEQ ID NO: 5338), TAKDHD (SEQ ID NO: 5339), MEVGHD (SEQ ID NO: 5340), CEIGHD (SEQ ID NO: 5341), ATNGHD (SEQ ID NO: 5342), MDGGHD (SEQ ID NO: 5343), QEVGHD (SEQ ID NO: 5344), ADQGHD (SEQ ID NO: 5345), N MNGHD (SEQ ID NO: 5346), TPWEHD (SEQ ID NO: 5347), IEMGHD (SEQ ID NO: 5348), TANEHD (SEQ ID NO: 5349), QQQGHD (SEQ ID NO: 5350), TPQDHD (SEQ ID NO: 5351). HDWGHD (SEQ ID NO: 5352), IEGGHD (SEQ ID NO: 5353)(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 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).150. The AAV particle of any one of embodiments 147-149, wherein [A][B] comprises:(i) TINGHDSPHKR (SEQ ID NO: 5354), MPEGHDSPHKS (SEQ ID NO: 5355), MEGGHDSPHKS (SEQ ID NO: 5356), MEYGHDSPHKS (SEQ ID NO: 5357), AEWGHDSPHKS (SEQ ID NO: 5358), CEWGHDSPHKS (SEQ ID NO: 5359), ANNGQDSPHKS (SEQ ID NO: 5360),IPEGHDSPHKS (SEQ ID NO: 5361), ADMGHDSPHKS (SEQ ID NO: 5362), IEYGHDSPHKS (SEQ ID NO: 5363), ADYGHDSPHKS (SEQ ID NO: 5364), IETGHDSPHKS (SEQ ID NO: 5365), MEWGHDSPHKS (SEQ ID NO: 5366), CEYGHDSPHKS (SEQ ID NO: 5367), RINGHDSPHKS (SEQ ID NO: 5368), MEIGHDSPHKS (SEQ ID NO: 5369), LEYGHDSPHKS (SEQ ID NO: 5370), ADWGHDSPHKS (SEQ ID NO: 5371), IEIGHDSPHKS (SEQ ID NO: 5372), TIKDNDSPHKS (SEQ ID NO: 5373), DIMGHDSPHKS (SEQ ID NO: 5374), FEQGHDSPHKS (SEQ ID NO: 5375), MEFGHDSPHKS (SEQ ID NO: 5376), CDQGHDSPHKS (SEQ ID NO: 5377), LPEGHDSPIIKS (SEQ ID NO: 5378), IENGHDSPHKS (SEQ ID NO: 5379). MESGHDSPHKS (SEQ ID NO: 5380), AEIGHDSPHKS (SEQ ID NO: 5381), VEYGHDSPHKS (SEQ ID NO: 5382), TSNGDDSPHKS (SEQ ID NO: 5383), IEVGHDSPHKS (SEQ ID NO: 5384), MEMGHDSPHKS (SEQ ID NO: 5385), AEVGHDSPHKS (SEQ ID NO: 5386), MDAGHDSPHKS (SEQ ID NO: 5387), VEWGHDSPHKS (SEQ ID NO: 5388), AEQGHDSPHKS (SEQ ID NO: 5389), LEWGHDSPHKS (SEQ ID NO: 5390), MELGHDSPHKS (SEQ ID NO: 5391), METGHDSPHKS (SEQ ID NO: 5392), MEAGHDSPHKS (SEQ ID NO: 5393), TINRQRSPHKS (SEQ ID NO: 5394), IESGHDSPHKS (SEQ ID NO: 5395), TAKDHDSPHKS (SEQ ID NO: 5396), MEVGHDSPHKS (SEQ ID NO: 5397), CEIGHDSPHKS (SEQ ID NO: 5398), ATNGHDSPHKS (SEQ ID NO: 5399), MDGGHDSPHKS (SEQ ID NO: 5400), QEVGHDSPHKS (SEQ ID NO: 5401), ADQGHDSPHKS (SEQ ID NO: 5402), NMNGHDSPHKS (SEQ ID NO: 5403), TPWEHDSPHKS (SEQ ID NO: 5404), IEMGHDSPHKS (SEQ ID NO: 5405), TANEHDSPHKS (SEQ ID NO: 5406), TINGHDSPHK.S (SEQ ID NO: 5407), QQQGHDSPHKS (SEQ ID NO: 5408), TPQDHDSPHKS (SEQ ID NO: 5409), HDWGHDSPHKS (SEQ ID NO: 5410), IEGGHDSPHKS (SEQ ID NO: 5411)(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 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).151. The AAV particle of any one of embodiments 147-150, wherein the AA V capsid variant further comprises one, two, three, four, or ah of an amino acid other than Q at position 456 (e.g., R or L), N at position 457 (e.g., H, K, or R), Q at position 458 (e.g., R or T), Q at position 459 (H), and / or T at position 460 (N or S), numbered according to SEQ ID NO: 138.152. The AAV particle of any one of embodiments 147-151, wherein the AAV capsid variant further comprises an R at position 456, numbered according to SEQ ID NO: 138.153. The AAV particle of any one of embodiments 147-151, wherein the AAV capsid variant further comprises an L at position 456, numbered according to SEQ ID NO: 138.154. The AAV particle of any one of embodiments 147-153 , wherein the AA V capsid variant further comprises an H at position 457 and an R at position 458, numbered according to SEQ ID NO: 138,155. The AAV particle of any one of embodiments 147-153, wherein the AAV capsid variant further comprises a K at position 457 and an N al position 460, numbered according to SEQ ID NO: 138.156. The AAV particle of any one of embodiments 147-153, wherein the AAV capsid variant further comprises a T at position 458, an H at position 459, and an S at position 460, numbered according to SEQ ID NO: 138.157. The AAV particle of any one of embodiments 147-151 , wherein the AAV capsid variant further comprises an R at position 456, an R at position 457, and an R at position 458, numbered according to SEQ ID NO: 138.158. The AAV particle of any one of embodiments 147-157, wherein [A][B] is present in loop IV.159. The AAV particle of any one of embodiments 147-158, wherein [A] is present immediately subsequent to position 449, numbered according to SEQ ID NO: 138.160. The AAV particle of any one of embodiments 147-159, wherein [A] replaces positions 450-453 (e.g., T450, 1451, N452, G453), numbered according to SEQ ID NO: 138.161. The AAV particle of any one of embodiments 147-160, wherein [A] is present immediately subsequent to position 449, and wherein [A] replaces positions 450-453 (e.g., T450, 1451 , N452,G4.53), numbered according to SEQ ID NO: 138.162. The AAV particle of any one of embodiments 147-161, wherein [A][B] replaces positions 450-455 (e.g., T450. 1451, N452, G453, S454, G455), numbered according to SEQ ID NO: 138.163. The AAV particle of any one of embodiments 147-162, wherein [A] [B] is present immediately subsequent to position 449. and wherein [A] [B] replaces positions 450-455 (e.g., T450, 1451. N452, G453, S454, G455), numbered according to SEQ ID NO: 138.164. The AAV particle of any one of embodiments 147-163, wherein [B] is present immediately subsequent [A], and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138.165. The AAV particle of any one of embodiments 147-164, wherein [B] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 4, 36, 981, or 982.166. The AAV particle of any one of embodiments 147-165, wherein [B] is present immediately subsequent to [A],167. The AAV particle of any one of embodiments 147-166, wherein the AAV capsid variant comprises, from N-terminus to C-terminus, [A] [B],168. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 6407), wherein:(i) [Nl] comprises X1, X2, and X3, wherein X2 is S and X3 is G:(ii) [N2] comprises the amino acid sequence SPH; and(iii) [N3] comprises X4, X5, and X6. wherein X5 is K.169. The AAV particle of embodiment 168, wherein:(i) X4 of [N3] is S, T, N, or A; and(ii) X5 of [N3] is A, V, T, S, G, R, L, or N; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (i) or (ii).170. The AAV particle of embodiment 168 or 169, wherein X4 is S and / or X5 is A.171. The AAV particle of any one of embodiments 168-170, wherein [N3] comprises SK, TK, NK, AK, KA, KV, KT, KS, KG. KR, KL, or KN.172. The AAV particle of any one of embodiments 168-171, wherein [N3] is or comprises SKA, SK V, SKT. SKS, SKG, SKR , TKA, NKA, SKL. SKN, or A K A.173. The AAV particle of any one of embodiments 168-172, wherein [N3] is or comprises SKA.174. The AAV particle of any one of embodiments 168-173, wherein [N2]-[N3] comprises SPHSK (SEQ ID NO: 4701), SPHTK (SEQ ID NO: 4725), SPHNK (SEQ ID NO: 4726), or SPHAK (SEQ ID NO: 4727).175. The AAV particle of any one of embodiments 168-174, wherein [N2]-[N3] is or comprises:(i) SPHSKA (SEQ ID NO: 941), SPHSKV (SEQ ID NO: 4737), SPHSKT (SEQ ID NO: 4731), SPHSKS (SEQ ID NO: 962), SPHSKG (SEQ ID NO: 4732), SPHSKR (SEQ ID NO: 978). SPHTKA (SEQ ID NO: 4739). SPHNKA (SEQ ID NO: 4734), SPHSKL (SEQ ID NO: 960), SPHSKN (SEQ ID NO: 4735), or SPHAK A (SEQ ID NO: 4736);(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 titan four modifications 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).176. The AAV particle of any one of embodiments 168-175, wherein [N2.]-[N3] is or comprises SPHSK A (SEQ ID NO: 941).177. The AAV particle of any one of embodiments 168-176, wherein the AAV capsid variant comprises an ammo acid other than G at position 453 (e.g.. M, T, I, E, S, A, N, V. L, K, H, P, R, W, or D), numbered according to SEQ ID NO: 138 or 981.178. The AAV particle of any one of embodiments 168-177, wherein the AAV capsid variant comprises the amino acid G at position 453, numbered according to SEQ ID NO: 138 or 981.179. The AAV particle of any one of embodiments 168-178, wherein X1 of [N1] is G, M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids.180. The AAV particle of any one of embodiments 168-179, wherein [N1] comprises SG, GS, MS, TS, IS, ES, SS, AS, NS, VS, LS, KS, HS. PS, RS, WS, or DS.181. The AAV particle of any one of embodiments 168-180, wherein [N1] is or comprises: GSG, MSG, TSG, ISG, ESG, SSG, ASG, NSG, VSG, LSG, KSG, HSG, PSG, RSG, WSG, orDSG.182. The AAV particle of any one of embodiments 168-181, wherein [N1 ] is or comprises GSG.183. The AAV particle of any one of embodiments 168-182, wherein [N1]-[N2] comprises SGSPH (SEQ ID NO: 4752).184. The AAV particle of any one of embodiments 168-183, wherein [N1]-[N2] is or comprises:(i) GSGSPH (SEQ ID NO: 4695), MSGSPH (SEQ ID NO: 4798), TSGSPH (SEQ ID NO: 4800), ISGSPH (SEQ ID NO: 4801), ESGSPH (SEQ ID NO: 4803), SSGSPH (SEQ ID NO: 4804). ASGSPII (SEQ ID NO: 4806), NSGSPH (SEQ ID NO: 4807), VSGSPH (SEQ ID NO: 4786), LSGSPH (SEQ ID NO: 4808), KSGSPH (SEQ ID NO: 4810), IISGSPH (SEQ ID NO: 4811). PSGSPH (SEQ ID NO: 4813), RSGSPH (SEQ ID NO: 4815), WSGSPH (SEQ ID NO: 4817), DSGSPH (SEQ ID NO: 4818);(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 relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).185. The AAV particle of any one of embodiments 168-184, wherein [N1]-[N2]-[N3] is or comprises:(i) GSGSPI ISK A (SEQ ID NO: 4697), GSGSPHSKV (SEQ ID NO: 4956). MSGSI-TISKA (SEQ ID NO: 4957), TSGSPIISKA (SEQ ID NO: 4959), ISGSPHSKA (SEQ ID NO: 4960), GSGSPHSKT (SEQ ID NO: 4962), ESGSPHSKA (SEQ ID NO: 4963), SSGSPHSKA (SEQ ID NO: 4964), GSGSPHSKS (SEQ ID NO: 4953), ASGSPHSKA (SEQ ID NO: 4966), NSGSPHSKA (SEQ ID NO: 4967), VSGSPHSKA (SEQ ID NO: 4913), LSGSPHSKA (SEQ ID NO: 4968), KSGSPHSKA (SEQ ID NO: 4970), GSGSPHSKG (SEQ ID NO: 4972), GSGSPHSKR (SEQ ID NO: 4945), HSGSPHSKA (SEQ ID NO: 4973), PSGSPHSKA (SEQ ID NO: 4975), RSGSPHSKA (SEQ ID NO: 4977), GSGSPHTKA (SEQ ID NO: 4978), WSGSPHSKA (SEQ ID NO: 4980), DSGSPHSKA (SEQ ID NO: 4981), GSGSPHNKA (SEQ ID NO: 4983), GSGSPHSKL (SEQ ID NO: 4943), GSGSPHSKN (SEQ ID NO: 4994). or GSGSPHAKA (SEQ ID NO: 4995);(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 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).186. The AAV particle of any one of embodiments 168-185, wherein [N1]-[N2]-[N3] is or comprises GSGSPHSKA (SEQ ID NO: 4697).187. The AAV capsid variant of any one of embodiments 168-186, which comprises an amino acid other than Q at position 456 (e.g., R, P, H, L, K, I, G, S, M, or E), an amino acid other than N at position 457 (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, zA, I, L, or M), an amino acid other than Q at position 458 (e.g., R, L, A. P, H. T, I, F, K. V, M, G, W, Y, S, E, N, or D), an amino acid other than Q al position 459 (e.g., H, K, A. L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G), and / or an ammo acid other than T at position 460 (e.g., I. N, S, H, R, L, D, Y, zA, or Q), numbered according to SEQ ID NO: 138.188. The AAV particle of any one of embodiments 168-187, wherein the AAV capsid variant comprises an amino acid other than Q at position 462 (e.g., R, P, H, L, K, I, G, S, M, or E), an amino acid other than N at position 463 (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M), an amino acid other than Q at position 464 (e.g., R, L, A, P, H, T, 1, F, K, V, M, G, W, Y, S, E, N, or D), an amino acid other than Q at position 465 (e.g., H, K, A, L, P, E, M, 1, S, N, R, Y, C, V, T, W, D, G), and / or an amino acid other than T at position 466 (e.g., I, N, S, H, R, L, D, Y, A, or Q), numbered according to SEQ ID NO: 981 .189. The AAV particle of any one of embodiments 168-188, wherein the zAzAV capsid variant comprises the amino acid Q at position 456, the amino acid N at position 457, the amino acid Q at position 458, the amino acid Q at position 459, and / or the amino acid T at position 460, numbered according to SEQ ID NO: 138.190. The AAV particle of any one of embodiments 168-189, wherein the AAV capsid variant comprises the amino acid Q at position 462, the amino acid N at position 463, the amino acid Q at position 464, the amino acid Q at position 465, and / or the amino acid T at position 466, numbered according to SEQ ID NO: 981.191. The AAV particle of any one of embodiments 168-190, wherein the AA V capsid variant further comprises [N4] wherein [N4] comprises X7, X8, X9, X10, and X11, wherein:(a) X7 is Q, R, P, H, L, K, I, G, S. M, or E;(b) X8 is N, D, V, S, P, T, G. Y, W. E, R, H, K, F, A, I. L, or M:(c) X9 is Q, R, L, A. P, H, T, I, F, K. V, M, G, W, Y, S, E, N, D;(d) X10 is Q, H, K, A, L, P. E, M, I, S, N, R, Y. C, V, T, W, D, G: and(e) X11 is T, I, N, S, H, R, L, D, Y, A, Q: optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(e).192. The AAV particle of embodiment 191, wherein [N4] is or comprises:(i) QNQQT (SEQ ID NO: 5412), QNRHT (SEQ ID NO: 5413), RDQQT (SEQ ID NO: 5414), PNLQT (SEQ ID NO: 5415), HVRQT (SEQ ID NO: 5416), PNQHT (SEQ ID NO: 5417), QSQQT (SEQ ID NO: 5418). QNQQI (SEQ ID NO: 5419), QPAKT (SEQ ID NO: 5420), QTQQN (SEQ ID NO: 5421), QNLAT (SEQ ID NO: 5422), QNQLT (SEQ ID NO: 5423), QGQQT (SEQ ID NO: 5424), LNRQS (SEQ ID NO: 5425). HNQQT (SEQ ID NO: 5426), QNPPT (SEQ ID NO: 5427), QNLQT (SEQ ID NO: 5428), QYQQ’T (SEQ ID NO: 5429). QDQET (SEQ ID NO: 5430), QNIIQT (SEQ ID NO: 5431), QDQQ’T (SEQ ID NO: 5432). HWQQT (SEQ ID NO: 5433), PNQQT (SEQ ID NO: 5434), QNQLI (SEQ ID NO: 5435), PEQQT (SEQ ID NO: 5436), QRTMT (SEQ ID NO: 5437), QNQQH (SEQ ID NO: 5438), LHQHT (SEQ ID NO: 5439), QHRIT (SEQ ID NO: 5440), QY1HT (SEQ ID NO: 5441), QKFET (SEQ ID NO: 5442), QFPST (SEQ ID NO: 5443), HNQQR (SEQ ID NO: 5444), QAI.KT (SEQ ID NO: 5445), QNRQT (SEQ ID NO: 5446), QYQHT (SEQ ID NO: 5447), QNPQS (SEQ ID NO: 5448), QHQLT (SEQ ID NO: 5449), QSPPT (SEQ ID NO: 5450), QAKLT (SEQ ID NO: 5451). KSQQT (SEQ ID NO: 5452), QDRPT (SEQ ID NO: 5453), QSQQL (SEQ ID NO: 5454), QAFHT (SEQ ID NO: 5455), QKQQD (SEQ ID NO: 5456), QNAQT (SEQ ID NO: 5457). HNQLT (SEQ ID NO: 5458). QNQQY (SEQ ID NO: 5459), QKLNT (SEQ ID NO: 5460), QNVQT (SEQ ID NO: 5461), QAQQT (SEQ ID NO: 5462), QNI..QA (SEQ ID NO: 5463), QTPPT (SEQ ID NO: 5464). QYQHA (SEQ ID NO: 5465), QGQQA (SEQ ID NO: 5466), QPPAT (SEQ ID NO: 5467), QERPT (SEQ ID NO: 5468), QDLQT (SEQ ID NO: 5469), QAMHT (SEQ ID NO: 5470), LNQQT (SEQ ID NO: 5471), Q HPS T (SEQ ID NO: 5472). PGLQT (SEQ ID NO: 5473), QGIRT (SEQ ID NO: 5474), QAPAT (SEQ ID NO: 5475), QSQQI (SEQ ID NO: 5476), QIPPT (SEQ ID NO: 5477), QTQLT (SEQ ID NO: 5478), QAPST (SEQ ID NO: 5479), QNTYA (SEQ ID NO: 5480), QNQHI (SEQ ID NO: 5481), QNHLT (SEQ ID NO: 5482), QIGMT (SEQ ID NO: 5483), LNKQT (SEQ ID NO: 5484), QLQQT (SEQ ID NO: 5485), QRMST (SEQ ID NO: 5486), QGILT (SEQ ID NO: 5487), QDRQT (SEQ ID NO: 5488), RDWQT (SEQ ID NO: 5489), QNTHD (SEQ ID NO: 5490), PNLQI (SEQ ID NO: 5491), QERST (SEQ ID NO: 5492), QNYQT (SEQ ID NO: 5493), QRTCT (SEQ ID NO: 5494), QIGHT (SEQ ID NO: 5495), QGAIT (SEQ ID NO: 5496), QVPPT (SEQ ID NO: 5497), QVQQI (SEQ ID NO: 5498), LMRQT (SEQ ID NO: 5499). QYSVT (SEQ ID NO: 5500), QAITT (SEQ ID NO: 5501), QKTLT (SEQ ID NO: 5502). QNQWT (SEQ ID NO: 5503), QLHHT (SEQ ID NO: 5504), QNIII (SEQ ID NO: 5505), QGHHT (SEQ ID NO: 5506), QSKVT (SEQ ID NO: 5507), QLPST (SEQ ID NO: 5508), IGKQ’T (SEQ ID NO: 5509). QAIHT (SEQ ID NO: 5510), QHGLT (SEQ ID NO: 5511), QFMCT (SEQ ID NO: 5512), QHLQT (SEQ ID NO: 5513), QNI-IQN (SEQ ID NO: 5514), QPART (SEQ ID NO: 5515), QSLQT (SEQ ID NO: 5516), QSQLT (SEQ ID NO: 5517), QDRQS (SEQ ID NO: 5518), QMPST (SEQ ID NO: 5519), QGSLT (SEQ ID NO: 5520), QVPAT (SEQ ID NO: 5521), QDKQT (SEQ ID NO: 5522), HYQQT (SEQ ID NO: 5523), QVPST (SEQ ID NO: 5524), RGEQT (SEQ ID NO: 5525), PGQQT (SEQ IDNO: 5526), QSLQI (SEQ ID NO: 5527), LEQQT (SEQ ID NO: 5528), QNQST (SEQ ID NO: 5529), QKVIT (SEQ ID NO: 5530). QNNDQ (SEQ ID NO: 5531), QSVHT (SEQ ID NO: 5532). QPLGT (SEQ ID NO: 5533), HNQET (SEQ ID NO: 5534), QNLQI (SEQ ID NO: 5535). QIQQT (SEQ ID NO: 5536), QVRNT (SEQ ID NO: 5537), PSNQT (SEQ ID NO: 5538), QVGHT (SEQ ID NO: 5539), QRDIT (SEQ ID NO: 5540), QMPNT (SEQ ID NO: 5541). RGLQT (SEQ ID NO: 5542), QKQQT (SEQ ID NO: 5543), PSLQT (SEQ ID NO: 5544), QRDQT (SEQ ID NO: 5545), QAKGT (SEQ ID NO: 5546), QSAHT (SEQ ID NO: 5547), QSTMT (SEQ ID NO: 5548), QREMT (SEQ ID NO: 5549), QYRAT (SEQ ID NO: 5550), QWQQT (SEQ ID NO: 5551), QRMNT (SEQ ID NO: 5552), GDSQT (SEQ ID NO: 5553). QKIST (SEQ ID NO: 5554), PSMQT (SEQ ID NO: 5555), SPRQT (SEQ ID NO: 5556), MEQQT (SEQ ID NO: 5557), QYQNT (SEQ ID NO: 5558), QHQQT (SEQ ID NO: 5559), INQQT (SEQ ID NO: 5560), PNQQH (SEQ ID NO: 5561), ENRQT (SEQ ID NO: 5562), QTQQA (SEQ ID NO: 5563), or QNQAT (SEQ ID NO: 5564);(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 relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).193. The AAV particle of embodiment 191 or 192. wherein [N1]-[N2]-[N3]-[N4] is or comprises:(i) the amino acid sequence of any of SEQ ID NOs: 200 or 2887-3076;(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 ammo acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifica tions 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).194. The AAV particle of any one of embodiments 191-193, wherein [N1]-[N2]-[N3]-[N4] is or comprises GSGSPHSKAQNQQT (SEQ ID NO: 200).195. The AAV particle of any one of embodiments 191-193, wherein [N1]-[N2]-[N3]-[N4] is or comprises VSGSPHSKAQNQQT (SEQ ID NO: 903).196. The AAV particle of any one of embodiments 168-195, wherein the AAV capsid variant comprises an amino acid other titan K at position 449 (e.g., T, E, or N), T at position 450 (e.g., S, E, A, N, V, Q, or G), an amino acid other than I at position 451 (e.g., F, E, V, L, D, S, C, T, A, N, H, R,G, or W), and / or an amino add other than N at position 452 (e.g., I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G). numbered according to SEQ ID NO: i 38 or 98 E197. The AAV particle of any one of embodiments 168-196, wherein the AAV capsid variant comprises the amino acid K at position 449, the amino acid T at position 450, the amino acid I at position 451, and / or the amino acid N at position 452, numbered according to SEQ ID NO: 138 or 981.198. The AAV particle of any one of embodiments 168-197, wherein the AA V capsid variant further comprises [NO], wherein [N0] comprises XA, XB, Xc, and XD, wherein:(a) XAis K, T, E, or N;(b) XBis T, S, E, A, N, V, Q, or G:(c) Xcis I, F, E, V, L, D, S, C, T, A, N, H, R, G, or W; and(d) XDis N, I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G; optionally wherein the AAV capsid variant comprises an amino add modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(d).199. The AAV particle of embodiment 198, wherein [NO] is or comprises:(i) KTII (SEQ ID NO: 5565), KTFP (SEQ ID NO: 5566). KTEK (SEQ ID NO: 5567), KTVN (SEQ ID NO: 5568), KTFN (SEQ ID NO: 5569), KTIN (SEQ ID NO: 5570), TTIN (SEQ ID NO: 5571), KSIN (SEQ ID NO: 5572), KTER (SEQ ID NO: 5573), KELH (SEQ ID NO: 5574), KAIN (SEQ ID NO: 5575), KTDN (SEQ ID NO: 5576), KTFH (SEQ ID NO: 5577), KTSN (SEQ ID NO: 5578), ETIN (SEQ ID NO: 5579), NTIN (SEQ ID NO: 5580), KTEN (SEQ ID NO: 5581), KTSS (SEQ ID NO: 5582), KTCN (SEQ ID NO: 5583), KTEH (SEQ ID NO: 5584), KAEM (SEQ ID NO: 5585), KATN (SEQ ID NO: 5586), KAIK (SEQ ID NO: 5587), KTDK (SEQ ID NO: 5588), KTFK (SEQ ID NO: 5589), KSDQ (SEQ ID NO: 5590), KTEI (SEQ ID NO: 5591), KTID (SEQ ID NO: 5592), KNTN (SEQ ID NO: 5593), KTET (SEQ ID NO: 5594), KIEL (SEQ ID NO: 5595), KNIN (SEQ ID NO: 5596), KTEA (SEQ ID NO: 5597), KT AN (SEQ ID NO: 5598), NTIY (SEQ ID NO: 5599), KTFS (SEQ ID NO: 5600), KTES (SEQ ID NO: 5601), KTTN (SEQ ID NO: 5602), KTED (SEQ ID NO: 5603), KTNN (SEQ ID NO: 5604). KEVH (SEQ ID NO: 5605), KTIS (SEQ ID NO: 5606), KTVR (SEQ ID NO: 5607), KTDR (SEQ ID NO: 5608), ETIK (SEQ ID NO: 5609), KNHI (SEQ ID NO: 5610), KESD (SEQ ID NO: 5611), KTIK (SEQ ID NO: 5612), KTDL (SEQ ID NO: 5613), KTVP (SEQ ID NO: 5614), KTVI (SEQ ID NO: 5615). KAEH (SEQ ID NO: 5616), KNCL (SEQ ID NO: 5617), KTVK (SEQ ID NO: 5618), KNAD (SEQ ID NO: 5619), KTIT (SEQ ID NO: 5620), KNCV (SEQ ID NO: 5621), KNAL (SEQ ID NO: 5622), KVIN (SEQ ID NO: 5623), KIEF (SEQ ID NO: 5624), KTRE (SEQ ID NO: 5625), KQGE (SEQ ID NO: 5626), KSEK (SEQ ID NO: 5627), KNVN (SEQ ID NO: 5628), KGGE (SEQ ID NO: 5629), KEFV (SEQ ID NO: 5630), KSDK(SEQ ID NO: 5631), KTEQ (SEQ ID NO: 5632), KEVQ (SEQ ID NO: 5633), KTEY (SEQ ID NO: 5634), KNOW (SEQ ID NO: 5635), KTDV (SEQ ID NO: 5636), KSDI (SEQ ID NO: 5637), KNSI (SEQ ID NO: 5638), KNSL (SEQ ID NO: 5639), KEVV (SEQ ID NO: 5640), KTEP (SEQ ID NO: 5641), KSEL (SEQ ID NO: 5642), KTWQ (SEQ ID NO: 5643), KTEV (SEQ ID NO: 5644), KAVN (SEQ ID NO: 5645), KGVL (SEQ ID NO: 5646), KTEG (SEQ ID NO: 5647), KTRD (SEQ ID NO: 5648), KTGN (SEQ ID NO: 5649). KNAI (SEQ ID NO: 5650), KAEN (SEQ ID NO: 5651), KAET (SEQ ID NO: 5652), KTVH (SEQ ID NO: 5653), KETA (SEQ ID NO: 5654), KNNL (SEQ ID NO: 5655), EAIN (SEQ ID NO: 5656), KSLN (SEQ ID NO: 5657), KTIP (SEQ ID NO: 5658). or K TIH (SEQ ID NO: 5659);(ii) an amino acid sequence comprising any portion of an ammo acid sequence in (i), e.g., any 2, or 3 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more titan four modifications 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).200. The AAV particle of embodiment 198 or 199, wherein [NO]-[N1]-[N2]’[N3]-[N4] is or comprises:(i) the amino acid sequence of any one of SEQ ID NOs: 3239-352.6 or 3591-3605;(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications to any of the ammo acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more Ilian four different amino acids, relative to any one of the amino acid sequences in (i).201. The AAV particle of any one of embodiments 198-200, wherein [N0]-[NI]-[N2]-[N3]-[N4] is or comprises KTINGSGSPHSKAQNQQT (SEQ ID NO: 5660).202. The AAV particle of any one of embodiments 198-200, wherein [NO]-[N1]-[N2]-[N3]-[N4] is or comprises KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589).203. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase -like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 6408), wherein:(i) [N1] comprises XI, X2, and X3, wherein X2 is an amino acid other than S and X3 is an amino acid other than G;(ii) [N2] comprises the amino acid sequence SPH; and(iii) [N3] comprises X4, X5, and X6, wherein X4 is K.204. The AAV particle of embodiment 203, wherein:(i) X5 of [N3] is S. I, T, R. H, Y, L, or M; and(ii) X6 of [N3] is G. A, L, E, V, R, W, N, Q. or K ; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (i) or (ii).205. The AAV particle of embodiment 203 or 204, wherein X5 is S and / or X6 is G.206. The AAV particle of any one of embodiments 203-205, wherein [N3] comprises KS, KI, KT, KR, KH. KY, KL, KM, SG, IG, TG, RG, SA, SL, SE, SV, SR. SW, SN, HG. YG, SQ, IV, SK, LW, MG, or MA.207. The AAV particle of any one of embodiments 2.03-206, wherein [N3] is or comprises KSG, KIG, KTG, KRG, KSA, KSL, KSE. KSV. KSR, KSW, KSN, KHG, KYG, KSQ, KIV, KSK, KI. ,W, KMG, or KMA.208. The AAV particle of any one of embodiments 203-207, wherein [N3] is or comprises KSG.209. The AAV particle of any one of embodiments 203-208, wherein [N2]-[N3] comprises SPHKS (SEQ ID NO: 4704), SPHKI (SEQ ID NO: 4713), SPHKT (SEQ ID NO: 4711), SPHKR (SEQ ID NO: 4717), NPHKS (SEQ ID NO: 5661). SPHKH (SEQ ID NO: 4728), SPHKY (SEQ ID NO: 4715). SPHKL (SEQ ID NO: 4714), or SPHKM (SEQ ID NO: 4729).210. The AAV particle of any one of embodiments 203-209, wherein [N2]-[N3] is or comprises:(i) SPHKSG (SEQ ID NO: 946), SPHKIG (SEQ ID NO: 958). SPHKTG (SEQ ID NO: 4738), SPHKRG (SEQ ID NO: 974), NPHKSG (SEQ ID NO: 5662), SPHKSA (SEQ ID NO: 977), SPHKSL (SEQ ID NO: 4740), SPHKSE (SEQ ID NO: 4741). SPHKSV (SEQ ID NO: 4742), SPHKSR (SEQ ID NO: 951), SPHKSW (SEQ ID NO: 4743), SPHKSN (SEQ ID NO: 4744), SPHKHG (SEQ ID NO: 4745), SPHKYG (SEQ ID NO: 966), SPHKSQ (SEQ ID NO: 4746), SPHKIV (SEQ ID NO: 5663), SPHKSK (SEQ ID NO: 4747), SPHKL W (SEQ ID NO: 4748), SPHKMG (SEQ ID NO: 4750), or SPH KMA (SEQ ID NO: 4751);(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 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).211. The AAV particle of any one of embodiments 203-210, wherein [N2]-[N3] is or comprises SPHKSG (SEQ ID NO: 946).212. The AAV particle of any one of embodiments 203-211, wherein the AAV capsid variant comprises an amino acid other than G at position 453 (e.g., A, K, W, R, L, I, M, N, T, E, Q, Y, H, F, or V), numbered according to SEQ ID NO: 138 or 981 .213. The AAV particle of any one of embodiments 203-212, wherein the AAV capsid variant comprises the amino acid G at position 453, numbered according to SEQ ID NO: 138 or 981.214. The AAV particle of any one of embodiments 203-214, wherein:(i) X1 of [ N 1] is G. A, K, W, R, L, I, M. N, T, E. Q, Y . H, F, or V;(ii) X2 of [Nl] is H, Y. R, Q, N, P, or D;(iii) X3 of [Nl] is D, E. G, V, or N: optionally wherein the AAV capsid variant comprises an ammo acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (i), (ii), or (iii).215. The AAV particle of any one of embodiments 203-214, wherein X2 of [Nl] is H and X3 of [N1] is D.216. The AAV particle of any one of embodiments 203-215, wherein XI of [Nl] is G, X2 of [N1] is H and X 3 of [N1] is D.217. The AAV particle of any one of embodiments 203-216, wherein [N1] comprises GH, HD, GY, GR, GQ, AH. GN, KH GP, W H . RH, LH, IH, MH, GD, NH, TH, EH. QH, YH, HH. FH, VH. YD, HE. RG, QD, RD. ND, PD, QV, DD, HN. or NG.218. The AAV capsid variant of any one of embodiments 203-217, wherein [Nl] is or comprises GHD, GYD, GHE, GRG, GQD, GRD, AHD, GND, KHD, GPD, WHD, RHD, LHD, GQV, IHD, MHD, GDD, GHN, NH D , THD, GNG, EHD, QHD, YHD, HHD, FHD, or VHD.219. The AAV particle of any one of embodiments 203-218, wherein [N 1] is or comprises GHD.220. The AAV particle of any one of embodiments 203-219, wherein [N 1]-[N2] comprises HDSPH (SEQ ID NO: 4703).221. The AAV particle of any one of embodiments 203-220, wherein [N1]-[N2] is or comprises:(i) GHDSPH (SEQ ID NO: 4784), GYDSPH (SEQ ID NO: 4829), GHESPII (SEQ ID NO: 4793), GRGSPH (SEQ ID NO: 4788), GHDNPH (SEQ ID NO: 5664), GQDSPH (SEQ ID NO: 4785), GRDSPH (SEQ ID NO: 4831), AHDSPH (SEQ ID NO: 5665), GNDSPH (SEQ ID NO: 4832), KHDSPH (SEQ ID NO: 5666), GPDSPH (SEQ ID NO: 4833), WHDSPH (SEQ ID NO: 5667), RHDSPH (SEQ ID NO: 5668), LHDSPH (SEQ ID NO: 5669), GQVSPH (SEQ ID NO: 4835), IHDSPH (SEQ ID NO: 5670), MHDSPH (SEQ ID NO: 5671), GDDSPH (SEQ ID NO: 4792), GHNSPH (SEQ ID NO: 4836), NHDSPH (SEQ ID NO: 5672), THDSPH (SEQ ID NO: 5673), GNGSPH (SEQ ID NO: 4805), EHDSPH (SEQ ID NO: 5674), QHDSPH (SEQ ID NO: 5675). YHDSPH (SEQ ID NO: 5676), HHDSPH (SEQ ID NO: 5677), FHDSPH (SEQ ID NO: 5678), or VHDSPH (SEQ ID NO: 5679);(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 relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more Ilian four different amino acids, relative to any one of the amino acid sequences in (i).222. The AAV particle of any one of embodiments 203-221, wherein [N1]-[N2]-[N3] is or comprises:(i) GHDSPHKSG (SEQ ID NO: 4698), GHDSPHKIG (SEQ ID NO: 4996). GYDSPHKSG (SEQ ID NO: 4997), GHESPHKSG (SEQ ID NO: 4998), GHDSPHKTG (SEQ ID NO: 4999), GRGSPHKRG (SEQ ID NO: 5000), GHDNPHKSG (SEQ ID NO: 5680). GQDSPHKSG (SEQ ID NO: 4908), GHDSPHKSA (SEQ ID NO: 4940), GHDSPHKSL (SEQ ID NO: 5001), GHDSPIIKSE (SEQ ID NO: 5003), GRDSPHKSG (SEQ ID NO: 5004), AHDSPHKSG (SEQ ID NO: 5681), GNDSPIIKSV (SEQ ID NO: 5005). AHDSPHKIG (SEQ ID NO: 5682), GHESPHKSA (SEQ ID NO: 4939), GQDSPHKIG (SEQ ID NO: 5006), GHDSPHKSV (SEQ ID NO: 5007), GIIDSPHKSR (SEQ ID NO: 4942), KHDSPHKSG (SEQ ID NO: 5683), GPDSPHKIG (SEQ ID NO: 5008), GPDSPHKSG (SEQ ID NO: 5009), GHDSPHKSW (SEQ ID NO: 5010). WHDSPHKSG (SEQ ID NO: 5684), RHDSPHKSG (SEQ ID NO: 5685), GHDSPHKSN (SEQ ID NO: 5011), GHDSPHKRG (SEQ ID NO: 4937), GHDSPHKHG (SEQ ID NO: 5013), LHDSPHKSG (SEQ ID NO: 5686), GQVSPHKSG (SEQ ID NO: 5014), IHDSPHKSG (SEQ ID NO: 5687), MHDSPHKSG (SEQ IDNO: 5688), GDDSPHKSV (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016). NHDSPHKSG (SEQ ID NO: 5689), THDSPHKSG (SEQ ID NO: 5690), GNGSPHKRG (SEQ ID NO: 5017), EHDSPHKSG (SEQ ID NO: 5691), GHDSPHKYG (SEQ ID NO: 5018), GHDSPHKSQ (SEQ ID NO: 5019), QHDSPHKSG (SEQ ID NO: 5692), RHDSPHK IV (SEQ ID NO: 5693), YHDSPHKSG (SEQ ID NO: 5694), GNDSPHKIG (SEQ ID NO: 5020), HHDSPHKSG (SEQ ID NO: 5695), GHDSPHKSK (SEQ ID NO: 5021). FHDSPHKSG (SEQ ID NO: 5696), GHDSPHKLW (SEQ ID NO: 5022), VHDSPHKSG (SEQ ID NO: 5697), GHDSPHKMG (SEQ ID NO: 5024), GHDSPHKMA (SEQ ID NO: 5025), or GDDSPI I KSG (SEQ ID NO: 4938);(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 amnio acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications 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).223. The AAV particle of any one of embodiments 203-222, wherein [N1]-[N2]-[N3] is or comprises GHDSPHKSG (SEQ ID NO: 4698).224. The AAV particle of any one of embodiments 203-2.23, wherein the A AV capsid variant comprises an amino acid other than Q at position 456 (e.g.. R, P, II, K, L, V, A, E. or I), an amino acid oilier than N al position 457 (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q. or M), an amino acid other than Q at position 458 (e.g., R, V, K, P, Y, H, L, I, E, or M), an amino acid other than Q at position 459 (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N), and / or an amino acid other than T at position 460 (e.g., A, E, K, S, I, P, G, or N), numbered according to SEQ ID NO: 138.225. The AAV particle of any one of embodiments 203-224, wherein the AAV capsid variant comprises an amino acid other than Q at position 462 (e.g., R, P, H, K. L, V, A, E, or I), an amino acid other than N at position 463 (e.g., I, K, S, H, R, T. D, Y, L, W, F, A, Q, or M), an amino acid other than Q at position 464 (e.g,, R, V, K, P, Y, H, L, I, E, or M), an amino acid other than Q at position 465 (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N), and / or an amino acid other than T at position 466 (e.g., A, E, K, S, I, P, G, orN), numbered according to SEQ ID NO: 982.226. The AAV particle of any one of embodiments 203-225, wherein the AA V capsid variant comprises the amino acid Q at position 456. the amino acid N at position 457. the amino acid Q at position 458, the amino acid Q at position 459, and / or the ammo acid T at position 460, numbered according to SEQ ID NO: 138.227. The AAV particle of any one of embodiments 203-226, wherein the AAV capsid variant comprises the amino acid Q at position 462. the amino acid N at position 463. the amino acid Q at position 464, the amino acid Q at position 465, and / or the amino acid T at position 466, numbered according to SEQ ID NO: 138.22.8. The AAV particle of any one of embodiments 203-227 , wherein the AA V capsid variant further comprises [N4], wherein [N4] comprises X7, X8, X9, X10, and XI 1, wherein:(a) X7 is Q, R, P, H, L, K, I, G, S, M, or E;(b) X8 is N, D, V, S, P, T, G. Y, W. E, R, H, K, F, A, I. L, or M;(c) X9 is Q, R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, D;(d) X10 is Q, H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G; and(e) X11 ;s T, I, N, S. H. R, L, D, Y, A, Q. optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(e).229. The AAV particle of embodiment 228, wherein [N4] is or comprises:(i) QNQQT (SEQ ID NO: 5412), QIRQT (SEQ ID NO: 5698), QNQHA (SEQ ID NO: 5699), QKQQT (SEQ ID NO: 5543), QSVQT (SEQ ID NO: 5700), RSQQT (SEQ ID NO: 5701), QNKLE (SEQ ID NO: 5702), QNQQK (SEQ ID NO: 5703). QHQQA (SEQ ID NO: 5704), QIQHT (SEQ ID NO: 5705), PRQQT (SEQ ID NO: 5706), HTQQT (SEQ ID NO: 5707), QRQI IT (SEQ ID NO: 5708), QSQQT (SEQ ID NO: 5418), QNQQS (SEQ ID NO: 5709), RNQET (SEQ ID NO: 5710), QTQLT (SEQ ID NO: 5478), KNQQT (SEQ ID NO: 5711), QDQQT (SEQ ID NO: 5432), HNQQT (SEQ ID NO: 5426), QNQLT (SEQ ID NO: 5423), QTQQT (SEQ ID NO: 5712), QTQQ1 (SEQ ID NO: 5713), QSKQA (SEQ ID NO: 5714), QNQPP (SEQ ID NO: 5715), QSPQT (SEQ ID NO: 5716), QNYQT (SEQ ID NO: 5493), QNHQT (SEQ ID NO: 5431), QNRQT (SEQ ID NO: 5446), QNQQG (SEQ ID NO: 5717), QNHLT (SEQ ID NO: 5482), QYQHT (SEQ ID NO: 5447). QNQWT (SEQ ID NO: 5503), QNQHT (SEQ ID NO: 5718), QTRQT (SEQ ID NO: 5719), QNLHT (SEQ ID NO: 5720), LNQQT (SEQ ID NO: 5471), QNQET (SEQ ID NO: 5721), QHLQT (SEQ ID NO: 5513), LNQPT (SEQ ID NO: 5722), QNQDT (SEQ ID NO: 5723). RNQQT (SEQ ID NO: 5724), QNLLT (SEQ ID NO: 5725), QLVIT (SEQ ID NO: 5726), RTQET (SEQ ID NO: 572.7), QTHQT (SEQ ID NO: 572.8), QNQPA (SEQ ID NO: 5729), QDQHT (SEQ ID NO: 5730), QSQHT (SEQ ID NO: 5731), RNQQI (SEQ ID NO: 5732), VRQQT (SEQ ID NO: 5733), QNQIIS (SEQ ID NO: 5734), AWQQT (SEQ ID NO: 5735), QSVPT (SEQ ID NO: 5736), QNIQP (SEQ ID NO: 5737), QNHLN (SEQ ID NO: 5738), LDQQT (SEQ ID NO: 5739), PDQQS (SEQ ID NO: 5740), ESQQT (SEQ ID NO: 5741), QNKQT (SEQ ID NO: 5742), QRQLT (SEQ ID NO: 5743), QI1VT (SEQ ID NO: 5744), QKQST (SEQ ID NO: 5745), QSHQT (SEQ ID NO: 5746), QFVVT (SEQ ID NO: 5747), QNLQT (SEQ ID NO: 5428), QNQQI (SEQ ID NO: 5419), QSQPT (SEQ ID NO: 5748), QNEQT (SEQ IDNO: 5749), QSLQT (SEQ ID NO: 5516), RNRQT (SEQ ID NO: 5750), QSKQT (SEQ ID NO: 5751), QNPLT (SEQ ID NO: 5752), RDQKT (SEQ ID NO: 5753), HNQQN (SEQ ID NO: 5754). QWKRT (SEQ ID NO: 5755), QSQQI (SEQ ID NO: 5476), QAQQT (SEQ ID NO: 5462), QNHQT (SEQ ID NO: 5756), QNQQA (SEQ ID NO: 5757), QNQLN (SEQ ID NO: 5758), QTQPT (SEQ ID NO: 5759), INQQT (SEQ ID NO: 5560), QKQLT (SEQ ID NO: 5760), RNQLA (SEQ ID NO: 5761). RNQQS (SEQ ID NO: 5762), ISIQT (SEQ ID NO: 5763). QNQQN (SEQ ID NO: 5764), QSQQS (SEQ ID NO: 5765), QTVCT (SEQ ID NO: 5766), QYQQI (SEQ ID NO: 5767), QQIMT (SEQ ID NO: 5768), QNEQS (SEQ ID NO: 5769), LNTIQT (SEQ ID NO: 5770), QMIHT (SEQ ID NO: 5771), RNHQS (SEQ ID NO: 5772), QKMNT (SEQ ID NO: 5773), QSQQN (SEQ ID NO: 5774), QYQHA (SEQ ID NO: 5465);(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 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).230. The AAV particle of embodiment 228 or 229, wherein [N1]-[N2]-[N3]-[N4] is or comprises:(i) the amino acid sequence of any of SEQ ID NOs: 201 or 3160-3237;(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications 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, rela tive to any one of the amino acid sequences in (i).231. The AAV particle of any one of embodiments 228-230, wherein [N1]-[N2]-[N3]-[N4] is or comprises GHDSPHKSGQNQQT (SEQ ID NO: 201).232. The AAV particle of any one of embodiments 203-231, wherein the AA V capsid variant comprises an amino acid other than K at position 449 (e.g., T), T at position 450 (e.g., A, S, I, V, N. E, Y, C, G, W, or Q), an amino acid other than I at position 451 (e.g., E. V, S, T, N, D, C, G. Q, L, P, A), and / or an amino acid other than N at position 452 (e.g., S, Y, I, K, F, T. D, E, G, V. L, A, M, Q. H, P, orR), numbered according to SEQ ID NO: 138 or 982.233. The AAV particle of any one of embodiments 203-232, wherein the AAV capsid variant comprises tlie amino acid K at position 449, the amino acid T at position 450, the amino acid I atposition 451 , and / or the amino acid N at position 452, numbered according to SEQ ID NO: 138 or 982.234. The AAV particle of any one of embodiments 203-233, wherein the AA V capsid variant further comprises [NO], wherein [NO] comprises XA, XB, XC, and XD, wherein:(a) XAis K or T ;(b) XBis T, A, S, I, V, N. E, Y, C, G, W, or Q;(c) Xcis I, E. V, S, T, N, D, C, G, Q, L, P, A; and(d) XDis N, S, Y, I. K, F. T, D, E. G, V, L, A. M, Q, H, P, or R; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid ammo acids in (a)-(d).235. The AAV particle of embodiment 234, wherein [NO] is or comprises:(i) KAIN (SEQ ID NO: 5575), KTIN (SEQ ID NO: 5570), KTES (SEQ ID NO: 5601), TTIN (SEQ ID NO: 5571), KSIN (SEQ ID NO: 5572), KTVN (SEQ ID NO: 5568), KSIY (SEQ ID NO: 5775), KTSN (SEQ ID NO: 5578), KTTN (SEQ ID NO: 5602), KILN (SEQ ID NO: 5776), KTIS (SEQ ID NO: 5606), KAII (SEQ ID NO: 5777), KTIK (SEQ ID NO: 5612), KTEF (SEQ ID NO: 5624), KTIT (SEQ ID NO: 5620), KTNN (SEQ ID NO: 5604), KTID (SEQ ID NO: 5592), KAIS (SEQ ID NO: 5778), KTVD (SEQ ID NO: 5779), KTIE (SEQ ID NO: 5780), KTEG (SEQ ID NO: 5647), KVIN (SEQ ID NO: 5623), KAVN (SEQ ID NO: 5645), KTIY (SEQ ID NO: 5781), KTDN (SEQ ID NO: 5576), KTCN (SEQ ID NO: 5583), KNVV (SEQ ID NO: 5782), KTEL (SEQ ID NO: 5595), KTDA (SEQ ID NO: 5783), KTEV (SEQ ID NO: 5644), KSEL (SEQ ID NO: 5642), KTEM (SEQ ID NO: 5784), KTEQ (SEQ ID NO: 5632), KTII (SEQ ID NO: 5565), KIVN (SEQ ID NO: 5785), KTEK (SEQ ID NO: 5567), KTEN (SEQ ID NO: 5581), KIGN (SEQ ID NO: 5786), KEVM (SEQ ID NO: 5787), KYQV (SEQ ID NO: 5788), KTEA (SEQ ID NO: 5597), KATN (SEQ ID NO: 5586), KTEH (SEQ ID NO: 5584), KTVE (SEQ ID NO: 5789), KAID (SEQ ID NO: 5790), KTIM (SEQ ID NO: 5791), KEVG (SEQ ID NO: 5792), KSEM (SEQ ID NO: 5793), KAQQ (SEQ ID NO: 5794), KCGE (SEQ ID NO: 5795), KASN (SEQ ID NO: 5796), KTET (SEQ ID NO: 5594), KTIG (SEQ ID NO: 5797), KTDP (SEQ ID NO: 5798), KELV (SEQ ID NO: 5799), KELM (SEQ ID NO: 5800), KNEI (SEQ ID NO: 5801), KTPN (SEQ ID NO: 5802), KITN (SEQ ID NO: 5803), KTDI (SEQ ID NO: 5804), KTDQ (SEQ ID NO: 5805). KGIN (SEQ ID NO: 5806), KSEI (SEQ ID NO: 5807), KSEK (SEQ ID NO: 5627), KWSA (SEQ ID NO: 5808), KELA (SEQ ID NO: 5809), KQTQ (SEQ ID NO: 5810), KGAD (SEQ ID NO: 5811), KVGE (SEQ ID NO: 5812), KANE (SEQ ID NO: 5813), KT DT (SEQ ID NO: 5814), KTCI (SEQ ID NO: 5815), KELR (SEQ ID NO: 5816), KCQI (SEQ ID NO: 5817), KGVM (SEQ ID NO: 5818), KACD (SEQ ID NO: 5819), KNEL (SEQ ID NO: 5820), KAAE (SEQ ID NO: 5821), KGQN (SEQ ID NO: 5822), KNEF (SEQ ID NO: 5823), KTSI (SEQ ID NO: 5824), KAEH (SEQ ID NO: 5616), KCDQ (SEQ ID NO: 5825), KEIL (SEQ ID NO:5826), KTER (SEQ ID NO: 5573), KNAI (SEQ ID NO: 5650), KTDK (SEQ ID NO: 5588), KTPD (SEQ ID NO: 5827), KTIH (SEQ ID NO: 5659), orKTEI (SEQ ID NO: 5591);(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any2, or 3 amino acids, e.g,, consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any of the amino acid sequences in (i); or(iv) an ammo 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).236. The AAV particle of embodiment 234 or 235, wherein [NO]-[N1]-[N2]-[N3]-[N4] is or comprises:(i) the amino acid sequence of any one of SEQ ID NOs: 3606-3836;(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i). e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 amino acids, e.g.. consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications 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).2.37. The AA V particle of any one of embodiments 234-2.36, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KTINGHDSPHKSGQNQQT (SEQ ID NO: 5828).238. The AAV particle of any one of embodiments 234-236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754).239. The AAV particle of any one of embodiments 234-236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or comprises KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241).240. The AAV particle of any one of embodiments 168-239, wherein [N1]-[N2]-[N3] is present in loop IV, e.g., numbered according to SEQ ID NO: 4, 36, 138, 981, or 982.241. The AAV particle of any one of embodiments 198-202 or 234-240, wherein [N0] and [N4] are present in loop IV. e.g., numbered according to SEQ ID NO: 4, 36, 138, 981, or 982.242. The AAV particle of any one of embodiments 198-202 or 234-241 , wherein [N0] is present immediately subsequent to position 448, numbered according to the amino acid sequence of SEQ ID NO: 4, 36, 138, 981, or 982.243. The AAV particle of any one of embodiments 198-202 or 234-242, wherein [N0] replaces positions 449-452 (e.g,, K449, T450, 1451, and N452), numbered according to SEQ ID NO: 4, 36,138, 981, or 982.244. The AAV particle of any one of embodiments 198-202 or 234-243, wherein [N0] is present immediately subsequent to position 448 and wherein [N0] replaces positions 449-452 (e.g., K449, T450, 1451, and N452), numbered according to SEQ ID N0: 4, 36, 138, 981, or 982.245. The AAV particle of any one of embodiments 198-202 or 234-244, wherein [N0] corresponds to positions 449-452 (e.g., K449, T450, 1451, and N452) of any one of SEQ ID NOs: 4, 36, 138, 981 , or 982.246. The AAV particle of any one of embodiments 168-245, wherein [Nl] is present immediately subsequent to position 452, numbered according to SEQ ID NO: 4, 36, 138. 981, or 982.247. The AAV particle of any one of embodiments 168-246, wherein [Nl] replaces positions 453-455 (e.g., G453, S454, and G455), numbered according to SEQ ID NO: 4, 36, 138. 981, or 982.248. The AAV particle of any one of embodiments 168-246, wherein [N 1] replaces position 453 (e.g., G453), numbered according to SEQ ID NO: 4, 36, 138, 981, or 982.249. The AAV particle of any one of embodiments 168-177, 179-181, 183-185, 187-193, 195-200, 202, or 240-246, wherein:(i) X1 of [N 1] replaces position 453 (e.g., G453);(ii) X2. of [N1] corresponds to position 454 (e.g,, S454); and(iii) X3 of [N1] corresponds to position 455 (e.g., G455), wherein (i), (ii), and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981.250. The AAV particle of any one of embodiments 168-176, 178-201. or 240-246, wherein:(i) X1 of [N1] corresponds to position 453 (e.g., G453):(ii) X2 of [N1] corresponds to position 454 (e.g., S454); and(iii) X3 of [N1 J corresponds to position 455 (e.g., G455); wherein (i), (ii), and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981251. The AAV particle of any one of embodiments 203-248, wherein:(i) X1 of [N1] corresponds to position 453 (e.g., G453);(ii) X2 of [N1] replaces position 454 (e.g., S454); and(iii) X3 of [N1] replaces position 455 (e.g.. G455). wherein (i), (ii), and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 982.252. The AAV particle of any one of embodiments 203-248 or 251, wherein [Nl] corresponds to positions 453-455 (e.g., G453, II454, D455) of SEQ ID NO 982.253. The AAV particle of any one of embodiments 168-176, 178-201, 240-247, or 250, wherein [N1] corresponds to positions 453-455 (e.g., G453, S454, G455) of SEQ ID NO: 138 or 981.254. The AAV particle of any one of embodiments 168-253, wherein [N2] is present immediately subsequent to position 455, numbered according to of SEQ ID NO: 4, 36, 138, 981 , or 982.255. The AAV particle of any one of embodiments 168-254, wherein [N2] corresponds to positions 456-458 (e.g., S456, P457, and H458) of SEQ ID NO: 981 or 982.256. The AAV particle of any one of embodiments 168-254, wherein [N2] corresponds to positions 456-458 (e.g., S456. P457, and H458) of any one of SEQ ID NOs: 4 or 36-59.257. The AAV particle of any one of embodiments 168-256, wherein [N2] is present immediately subsequent to [N1],258. The AAV particle of any one of embodiments 168-202, 240-247, or 249-257, wherein [N3j corresponds to positions 459-460 (e.g., S459, K460, A461) of SEQ ID NO: 981.259. The AAV particle of any one of embodiments 168-202, 240-247, or 249-2.57, wherein [N3] corresponds to positions 459-460 (e.g., S459, K460, A461) of SEQ ID NO: 36, 38, 39, 40, 41, 42, 43, 44, 45. 46, 47, 48, 49, 50, 51 , 52. 53, 54, 55, 57, or 59.260. The AAV particle of any one of embodiments 168-259, wherein [N2]-[N3] is present immediately subsequent to position 455, numbered according to any one of SEQ ID NOs: 4, 36, 138,981, or 982.261. The AAV particle of any one of embodiments 168-259, wherein [N2]-[N3] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 981 .262. The AAV particle of any one of embodiments 168-261, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457. H458, S459, K460. A461) of SEQ ID NO: 981.263. The AAV particle of any one of embodiments 168-262, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, S459, K460, A461) of any one of SEQ ID NOs: 36, 38.39, 40, 41. 42, 43, 44, 45, 46, 47, 48. 49, 50, 51, 52, 53, 54, 55. 57, or 59.264. The AAV particle of any one of embodiments 203-257 or 259-261, wherein [N3] corresponds to positions 459-460 (e.g., K459, S460, G461) of SEQ ID NO: 982.265. The AAV particle of any one of embodiments 203-257 or 259-261, wherein [N3] corresponds to positions 459-460 (e.g., K459, S460, G461) of SEQ ID NO: 37.266. The AAV particle of any one of embodiments 203-265, wherein [N2]-[N3] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 982.267. The AAV particle of any one of embodiments 203-246, 248, 252, 255, 257, 260, 263-266, wherein [N3] replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138.268. The AAV particle of any one of embodiments 203-246, 248, 252, 255, 257, 260, 263-267, wherein [N3] is present immediately subsequent to [N2] and replaces positions 454 and 455 (e.g., S454 and G455), numbered according to SEQ ID NO: 138.269. The AAV particle of any one of embodiments 203-246, 248, 252, 255, 257, 260, 263-268, wherein [N3] is present immediately subsequent to [N1]-[N2] and replaces positions 454 and 455 (e.g,, S454 and G455), numbered according to SEQ ID NO: 138.270. The AAV particle of any one of embodiments 203-257, 260, 264-269, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, K459, S460. G461) of SEQ ID NO: 982.271. The AAV particle of any one of embodiments 203-257, 260, 264-270, wherein [N2]-[N3] corresponds to positions 456-461 (e.g., S456, P457, H458, K459, S460, G461) of SEQ ID NO: 37.272. The AAV particle of any one of embodiments 191 -202 or 228-271 , wherein [N4] is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.273. The AAV particle of any one of embodiments 191-202 or 228-272, wherein [N4] replaces positions 456-460 (e.g., Q456, N457, Q458. Q459, and T460), numbered according to SEQ ID NO: 138.274. The AAV particle of any one of embodiments 191-202 or 228-273, wherein [N4] corresponds to positions 462-466 (e.g., Q462, N463, Q464, Q465, and T466) of SEQ ID NO: 981 or 982.275. The AAV particle of any one of embodiments 191-202 or 228-273, wherein [N4] corresponds to positions 462-466 of any one of SEQ ID NOs: 4 or 36-59.276. The AAV particle of any one of embodiments 191-202 or 228-274, wherein [N4] corresponds to positions 456-460 (e.g., Q456, N457, Q458, Q459, and T460) of SEQ ID NO: 138.277. The AAV particle of any one of embodiments 191-202. or 228-276, wherein [N2]-[N3]-[N4] replaces positions 456-460 (e.g,, Q456, N457, Q458. Q459, and T460), numbered according to SEQ ID NO: 138.2.78. The AAV particle of any one of embodiments 191-2.02 or 228-277, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 456- 460 (e.g., Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138.279. The AAV particle of any one of embodiments 191-202 or 228-278, wherein [N1]-[N2]-[N3J- [N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138.280. The AAV particle of any one of embodiments 191-202 or 228-279, wherein [N1]-[N2]-[N3J-[N4] is present immediately subsequent to position 452, and wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138.281. The AAV particle of any one of embodiments 191-202, 240-247, 2.49, 250, 253-263, 2.66, or 272-280, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, and T466) of SEQ ID NO: 981.282. The AAV particle of any one of embodiments 168-202, 240-247, 249, 250, 253-263, 266, or 272-280, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461) of SEQ ID NO: 981.283. The AAV particle of any one of embodiments 228-257, 260, 261, 264-282, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 (e.g.. G453, H454, D455, S456, P457, H458, K459,S460, G461, Q462, N463, Q464, Q465, T466) of SEQ ID NO: 982.284. The AAV particle of any one of embodiments 203-257, 260, 261, 264-283, wherein [N1]-[N2]-[N3] corresponds to positions 453-461 (e.g., G453, H454, D455, S456, P457, H458, K459, S460,G461) of SEQ ID NO: 982.285. The AAV particle of any one of embodiments 228-257, 260, 261, 264-282, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 453-466 of any one of SEQ ID NOs: 4 or 36-59.286. The AAV particle of any one of embodiments 198-202 or 234-286, wherein [N0]-[N1]-[N2]~[N3]-[N4] replaces positions 449-460 (e.g., K449, T450, 1451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138.287. The AAV particle of any one of embodiments 198-202 or 234-286, wherein [N0]-[N1]-[N2]- [N3]-[N4] is present immediately subsequent to position 448, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449-460 (e.g., K449, T450, 1451, N452, G453, S454, G455, Q456, N457, Q458, Q459, and T460), numbered according to SEQ ID NO: 138.288. The AAV particle of any one of embodiments 198-202, 240-247, 249, 250, 253-263, 266, 272- 281, 286, or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 (e.g., K449, T450, 1451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466) of SEQ ID NO: 981 .289. The AAV particle of any one of embodiments 234-257, 260, 261, 264-284, 286, or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 (e.g.. K449, T450. 1451, N452, G453, H454, D455, S456, P457, H458. K459, S460, G461, Q462, N463, Q464, Q465. T466) of SEQ ID NO: 982.290. The AAV particle of any one of embodiments 234-257, 260, 261, 264-284, 286, or 287, wherein[N0]-[NI]-[N2]-[N3]-[N4] corresponds to positions 449-466 of any one of SEQ ID NOs: 4 or 36-59.291. The AAV particle of any one of embodiments 191 -202 or 228-290, wherein [N4 ] is present immediately subsequent to position 461, numbered according to SEQ ID NO: 4, 36, 981 , or 982.292. The AAV particle of any one of embodiments 191-202 or 228-291 , wherein [N4] replaces positions 462-466 (e.g., Q462, N463, Q464, Q465, and T466), numbered according to SEQ ID NO: 4,36, 981, or 982.293. The AAV particle of any one of embodiments 191-202 or 228-292, wherein [N2]-[N3]-[N4] replaces positions 462-466 (e.g., Q462, N463, Q464, Q465, and T466), numbered according to SEQ ID NO: 4, 36, 981, or 982.294. The AAV particle of any one of embodiments 191-202 or 228-293, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 455, and wherein [N2]-[N3]-[N4] replaces positions 462- 466 (e.g., Q462, N463, Q464, Q465, and T466), numbered according to SEQ ID NO: 4, 36, 981, or 982.295. The AAV particle of any one of embodiments 168-294, wherein the AAV capsid variant comprises, from N-terminus to C-terminus, [N2]-[N3] .296. The AAV particle of any one of embodiments 168-295, wherein the AAV capsid variant comprises, from N-tenninus to C-terminus. [N1]-[N2]-[N3],297. The AAV particle of any one of embodiments 168-296, wherein the AAV capsid variant comprises, from N-tenninus to C-terminus, [N0]-[N1]-[N2]-[N3].298. The AAV particle of any one of embodiments 168-297, wherein the AAV capsid variant comprises, from N-terminus to C-terminus, [N1]-[N2]-[N3]-[N4].299. The AAV particle of any one of embodiments 168-298, wherein the AA V capsid variant comprises, from N-terminus to C-terminus, [N0]-[N1]-[N2]-[N3]-[N4J.300. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein tire AAV capsid variant comprises the formula [A]-[B] (SEQ ID NO: 4696), wherein:(i) [A] comprises GSGSPH (SEQ ID NO: 4695); and(ii) [B] comprises X1 X2, X3, X4, and X5, wherein:(a) XI is S, I, F, V, C, Y, W, R, P, L, Q, M, K, or G;(b) X2 is K, M, R, F. V, C, P. Y, L, W, G, N, S, T. I, or A;(c) X3 is A, Y, L. R, W, C, T, F, H, I, P, M, K, S, V. G, Q, or N;(d) X4 is Q. M, F, K, H, R, C, W, P, V, L, G, S. Y, I, A, T. D, N, or E; and(e) X5 is A, N, Y, R, K. L, I, M, Q, S, C, W. F, T, G, V, or P; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g,, a conservative substitution, of any of the aforesaid ammo acids in (a)-(e).301. The AAV particle of embodiment 300, wherein:(a) XI is S, L, R, V, or P;(b) X2 is K, C, F, L, P, R, S, or V;(c) X3 is A, C, F, I, K, L, M, P, R, T, W, or Y;(d) X4 is Q, R, S, T, C, F, K, L, P or Y; and(e) X5 is N, R, S, T, K, M, Q or Y; optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(e).302. The AAV particle of embodiment 300 or 301, wherein [B] comprises SKA, SMY, SKL, SKR, SKW, SRC, SFT, SKF, 1VW, SKY, SCH, FPW, SKI, VYY, SLY, SKP, SRF, SRM, SVK, SWA, SLW, SFR, SKK, SYA, SCS, SGA, SFP, SFF, SMC, SKT, SGK, FYR, CRV. YGI, VNC, SLA, WSY, RWL, PSC, SSW, SKG, VPW, SGC, STT, PKR, SKC, WVP, SFW, RIK, SKM, LRW, LPT. SYM, LLC, RCC, LCV, SYL, QGC, MAF, SFQ, SLC, RPW, RPR, SCP, SVR, SLP, VYH, SYT, LVY, YRY, SWL, CPA, SPP, RWT, PRK, PFV, SKS, WVA, SKV, CAL, SSC, SKN, LCT, STC, SKQ, KSG, SYY, SLT, SCQ, FPF, SVF, GRY, AQA, AQN, YMN, AFY, LKR, RHR, AQK, WRL, CRN, TCN, FFI, AQY, WQN, YFM, ARQ, HQN, IRR, YQN, YWN, AFS, FWN, AQC, MRN, KKN, APN, WKN, ARW, RPN, KVF, AFN, ACS, RLW, SRN, CPN, ACN, FRQ, PFN, FGN, CQN, LFW, TRK, KRN, RQN, VQN, IQN, AQR, PFR, AWN, RSY, LQN, WLN, RRA, AQT, GCT, RYT, TPN, ARM, CFL, PQN, WSN, FKN, KQN, APR, RYN, MIC, TQN, WKS, AAR, LTR, IRG, LVN, FQN, ACQ. WGL, ILR, QIN, ACI, ALR, AHA, CLN, AFV, AQF, RCN, MPC, KTS, PYN, AQS, TRN, LKN, AQM, CTN, PDN, RNY, ACR, CSV, ARI, LPK, SEQ, VRM, NSR, RKR, ARN, QRP, RW, GQN, YSN, QSN, AKG, CTS, FEN, AKK, KAQ, MYM, KAF, KI..K. KRH, KW'R, RCR, FTC, KFF, VW Q. KYF. KAR, CHQ, PWQ, KIR, YYQ, LYW, KPK, RFW, RMR, VKK, WAP, L W'K. FRP, KKV, YAF, KAC, KRL, CSR, RCP, GAC, KFR, FFG, MCQ, KLF, KTR, GKR, YRQ. RVQ, GIQ, NCQ, KPF, LAW, KRS, SYQ, WLQ, KRR, KGC, KRY, GCQ, FTP. TTC, K RQ, KCF. VPQ, FWS, KFK, IKQ, KAP, FRY, KMI, RWQ, PTQ, KWK, YMR, KAA, LCQ, CCQ, CVQ, KLT, KLC, YLV, AFQ, KWG, KIL, FQI, KAL, KAH, LCL, PRQ, CPQ, VRY, VRC, KMP, KKT, LPY, YHQ, YTR, VYQ. RYQ, WLK, PAQ, MCT, PPD, WTQ, RKQ, KCS, FVQ, KLP, KSE, VAQ, LYQ,KVR. ALQ, SCT, KNS, KRK, CTQ, TCL, YAR, KQR, KRV, SGQ, YYS, LTC, CQS, KAK, KPQ, PFQ, KCT, or VFE.303. The AAV particle of any one of embodiments 300-302, wherein [B] comprises SKAQ (SEQ ID NO: 5829), SMYM (SEQ ID NO: 5830), SKAF (SEQ ID NO: 5831), SKLK (SEQ ID NO: 5832), SKRH (SEQ ID NO: 5833), SKWR (SEQ ID NO: 5834), SRCR (SEQ ID NO: 5835), SFTC (SEQ ID NO: 5836), SKFF (SEQ ID NO: 5837), IVWQ (SEQ ID NO: 5838), SKYE (SEQ ID NO: 5839), SKAR (SEQ ID NO: 5840), SCHQ (SEQ ID NO: 5841), FPWQ (SEQ ID NO: 5842), SKIR (SEQ ID NO: 5843), VYYQ (SEQ ID NO: 5844). SLYW (SEQ ID NO: 5845). SKPK (SEQ ID NO: 5846), SRFW (SEQ ID NO: 5847), SRMR (SEQ ID NO: 5848), SVKK (SEQ ID NO: 5849), SWAP (SEQ ID NO: 5850), SLWK (SEQ ID NO: 5851), SFRP (SEQ ID NO: 5852), SKKV (SEQ ID NO: 5853), SYAF (SEQ ID NO: 5854), SKAC (SEQ ID NO: 5855), SKRL (SEQ ID NO: 5856), SCSR (SEQ ID NO: 5857), SRCP (SEQ ID NO: 5858), SGAC (SEQ ID NO: 5859), SKFR (SEQ ID NO: 5860), SFPF (SEQ ID NO: 5861), SFFG (SEQ ID NO: 5862), SMCQ (SEQ ID NO: 5863), SKLF (SEQ ID NO: 5864), SKTR (SEQ ID NO: 5865), SGKR (SEQ ID NO: 5866). FYRQ (SEQ ID NO: 5867), CRVQ (SEQ ID NO: 5868), YGIQ (SEQ ID NO: 5869), VNCQ (SEQ ID NO: 5870), SKPF (SEQ ID NO: 5871). SLAW (SEQ ID NO: 5872), SKRS (SEQ ID NO: 5873), WSYQ (SEQ ID NO: 5874), RWLQ (SEQ ID NO: 5875), PSCQ (SEQ ID NO: 5876), SSWL (SEQ ID NO: 5877), SKRR (SEQ ID NO: 5878). SKGC (SEQ ID NO: 5879), VP WQ (SEQ ID NO: 5880), SKRY (SEQ ID NO: 5881), SGCQ (SEQ ID NO: 5882), SFTP (SEQ ID NO: 5883), STTC (SEQ ID NO: 5884), PKRQ (SEQ ID NO: 5885), SKCF (SEQ ID NO: 5886), WVPQ (SEQ ID NO: 5887), SFWS (SEQ ID NO: 5888), SKFK (SEQ ID NO: 5889), RIKQ (SEQ ID NO: 5890), SKAP (SEQ ID NO: 5891), SFRY (SEQ ID NO: 5892), SKMI (SEQ ID NO: 5893), LRWQ (SEQ ID NO: 5894), LPTQ (SEQ ID NO: 5895), SKWK (SEQ ID NO: 5896), SYMR (SEQ ID NO: 5897), SKAA (SEQ ID NO: 5898), LLCQ (SEQ ID NO: 5899), RCCQ (SEQ ID NO: 5900), LCVQ (SEQ ID NO: 5901), SKLT (SEQ ID NO: 5902), SKLC (SEQ ID NO: 5903), SYLV (SEQ ID NO: 5904). QGCQ (SEQ ID NO: 5905), M.AFQ (SEQ ID NO: 5906), SKWG (SEQ ID NO: 5907), SKIL (SEQ ID NO: 5908). SFQI (SEQ ID NO: 5909), SKAL (SEQ ID NO: 5910), SKAH (SEQ ID NO: 5911). SLCL (SEQ ID NO: 5912), RPWQ (SEQ ID NO: 5913), RPRQ (SEQ ID NO: 5914), SCPQ (SEQ ID NO: 5915), SVRY (SEQ ID NO: 5916), SVRC (SEQ ID NO: 5917), SKMP (SEQ ID NO: 5918), SKKT (SEQ ID NO: 5919), SLPY (SEQ ID NO: 592.0), VYHQ (SEQ ID NO: 5921), SYTR (SEQ ID NO: 592.2), LVYQ (SEQ ID NO: 592.3), YRYQ (SEQ ID NO: 592.4), SWLK (SEQ ID NO: 5925), CPAQ (SEQ ID NO: 5926), SMCT (SEQ ID NO: 592.7), SPPD (SEQ ID NO: 5928), SKRN (SEQ ID NO: 5929), RWTQ (SEQ ID NO: 5930), PRKQ (SEQ ID NO: 5931), SKCS (SEQ ID NO: 5932). PFVQ (SEQ ID NO: 5933), SKIP (SEQ ID NO: 5934), SKSE (SEQ ID NO: 5935), WVAQ (SEQ ID NO: 5936), SLYQ (SEQ ID NO: 5937), SKVR (SEQ ID NO: 5938), CALQ (SEQ ID NO: 5939), SSCT (SEQ ID NO: 5940), SKNS (SEQ ID NO: 5941), SKRK (SEQ ID NO: 5942), LCTQ (SEQ ID NO: 5943), STCL (SEQ ID NO: 5944),SYAR (SEQ ID NO: 5945), SKQR (SEQ ID NO: 5946), SKR V (SEQ ID NO: 5947), KSGQ (SEQ ID NO: 5948), SYYS (SEQ ID NO: 5949), SLTC (SEQ ID NO: 5950), SCQS (SEQ ID NO: 5951), SKAK (SEQ ID NO: 5952). SKPQ (SEQ ID NO: 5953), FPFQ (SEQ ID NO: 5954), SKCT (SEQ ID NO: 5955), SVFE (SEQ ID NO: 5956), GRYQ (SEQ ID NO: 5957), KAQA (SEQ ID NO: 5958). KAQN (SEQ ID NO: 5959), MYMN (SEQ ID NO: 5960), KAFY (SEQ ID NO: 5961), KLKR (SEQ ID NO: 5962), KRHR (SEQ ID NO: 5963), K AQK (SEQ ID NO: 5964), KWRL (SEQ ID NO: 5965), RCRN (SEQ ID NO: 5966). FTCN (SEQ ID NO: 5967), KFFI (SEQ ID NO: 5968), KAQY (SEQ ID NO: 5969), VWQN (SEQ ID NO: 5970), KYFM (SEQ ID NO: 5971), KARQ (SEQ ID NO: 5972), CHQN (SEQ ID NO: 5973), PWQN (SEQ ID NO: 5974), KIRR (SEQ ID NO: 5975). YYQN (SEQ ID NO: 5976), LYWN (SEQ ID NO: 5977), KPKR (SEQ ID NO: 5978), KAFS (SEQ ID NO: 5979), RFWN (SEQ ID NO: 5980), KAQC (SEQ ID NO: 5981), RMRN (SEQ ID NO: 5982), VKKN (SEQ ID NO: 5983), WAPN (SEQ ID NO: 5984), LWKN (SEQ ID NO: 5985), KARW (SEQ ID NO: 5986), FRPN (SEQ ID NO: 5987), KKVF (SEQ ID NO: 5988), YAFN (SEQ ID NO: 5989), KACS (SEQ ID NO: 5990), KRLW (SEQ ID NO: 5991), CSRN (SEQ ID NO: 5992), RCPN (SEQ ID NO: 5993), GACN (SEQ ID NO: 5994), KFRQ (SEQ ID NO: 5995), FPFN (SEQ ID NO: 5996), FFGN (SEQ ID NO: 5997), MCQN (SEQ ID NO: 5998), KLFW (SEQ ID NO: 5999). KTRK (SEQ ID NO: 6000), GKRN (SEQ ID NO: 6001), YRQN (SEQ ID NO: 6002), RVQN (SEQ ID NO: 6003). GIQN (SEQ ID NO: 6004), KAQR (SEQ ID NO: 6005). NCQN (SEQ ID NO: 6006). KPFR (SEQ ID NO: 6007), LAWN (SEQ ID NO: 6008), KRSY (SEQ ID NO: 6009), SYQN (SEQ ID NO: 6010), WLQN (SEQ ID NO: 6011), SCQN (SEQ ID NO: 6012), SWLN (SEQ ID NO: 6013), KRRA (SEQ ID NO: 6014), KAQT (SEQ ID NO: 6015), KGCT (SEQ ID NO: 6016), KRYT (SEQ ID NO: 6017), GCQN (SEQ ID NO: 6018), FTPN (SEQ ID NO: 6019), TTCN (SEQ ID NO: 6020), KARM (SEQ ID NO: 6021), KRQN (SEQ ID NO: 6022), KCFL (SEQ ID NO: 6023), VPQN (SEQ ID NO: 6024), FWSN (SEQ ID NO: 6025), KFKN (SEQ ID NO: 6026), IKQN (SEQ ID NO: 6027), KAPR (SEQ ID NO: 6028), FRYN (SEQ ID NO: 6029), KMIC (SEQ ID NO: 6030), RWQN (SEQ ID NO: 6031), PTQN (SEQ ID NO: 6032), KWKS (SEQ ID NO: 6033), YNIRN (SEQ ID NO: 6034), KAAR (SEQ ID NO: 6035), LCQN (SEQ ID NO: 6036), CCQN (SEQ ID NO: 6037), CVQN (SEQ ID NO: 6038), KLTR (SEQ ID NO: 6039), KLCT (SEQ ID NO: 6040), KIRG (SEQ ID NO: 6041), YLVN (SEQ ID NO: 6042), AFQN (SEQ ID NO: 6043), KACQ (SEQ ID NO: 6044), KWGL (SEQ ID NO: 6045), KILR (SEQ ID NO: 6046), FQIN (SEQ ID NO: 6047), KACI (SEQ ID NO: 6048). KALR (SEQ ID NO: 6049), KARA (SEQ ID NO: 6050), LCLN (SEQ ID NO: 6051), KAFV (SEQ ID NO: 6052). PRQN (SEQ ID NO: 6053), CPQN (SEQ ID NO: 6054), KAQF (SEQ ID NO: 6055), VRYN (SEQ ID NO: 6056), VRCN (SEQ ID NO: 6057), KMPC (SEQ ID NO: 6058), KKTS (SEQ ID NO: 6059), LPYN (SEQ ID NO: 6060), YHQN (SEQ ID NO: 6061), KAQS (SEQ ID NO: 6062), YTRN (SEQ ID NO: 6063), VYQN (SEQ ID NO: 6064), RYQN (SEQ ID NO: 6065), WLKN (SEQ ID NO: 6066), KAQM (SEQ ID NO: 6067), PAQN (SEQ ID NO: 6068), MC TN (SEQ ID NO: 6069), PPDN (SEQ ID NO: 6070), KRNY (SEQ ID NO: 6071), WTQN (SEQ ID NO: 6072), KACR (SEQ ID NO: 6073),RKQN (SEQ ID NO: 6074), KCSV (SEQ ID NO: 6075), KARI (SEQ ID NO: 6076), FVQN (SEQ ID NO: 6077), KLPK (SEQ ID NO: 6078), KSEQ (SEQ ID NO: 6079), VAQN (SEQ ID NO: 6080), LYQN (SEQ ID NO: 6081), KVRM (SEQ ID NO: 6082), ALQN (SEQ ID NO: 6083), SCTN (SEQ ID NO: 6084), KNSR (SEQ ID NO: 6085), KRKR (SEQ ID NO: 6086), CTQN (SEQ ID NO: 6087), TCLN (SEQ ID NO: 6088), YARN (SEQ ID NO: 6089), KQRP (SEQ ID NO: 6090), KRW (SEQ ID NO: 6091), SGQN (SEQ ID NO: 6092), YYSN (SEQ ID NO: 6093), LTCN (SEQ ID NO: 6094), CQSN (SEQ ID NO: 6095), KAKG (SEQ ID NO: 6096). KPQN (SEQ ID NO: 6097), PFQN (SEQ ID NO: 6098), KCTS (SEQ ID NO: 6099), VFEN (SEQ ID NO: 6100). or KAKK (SEQ ID NO: 6101).304. The AAV particle of any one of embodiments 300-303, wherein [B] is or comprises:(i) SKAQA (SEQ ID NO: 6102), SKAQN (SEQ ID NO: 6103), SMYMN (SEQ ID NO: 6104), SKAFY (SEQ ID NO: 6105), SKLKR (SEQ ID NO: 6106), SKRHR (SEQ ID NO: 6107), SKAQK (SEQ ID NO: 6108), SKWRL (SEQ ID NO: 6109), SRCRN (SEQ ID NO: 6110), SFTCN (SEQ ID NO: 6111), SKFFI (SEQ ID NO: 6112), SKAQY (SEQ ID NO: 6113), IVWQN (SEQ ID NO: 6114), SKYFM (SEQ ID NO: 6115), SKARQ (SEQ ID NO: 6116), SCHQN (SEQ ID NO: 6117), FPWQN (SEQ ID NO: 6118), SKIRR (SEQ ID NO: 6119). VYYQN (SEQ ID NO: 6120), SLYWN (SEQ ID NO: 612.1), SKPKR (SEQ ID NO: 6122), SKAFS (SEQ ID NO: 612.3), SRFWN (SEQ ID NO: 6124), SKAQC (SEQ ID NO: 6125), SR.MRN (SEQ ID NO: 6126), SVKKN (SEQ ID NO: 6127), SWAPN (SEQ ID NO: 6128), SLWKN (SEQ ID NO: 6129), SKARW (SEQ ID NO: 6130), SFRPN (SEQ ID NO: 6131), SKKVF (SEQ ID NO: 6132), SYAFN (SEQ ID NO: 6133). SKACS (SEQ ID NO: 6134), SKRLW (SEQ ID NO: 6135), SCSRN (SEQ ID NO: 6136), SRCPN (SEQ ID NO: 6137), SGACN (SEQ ID NO: 6138), SKFRQ (SEQ ID NO: 6139), SFPFN (SEQ ID NO: 6140), SFFGN (SEQ ID NO: 6141), SMCQN (SEQ ID NO: 6142), SKLFW (SEQ ID NO: 6143), SKTRK (SEQ ID NO: 6144), SGKRN (SEQ ID NO: 6145), FYRQN (SEQ ID NO: 6146), CRVQN (SEQ ID NO: 6147). YGIQN (SEQ ID NO: 6148), SKAQR (SEQ ID NO: 6149), VNCQN (SEQ ID NO: 6150), SKPFR (SEQ ID NO: 6151), SLAWN (SEQ ID NO: 6152), SKRSY (SEQ ID NO: 6153), WSYQN (SEQ ID NO: 6154), RWLQN (SEQ ID NO: 6155), PSCQN (SEQ ID NO: 6156), SSWLN (SEQ ID NO: 6157), SKRRA (SEQ ID NO: 6158), SKAQT (SEQ ID NO: 6159), SKGCT (SEQ ID NO: 6160), WWQN (SEQ ID NO: 6161), SKRYT (SEQ ID NO: 6162), SGCQN (SEQ ID NO: 6163), SFTPN (SEQ ID NO: 6164), STTCN (SEQ ID NO: 6165), SKARM (SEQ ID NO: 6166), PKRQN (SEQ ID NO: 6167), SKCFL (SEQ ID NO: 6168), WVPQN (SEQ ID NO: 6169), SFWSN (SEQ ID NO: 6170). SKFKN (SEQ ID NO: 6171), RIKQN (SEQ ID NO: 6172), SKAPR (SEQ ID NO: 6173), SFRYN (SEQ ID NO: 6174), SK MIC (SEQ ID NO: 6175), LRWQN (SEQ ID NO: 6176), LPTQN (SEQ ID NO: 6177), SKWKS (SEQ ID NO: 6178), SYMRN (SEQ ID NO: 6179), SKAAR (SEQ ID NO: 6180), LLCQN (SEQ ID NO: 6181), RCCQN (SEQ ID NO: 6182), LCVQN (SEQ ID NO: 6183), SKLTR (SEQ ID NO: 6184), SKLCT (SEQ ID NO: 6185),SKIRG (SEQ ID NO: 6186), SYLVN (SEQ ID NO: 6187), QGCQN (SEQ ID NO: 6188), M.AFQN (SEQ ID NO: 6189), SKACQ (SEQ ID NO: 6190), SKWGL (SEQ ID NO: 6191), SKIER (SEQ ID NO: 6192), SFQIN (SEQ ID NO: 6193). SKACI (SEQ ID NO: 6194), SKALR (SEQ ID NO: 6195), SKAHA (SEQ ID NO: 6196), SLCLN (SEQ ID NO: 6197), SKAFV (SEQ ID NO: 6198), RPWQN (SEQ ID NO: 6199), RPRQN (SEQ ID NO: 6200). SCPQN (SEQ ID NO: 62.01), SKAQF (SEQ ID NO: 6202), SV RY N (SEQ ID NO: 6203), SVRCN (SEQ ID NO: 6204), SKMPC (SEQ ID NO: 6205), SKKTS (SEQ ID NO: 6206), SLPYN (SEQ ID NO: 6207). VYIIQN (SEQ ID NO: 6208), SKAQS (SEQ ID NO: 6209), SYTRN (SEQ ID NO: 6210), LVYQN (SEQ ID NO: 6211), YRYQN (SEQ ID NO: 6212), SWLKN (SEQ ID NO: 6213), SKAQM (SEQ ID NO: 6214), CPAQN (SEQ ID NO: 6215), SMCTN (SEQ ID NO: 6216), SPPDN (SEQ ID NO: 6217), SKRNY (SEQ ID NO: 6218), RWTQN (SEQ ID NO: 6219), SKACR (SEQ ID NO: 6220), PRKQN (SEQ ID NO: 6221), SKCSV (SEQ ID NO: 6222), SKARI (SEQ ID NO: 6223), PFVQN (SEQ ID NO: 6224), SKLPK (SEQ ID NO: 6225), SKSEQ (SEQ ID NO: 6226). WVAQN (SEQ ID NO: 6227), SLYQN (SEQ ID NO: 6228), SKVRM (SEQ ID NO: 6229), CALQN (SEQ ID NO: 6230). SSCTN (SEQ ID NO: 6231), SKNSR (SEQ ID NO: 6232). SKRKR (SEQ ID NO: 6233), LCTQN (SEQ ID NO: 6234), STCLN (SEQ ID NO: 6235), SYARN (SEQ ID NO: 6236). SKQRP (SEQ ID NO: 6237), SKRVV (SEQ ID NO: 6238). KSGQN (SEQ ID NO: 6239), SYYSN (SEQ ID NO: 6240), SLTCN (SEQ ID NO: 6241), SCQSN (SEQ ID NO: 6242). SKAKG (SEQ ID NO: 6243), SKPQN (SEQ ID NO: 6244), FPFQN (SEQ ID NO: 6245), SKCTS (SEQ ID NO: 6246), SWEN (SEQ ID NO: 6247), SKAKK (SEQ ID NO: 6248), or GRYQN (SEQ ID NO: 6249):(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 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).305. The AAV particle of any one of embodiments 300-304, wherein [A]-[B] is or comprises:(i) GSGSPHSKAQA (SEQ ID NO: 62.50), GSGSPHSKAQN (SEQ ID NO: 6251), GSGSPHSMYMN (SEQ ID NO: 6252), GSGSPHSKAFY (SEQ ID NO: 62.53). GSGSPHSKLKR (SEQ ID NO: 62.54), GSGSPHSKRHR (SEQ ID NO: 62.55), GSGSPHSKAQK (SEQ ID NO: 6256), GSGSPHSKWRL (SEQ ID NO: 62.57), GSGSPHSRCRN (SEQ ID NO: 6258), GSGSPHSFTCN (SEQ ID NO: 6259), GSGSPHSKFFI (SEQ ID NO: 6260). GSGSPHSKAQY (SEQ ID NO: 6261), GSGSPIIIVWQN (SEQ ID NO: 6262), GSGSPHSKYFM (SEQ ID NO: 62.63), GSGSPHSKARQ (SEQ ID NO: 6264), GSGSPHSCHQN (SEQ ID NO: 6265), GSGSPHFPWQN (SEQ ID NO: 6266), GSGSPHSKIRR (SEQ ID NO: 6267), GSGSPHVYYQN (SEQ ID NO: 6268), GSGSPHSLYWN (SEQ ID NO: 6269), GSGSPHSKPKR (SEQ ID NO: 6270), GSGSPHSKAFS (SEQ ID NO: 6271),GSGSPHSRFWN (SEQ ID NO: 6272), GSGSPHSKAQC (SEQ ID NO: 6273). GSGSPHSRMRN (SEQ ID NO: 6274), GSGSPHSVKKN (SEQ ID NO: 6275), GSGSPHSWAPN (SEQ ID NO: 6276), GSGSPHSLWKN (SEQ ID NO: 6277), GSGSPHSKARW (SEQ ID NO: 6278), GSGSPHSFRPN (SEQ ID NO: 6279), GSGSPHSKKVF (SEQ ID NO: 6280), GSGSPHSYAFN (SEQ ID NO: 6281), GSGSPHSKACS (SEQ ID NO: 6282), GSGSPHSKRLW (SEQ ID NO: 6283), GSGSPHSCSRN (SEQ ID NO: 6284), GSGSPHSRCPN (SEQ ID NO: 6285), GSGSPHSGACN (SEQ ID NO: 6286), GSGSPHSKFRQ (SEQ ID NO: 6287), GSGSPHSFPFN (SEQ ID NO: 6288), GSGSPHSFFGN (SEQ ID NO: 6289), GSGSPHSMCQN (SEQ ID NO: 6290), GSGSPHSKLFW (SEQ ID NO: 6291), GSGSPHSKTRK (SEQ ID NO: 6292), GSGSPHSGKRN (SEQ ID NO: 6293). GSGSPHFYRQN (SEQ ID NO: 6294), GSGSPHCRVQN (SEQ ID NO: 6295), GSGSPHYGIQN (SEQ ID NO: 6296), GSGSPHSKAQR (SEQ ID NO: 6297), GSGSPHVNCQN (SEQ ID NO: 6298), GSGSPHSKPFR (SEQ ID NO: 6299), GSGSPHSLAWN (SEQ ID NO: 6300), GSGSPHSKRSY (SEQ ID NO: 6301), GSGSPH WSYQN (SEQ ID NO: 6302), GSGSPHRWLQN (SEQ ID NO: 6303). GSGSPHPSCQN (SEQ ID NO: 6304), GSGSPHSSWLN (SEQ ID NO: 6305). GSGSPHSKRRA (SEQ ID NO: 6306), GSGSPHSKAQT (SEQ ID NO: 6307), GSGSPHSKGCT (SEQ ID NO: 6308), GSGSPHVPWQN (SEQ ID NO: 6309), GSGSPHSKRYT (SEQ ID NO: 6310), GSGSPHSGCQN (SEQ ID NO: 6311), GSGSPHSFTPN (SEQ ID NO: 6312), GSGSPHSTTCN (SEQ ID NO: 6313), GSGSPHSKARM (SEQ ID NO: 6314), GSGSPHPKRQN (SEQ ID NO: 6315), GSGSPHSKCFL (SEQ ID NO: 63 : 6), GSGSPHWVPQN (SEQ ID NO: 6317), GSGSPHSFWSN (SEQ ID NO: 6318), GSGSPHSKFKN (SEQ ID NO: 6319), GSGSPIIRIKQN (SEQ ID NO: 6320), GSGSPHSK APR (SEQ ID NO: 6321). GSGSPI ISFR YN (SEQ ID NO: 6322), GSGSPI ISKMIC (SEQ ID NO: 6323). GSGSPI ILRWQN (SEQ ID NO: 6324), GSGSPHLPTQN (SEQ ID NO: 6325), GSGSPHSKWKS (SEQ ID NO: 6326), GSGSPHSYMRN (SEQ ID NO: 6327), GSGSPHSKAAR (SEQ ID NO: 6328), GSGSPHLLCQN (SEQ ID NO: 6329), GSGSPHRCCQN (SEQ ID NO: 6330), GSGSPHLCVQN (SEQ ID NO: 6331), GSGSPHSKLTR (SEQ ID NO: 6332), GSGSPHSKLCT (SEQ ID NO: 6333), GSGSPHSKIRG (SEQ ID NO: 6334), GSGSPHSYLVN (SEQ ID NO: 6335), GSGSPHQGCQN (SEQ ID NO: 6336), GSGSPHMAFQN (SEQ ID NO: 6337), GSGSPHSKACQ (SEQ ID NO: 6338), GSGSPHSKWGL (SEQ ID NO: 6339), GSGSPHSKILR (SEQ ID NO: 6340), GSGSPHSFQIN (SEQ ID NO: 6341), GSGSPIISKACI (SEQ ID NO: 6342), GSGSPHSKALR (SEQ ID NO: 6343), GSGSPHSKAHA (SEQ ID NO: 6344), GSGSPHSLCLN (SEQ ID NO: 6345), GSGSPHSKAFV (SEQ ID NO: 6346), GSGSPH RPWQN (SEQ ID NO: 6347), GSGSPHRPRQN (SEQ ID NO: 6348), GSGSPHSCPQN (SEQ ID NO: 6349), GSGSPHSKAQF (SEQ ID NO: 6350), GSGSPHSVRYN (SEQ ID NO: 6351). GSGSPHSVRCN (SEQ ID NO: 6352), GSGSPHSKMPC (SEQ ID NO: 6353), GSGSPHSKKTS (SEQ ID NO: 6354), GSGSPHSLPYN (SEQ ID NO: 6355), GSGSPHV YHQN (SEQ ID NO: 6356), GSGSPHSKAQS (SEQ ID NO: 6357), GSGSPHSYTRN (SEQ ID NO: 6358), GSGSPHLVYQN (SEQ ID NO: 6359), GSGSPHYRYQN (SEQ ID NO: 6360), GSGSPHSWLKN (SEQ ID NO: 6361), GSGSPHSKAQM (SEQ ID NO: 6362), GSGSPHCPAQN (SEQ ID NO: 6363), GSGSPHSMCTN(SEQ ID NO: 6364), GSGSPHSPPDN (SEQ ID NO: 6365), GSGSPHSKRNY (SEQ ID NO: 6366), GSGSPHRWTQN (SEQ ID NO: 6367), GSGSPHSKACR (SEQ ID NO: 6368), GSGSPHPRKQN (SEQ ID NO: 6369), GSGSPHSKCSV (SEQ ID NO: 6370), GSGSPHSKARI (SEQ ID NO: 6371), GSGSPHPFVQN (SEQ ID NO: 6372), GSGSPHSKLPK (SEQ ID NO: 6373), GSGSPHSKSEQ (SEQ ID NO: 6374), GSGSPHWVAQN (SEQ ID NO: 6375), GSGSPHSLYQN (SEQ ID NO: 6376), GSGSPHSKVRM (SEQ ID NO: 6377), GSGSPHCALQN (SEQ ID NO: 6378), GSGSPHSSCTN (SEQ ID NO: 6379), GSGSPHSKNSR (SEQ ID NO: 6380), GSGSPHSKRKR (SEQ ID NO: 6381), GSGSPHLCTQN (SEQ ID NO: 6382), GSGSPHSTCLN (SEQ ID NO: 6383), GSGSPHSYARN (SEQ ID NO: 6384), GSGSPHSKQRP (SEQ ID NO: 6385), GSGSPHSKRW (SEQ ID NO: 6386), GSGSPHKSGQN (SEQ ID NO: 6387), GSGSPHSYYSN (SEQ ID NO: 6388), GSGSPHSLTCN (SEQ ID NO: 6389), GSGSPHSCQSN (SEQ ID NO: 6390), GSGSPHSKAKG (SEQ ID NO: 6391), GSGSPHSKPQN (SEQ ID NO: 6392), GSGSPHFPFQN (SEQ ID NO: 6393), GSGSPHSKCTS (SEQ ID NO: 6394), GSGSPHSVFEN (SEQ ID NO: 6395), GSGSPHSKAKK (SEQ ID NO: 6396), or GSGSPHGRYQN (SEQ ID NO: 6397);(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 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)306. The AAV particle of any one of embodiments 300-305, wherein [A]-[B] does not comprise the amino acid sequence of GSGSPHSKAQN (SEQ ID NO: 6251).307. The AAV particle of any one of embodiments 300-306, wherein the AAV capsid variant comprises one, two, or all of an amino acid other than Q at position 458 (e.g., R, C, S. W, L, F, Y, H, I, V, A, or P), an amino acid other than Q at position 459 (e.g., K, I, R. L or S), and / or an amino acid other than T at position 460 (e.g., R), numbered according to SEQ ID NO: 138.308. The AAV particle of any one of embodiments 300-307, wherein the AA V capsid variant comprises:(i) the amino acid R at position 458;(ii) the amino acid W at position 458;(iii) the amino acid Y at position 458;(iv) the amino acid F at position 458;(v) the amino acid S at position 458;(vi) the amino acid C at position 458;(vii) the amino acid I at position 458;(viii) the amino acid L at position 458;(ix) the amino acid P at position 458;(x) the amino acid I at position 459;(xi) the amino acid H at position 458; or(xii) the amino acid V at position 458; wherein (i)-(xii) are numbered according to SEQ ID NO: 138.309. The AAV particle of any one of embodiments 300-307, wherein the AA V capsid variant comprises:(i) die amino acid R at position 458 and the amino acid K at position 459;(ii) the amino acid C at position 458 and the amino acid I at position 459;(iii) the amino acid S at position 458 and the amino acid R at position 459’(iv) the amino acid L at position 458 and the amino acid K at position 459;(v) the amino acid F at position 458 and the amino acid K at position 459;(vi) the amino acid C at position 458 and the amino acid R at position 459;(vii) the amino acid H at position 458 and the amino acid R at position 459;(viii) the amino acid I at position 458 and the amino acid I., at position 459;(ix) the amino acid V at position 458 and the amino acid R at position 459;(x) the amino acid A at positron 458 and the amino acid K at position 459;(xi) the amino acid I at position 458 and the amino acid K at position 459;(xii) the amino acid C at position 458 and the amino acid S at position 459; or(xiii) the ammo acid C at position 458 and the amino acid L at position 459 wherein (i)-(xiii) are numbered according to SEQ ID NO: 138.310. The AAV particle of any one of embodiments 300-307, wherein the A AV capsid variant comprises the amino acid F at position 458, the amino acid K at position 459, and the amino acid R at position 460, numbered according to SEQ ID NO: 138.311. The AAV particle of any one of embodiments 300-310, wherein the AAV capsid variant comprises one, two, or all of an amino acid other than T at position 450 (e.g., Y, P, W, R, K, S, or F), an amino acid other than I at position 451 (e.g.. R, S, Y. L, V, H, P, A, or F), and / or an amino acid other than N at position 452 (e.g., V, W, A, T, F, Y, L, R, H, S, or M), numbered according to SEQ ID NO: 138.312. The AAV particle of any one of embodiments 300-311 , wherein the AAV capsid variant comprises the amnio acid V at position 452, numbered according to SEQ ID NO: 138.313. The AAV particle of any one of embodiments 300-312, wherein the AAV capsid variant comprises the amino acid Y at position 450 and the amino acid V at position 452, numbered according to SEQ ID NO: 138.314. The AAV particle of any one of embodiments 300-312, wherein the AAV capsid variant comprises the amino acid R at position 450 and the amino acid Y at position 451, numbered according to SEQ ID NO: 138.315. The AAV particle of any one of embodiments 300-311, wherein the AAV capsid variant comprises:(i) the amino acid P at position 450, the amino acid R at position 451, and the amino acid W at position 452;(ii) the amino acid Y at position 450, the amino acid S at position 451, and the amino acid A at position 452;(iii) the amino acid Y at position 450, the amino acid Y at position 451, and the amino acid T at position 452;(iv) the amino acid P at position 450, the amino acid R at position 451, and the amino acid F at position 452;(v) the amino acid W at position 450, the amino acid L at position 451, and the ammo acid T at position 452;(vi) the amino acid R at position 450, the amino acid S at position 451, and the amino acid Y at position 452;(vii) the amino acid Y at position 450, the amino acid V at position 451, and the amino acid F at position 452;(viii) the amino acid K at position 450, the amino acid H at position 451, and the amino acid L at position 452;(ix) the amino acid P at position 450, the amino acid P at position 451, and the amino acid L at position 452;(x) the amino acid P at position 450, the amino acid A at position 451. and the amino acid R at position 452;(xi) the amino acid S at position 450, the amino acid R at position 451, and tlie amino acid R at position 452;(xii) the amino acid F at position 450, the amino acid F at position 451, and the amino acid H at position 452;(xiii) the amino acid R at position 450, the amino acid F at position 451, and the amino acid S at position 452;(xiv) the amino acid Y at position 450, the amino acid S at position 451, and the amino acid M at position 452; or(xv) the amino acid P at position 450, the amino acid F at position 451. and the amino acid L at position 452; wherein (i)-(xv) is numbered according to SEQ ID NO: 138.316. The AAV particle of any one of embodiments 300-315, wherein the AA V capsid variant comprises:(i) the amino acid sequence of any one of SEQ ID NOs: 3849-3982, 2984-4010, 4681-4693;(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 ammo acids, e.g., consecutive ammo acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more titan four modifications 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).317. The AAV particle of any one of embodiments 300-316, wherein the A AV capsid variant does not comprise the amino acid sequence of GSGSPHSKAQNQQ (SEQ ID NO: 1801 ) or GSGSPHSKAQNQQT (SEQ ID NO: 200).318. The AAV particle of any one of embodiments 300-317, wherein [A]-[B] is present in loop IV.319. The AAV particle of any one of embodiments 300-318, wherein [A] is present immediately subsequent to position 452, numbered according to SEQ ID NO: 138 or 981.320. The AAV particle of any one of embodiments 300-319, wherein [A] replaces positions 453-455 (e.g., G453, S454, G455), numbered according to SEQ ID NO: 138 or 981.321. The AAV particle of any one of embodiments 300-320, wherein [A] is present immediately subsequent to position 452. and wherein [A] replaces positions 453-455 (e.g., G453, S454, G455), numbered according to SEQ ID NO: 138 or 981.322. The AAV particle of any one of embodiments 300-321, wherein [B] is present immediately subsequent to [A],323. The AAV particle of any one of embodiments 300-322, wherein [B] replaces positions 456 and457 (e.g., Q456, N457), numbered according to SEQ ID NO: 138.324. The AAV particle of any one of embodiments 300-323, wherein [A]-[B] replaces positions 453-457 (e.g., G453, S454. G455, Q456, N457), numbered according to SEQ ID NO: 138.325. The AAV particle of any one of embodiments 300-324, wherein [A] -[B] is present immediately subsequent to position 452, and wherein [A]-[B] replaces positions 453-457 (e.g., G453, S454, G455, Q456, N457), numbered according to SEQ ID NO: 138.326. The AAV particle of any one of embodiments 300-325, wherein the AAV capsid variant comprises, from N-terminus to C-terminus, [A] [B],327. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises at least one, at least two, at least three, or at least four (e.g., from 1-4 to 1 -5) charged amino acid residues (e.g., acidic and / or basic amino acid residues) relative to SEQ ID NO: 138, which is present N-terminal to the amino acid sequence of SPH (e.g., within 1 , 2, 3, 4, 5, or 6 amino acids from the start of the SPH amino acid sequence (e.g.. within positions 450-455 numbered according to SEQ ID NO: 138)), optionally wherein the amino acid sequence of SPH is present at positions 456-458 numbered according to any one of SEQ ID NOs: 36-59, 981, or 982.328. The AAV particle of embodiment 327, wherein the amino acid sequence of SPH is present at positions 456-458 numbered according to any one of SEQ ID NOs: 36-59, 981, or 982.329. The AAV particle of embodiment 327 or 328, wherein the AAV capsid variant comprises less than four, less than three, less than two (e.g., two or one) charged amino acid residues (e.g., acidic and / or basic amino acid residues) relative to SEQ ID NO: 138.330. The AAV particle of any one of embodiments 327-329, wherein the AA V capsid variant comprises one charged amino acid residues (e.g., an acidic or basic amino acid residue) relative to SEQ ID NO: 138, optionally at any one of positions 450-455 numbered relative to SEQ ID NO: 138,331. The AAV particle of any one of embodiments 327-330, wherein the charged amino acid residue is an acidic amino acid (e.g., D orE).332. The AAV particle of any one of embodiments 327-331, wherein the charged ammo acid residue is a negatively charged amino acid (e.g., D or E).333. The AAV particle of any one of embodiments 327-332, wherein the charged amino acid residue is D.334. The AAV particle of any one of embodiments 327-333, wherein the charged amino acid residue is E,335. The AAV particle of any one of embodiments 327-334, wherein the charged amino acid residue is a basic amino acid (e.g., K, R, or H).336. The AAV particle of any one of embodiments 327-335, wherein the charged ammo acid residue is a positively charged amino acid (e.g., K, R, or H).337. The AAV particle of any one of embodiments 327-336, wherein the charged amino acid residue is H.338. The AAV particle of any one of embodiments 327-337, wherein the charged amino acid residue is R.339. The AA V particle of any one of embodiments 327-338, wherein the charged amino acid residue is K.340. The AAV particle of any one of embodiments 327-339, wherein the AAV capsid variant comprises an acidic amino acid (e.g., E or D) and a basic amino acid (e.g., R, K, or H).341. The AAV particle of any one of embodiments 327-340, wherein at least one, two, three or four charged amino acid residues is present within 1, 2, 3, 4, 5, or 6 (e.g., 1-6) amino acids from the start of the SPH amino acid sequence.342. The AAV particle of any one of embodiments 327-341, wherein the AA V capsid variant comprises two charged amino acid residues immediately preceding the amino acid sequence of SPH (e.g., at positions 454 and 455, numbered according to SEQ ID NO: 138 or SEQ ID NO: 982).343. The AAV particle of any one of embodiments 327-342, wherein the AA V capsid variant comprises a charged amino acid residue (e.g., E) within 1, 2, 3, 4, 5 (e.g., 5) amino acids from the start of the SPH amino acid sequence.344. The AAV particle of any one of embodiments 327-343, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., E) at position 451, numbered according to any one of SEQ ID NO: 138, 981, or 982.345. The AAV particle of any one of embodiments 327-344, wherein the AA V capsid variant comprises E at position 451 , numbered according to any one of SEQ ID NOs: 138, 981, or 982.346. The AAV particle of any one of embodiments 327-345, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., R or K) at position 452, numbered according to any one of SEQ ID NOs: 138, 981, or 982.347. The AAV particle of any one of embodiments 327-346, wherein the AAV capsid variant comprises R at position 452, numbered according to SEQ ID NO: 138 or SEQ ID NO: 982.348. The AAV particle of any one of embodiments 327-347, wherein the AAV capsid variant comprises E at position 451 and R at position 452, numbered according to SEQ ID NO: 138 or SEQ ID NO: 982.349. The AAV particle of any one of embodiments 327-348, wherein the AAV capsid variant has decreased tropism for a liver cell or tissue, relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981.350. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises at least one, at least two, at least three, or at least four (e.g., from 1-4 to 1-5) charged amino acid residues (e.g., basic amino acid residues) relative to SEQ ID NO: 138, which is present C- terminal to the amino acid sequence of SPH (e.g., within 1, 2, 3, 4, 5, 6, or 7 amino acids from the end of the SPH amino acid sequence (e.g., within positions 459-465 numbered according to any one of SEQ ID NOs: 36-59, or 981)), optionally wherein the amino acid sequence of SPH is present at positions 456-458 numbered according to any one of SEQ ID NOs: 36-59, 981 , or 982.351. The AAV particle of embodiment 350, wherein the amino acid sequence of SPH is present: at: positions 456-458 numbered according to any one of SEQ ID NOs: 36-59, 981, or 982.352. The AAV particle of embodiment 350 or 351, wherein the AAV capsid variant comprises less than four, less than three, less than two (e.g., two or one) charged amino acid residues (e.g., basic amino acid residues) relative to SEQ ID NO: 138.353. The AAV particle of any one of embodiments 350-352, wherein the AAV capsid variant comprises one charged amino acid residues (e.g., a basic amino acid residue) relative to SEQ ID NO: 138, optionally at any one of positions 456-460, numbered according to SEQ ID NO: 138, or at positions 462-466, numbered according to any one of SEQ ID NOs: 36-59, 981, or 982.354. The AAV particle of any one of embodiments 350-353, wherein the charged amino acid residue is a basic amino acid (e.g., R or K).355. The AAV particle of any one of embodiments 350-354, wherein the charged amino acid residue is a positively charged amino acid (e.g., R or K).356. The AAV particle of any one of embodiments 350-355, wherein the charged ammo acid residue is R.357. The AAV particle of any one of embodiments 350-355, wherein the charged amino acid residue is K.358. The AAV particle of any one of embodiments 350-357, wherein at least one, two, three or four charged amino acid residues is present within 1, 2, 3, 4, 5, 6, 7 (e.g., 1 -7) amino acids from the end of the SPH amino acid sequence.359. The AAV particle of any one of embodiments 350-358, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., K orR) immediately after the SPH sequence (e.g., at position 459 numbered according to SEQ ID NO: 981).360. The AAV particle of any one of embodiments 350-359, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., K orR) at position 459, numbered according to SEQ ID NO: 138 or SEQ ID NO: 982.361. The AAV particle of any one of embodiments 350-360, wherein the AA V capsid variant comprises K at position 459, numbered according to SEQ ID NO: 981.362. The AAV particle of any one of embodiments 350-360, wherein the AAV capsid variant comprises R at position 459, numbered according to SEQ ID NO: 981.363. The AAV particle of any one of embodiments 350-362, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., R or K) at one, two three, four, five, or all of positions460, 461, 462, 463, 464, and / or 465, numbered according to SEQ ID NO: 138 or 981 .364. The AAV particle of any one of embodiments 300-326 or 350-363, wherein the AAV capsid variant has increased tropism for a liver cell or tissue, relative to the tropism of an A AV capsid comprising the amino acid sequence of SEQ ID NO: 138.365. The AAV particle of any one of embodiments 300-326 or 350-364, wherein the AAV capsid variant is enriched at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, at least 125, at least 130, at least 135, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, or at least 200-fold, in the liver compared to an AAV capsid comprising the amino acid sequence of SEQID NO: 138, e.g., when measured by an assay as described in Example 4.366. The AAV particle of any one of embodiments 300-326, 364, or 365, wherein the AAV capsid variant has reduced tropism for a CNS ceil or tissue, e.g.. a brain ceil, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138.367. The AAV particle of any one of embodiments 300-326 or 364-366, wherein the AAV capsid variant shows preferential transduction in a liver region relative to the transduction in the brain and / or dorsal root ganglia (DRG).368. The AAV particle of any one of embodiments 300-326 or 364-367, wherein the AAV capsid variant shows preferentiai transduction in a liver region relative to the transduction in the heart and / or muscle (e.g., quadriceps).369. An adeno-associated virus (A AV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises:(a) the amino acid sequence of any of the sequences provided in Table 1, 2A, 2B, or 20-26;(b) an amino acid sequence comprising at least 3, al least 4, at least 5. at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, or at least 17 consecutive amino acids from any one of the sequences provided in Table 1, 2A, 2B, or 20- 26; or(c) an amino acid sequence comprising at least one. at least two, or at least three but no more than four different amino acids, relative to any one of the sequences provided in Table 1, 2 A, 2B, or 20-26; or(d) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of any one of the sequences provided in Table 1, 2 A, 2B, or 20-26.370. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises:(a) the amino acid sequence of any of SEQ ID NOs: 945-980 or 985-986;(b) an amino acid sequence comprising at least 3, at least 4, or at least 5 consecutive amino acids from any one of SEQ ID NOs: 945-980 or 985-986; or(c) an amino acid sequence comprising at least one, at least two. or at least three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 945- 980 or 985-986;(d) an amino sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of any one of SEQ ID NOs: 945-980 or 985- 986.371. An adeno-associated virus (AA V) particle comprising an AAV capsid variant (e.g., an AA V9 capsid variant) and a vital genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises:(a) the arnino acid sequence of any of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909;(b) an amino acid sequence comprising at least 3, at least 4, at least 5. at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 consecutive amino acids from any one of SEQ ID NOs: 2, 200, 201, 941 , 943, 204. 208, 404. or 903-909;(c) an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; or(d) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.372. An adeno-associated vims (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises:(a) the amino acid sequence of any of SEQ ID NOs: 3849-4051 or 4681-4693;(b) an amino acid sequence comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14. at least 15. at least 16 or at least 17 consecutive amino acids from any one of SEQ ID NOs: 3849-4051 or 4681-4693;(c) an amino acid sequence comprising at least one. at least two, or at least three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 3849- 4051 or 4681-4693; or(d) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of any one of SEQ ID NOs: 3849-4051 or 4681-4693.373. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the A AV capsid variant comprises:(a) the amino acid sequence of any of SEQ ID NOs: 4052-4092;(b) an amino acid sequence comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8. at least 9, at least 10, at least I I, at least 12. at least 13, at least 14, at least 15, at least 16 or at least 17 consecutive amino acids from any one of SEQ ID NOs: 4052-4092;(c) an amino acid sequence comprising at least one, at least two, or at least three but no more than four different ammo acids, relative to the amino acid sequence of any one of SEQ ID NOs: 4052- 4092; or(d) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of any one of SEQ ID NOs: 4052-4092.374. An adeno-associated vims (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a cyclin-dependent kinase-like 5 (CDKL5)-encoding sequence (e.g., encoding a human CDKL5 protein), wherein the AAV capsid variant comprises:(a) the amino acid sequence of any of SEQ ID NOs: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097;(b) an amino acid sequence comprising at least 3, al least 4, at least 5. at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, al least 13, at least 14, at least 15, at least 16 or al least 17 consecutive amino acids from any one of SEQ ID NOs: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097:(c) an amino acid sequence comprising at least one. at least two, or at least three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 40564058, 4059, 4062-4064. 4066, 4067, 4080, 4084, 4090, or 4095-4097; or(d) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of any one of SEQ ID NOs: 4056, 4058,4059, 4062-4064, 4066, 4067, 4080. 4084, 4090, or 4095-4097.375. The AAV particle of embodiment 369 or 371, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 4, at least 5, at least 6. at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 consecutive amino acids from any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.376. The AAV particle of any one of embodiments 369-374, wherein the at least 3 consecutive amino acids comprise SPH.377. The AAV particle of any one of embodiments 369-371 or 376, wherein the at least 4 consecutive amino acids comprise SPHS (SEQ ID NO: 4700).378. The AAV particle of any one of embodiments 369-371 , 376, or 377, wherein the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 4701).379. The AAV particle of any one of embodiments 369-371 or 376-378, wherein the at least 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941).380. The AAV particle of embodiment 369-371, wherein the at least 3 consecutive amino acids comprise HDS.381. The AAV particle of any one of embodiments 369-371 or 380, wherein the at least 4 consecutive amino acids comprise HDSP (SEQ ID NO: 4702).382. The AAV particle of any one of embodiments 369-371, 380, or 381, wherein the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 4703).383. The AAV particle of any one of embodiments 369-371 or 380-382, wherein the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2).384. The AAV particle of any one of embodiments 369-371, wherein:(i) the at least 3 consecutive amino acids comprise SPH;(ii) the at least 4 consecutive amino acids comprise SPHK (SEQ ID NO: 6398);(iii) the at least 5 consecutive amino acids comprise SPHKY (SEQ ID NO: 4715); and / or(iv) the at least 6 consecutive amino acids comprise SPHKYG (SEQ ID NO: 966).385. The AAV particle of embodiment 369 or 371, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two. or at least three but no more than four modifications relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.386. The AAV particle of any one of embodiments 369, 371, or 385, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941).387. The AAV particle of any one of embodiments 369, 371 , or 385, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of HD SPHK (SEQ ID NO: 2).388. The AAV particle of any one of embodiments 369-371 , 384, or 385, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications relative to the amino acid sequence of SPHKYG (SEQ ID NO: 966).389. The AAV particle of embodiment 370, wherein the AAV capsid variant comprises:(i) an ammo acid sequence comprising at least one, at least two, or at least three but no more than four modifications, relative to the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589);(ii) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications, relative to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754)(iii) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications, relative to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241);(iv) an ammo acid sequence comprising at least one, at least two, or at least three but no more than four modifications, relative to the amino acid sequence of KTINGHDSPIISKAQNLQT (SEQ ID NO: 4100); or(v) an amino acid sequence comprising at least one, at least two, or at least three but no more than four modifications, relative to the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062).390. The AAV particle of embodiment 369 or 371, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.391. The AAV particle of any one of embodiments 369, 371, or 390, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941).392. The AAV particle of any one of embodiments 369, 371 , or 390, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2).393. The AAV particle of any one of embodiments 369, 371 , 384, or 390, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two. or at least three but no more than four different ammo acids relative to the amino acid sequence of SPHK.YG (SEQ ID NO: 966).394. The AAV particle of embodiment 369, wherein the AAV capsid variant comprises:(i) an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the amino acid sequence of KTER VSGSPHSKAQNQQT (SEQ ID NO: 3589);(ii) an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754);(iii) an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241);(iv) an ammo acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the ammo acid sequence of KIINGHDSPHSKAQNLQT (SEQ ID NO: 4100); or(v) an amino acid sequence comprising at least one, at least two, or at least three but no more than four different amino acids relative to the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062).395. The AAV particle of any one of embodiments 1-129, 269, 271, 375-388, or 390-394, wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 2, 200, 2.01, 941, 943, 204, 208, 404, or 903-909.396. The AAV particle of any one of embodiments 295-297, 301-305, 313, 314, 318, 319, or 323. wherein the AAV capsid variant comprises the amino acid sequence of ERVSGSPHSKA (SEQ IDNO: 6399), optionally wherein the amino acid sequence is present immediately subsequent to position450 and replaces positions 451-455 (e.g., 1451, N542, G453, S454, G455), numbered according to SEQ ID NO: 138.397. The AAV particle of any one of embodiments 369-371 , 375-379, 385, 386, 389-391, or 394-396, wherein the AAV capsid variant comprises the amino acid sequence of KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, 1451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138.398. The AAV particle of any one of embodiments 269-371, 375, 380-383, 385, 387, 389, 390, 393, or 394, wherein the AAV capsid variant comprises the amino acid sequence of AEIGHDSPHKSG (SEQ ID NO: 6400), optionally w herein the amino acid sequence is present immediately subsequent to position 449 and replaces positions 450-455 (e.g., T450, 1451, N452, G453, S454, G455), numbered according to SEQ ID NO: 138.399. The AAV particle of any one of embodiments 369-371, 375, 380-383, 385, 387, 389, 390, 393, 394, or 398, wherein the AAV capsid variant comprises the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, 1451, N452, G453, S454, G455, Q456. N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138.400. The AAV particle of any one of embodiments 369-371, 375-379, 390, 391, or 395, wherein tireAAV capsid variant comprises the amino acid sequence of EKMSGSPHSKA (SEQ ID NO: 6401), optionally wherein the amino acid sequence is present immediately subsequent to position 450 andreplaces positions 451-455 (e.g., 1451, N452, G453, S454, G455), numbered according to SEQ IDNO: 138.401. The AAV particle of any one of embodiments 369-371, 375-379, 390, 391, or 395, wherein theAAV capsid variant comprises the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, 1451, N452, G453, S454. G455, Q456, N457,Q458, Q459, T460), numbered according to SEQ ID NO: 138.402. The AAV particle of any one of embodiments 369-371, 375-379, 390, 391, or 395, wherein the AAV capsid variant comprises the amino acid sequence of HDSPHSKAQNL (SEQ ID NO: 6402), optionally wherein the amino acid sequence is present immediately subsequent to position 453 and replaces positions 456-458 (e.g., Q456, N457, Q458), numbered according to SEQ ID NO: 138.403. The AAV particle of any one of embodiments 369-371 , 375-379, 390, 391 , or 395, wherein the AAV capsid variant comprises the amino acid sequence of KT1NGHDSPHSKAQNLQT (SEQ ID NO: 4100). optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g, K449, T450, 1451, N452, G453. S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138.404. The AAV particle of any one of embodiments 369-371, 375-379, 390, 391, or 395, wherein theAAV capsid variant comprises the amino acid sequence of VNGHDSPHSKA (SEQ ID NO: 6403), optionally wherein the amino acid sequence is present immediately subsequent to position 450 and replaces positions 451-455 (e.g., 1451, N452, G453, S454, G455), numbered according to SEQ ID NO: 138.405. The AAV particle of any one of embodiments 369-371, 375-379, 390, 391, or 395, wherein the AAV capsid variant comprises the amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062), optionally wherein the amino acid sequence is present immediately subsequent to position 448 and replaces positions 449-460 (e.g., K449, T450, 1451. N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), numbered according to SEQ ID NO: 138.406. The AAV particle of any one of embodiments 1-23, 26-2.9, 32, 35-43, 46-51, 54-72, 69-89. 91, 94-99, 102-104, 107, 110-112, 115-129. 168-202, 240-247, 249, 250, 253-263, 266, 272-281, 2.86, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, or 395, wherein the AAV capsid variant comprises an amino acid sequence encoded by: the nucleotide sequence of SEQ ID NO: 942; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g.substitutions (e.g., conservative substitutions), but no more than ten modifications, e.g., substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 942; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942.407. The AAV particle of any one of embodiments 1-9, 11, 12-22, 2.4, 26, 28, 30, 33, 35-42. 44, 46- 50, 52, 54-77. 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, or 395, wherein the AAV capsid valiant comprises an amino acid sequence encoded by : the nucleotide sequence of SEQ ID NO: 3; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions (e.g., conservative substitutions), but no more than ten modifications, e.g., substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 3; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3.408. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91 94-99, 102-104, 107, 1 10-112, 115-129, 168-2.02, 240-247, 249. 2.50, 253-263, 266, 272-2.81, 286, 2.88, 291-2.99, 32.7-363, 369-371, 375-379, 385, 386, 390, 391, 395, or 406, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 942; a nucleotide sequence comprising al least one, two, three, four, five, six, or seven modifications, e.g., substitutions (e.g., conservative substitutions), but no more than ten modifications, e.g., substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 942; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942.409. The AAV particle of any one of embodiments 1-9, l 1 , 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111 , 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371 , 380-383, 385, 386, 390, 392, 395, or 407, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 3; a nucleotide sequence comprising at least one, two. three, four, five, six, or seven modifications, e.g., substitutions (e.g., conservative substitutions), but no more than ten modifications, e.g., substitutions (e.g., conservative substitutions), relative to the nucleotide sequence of SEQ ID NO: 3; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3.410. The AAV particle of any one of embodiments 369-409, wherein the ammo acid sequence is present in loop IV, e.g., relative to the amino acid sequence of SEQ ID NO: 138.41 1. The AAV particle of any one of embodiments 369-410, wherein the amino acid sequence is present immediately subsequent to position 448, 449, 450, 451, 452, 453, 454, or 455, numbered according to SEQ ID NO: 138.412. The AAV particle of any one of embodiments 369-411, wherein the amino acid sequence replaces amino acids 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, and / or 460 (e.g., K449, T450, 1451, N452, G453, S454, G455, Q456, N457. Q458, Q459, and / or T460), numbered according SEQ ID NO: 138.413. The AAV particle of any one of embodiments 369-412, wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.414. The AAV particle of any one of embodiments 369-413, wherein the amino acid sequence is present immediately subsequent to position 453, numbered according SEQ ID NO: 138.415. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-2.02, 02, 240-247, 249, 250, 253-263, 266. 2.72-281 , 2.86, 288, 291-299, 32.7-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, or 410-413, wherein the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.416. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371 , 375-379, 385, 386, 390, 391 , 395, 406, 408, 410-413, or 415, wherein the AAV capsid variant the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 981.417. The AAV particle of embodiment 415 or 416, wherein the A AV capsid variant farther comprises an amino acid other than I at position 451, an ammo acid other than N at position 452, and an amino acid oilier than G at position 453, numbered according to any one of SEQ ID NOs: 36. 138, or 981.418. The AAV particle of any one of embodiments 415-417, wherein the AAV capsid variant further comprises E at position 451, R at position 452, and V at position 453, numbered according to any one of SEQ ID NOs: 36, 138, or 981.419. The AAV particle of any one of embodiments 415-418, wherein the AAV capsid variant further comprises the substitutions 145 IE, N452R, and G453V, numbered according to any one of SEQ ID NOs: 36, 138. or 981.420. The AAV particle of any one of embodiments 415-419, wherein the AAV capsid variant comprises:(i) E at position 451, R at position 452, and V at position 453, numbered according io any one of SEQ ID NOs: 36, 138, or 981; and(ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to any one of SEQ ID NOs: 36, 138, or 981.421. The AAV particle of embodiment 415 or 416, wherein the AAV capsid variant further comprises an amino acid other than I at position 451, an amino acid other than N at position 452, and / or G at position 453, numbered according to SEQ ID NO: 39 or 138.422. The AAV particle of any one of embodiments 415, 416, or 421, wherein the AAV capsid variant further comprises E at position 451, K at position 452, and / or M at position 453, numbered according to SEQ ID NO: 138 or 39.423. The AAV particle of any one of embodiments 415, 416, 421, or 422, wherein the AAV capsid variant further comprises the substitutions I451E, N452K, and G453M, numbered according to SEQ ID NO: 39 or 138.424. The AAV particle of any one of embodiments 415, 416, or 421-423, wherein the AAV capsid variant comprises:(i) E at position 451 , K at position 452, and M at position 453, numbered according to SEQ ID NO: 39 or 138; and(ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 39 or 138.425. The AAV particle of embodiment 415 or 416, wherein the AAV capsid variant further comprises an amino acid other than S at position 454, an amino acid other than G at position 455, and / or Q at position 458, numbered according to SEQ ID NO: 138.426. The AAV particle of any one of embodiments 415, 416, or 425, wherein the AAV capsid variant further comprises H at position 454, D at position 455, and / or L at position 458, numbered according to SEQ ID NO: 138.427. The AAV particle of any one of embodiments 415, 416, 425, or 426, wherein the AAV capsid variant further comprises the substitutions S454H, G455D. and Q458L, numbered according to SEQ ID NO: 138.428. The AAV particle of any one of embodiments 415, 416, or 425-427, wherein the AAV capsid variant comprises:(i) H at position 454, D at position 455, and / or L at position 458, numbered according to SEQ ID NO: 138; and(ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.429. The AAV particle of embodiment 415 or 416, wherein the AAV capsid variant further comprises an amino acid other than I at position 451, an amino acid other than S at position 454, and / or an amino acid other than G at position 455, numbered according to SEQ ID NO: 52 or 138.430. The AAV particle of any one of embodiments 415, 416, or 429, wherein the AAV capsid variant further comprises V at position 451, H at position 454, and / or D at position 455, numbered according to SEQ ID NO: 52 or 138.431. The AAV particle of any one of embodiments 415, 416, 429, or 430, wherein the AAV capsid variant further comprises the substitutions 1451 V, S454H, and / or G455D, numbered according to SEQ ID NO: 52 or 138.432. The AAV particle of any one of embodiments 415, 416, or 42.9-431, wherein the AAV capsid variant comprises:(i) V at position 451, H at position 454, and / or D at position 455, numbered according to SEQ ID NO: 52 or 138; and(ii) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 52 or 138.433. The AAV particle of any one of embodiments 1-9. l i , 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111 , 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371 , 380-383, 385, 386, 390, 392, 395, 407, 409-412, or 414, wherein the A AV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 138.434. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44. 46- 50, 52, 54-77. 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, or 433, wherein the AAV capsid variant comprises the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 982.435. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 11 1, 113-129, 203-248, 251, 252, 254-257. 260, 261, 264-280, 283-287, 289-299. 327-363, 369, 369, 371, 380-383, 385, 386, 390. 392, 395. 407, 409-412, 414, 433, or 434, wherein the AAV capsid variant comprises the amino acid sequence of SPHKSG (SEQ ID NO: 946), wherein the amino acid sequence is present immediately subsequent: to position 455, numbered according to the ammo acid sequence of SEQ ID NO: 982.436. The AAV particle of any one of embodiments 369-435, wherein the AAV capsid variant comprises:(i) the amino acid sequence of HDSPHSKA (SEQ ID NO: 4486), which is present immediately subsequent to position 453; and(ii) a deletion of amino acids SG at position 454 and 455; wherein (i) and (ii) are numbered according to SEQ ID NO: 138.437. The AAV particle of any one of embodiments 369-436, wherein the AA V capsid variant comprises the amino acids HD at position 454 and 455, and further comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), which is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138.438. The AAV particle of any one of embodiments 433-435, wherein the AAV capsid variant further comprises an amino acid other titan T at position 450, an ammo acid other than 1 at position 451, and an ammo acid other than N at position 452, numbered according to SEQ ID NO: 138 or 982.439. The AAV particle of any one of embodiments 433-435 or 438, wherein the AAV capsid variant further comprises A at position 450, E at position 451, and I at position 452, numbered according to SEQ ID NO: 138 or 982.440. The AAV particle of any one of embodiments 433-435, 438, or 439, wherein the AAV capsid variant further comprises the substitutions T450A, 145 IE, and N452I, numbered according to SEQ ID NO: 138 or 982.441. The AAV particle of any one of embodiments 433, 434, or 438-440, wherein the AAV capsid variant comprises:(i) A at position 450, E at position 451, and I at position 452, numbered according to SEQ ID NO: 138 or 982; and(ii) the amino acid sequence of HDSPHK (SEQ ID NO: 2), which is present immediately subsequent to positions 453, numbered according to SEQ ID NO: 138 or 982.442. The AAV particle of any one of embodiments 1-22, 25-27, 31 , 34-42, 45-50, 53-63, 69, 79, 83- 86, 91-98, 102. 103, 110. 111, 118-129, 369-371, 384. 385, 390. 393, 395. 410-413. wherein the AAV capsid variant comprises the amino acid sequence of SPHKYG (SEQ ID NO: 966), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 138.443. An adeno-associated vims (AAV) particle comprising an AAV capsid variant comprising the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ ID NO: 982, wherein the AAV particle further comprises a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a hitman CDKL5 protein).444. An adeno-associated vims (AAV) particle comprising an AAV capsid variant and a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein), wherein the AAV capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of SEQ ID NO: 981.445. An adeno-associated virus (AAV) particle comprising an AAV capsid variant comprising the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately subsequent to position 453, numbered according to the amino acid sequence of SEQ IDNO: 37, and optionally further comprising:(i) one. two, or all of an amino add other than T at position 450, an amino acid other than I at position 541. and / or an amino acid other than N at position 452, numbered according to SEQ ID NO: 138 or 37;(ii) one, two, or all of A at position 450, E at position 451, and / or I at position 452, numbered according to SEQ ID NO: 138 or 37; wherein the AAV particle further comprises a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein).446. An adeno-associated virus (AAV) particle comprising an AAV capsid variant comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amnio acid sequence is present immediately subsequent to position 455, numbered according to the amino acid sequence of any one of SEQ ID NO: 36, 38-55, 57, or 59, wherein the AAV particle further comprises a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein).447. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant further comprises:(i) a modification in loop I, II, VI and / or VIII; and / or(ii) a substitution at position K449, e.g., aK449R substitution, numbered according to SEQ ID NO: 138.448. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, not more than 20, or not more than 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 138.449. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two. or at least three, but no more than 30, not more than 20, or not more than 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 138.450. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NO: 138.451. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid sequence with at least 98% identity to SEQ ID NO: i 38.452. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises an amino acid sequence encoded by a sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%. at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NO: 137.453. The AAV particle of any one of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant comprises a sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NO: 137.454. The AAV particle of any one of the preceding embodiments, wherein the AAV capsid variant comprises a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof.455. The AAV particle of any one of embodiments 1 -454, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 138-742, e.g., a VP2, of SEQ ID NO: 981, 982, 36, or 4, or a sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%. at least 97%, at least 98%, or at least 99%) sequence identity thereto.456. The AAV particle of any one of embodiments 1-455, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 203-742, e.g., a VP3, of SEQ ID NO: 981, 982, 36, or 4, or a sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto.457. The AAV particle of any one of embodiments 1 -456, wherein the AAV capsid variant comprises an amino acid sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NO: 138.458. The AAV particle of any one of embodiments 1-457, wherein the AAV capsid variant comprises an amino acid sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NO: 138.459. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444,or 446-458, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, at least 4, at least 5, or at least 6 consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein:(i) the at least 3 consecutive amino acids comprise SPH;(ii) the at least 4 consecutive amino acids comprise SPHS (SEQ ID NO: 4700);(iii) the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 4701); or(iv) the at least 6 consecutive amino acids comprise SPHSKA (SEQ ID NO: 941); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 981; (b) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 981 ; (c) a VP3 protein comprising the amino acid sequence of positions 203- 742 of SEQ ID NO: 981; or (d) an ammo acid sequence with at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to any of the amino acid sequences in (a)-(c).460. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 1 10-1 12, 115-129, 168-202, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390. 391, 395. 406, 408. 410-413. 415-432, 444, or 446-459, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, at least 4. at least 5, or at least 6 consecutive amino acids from the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein:(i) the at least 3 consecutive amino acids comprise SPH;(ii) the at least 4 consecutive amino acids comprise SPHS (SEQ ID NO: 4700);(iii) the at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 4701); or(iv) the at least 6 consecutive ammo acids comprise SPHSKA (SEQ ID NO: 941); wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to the amino acid sequence of SEQ ID NO: 981.461. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51 , 54-72. 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202. 240-247, 249, 250. 253-263, 266, 272-281, 286, 288, 291-299, 327-363. 369-371 , 375-379, 385, 386. 390, 391. 395, 406. 408, 410-413, 415-432, 444, or 446-460, wherein the AAV capsid vanant comprises one or two, but no more than three substitutions relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the AAV capsid variant comprises:(a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 981;(b) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 981;(c) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO:981; or(d) an amino acid sequence with at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to any of the amino acid sequences in (a)- (c).462. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89. 91, 94-99, 102-104, 107, 110-112, 115-129. 168-202, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299. 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, or 446-461, wherein the AAV capsid variant comprises one or two, but no more than three substitutions relative to the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981.463. The AAV particle of any one of embodiments 459-462, wherein the amino acid sequence is present immediately subsequent to position 455, numbered according to SEQ ID NO: 138 or 981.464. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257. 260, 261, 264-280. 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, or 447-458, wherein the AAV capsid variant an amino acid sequence comprising at least 3, at least 4, at least 5, or at least 6 consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein:(i) the at least 3 consecutive amino acids comprise HDS;(ii) the at least 4 consecutive amino acids comprise HDSP (SEQ ID NO: 4702);(iii) the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 4703); or(iv) the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2); wherein the AAV capsid variant comprises: (a) a VP 1 protein comprising the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 203- 742 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g.. at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to any of the amino acid sequences in (a)-(c).465. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46-50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261,264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 434, 433-435, 438-441, 443, 445, 447-458, or 464, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, at least 4, at least 5, or at least 6 consecutive amino acids from the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein:(i) the at least 3 consecutive amino acids comprise HDS;(ii) the at least 4 consecutive amino acids comprise HDSP (SEQ ID NO: 4702);(iii) the at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 4703); or(iv) the at least 6 consecutive amino acids comprise HDSPHK (SEQ ID NO: 2); wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 982.466. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 11 1, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464, or 465, wherein the AAV capsid variant comprises one or two , but no more than three substitutions relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the AAV capsid variant comprises:(a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982;(b) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982;(c) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982; or(d) an amino acid sequence with at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to any of the amino acid sequences in (a)- (c).467. The AAV particle of any one of embodiments 1-9, 11 , 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52. 54-77, 83-88, 90-97, 100-103, 105, 110, 111 , 113-129, 203-248, 251, 252, 254-2.57, 260, 2.61, 264-2.80, 283-287, 289-299, 327-363, 369, 369, 371 , 380-383, 385, 386, 390, 392, 395, 407. 409-412, 414, 433-435, 438-441 , 443, 445, 447-458, or 464-466, wherein the AA V capsid variant comprises one or two, but no more than three substitutions relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), w herein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 982.468. The AAV particle of any one of embodiments 464-468, wherein the amino acid sequence is present immediately subsequent to position 453. numbered according to SEQ ID NO: 138 or 982.469. The AAV particle of any one of embodiments 1-468, wherein the A AV capsid variant comprises the amino acid sequence of SEQ ID NO: 981 or 982, or an amino acid sequence with at least 80% (e.g,, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%. or al least 99%) sequence identity thereto.470. The AAV particle of any one of embodiments 1-469, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two or at least three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, not more than 20 or not more than 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the ammo acid sequence of SEQ TD NO: 981 or 982.471. The AAV particle of any one of embodiments, 1-470, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two or at least three, but not more than 30, not more than 20 or not more than 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 981 or 982.472. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43. 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371 , 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, 446-463, or 469-471, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981, or an ammo acid sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto.473. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51 , 54-72, 69-89, 91, 94-99, 102-104, 107, 1 10-112, 1 15-129. 168-202, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363. 369-371 , 375-379, 385, 386. 390, 391. 395, 406. 408, 410-413, 415-432, 444, 446-463, or 469-472, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two or at least three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, not more than 20 or not more than 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 981.474. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 240-247, 249, 250, 253-263, 266, 272-281, 286,288, 291-299. 327-363, 369-371 , 375-379, 385, 386, 390, 391 , 395, 406, 408, 410-413, 415-432, 444, 446-463, or 469-473, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two or at least three, but not more than 30. not more than 20 or not more than 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 981 .475. The AAV particle of any one of embodiments 1-9, 11. 12-22, 2.4, 26, 28, 30, 33, 35-42. 44, 46- 50, 52, 54-77. 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435. 438-441, 443, 445. 447-458, or 464-471, wherein tiie AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, or an amnio acid sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto.476. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 11 1, 113-129, 203-248, 251, 252, 254-257. 260, 261, 264-280. 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464-471, or 475, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two or at least three modifications, e.g.. substitutions (e.g., conservative substitutions), but not more than 30, not more than 20 or not more than 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 982.477. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441 , 443, 445, 447-458, 464-471 , 475, or 476, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two or at least three, but not more than 30, not more than 20 or not more than 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 982.478. The AAV particle of any one of embodiments 1-477, wherein the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 983 or 984, or a nucleotide sequence with at least 80% (e.g., at least 80%, at least 85%. at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto.479. The AAV particle of any one of embodiments 1-478, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NOs: 983 or 984, or a nucleotidesequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto.480. The AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51 , 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202. 02, 2.40-247. 2.49, 250, 253-263, 2.66, 272.-281, 286. 288, 2.91-299, 327-363. 369-371 , 375-379, 385, 386, 390, 391. 395, 406. 408, 410-413, 415-432, 444, 446-463, 469-474, 478, or 479, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence with al least 80% (e.g., at least 80%, at least 85%, at least 90%. at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto.481. The AAV particle of any one of embodiments 1-9, 11, 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 11 1, 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371, 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441, 443, 445, 447-458, 464-471, or 475-479, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%. at least 97%, at least 98%, or at least 99%) sequence identity thereto.482. The AA V particle of any one of the preceding embodiments, wherein the nucleotide sequence encoding the capsid variant is codon optimized.483. An AAV particle of any one of embodiments 1-23, 26-29, 32, 35-43, 46-51, 54-72, 69-89, 91, 94-99, 102-104, 107, 110-112, 115-129, 168-202, 02, 240-247, 249, 250, 253-263, 266, 272-281, 286, 288, 291-299, 327-363, 369-371, 375-379, 385, 386, 390, 391, 395, 406, 408, 410-413, 415-432, 444, 446-463, 469-474, 478-480, or 482, and further comprising an amino acid sequence at least 95% identical to SEQ ID NO: 981 .484. An adeno-associated virus ( AAV) particle comprising an AAV capsid variant and a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981 ,485. The AAV particle of embodiment 483 or 484, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 983, or a nucleotide sequence at least 90%, at least 95%, or at least 99% identical thereto.486. The AAV particle of any one of embodiments 1-9, 11 , 12-22, 24, 26, 28, 30, 33, 35-42, 44, 46- 50, 52, 54-77, 83-88, 90-97, 100-103, 105, 110, 111 , 113-129, 203-248, 251, 252, 254-257, 260, 261, 264-280, 283-287, 289-299, 327-363, 369, 369, 371 , 380-383, 385, 386, 390, 392, 395, 407, 409-412, 414, 433-435, 438-441 , 443, 445, 447-458, 464-471 , 475-479, 481, or 482, and further comprising an amino acid sequence at least 95% identical to SEQ ID NO: 982.487. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a cyclin- dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein), wherein the AAV capsid vanant comprises the amino acid sequence of SEQ ID NO: 982.488. The AAV particle of embodiment 486 or 487, wherein the nucleotide sequence encoding theAAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence at least 90%, at least 95%, or at least 99% identical thereto.489. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein), wherein the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NOs: 983 or 984, or a nucleotide sequence at least 95% identical thereto.490. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein), wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 4 or 36-59, optionally wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 4 or491. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a nucleic acid encoding a cyclin-dependent kinase-like 5 (CDKL5) protein (e.g., a human CDKL5 protein), wherein the AAV capsid variant comprises an amino acid sequence encoded by the nucleotide sequence of any one of SEQ ID NOs: 12-35, or a nucleotide sequence at least 95% identical thereto.492. The AAV particle of 490 or 491, wherein the nucleotide sequence encoding the AAV capsid vanant comprises the nucleotide sequence of any one of SEQ ID NOs: 12-35, or a nucleotide sequence at least 95% identical thereto.493. The AAV particle of any one of embodiments 1-299, 369-371, or 375-492, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinalcord tissue, relative to the tropism of an AAV particle comprising a capsid comprising the amino acid sequence of SEQ ID NO: 138.494. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, or 375-493, which transduces a brain region, e.g., a midbrain region (e.g,, the hippocampus, or tlralamus) or the brain stem, optionally wherein the level of transduction is at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35. at least 40, at least 45, at least 50, at least 55, al least 60, or at least 65- fold greater as compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g.. when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 2.495. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, or 375-494, which transduces a brain region, e.g., a midbrain region (e.g., the hippocampus, or thalamus) or the brain stem, optionally wherein the level of transduction is at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, or at least 65-fold greater as compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 2.496. The AAV particle of any one of embodiments 1-129, 168-299. 369-371 , or 375-495, which is enriched at least 3, at least 4, at least 5. at least 6, at least 7, al least 8, at least 9. or at least 10-fold, in the brain compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1.497. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, or 375-496, which is enriched at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80 or at least 85-fold, in the brain compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1.498. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, or 375-497, which is enriched in the brain of at least two to at least three species, e.g., a non-human primate and rodent(e.g., mouse), e.g., as compared to an AAV particle comprising a capsid of SEQ ID NO: 138.499. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, or 375-498, which is enriched at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 115, at least 120, at least 125, at least 130, at least 135, atleast 140, at least 145, at least 150, at least 155, at least 160, at least 165, at least 170, at least 175, at least 180, at least 190, at least 200, at least 205, or at least 210-fold, in the brain of at least two to at least three species, e.g.. a non-human primate and rodent (e.g., mouse), compared to an AAV particle comprising a capsid of SEQ ID NO: 138. e.g,, when measured by an assay as described in Example I or 5.500. The AAV particle of embodiment 498 or 499, wherein the at least two to at least three species are Macacafascicularis, C.hlorocebus sabaeus, Callilhrixjacchus, and / or mouse (e.g., BALB / c mice, C57B1 / 6 mice, and / or CD-I outbred mice).501. The AAV particle of any one of embodiments 130-146, 369, 410-414, 447-454, 457, 458, 482, or493, which is enriched at least 2, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, at least 5, at least 5.5. at least 6, at least 6.5, at least 7, at least 7.5, or at least 8-fold, in the brain compared to an AAV particle comprising a capsid of SEQ ID NO: 981 , e.g., when measured by an assay as described in Example 3.502. The AAV particle of any one of embodiments 147-167, 369, 410-414, 447-454, 457, 458, 482, or 493, which is enriched at least 2, at least 2.5. at least 3, at least 3.5, at least 4, at least 4,5, at least 5, or at least 5.5-fold, in the brain compared to an AAV particle comprising a capsid of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 3.503. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, or 375-500, which delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 10, at least 12, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, or at least 70-fold, as compared to anAAV particle comprising a capsid of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2 or 8).504. The AAV particle of any one of embodiments 1-129, 168-2.99, 369-371, 375-500, or 503, which delivers an increased level of viral genomes to a brain region, optionally wherein the level of viral genomes is increased by at least 5. at least 10, at least 15, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30. at least 35, at least 40, at least 45, or at least 50-fold, as compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g.. when measured by an assay, e.g., a qRT- PCR or a qPCR assay (e.g., as described in Example 2 or 8).505. The AAV particle of embodiment 503 or 504, wherein the brain region is a midbrain region (e.g., the hippocampus or thalamus), frontal cortex, temporal cortex, motor cortex, cerebral cortex, caudate, putamen, dentate nucleus, substantia nigra, or the brainstem.506. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, 375-500, or 503-505, which is enriched at least 4, at least 5, at least 10. at least 15, at least 20, at least 25, at least 30, or at least 35-fold, in the spinal cord compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1 or 8, optionally wherein the region of the spinal cord is a thoracic spinal cord region, cervical spinal cord region. C5 ventral hom region, lumbar spinal cord region, or L5 ventral hom region.507. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, 375-500, or 503-506, which shows preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG).508. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, 375-500, or 503-507, which shows preferential transduction in a brain region relative to the liver.509. The AAV particle of any one of embodiments 1-12.9, 168-299. 369-371. 375-500, or 503-508, which shows preferential transduction in a brain region relative to the transduction in the heart.510. The AAV particle of any one of embodiments 1-129, 168-299, 369-371, 375-500, or 503-509, which shows preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG) and the heart.511. The AAV particle of any one of the preceding embodiments, which is capable of transducing non-neuronal cells, e.g., glial cells (e.g., oligodendrocytes or astrocytes).512. The AAV particle of embodiment 511, wherein the non-nemonal ceils comprise glial ceils, oligodendrocytes (e.g., Olig2 positive oligodendrocytes), or astrocytes (e.g.. Olig2 positive astrocytes).513. The AAV particle of any one of the preceding embodiments, which is capable of transducing Olig2 positive cells, e.g.. Ohg2 positive astrocytes or Olig2 positive oligodendrocytes.514. The AAV particle of any one of embodiments 369, 373, 447-454, 457, 458, or 482, which lias increased tropism for a heart cell or tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of an AAV particle comprising a capsid of SEQ ID NO: 138.515. The AAV particle of any one of embodiments 369, 373, 447-454, 457, 458, 482. or 514, which is enriched at least 4, at least 5, at least 8, at least 10, at least 11, at least 12, at least 13. at least 14, at least 18, at least 19, at least 20. at least 21, at least 22, at least 24, at least 25, al least 27, at least 31, at least 33, or at least 34-fold, in the heart compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 4.516. The AAV particle of any one of embodiments 369, 374, 447-454, 457, 458, 482, which has an increased tropism for a muscle ceil or tissue (e.g., a quadriceps cell or a quadriceps tissue), relative to the tropism of an AAV particle comprising a capsid comprising the amino acid sequence of SEQ ID NO: 138.517. The AAV particle of any one of embodiments 369, 374, 447-454, 457, 458, 482, which is enriched at least 4, at least 5, at least 8, at least 12, at least 17, at least 18, at least 20, at least 26, at least 27, at least 28, at least 30, or at least 36-fold, in the muscle compared to an AAV particle comprising a capsid of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 4,518. The AAV particle of embodiment 516 or 517, wherein tire muscle cell or tissue is a heart muscle (e.g., a heart ventricle or a heart atrium, or both), a quadriceps muscle, or both.519. The AAV particle of any one of the preceding embodiments, which is isolated and / or recombinant.[Embodiments 520-585 are intentionally absent.]586. The AAV particle of any one of the preceding embodiments, wherein the viral genome comprises a promoter operably linked to the CDKL5-encoding sequence.587. The AAV particle of embodiment 586, wherein the promoter is human elongation factor la- subunit (EFla) promoter, cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken p-acrin (CBA promoter), CAG promoter, CAG derivative promoter, p glucuronidase (GU SB) promoter, ubiquitin C (UBC) promoter, neuron-specific enolase (NSE) promoter, platelet-derived growth factor (PDGF) promoter, platelet-derived growth factor B-chain (PDGF-β) promoter, intercellular adhesion molecule 2 (ICAM-2) promoter, synapsin (Syn) promoter, methyl-CpG bindingprotein 2 (MeCP2) promoter, Ca2+ / calmodulin-dependent protein kinase II (CaMKII) promoter, metabotropic glutamate receptor 2 (mGluR2) promoter, neurofilament light (NFL) or heavy (NFH) promoter, p-globin minigene nβ2 promoter, preproenkepbalin (PPE) promoter, enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, glial fibrillaty acidic protein (GFAP) promoter, myelin basic protein (MBP) promoter, a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-ML C2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a fragment, e.g., a truncation, or a functional variant thereof.[Embodiments 588 and 589 are intentionally absent.]590. The AAV particle of any one of embodiments 586-589, wherein the viral genome further comprises a polyadenylation (poly A) sequence.591. The AAV particle of any one of embodiments 586-590, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.592. The AAV particle of any one of embodiments 586-591 , wherein the viral genome comprises anITR sequence positioned 5’ relative to the CDKL5-encoding sequence (e.g., encoding a human CDKL5 protein).593. The AAV particle of any one of embodiments 586-592, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the CDKL5-encoding sequence (e.g., encoding a human CDKL5 protein).594. The AAV particle of any one of embodiments 586-593, wherein the viral genome comprises anITR sequence positioned 5’ relative to the CDKL5-encoding sequence (e.g., encoding a human CDKL5 protein) and an ITR sequence positioned 3’ relative to the CDKL5-encoding sequence (e.g., encoding a human CDKL5 protein).595. The AAV particle of any one of embodiments 586-594, wherein the viral genome further comprises an enhancer, a Kozak sequence, an intron region, and / or an exon region.[Embodiments 596-615 are intentionally absent.]616. The AAV particle of any one of the embodiments 586-595, wherein the viral genome further comprises a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein theRep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein(e.g., a Rep78 and a Rep52 protein).617. The AAV particle of embodiment 616, wherein the AAV particle further comprises a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 and a Rep.52 protein).618. The AAV particle of embodiment 616 or 617, wherein the Rep78 protein, tlie Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene.619. The AAV particle of any one of embodiments 586-618, wherein the viral genome further comprises a nucleic acid sequence encoding the AAA' capsid variant of the AAV particle of any one of embodiments 1-519, 566, or 574.620. The AAV particle of any one of embodiments 575-619, wherein the AAV particle is an isolated and / or recombinant AAV particle.[Embodiment 621 is intentionally absent.]622. A cell, e.g., a host cell, comprising the AAV particle of any one of the preceding embodiments.623. The cell of embodiment 622, wherein the cell is a mammalian cell or an insect ceil.624. The cell of embodiment 622 or 623, wherein the cell is a cell of a brain region or a spinal cord region, optionally a cell of the brain stem, hippocampus, or thalamus.625. The cell of any one of embodiments 622-624, wherein the cell is a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, oligodendrocyte, or a muscle cell (e.g., a cell of the heart, diaphragm, or quadriceps).[Embodiment 626 is intentionally absent.]627. A method of making an adeno-associated virus (AAV) particle, comprising(i) providing a host cell comprising tlie viral genome comprising a CDKL5-encoding sequence; and(ii) incubating the host cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant as described in any one of embodiments 1 -620; thereby making the AAV particle.628. The method of embodiment 627, further comprising, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the host cell.629. The method of embodiment 628. wherein the host cell comprises a second nucleic acid encoding the capsid variant.630. The method of embodiment 629, wherein the second nucleic acid molecule is introduced into tlie host cell prior to, concurrently with, or after tlie first nucleic acid molecule.631. A pharmaceutical composition comprising the AAV particle of any one of embodiments 1-620, and a pharmaceutically acceptable excipient.632. A method of delivering a payload to a cell or tissue (e.g.. a CNS cell or CNS tissue), comprising administering an effective amount of the pharmaceutical composition of embodiment 631 or the AA V particle of any one of embodiments 1-620.633. The method of embodiment 632, wherein the cell is a cell of a brain region or a spinal cord region, optionally a cell of the frontal cortex, sensory cortex, motor cortex, caudate, cerebellar cortex, cerebral cortex, brain stem, hippocampus, or thalamus.634. The method of embodiment 632 or 633, wherein the cell is a neuron, a sensors neuron, a motor neuron, an astrocyte, a glial cell, or an oligodendrocyte.[Embodiment 635 is intentionally absent.]636. The method of any one of embodiments 632-634, wherein the cell or tissue is within a subject.637. The method of embodiment 636. wherein tire subject has, has been diagnosed with having, or is at risk of having a genetic disorder, e.g.. a monogenic disorder or a polygenic disorder.638. The method of embodiment 636 or 637, wherein the subject has, has been diagnosed with having, or is at risk of having a neurological, e.g., a neurodegenerative, disorder.[Embodiment 639 is intentionally absent.]640. The method of embodiment 636 or 637, wherein the subject has, lias been diagnosed with having, or is at risk of having, a muscular disorder or a neuromuscular disorder.641. A method of treating a subject liaving or diagnosed with having a genetic disorder, e.g., a monogenic disorder or a polygenic disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1-620.642. A method of treating a subject having or diagnosed with having a neurological disorder, e.g., a neurodegenerative disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1- 620.643. A method of treating a subject having or diagnosed with having a muscular disorder or a neuromuscular disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1- 620.[Embodiment 644 is intentionally absent.]645. The method of any one of embodiments 637-643, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, muscular disorder, or neuromuscular disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, or atypical Rett syndrome.646. The method of any one of embodiments 641-645, wherein treating comprises prevention of progression of the disorder in the subject.647. The method of embodiment 636-646, wherein the subject is a human,648. The method of any one of embodiments 636-647. wherein the AAV particle is administered to the subject intravenously, via intra-cistema magna injection (ICM). intracerebrally, intrathecally. intracerebroventricularly, via intraparenchymal administration, intraarterially, or intramuscularly.649. The method of any one of embodiments 636-648, wherein the AAV particle is administered to the subject via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), orMRI-guided FUS coupled with intravenous administration.650. The method of any one of embodiments 636-649, wherein the AAV particle is administered to the subject intravenously.651. The method of any one of embodiments 636-650. wherein the AAV particle is administered to the subject via intra-cisterna magna injection (ICM).652. The method of any one of embodiments 636-651. wherein the AAV particle is administered to the subject intraarterially.[Embodiment 653 is intentionally absent.]654. The method of any one of embodiments 648-652, wherein administration of the AAV particle results in an increased presence, level, and / or activity of an CDKL5 gene, mRNA, protein, or a combination thereof.655. The pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1-620 for use in a method of delivering an CDKL.5 -encoding sequence to a cell or tissue.656. The pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1-620 for use in a method of treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, or a neuromuscular disorder.657. The pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1-620 for use in the manufacture of a medicament.658. Use of the pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1-620 in the manufacture of a medicament.659. Use of the pharmaceutical composition of embodiment 631 or the AAV particle of any one of embodiments 1-620 in the manufacture of a medicament for treating a genetic disorder, a neurological disorder, or a neurodegenerative disorder, a muscular disorder, or a neuromuscular disorder.660. An AAV particle of any one of the preceding embodiments, wherein the CDKL 5 -encoding sequence comprises a nucleotide sequence of SEQ ID NO: 6414 or that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 6414.661. The AAV particle of embodiment 660, wherein the encoded CDKL5 protein comprises the amino acid sequence of SEQ ID NO: 6413, or an amino acid sequence at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%. at least 90%, at least 92%, at least 95%, at least 97%. at least 98%, or at least 99%) identical thereto.662. The AAV particle of embodiment 660 or embodiment 661, wherein tire CDKL5-encoding sequence comprises a nucleotide sequence that is at least 93% identical to SEQ ID NO: 6414.663. The AAV particle of any one of embodiments 660-662, wherein die CDKL5-encoding sequence comprises a nucleotide sequence that is at least 95% identical to SEQ ID NO: 6414.664. The AAV particle of any one of embodiments 660-663, wherein the CDKL5-encoding sequence comprises a nucleotide sequence that is at least 97%> identical to SEQ ID NO: 6414.665. The AAV particle of any one of embodiments 660-664, wherein the CDKL5-encoding sequence comprises a nucleotide sequence that is at least 99% identical to SEQ ID NO: 6414,666. The AAV particle of any one of embodiments 660-665, wherein the CDKL 5 -encoding sequence comprises the nucleotide sequence of SEQ ID NO: 6414.667. The AAV particle of any one of embodiments 660-666, wherein the CDKL5-encoding sequence consists of the nucleotide sequence of SEQ ID NO: 6414.668. The AAV particle of any one of embodiments 660-667, wherein the viral genome further comprises an enhancement element.669. The AAV particle of any one of embodiments 660-668, wherein the AAV capsid variant comprises (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or a sequence at least 90% identical thereto; (b) a VP2 protein comprising the amino acid sequence of positions 138- 742 of SEQ ID NO: 982 or a sequence at least 90% identical thereto; or (c) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982 or a sequence at least 90%identical thereto; or wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQID NO: 984 or a sequence at least 90% identical (e.g., at least 90%. at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.670. The AAV particle of any one of embodiments 660-668, wherein the AA V capsid variant comprises no more than three ammo acid substitutions relative to the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the AA V capsid variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 982.[Embodiments 671-677 are intentionally absent.]678. The AAV particle of any one of embodiments 660-670, wherein the viral genome further comprises a promoter operably linked to the CDKL5-encoding sequence.679. The AAV particle of any one of embodiments 660-678, wherein the viral genome further comprises an enhancer.680. The AAV particle of embodiment 678 or embodiment 679, wherein the promoter comprises a tissue-specific promoter.681. The AAV particle of embodiment 678 or embodiment 679, wherein the promoter comprises a ubiquitous promoter.682. The AAV particle of any one of embodiments 678-681, wherein the promoter comprises:(i) an EF- 1a promoter, a CB promoter, a chicken [3-actin (CBA) promoter and / or its derivative CAG. a CMV immediate -early enhancer and / or promoter, a β glucuronidase (GUSB) promoter, a ubiquitin C (UBC) promoter, a neuron-specific enolase (NSE), a platelet-derived growth factor (PDGF) promoter, a platelet-derived growth factor B-chain (PDGF-0) promoter, an intercellular adhesion molecule 2 (ICAM-2) promoter, a synapsin (Syn) promoter, a synapsin 1 promoter (Synl), a methyl-CpG binding protein 2 (MeCP2) promoter, a Ca2+ / calmodulin-dependent protein kinase II (CaMKII) promoter, a metabotropic glutemate receptor 2 (mGluR2) promoter, a neurofilament light (NFL) or heavy (NFH) promoter, a β-globin minigene n£2 promoter, a preproenkephalin (PPE) promoter, an enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) , a glial fibrillary acrdic protein (GFAP) promoter, a myelin basic protein (MBP) promoter, a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a fragment, e.g., a truncation, or a functional variant thereof.[Embodiments 683-712 are intentionally absent.]713. The AAV particle of any one of embodiments 660-683, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.714. The AAV particle of embodiment 713, wherein the ITR sequence is positioned 5’ relative to the CDKL 5 -encoding sequence.715. The AAV particle of embodiment 713 or embodiment 714, wherein tire ITR sequence is positioned 3’ relative to the CDKL5-encoding sequence.716. The AAV particle of any one of embodiments 713-715, wherein the viral genome comprises an ITR positioned 5’ relative to the CDKL5-encoding sequence and an ITR positioned 3’ relative to the CDKL5-encoding sequence.722. The AAV particle of any one of embodiments 660-721, wherein the viral genome further comprises a polyadenylation (poly A) region.723. The AAV particle of any one of embodiments 660-722, wherein the viral genome further comprises an intron.724. The AAV particle of any one of embodiments 660-723, wherein the viral genome further comprises an exon, e.g., at least one, at least two, or at least three exons.725. The AAV particle of any one of embodiments 660-724, wherein the viral genome further comprises a Kozak sequence.726. The AAV particle of any one of embodiments 660-725, 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.727. The AAV particle of embodiment 72.6, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene.728. A vector encoding the AAV particle of any one of embodiments 660-727.729. A cell comprising the AAV particle of any one of embodiments 660-727 or the vector of embodiment 728.730. The cell of embodiment 729, which is a mammalian cell, e.g., an HEK293 cell, an insect cell, e.g., an Sf9 cell, or a bacterial cell.[Embodiments 731-766 are intentionally absent.]767. A method of making a recombinant AA V particle, the method comprising(i) providing a host cell comprising a viral genome comprising the nucleotide sequence of SEQ ID NO: 6414, or a sequence at least 97% identical thereto; and(ii) incubating the host cell under conditions suitable to enclose the viral genome in a capsid variant comprising the amino acid sequence of SEQ ID NO: 982; thereby making the recombinant AAV particle.768. The method of embodiment 767, further comprising, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the host cell.769. The method of embodiment 767 or embodiment 768, wherein the host cell comprises a second nucleic acid encoding the capsid variant.770. The method of embodiment 769, further comprising introducing the second nucleic acid into the cell.771. The method of embodiment 769 or embodiment 770, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule.772. The method of any one of embodiments 767-771 , wherein the host cell comprises a mammalian cell, e.g., an HEK293 cell, an insect cell, e.g., an Sf9 cell, or a bacterial cell.773. A pharmaceutical composition comprising the AAV particle of any one of embodiments 660-727 and a pharmaceutically acceptable excipient.774. A method of delivering a CDKL5 protein to a subject comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 773 or the AAV particle of any one of embodiments 660-727, thereby delivering the CDKL5-encoding sequence to the subject.775. The method of embodiment 774, wherein the subject has, has been diagnosed with having, or is at risk of having a disease associated with expression of CDKL5, e.g., aberrant or reduced CDKL5 expression, e.g., expression of a CDKL5 gene, CDKL5 mRNA, and / or CDKL5 protein (e.g., a CDKL5 -related disorder) .776. The method of embodiment 774 or embodiment 775, wherein the subject has, has been diagnosed with having, or is at risk of having a neurodegenerative or neuromuscular disorder.777. A method of treating a subject having or diagnosed with having a CDKL5-related disorder comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 773 or the AAV particle of any one of embodiments 660-727, thereby treating theCDKL5-related disorder in the subject.778. A method of treating a subject having or diagnosed with having a neurodegenerative or neuromuscular disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 773 or the AAV particle of any one of embodiments 660- 727, thereby treating the neurodegenerative or neuromuscular disorder in the subject.779. The method of embodiment 777 or embodiment 778, wherein the CDKL5 -related disorder or the neurodegenerative or neuromuscular disorder comprises CDD, developmental and epileptic encephalopathy 2, or atypical Rett syndrome.780. A method of treating a subject having or diagnosed with having CDD, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 773 or the AAV particle of any one of embodiments 660-727, thereby treating CDD in the subject.781. The method of embodiment 779 or embodiment 780, wherein the subject has one or more mutations in CDKL5.782. A method of treating a subject hatring or diagnosed with having developmental and epileptic encephalopathy 2, comprising administering an effective amount of the pharmaceutical composition of embodiment 773 or the AAV particle of any one of embodiments 660-727, thereby treating developmental and epileptic encephalopathy 2 in the subject.783. A method of treating a subject having or diagnosed with having atypical Rett syndrome, comprising administering an effective amount of the pharmaceutical composition of embodiment 773or the AAV particle of any one of embodiments 660-727, thereby treating atypical Rett syndrome in the subject.784. The method of any one of embodiments 774-783. wherein the subject has a reduced level ofCDKL5 activity as compared to a reference level785. The method of embodiment 784. wherein the reference level comprises the level of CDKL5 activity in a subject that does not have a disease associated with CDKL5 expression (e.g., a CDKL5- reiated disorder), a neuromuscular disorder, and / or a neurodegeneraiive disorder.[Embodiments 786-790 are intentionally absent.]791. The method of any one of embodiments 777-785, wherein treating results in amelioration of at least one symptom and / or biomarker of the disease associated with CDKL5 expression (e.g., a CDKL5-related disorder), the neurodegeneraiive disorder, and / or the neuromuscular disorder in t.be subject.792. The method of embodiment 791, wherein the at least one symptom and / or biomarker of the disease associated with CDKL5 expression (e.g., the CDKL5-related disorder) comprises reduced CDKL5 activity, accumulation of neurofilament light drain (e.g.. in a biofluid such as cerebrospirral fluid), 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 disrupted sleep), facial appearance changes (including microcephaly, a high, broad forehead, large, deep-set eyes, smaher-than normal space between the nose and upper lip, an upturned nose, 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 band movements, gastroesophageal reflux, constipation, or a combination thereof.793. The method of any one of embodiments 774-792, wherein the subject is a human.794. The method of any one of embodiments 774-793, wherein the subject is a juvenile, e.g., between 6 years of age to 20 years of age.795. The method of any one of embodiments 774-793, wherein the subject is an adult, e.g., above 20 years of age.796. The method of any one of embodiments 774-795, wherein the subject has one or more mutations in a CDKL5 gene, CDKL5 mRN A, and / or CDKL5 protein.797. The method of any one of embodiments 774-796, wherein the AAV particle is administered to the subject intravenously, intracerebrally, via intrathalamic (ITH) administration, intramuscularly, intathecally, intracerebroventricularly, via inlraparenchymal administration, via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration, or via intra-cisterna magna injection (ICM).798. The method of any one of embodiments 774-797, wherein the AAV particle is administered intravenously.799. The method of any one of embodiments 774-798, wherein the AAV particle is administered to a cell, tissue, or region of the CNS of the subject, e.g., a region of the brain or spinal cord, e.g., the parenchyma, the cortex, substantia nigra, caudate cerebellum, striatum, corpus callosum, cerebellum, brain stem caudate-putamen, thalamus, superior colliculus, the spinal cord, or a combination thereof.800. The method of any one of embodiments 774-799, wherein the A AV particle is administered to at least two tissues, or regions of the CNS, e.g., bilateral administration.801. The method of any one of embodiments 774-799, wherein the AAV particle is administered to the cerebral spinal fluid, the serum, or a combination thereof.802. The method of any one of embodiments 774-801 , which further comprises evaluating, e.g., measuring, the level of CDKL5 expression, e.g., CDKL5 gene, CDKL5 mRN A, and / or CDKL5 protein expression, in the subject, e.g., in a ceil, tissue, or fluid, of the subject, optionally wherein the level of CDKL5 protein is measured by, e.g., an ELISA, a Western blot, or an immunohistochemistry assay.803. The method of embodiment 802, wherein measuring the level of CDKL5 expression is performed prior to, during, or subsequent to treatment with the AAV particle.804. The method of embodiment 802 or embodiment 803, wherein the cell or tissue is a cell or tissue of the central nervous system (e.g., parenchyma) or a peripheral cell or tissue (e.g., the liver, heart, and / or spleen).805. The method of any one of embodiments 774-804, wherein the administration results in increased level of CDKL5 protein expression in a cell or tissue of the subject, relative to reference level, e.g., a subject that has not received treatment, e.g., lias not been administered the AAV particle.806. The method of any one of embodiments 774-805, which further comprises evaluating, e.g., measuring, the level of CDKL5 activity in the subject after administration, e.g,, in a cell or tissue of the subject.807. The method of any one of embodiments 774-806, wherein the administration results in an increase in at least one, at least two, or all of:(i) The level of CDKL5 activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., the cortex, striatum, thalamus, cerebellum, and / or brainstem), and / or fluid (e.g., CSF and / or serum), of the subject, as compared to a reference level, e.g., a subject that has not received treatment, e.g., has not been administered the AAV particle;(ii) the level of viral genomes (VG) per cell in a CNS tissue (e.g., the cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord) of the subject, as compared to a peripheral tissue, wherein the level of VGs per ceil is lower than the levels in the CNS tissue, e.g., as measured by an assay as described herein; and / or( iii) the level of CDKL5 mRNA expression in a cell or tissue (e.g, a cell or tissue of the CNS, e.g., the cortex, thalamus, and / or brainstem) as compared to a reference level, e.g.. a subject that has not received treatment (e.g.. has not been administered the AA V particle), or endogenous CDKL5 mRN A levels, e.g., as measured by an assay as described herein.808. The method of any one of embodiments 774-807, further comprising administering to the subject an additional therapeutic agent and / or therapy sui table for treatment or prevention of the disease associated CDKL5 expression (e.g., the CDKL5-related disorder), the neurodegenerative disorder, and / or the neuromuscular disorder.809. The method of embodiment 808, wherein the additional therapeutic agent and / or therapy comprises an anti-epileptic drug, e.g., valproate, levetiracetam, clobazam, lamotrigine, ganaxolone. topiramate, or a combination thereof810. The pharmaceutical composition of embodiment 773 or the AA V particle of any one of embodiments 660-727 for use in tire treatment of a disease associated with CDKL5 expression (e.g., a CDKL5-related disorder), a neuromuscular and / or a neurodegenerative disorder.813. Use of an effective amount of the pharmaceutical composition of embodiment 773 or the AAVparticle of any one of embodiments 660-727 in the manufacture of a medicament for the treatment of a disease associated with CDKL5 expression (e.g., a CDKL5-related disorder), a neuromuscular and / or a neurodegenerative disorder.

[0073] 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 forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, till 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

[0074] FIG. 1 depicts biodistribution (VG / cell) in the motor cortex, frontal cortex, putamen, substantia nigra, dentate nucleus, cervical spinal cord ventral hom, DRG, liver, and heart in cynomolgus monkeys at 28 days post-IV injection of TTM-002.GBA_VG17-HA, AAV9.GBA VG17-HA, or vehicle control.

[0875] FIG. 2 depicts mRNA expression of the GB Al transgene in the motor cortex, frontal cortex, putamen, substantia nigra, dentate nucleus, cervical spinal cord ventral hom, DRG, liver, and heart in cynomolgus monkeys at 28 days post-IV injection of TTM-002.GBA_VG 17-HA, AAV9.GBA_VG17-HA, or vehicle control.

[0076] FIG. 3A is a graph showing the percentage of HA positive cells (percent of cells transduced by the indicated capsid variant) in the cortex in mice on the Y axis at the indicated doses on the X-axis (from highest dose to lowest dose: 1e14 vg / kg, 3.2e13 vg / kg, le 13 vg / kg, 3.2e12 vg / kg, or 1e12 vg / kg) at 28 days post-intravenous administration of AAV particles comprising the TTM-002 or TTM-027 AAV capsid variant. FIG. 38 is a graph showing the mRNA transgene expression relative to the housekeeping gene in the brains of the mice on the Y axis at the indicated doses on the X-axis (from highest to lowest dose: 1e14 vg / kg, 3.2e13 vg / kg, 1e13 vg / kg, 3.2e12 vg / kg, or 1 e12 vg / kg) at 28 days post-intravenous administration of A AV particles comprising the TTM-002 or TTM-027 AAV capsid variant.

[0077] FIG. 4A is a graph showing the percentage of transduced cells having HA+ nuclei as measured by co-localization of nuclear I-I2B-HA staining and hematoxylin (%HA+ cells) in the indicated brain regions (temporal cortex, caudate, thalamus, or hippocampus) of African green monkeys. Measurements are at day 28 post-intravenous injection of AAV particles comprising the TTM-002 capsid variant or the AAV9 capsid control and a self-complementary genome encoding a histone 2B protein with an HA-tag at a dose of 1e13 VG / kg. FIG. 48 is a graph showing the percentage of HA+ cells among cells positive for the indicated marker (NeuN+ neurons, SM311+Neurons, GFAP+ astrocytes, or Sox9+ astrocytes) in the indicated brain regions (temporal cortex, caudate, thalamus, or hippocampus) of African green monkeys. Measurements are at day 28 post- intravenous injection of AAV particles comprising the TTM-002 capsid variant and a self- complementary genome encoding a histone 2B protein with an HA-tag at a dose of 1e13 VG / kg. Plotted data in FIGs. 4A-4B represent one slice per monkey (n=2). Quantitative image analysis was performed on 1e3 to le5 cells according to region size. All P values are derived from an unpaired two-tailed t-test.

[0078] FIGs. 5A-5D are a series of graphs showing tropism of TTM-001 and TTM-002 relative to the AAV9 control in the brain and liver at 28 days post-intravenous administration in mice at a dose of le 13 VG / kg. FIG. 5A shows the viral genomes (VG) / diploid genomes (DG) in the brain for the AAV9 control, TTM-001, or TTM-002; FIG. 5B shows brain RNA (fold vs AA V9) for the AAV9 control, TTM-001, or TTM-002; FIG. 5C shows the VG / DG in the liver for the AAV9 control, TTM- 001, or TTM-002; and FIG. 51) shows the liver RNA (fold vs AAV9) for the AAV9 control, TTM- 001, or TTM-002. Each data point represents an individual mouse and all plotted values represent mean i SD (n=3). P values are derived from an unpaired two-tailed t-test.DETAILED DESCRIPTIONOverview

[0079] Described herein, inter alia, are compositions comprising an AAV capsid variant comprising a sequence encoding a CDKL5 protein, e.g., a wildtype CDKL5 protein, e.g., a wiidtype human CDKL5 protein. In some embodiments, the present disclosure provides a method for 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., wildtype CDKL5 protein, e.g., a wildtype human CDKL5 protein, to a cell or tissue in a subject. In some embodiments, 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.

[0080] 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 ceils) 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 integration into the host genome, and long-term transgene expression in non-dividing cells. However, the transduction efficiency of naturally occurring AAVs in certain organs is too low for clinical applications, and capsid neutralization by pre-existing neutralizing antibodies may prevent treatmentof 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.

[0081] 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, 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 CDKL5 protein. In some embodiments, the target cell is a CNS cell. In some embodiments, tire target tissue is a CNS tissue. In some embodiments, the target CNS tissue is brain tissue.

[0082] In some embodiments, the genome encodes a wildtype CDKL5 protein. In some embodiments, the genome comprises a codon-optimized, CpG-reduced (e.g., CpG-depleted) nucleotide sequence encoding a wildtype CDKL5 protein. In some embodiments, the target cell is a CNS cell. In some embodiments, the target tissue is a CNS tissue. The target CNS tissue may be brain tissue. In some embodiments, the brain target comprises caudate, putamen, tlralamus, superior colliculus, cortex, and corpus collosum.

[0883] Gene therapy presents an alternative approach for CDD. and related diseases similar etiology, such as developmental and epileptic encephalopathy 2, atypical Rett syndrome, and related disorders. AAVs are commonly used in gene therapy approaches as a result of a number of advantageous features. Without being bound by theory, it is believed in some embodiments, an AAV particle described herein, can be used to administer and / or deliver a nucleic acid encoding CDKL5 protein (e.g., human CDKL5 protein), preferentially to the CNS. In some embodiments, an AAV particle described herein can be used to administer and / or deliver a nucleic acid encoding CDKL5 protein (e.g., human CDKL5 protein) preferentially' to the brain.

[0084] 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), and the periphery, and / or (iii) elevated payload expression, e.g., CDKL5 mRNA expression, in multiple brain regions (e.g,, cortex, thalamus, and brain stem) and the periphery; and (li) increased CDKL5 activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g.. the cortex, striatum, thalamus, cerebellum, and / or brainstem), and / or fluid (e.g., CSF and / or serum), of the subject. In some embodiments, an AAV viral genome comprising a nucleotide sequence encoding a wildtype CDKL5 protein (e.g., a nucleotide sequence comprising SEQ ID NO: 6414) results in high biodistribution in the CNS; increased CDKL5 activity in the CNS, peripheral tissues, and / or fluid; and successful tiansgene transcription and expression. In some embodiments, an AAV viral genomecomprising a codon-optimized, CpG-reduced (e.g., CpG-depleted) nucleotide sequence encoding a CDKL5 protein results in high biodistribution in the CNS; increased CDKL5 activity in the CNS, peripheral tissues, and / or fluid; and successful transgene transcription and expression.

[0085] Also provided herein are compositions comprising an AAV capsid variant, e.g., an AAV capsid variant described herein for delivery, e.g., vectorized delivery, of a nucleic acid encoding a CDKL5 protein, and methods of making and using the same. As demonstrated in the Examples below, certain AAV capsid variants described herein show multiple advantages over wild-type AAV9, including (i) increased penetrance through the blood brain barrier following intravenous administration, (ii) wider distribution throughout the multiple brain regions, e.g., frontal cortex, sensory cortex, motor cortex, putamen, thalamus, cerebellar cortex, dentate nucleus, caudate, and / or hippocampus, and / or (iii) elevated pay load expression in multiple brain regions. Without being bound by theory, these advantages may be due, in part, to the dissemination of the AAV capsid variants through the brain vasculature. In some embodiments, the AAV capsids described herein enhance the delivery of a payload to multiple regions of the brain including for example, the frontal cortex, sensory cortex, motor cortex, putamen, thalamus, cerebellar cortex, dentate nucleus, caudate, and / or hippocampus.

[0886] Thus, the compositions and methods described herein can be used in the treatment of disorders associated with a lack of a CDKL5 protein and / or CDKL5 activity, such as CDD, developmental and epileptic encephalopathy 2, and 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 encoding a CDKL5 protein (e.g., comprising the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence encoding the arnino acid sequence of SEQ ID NO: 6413) for use in treating disorders associated with a lack of a CDKL5 protein and / or CDKL5 activity, such as CDD, developmental and epileptic encephalopathy 2, and atypical Rett syndrome.I. CompositionsAdeno-associated viral (AA V) Particles

[0887] AAVs have a genome of about 5,000 nucleotides in length and contain two open reading frames encoding die proteins responsible for replication (Rep) and the structural protein of die capsid (Cap). The open reading frames are flanked by two Inverted Terminal Repeat (ITR) sequences, which serve as the origin of replication of the viral genome. The wild-type AAV viral genome comprises nucleotide sequences for two open reading frames, one for die 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 thegeneration 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 serotype, as a nonlimiting example, for AAV9 / hu, 14 (SEQ ID NO: 123 of US 7,906,111 , the contents of which are herein incorporated by reference in their entirety) VP 1 refers to amino acids 1 -736, VP2 refers to amino acids 138-736, and VP3 refers to amino acids 203-736. In some embodiments, with reference to the amino acid sequence of SEQ ID NO: 982, 36, or 4, VP1 comprises amino acids 1-742, VP2 comprises amino acids 138-742, and VP3 comprises amino acids 203-742. In other words, VP1 is the full-length capsid protein sequence, while VP2 and VP3 are shorter components of the whole. As a result, changes in the sequence in the VP3 region are also changes to VP1 and VP2; however, the percent difference as compared to the parent sequence will be greatest for VP3 since it is the shortest sequence of 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. Without being bound by theory, the AAV capsid typically comprises a molar ratio of 1:1: 10 of VP1:VP2:VP3.[0881 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.

[0089] 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; (hi) 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 particle, 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).

[0090] Typically, AAV particles for CDKL5 delivery may be recombinant viral particles which are replication defective as they lack sequences encoding functional Rep and Cap proteins within the viral genome. In some cases, the replication defective AzAV 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 CDKI.,5 protein (e.g., human CDKL5 protein).

[0091] In some embodiments, the AAV particles of the present disclosure may be introduced into mammalian cells.

[0092] 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 wtith minimal toxicity.

[0093] In other embodiments, AAV particles of the present disclosure may be used to deliverCDKL5 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.

[0094] 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.

[0095] In some embodiments, an AAV capsid variant disclosed herein comprises a modification in loop IV of AAV9, e.g., at positions between 449-460, e.g., at position 454 and / or 456, numbered relative to SEQ ID NO: 4, 36, 138, 981, or 982. In some embodiments, loop (e.g., loop IV) is used interchangeably herein with the term variable region (e.g., variable region IV), or VR (e.g., VR-IV). In some embodiments loop IV comprises positions 449-475 (e.g.. amino acids KT1NGSGQNQQTLKFS VAGPSNMAVQG (SEQ ID NO: 6404)), numbered according to SEQ ID NO: 138. In some embodiments loop IV comprises positions 449-460 (e.g., amino acids KTINGSGQNQQT (SEQ ID NO: 6405)), numbered according to SEQ ID NO: 138. In some embodiments, loop IV or variable region IV (VR-IV) is as described in DiMattia et al. “Structural Insights into the Unique Properties of the Adeno- Associated Vims Serotype 9,” Journal of Virology, 12(86):6947-6958 (the contents of which are hereby incorporated by reference in their entirety), e.g., comprising positions 452-460 (e.g., NGSGQNQQT (SEQ ID NO: 4487)), numbered according to SEQ ID NO: 138.

[0896] 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 demonstrate entranced 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 may, in addition, or alternatively, have decreased tropism for a cell-type, tissue or organ.

[0097] In some embodiments, AAV particles 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,

[0098] In some embodiments, the AAV particle is a recombinant AA V particle. 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 hairpinstructures 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.

[0099] In some embodiments, the wild-type A AV viral genome further 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 used for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid polypeptide, e.g., an AAV capsid variant. 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 serotype, as a non-limiting example, for AAV9 / hu.l4 (SEQ ID NO: 123 of US 7,906,111, the contents of which are herein incorporated by reference in their entirety) VP1 refers to amino acids 1- 736, VP2 refers to amino acids 138-736, and VP3 refers to amino acids 203-736. In some embodiments, for any one of the amino acid sequences of SEQ ID NO: 4, 36, 981 or 982, VP1 comprises amino acids 1 -742, VP2 comprises amino acids 138-742, and VP3 comprises amino acids 203-742, In other words, VP1 is the full-length capsid 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 protein. Without being bound by theory, the AAV capsid protein typically comprises a molar ratio of 1:1: 10 of VP1:VP2:VP3.

[0100] AAV particles of the present disclosure may be produced recombinantly and may be based on 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 that anneal together to form double-stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the transduced ceil. 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.

[0101] Methods for producing and / or modifying AAV particles are disclosed in the art such as pseudotyped AAV particles (PCT Patent Publication Nos. W0200028004; WO200123001;W02004112727; W02005005610; and W02005072364, the content of each of which is incorporated herein by reference in its entirety).

[0102] 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.AA V Capsid Variants

[0103] Disclosed herein are AAV particles comprising an AAV capsid variant comprising one or more modifications (e.g., comprising one or more insertions and / or substitutions relative to a wildtype AAV capsid) for enhanced or improved transduction of a target tissue (e.g., cells, regions, and / or tissues of the CNS and / or PNS). In some embodiments, the one or more modifications comprises a peptide insertion and / or amino acid substitutions relative to a wildtype A AV capsid. In some embodiments, the one or more modifications is present in a capsid protein of the AAV particle. In some embodiments, the one or more modifications is present in a VP1, VP2, and / or VP3 protein of the AAV particle.

[0104] In some embodiments, the one or more modifications (e.g., the peptide insertion and / or amino acid substitution relative to a wildtype AAV capsid) is in loop IV of the AAV capsid variant. In some embodiments, the AAV capsid variant is an AAV9 capsid vanant.

[0105] In some embodiments, the variant is an insertional variant. As used herein, the term “insertional variant” refers to a polypeptide comprising one or more amino acids inserted, e.g., “immediately adjacent” or “immediately subsequent” to a position in a reference amino acid sequence. “Immediately adjacent” or “immediately subsequent” to an amino acid refers to the insertion sequence being connected to either the alpha-carboxy or alpha-amino functional group of the amino acid. In some embodiments, the variant is a deletion variant. As used herein, the term “deletion variant” refers to a polypeptide comprising one or more amino acids removed from a reference amino acid sequence. In some embodiments, the vanant is a substitution vanant. As used herein, the term “substitution variant” refers to a polypeptide comprising one or more amino acid changes from a reference amino acid sequence. In some embodiments, the variant is an insertional variant and a substitution variant.

[0106] In some embodiments, the one or more modifications in the AAV cap...

Claims

CLAIMSWhat is claimed is:

1. An adeno-associated virus (AAV) particle comprising: a) an AAV capsid variant comprising an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein:(i) optionally [N1] comprises 1I , X2, and X3, wherein at least one of XI, X2, or X3 is G;(ii) [N2] comprises the ammo acid sequence of SPH; and(iii) [N3] comprises X4, X5, and X6, w herein at least one of X4, X5, or X6 is a basic amino acid: and b) a viral genome comprising a cy clin-dependent kinase-like 5 (CDKL5)-encoding sequence.

2. The AAV particle of claim 1 , wherein the amino acid sequence [N1]-[N2]-[N3] is in hypervariable loop IV of the AAV capsid variant.

3. The AAV particle of claim 1 or claim 2, wherein the AAV capsid variant is an AAV9 capsid variant.

4. The AAV particle of any one of claims 1-3, wherein [N1] comprises XI, X2, and X3, wherein at least one of XI, X2, or X3 is G.

5. The AAV particle of any one of claims 1-4, wherein [N2]-[N3] comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941).

6. An adeno-associated virus (AAV) particle comprising a viral genome comprising a cyclin- dependent kinase-like 5 (CDKL5)-encoding sequence and an AAV9 capsid variant comprising the amino acid sequence of SPHSKA (SEQ ID NO: 941).

7. The AAV particle of claim 6, wherein the amino acid sequence of SPHSKA (SEQ ID NO: 941) is in hypervariable loop IV of the AAV9 capsid variant.

8. The AAV particle of claim 6 or claim 7, wherein the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present immediately subsequent to an ammo acid position corresponding to position 455 of SEQ ID NO: 4 or SEQ ID NO: 36.

9. The AAV particle of any one of claims 6-8, wherein the AAV9 capsid variant further comprises one, two, or all of: an N at an amino acid position corresponding to position 452, an E at an aminoacid position corresponding to position 451. and / or a V at an amino acid position corresponding to position 453 of SEQ ID NO: 4.

10. The AA V particle of claim any one of claims 6-9, wherein the AAV9 capsid variant comprises the amino acid sequence of KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272).

11. The AAV particle of any one of claims 6-10, wherein the AAV9 capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 4;(ii) a VP2 protein comprising an amino acid sequence having at least 90% identity to positions 138-742 of SEQ ID NO: 4; and / or(iii) a VP3 protein comprising an amino acid sequence having at least 90% identity to positions 203-742 of SEQ ID NO: 4.

12. The AAV particle of any one of claims 6-11. wherein the AAV9 capsid variant comprises:(i) a ATI protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 4;(ii) a VP2 protein comprising an amino acid sequence having at least 95% identity to positions 138-742 SEQ ID NO: 4; and / or(iii) a VP3 protein comprising an amino acid sequence having at least 95% identity to positions 203-742 of SEQ ID NO: 4.

13. The AAV particle of any one of claims 6-12, wherein the AAV9 capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 4;(ii) a VP2 protein comprising an amino acid sequence having at least 99% identity to positions 138-742 of SEQ ID NO: 4; and / or(iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to positions 203-742 of SEQ ID NO: 4.

14. The AA V particle of any one of claims 6-13, wherein the AAV9 capsid variant comprises:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 4; and / or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO:4.

15. The AAV particle of any one of claims 6-13. wherein the AAV9 capsid variant comprises:(i) the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately subsequent to an amino acid position corresponding to position 455 of SEQ ID NO: 4;(ii) an E at an amino acid position corresponding to position 451 and a V at an amino acid position corresponding to position 453 of SEQ ID NO: 4; and(iii) no other modifications relative to wild type AAV9.

16. The AAV particle of any one of claims 6-8, wherein the AAV9 capsid variant further comprises one, two, or all of: an E at an amino acid position corresponding to position 451 , an R at an amino acid position corresponding to position 452, and / or a V at an amino acid position corresponding to position 453 of SEQ ID NO: 36.

17. The AAV particle of any one of claims 6-8 and 16, wherein the A.AV9 capsid variant comprises the amino acid sequence of KTERVSGSPHSK.AQNQQT (SEQ ID NO: 3589).

18. The AAV particle of any one of claims 6-8, 16, and 17, wherein the AAV9 capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 36;(ii) a VP2 protein comprising an amino acid sequence having at least 90% identity to positions 138-742 SEQ ID NO: 36; and / or(iii) a VP3 protein comprising an amino acid sequence having at least 90% identity to positions 203-742 of SEQ ID NO: 36.

19. The AAV particle of any one of claims 6-8 and 16-18, wherein the AAV9 capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 36;(ii) a VP2 protein comprising an amino acid sequence liaving at least 95% identity to positions 138-742 SEQ ID NO: 36; and / or(iii) a VP3 protein comprising an amino acid sequence liaving at least 95% identity to positions 203-742 of SEQ ID NO: 36.

20. The AAV particle of any one of claims 6-8 and 16-19, wherein the AAV9 capsid variant comprises:(i) a VP1 protein comprising an amino acid sequence having at least 99% identity to SEQ IDNO: 36;(ii) a VP2 protein comprising an amino acid sequence having at least 99% identity to positions 138-742 of SEQ ID NO: 36; and / or(iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to positions 203-742 of SEQ ID NO: 36.

21. The AAV particle of any one of claims 6-8 and 16-20, wherein the AAV9 capsid vanant comprises:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 36; and / or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

22. The AAV particle of any one of claims 6-8 and 16-20, wherein the AAV9 capsid variant comprises:(i) the amino acid sequence SPHSKA (SEQ ID NO: 941 ), wherein the amino acid sequence is present immediately subsequent to an amino acid position corresponding to position 455 of SEQ ID NO: 36;(ii) an E at an amino acid position corresponding to position 451. an R at an amino acid position corresponding to position 452, and a V at an amino acid position corresponding to position 453 of SEQ ID NO: 36; and(iii) no other modifications relative to wild type AAV9.

23. The AAV particle of any one of claims 1-4, wherein [N1]-[N2]-[N3] is present immediately subsequent to a position corresponding to the amino acid position 452 of SEQ ID NO: 982; and wherein the AAV capsid variant comprises an amino acid sequence at least 90% identical, e.g., at least 91%, at least 92%. at least 93%, at least 94%, at least 95%, at least 96%. at least 97%, at least 98%, at least 99%, or 100% identical, to the amino acid sequence of SEQ ID NO: 982, e.g., to positions 203-742 of SEQ ID NO: 982,24. The AAV particle of claim 23, wherein [Nl] comprises GHD.

25. The AAV particle of claim 23 or claim 24, wherein [N1] comprises the amino acid G at a position corresponding to position 453, the amino acid H at position 454, and the amino acid D at position 455 of SEQ ID NO: 138 or SEQ ID NO: 982.

26. The AAA7particle of any one of claims 23-25, wherein [N3] comprises KSG.

27. The AA V particle of any one of claims 23-26, wherein the AAV capsid variant comprises:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO:

982. or an amino acid sequence having at least 90% identity to SEQ ID NO: 982;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO:982 or an amino acid sequence having at least 90% identity to positions 138-742 SEQ ID NO: 982; or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO:982 or an amino acid sequence having at least 90% identity to positions 203-742 of SEQ ID NO: 982.

28. The AAV particle of any one of claims 23-27, wherein the AAV capsid variant comprises:(i) a VPI protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity to SEQ ID NO: 982;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity to positions 138-742 SEQ ID NO: 982; or(iii) a VP3 protein comprising the amino acid sequence of positions 2.03-742. of SEQ ID NO:

982. or an amino acid sequence having at least 95% identity to positions 203-742 of SEQ ID NO: 982.

29. The AAV particle of any one of claims 23-28, wherein the AAV capsid variant comprises:(i) a VPI protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity to SEQ ID NO: 982;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity to positions 138-742 SEQ ID NO: 982; or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity to positions 203-742 of SEQ ID NO: 982.

30. The AAV particle of any one of claims 23-29, wherein the AAV capsid variant comprises:(i) a VP 1 protein comprising the amino acid sequence of SEQ ID NO: 982;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742. of SEQ ID NO: 982; or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982.

31. The AAV particle of any one of claims 1-30, wherein tlie viral genome encodes a wildtypeCDKL5 protein or a fragment thereof.

32. The AAV particle of any one of claims 1-31, wherein the viral genome encodes a human CDKL5 protein.

33. The AA V particle of claim 31 or claim 32, wherein the CDKL5 protein comprises the amino acid sequence of SEQ ID NO: 6413.

34. The AAV particle of any one of claims 1-33, wherein the CDKL5 -encoding sequence comprises a nucleotide sequence that is at least 90% identical (e.g., at least 90% at least 91%, al ieasl 92% at least 93% at least 94% at least 95%, at least 96%, al ieasl 97%, at least 98% at least 99%, or 100% identical) to SEQ ID NO: 6414.

35. The AAV particle of claim 34, wherein the CDKL5 -encoding sequence comprises a nucleotide sequence that is at least 95% identical to SEQ ID NO: 6414.

36. The AAV particle of claim 35, wherein the CDKL5 -encoding sequence comprises a nucleotide sequence that is at least 99% identical to SEQ ID NO: 6414.

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

38. The AAV particle of claim 37, wherein the CDKL 5 -encoding sequence consists of the nucleotide sequence of SEQ ID NO: 6414.

39. The AAV particle of any one of claims 1-38, wherein the viral genome comprises a promoter operably linked to the CDKL5-encoding sequence.

40. The AAV particle of claim 39, wherein the promoter is human elongation factor la-subunit (EFla), cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken (3-actin (CBA) promoter, CAG promoter, CAG derivative promoter, p glucuronidase (GUSB) promoter, ubiquitin C (UBC) promoter, neuron-specific enolase (NSE) promoter, platelet-derived growth factor (PDGF) promoter, platelet-derived growth factor B-chain (PDGF -p) promoter, intercellular adhesion molecule 2 (ICAM-2) promoter, synapsin (Syn) promoter, synapsin 1 (Synl) promoter, methyi-CpG binding protein 2 (MeCP2) promoter, Ca2+ / cahnodulin-dependent protein kinase II (CaMKII) promoter, metabotropic glutamate receptor 2 (mGluR2) promoter, neurofilament light (NFL) or heavy (NFH) promoter, β -globin minigene np2 promoter, preproenkeplialin (PPE) promoter, enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, glial fibrillary acidic protein (GFAP) promoter, myelin basic protein (MBP) promoter, a cardiovascular promoter (e.g., aMHC, cTnT, andCMV-MLC2k), a liver promoter (e.g., h.AAT, TBG), a skeletal muscle promoter (e.g ., desmin, MCK C512) or a fragment, e.g., a truncation, or a functional variant thereof.

41. The AA V particle of any one of claims 1-40, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.

42. The AAV particle of claim 41. wherein the viral genome comprises an ITR sequence positioned 5’ relative to the CDKL 5 -encoding sequence.

43. The AAV particle of claim 41 or claim 42, wherein the viral genome comprises an ITR sequence positioned 3’ relative to the CDKL5-encoding sequence.

44. The AAV particle of any one of claims 41-43, 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.

45. An adeno-associated virus (AAV) particle comprising a viral genome comprising a cyclin- dependent kinase-like 5 (CDKL5)-encoding sequence and an AAV capsid variant comprising:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO:4; and / or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO:4.

46. An adeno-associated virus (AAV) particle comprising a viral genome comprising a cyclin- dependent kinase-like 5 (CDKL5)-encoding sequence and an AAV capsid variant comprising:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO:36; and / or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO:36.

47. A cell comprising the AAV particle of any one of claims 1-46, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

48. A method of making the AAV particle of any one of claims 1-46, 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 AAV particle.

49. The method of claim 48, wherein:(a) the viral genome comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (e.g., at least 90%, al least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and(b) the AAV capsid variant comprises:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to SEQ ID NO: 4;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%. at least 92%, at least 93%. at least 94%, at least 95%, at least 96%, at least 97%. at least 98%, or at least 99% identity) to positions 138-742 SEQ ID NO: 4; or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (e.g., at least 90% at least 91%. at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to positions 203-742 of SEQ ID NO: 4.

50. The method of claim 49, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of positions 138-742 of SEQ ID NO: 4, and / or the amino acid sequence of positions 203-742 of SEQ ID NO: 4.51 . The method of claim 48, wherein:(a) the viral genome comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%. at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and(b) the AAV capsid variant comprises:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to SEQ ID NO: 36;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity ) to positions 138-742 SEQ ID NO: 36; or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%. at least 92%, at least 93%, at least 94%, at least 95%, al least 96%, at least 97%, at least 98%, or at least 99% identity ) to positions 203-742 of SEQ ID NO: 36.

52. The method of claim 51, wherein the AAV capsid variant comprises the amino acid sequence ofSEQ ID NO: 36, the amino acid sequence of positions 138-742 of SEQ ID NO: 36, and / or the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

53. The method of claim 48, wherein:(a) the viral genome comprises a nucleic acid sequence of SEQ ID NO: 6414 or a nucleic acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%. or at least 99% identical) thereto; and(b) the AAV capsid variant comprises:(i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, al least 91%, at least 92%. at least 93%, at least 94%. at least 95%, at least 96%, at least 97%, at least 98%. or at least 99% identity) to SEQ ID NO: 982;(ii) a VP2 protein comprising the amino acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) to positions 138-742 SEQ ID NO: 982; or(iii) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%. at least 95%, at least 96%, at least 97%, at least 98%. or at least 99% identity) to positions 203-742 of SEQ ID NO: 982.

54. The method of claim 53, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of positions 138-742 of SEQ ID NO: 982, and / or die amino acid sequence of positions 203-742 of SEQ ID NO: 982.

55. The method of any one of claims 48-54, further comprising, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the cell.

56. The method of any one of claims 48-55, wherein the cell comprises a second nucleic acid molecule encoding the AAV capsid variant, optionally wherein the method further comprises, prior to step (i), introducing the second nucleic acid molecule into the cell.

57. The method of any one of claims 48-56, wherein the cell compri ses a mammalian cell (e.g., anHEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

58. A pharmaceutical composition comprising the AAV particle of any one of claims 1-46, and a pharmaceutically acceptable excipient.

59. A pharmaceutical composition comprising the AAV particle of any one of claims 5-22, and a pharmaceutically acceptable excipient.

60. A pharmaceutical composition comprising the AAV particle of any one of claims 9-15 and 45, and a pharmaceutically acceptable excipient.

61. A pharmaceutical composition comprising the AAV particle of any one of claims 16-22 and 46, and a pharmaceutically acceptable excipient.

62. A method of delivering an AAV particle encoding an CDKL5 protein to a subject, comprising administering to the subject an effective amount of tire pharmaceutical composition of any one of claims 58-61 or the AAV particle of any one of claims 1-46.

63. The method of claim 62, wherein the subject has, has been diagnosed with having, or is at risk of having a CDKL5-related disorder, optionally wherein the CDKL5-related disorder is a CDKL5- related neurodegenerative or neuromuscular disorder.

64. The method of claim 62 or claim 63, wherein the subject has, has been diagnosed with having, or is at risk of having CDD, developmental and epileptic encephalopathy 2, or atypical Ret syndrome.

65. A method of treating a subject having or diagnosed with having a CDKL5-related disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 58-61 or tire AAV particle of any one of claims 1-46.

66. A method of treating a subject having or diagnosed with having a CDKL5-related disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 60 or the AAV particle of any one of claims 9-15 and 45.

67. A method of treating a subject having or diagnosed with having a CDKL5-related disorder, comprising administering to the subject an effective amount of tire ph armaceutical composition of claim 61 or the AAV particle of any one of claims 16-22 and 46.

68. A method of treating a subject having or diagnosed with having a CDKL5-related disorder, comprising administering to the subject an effec tive amount of the pharmaceutical composition of claim 59 or the AAV particle of any one of claims 5-22.

69. The method of claim 35, wherein the CDKL5-related disorder is a CDKL5-related neurodegenerative or neuromuscular disorder.

70. The method of claim 69, wherein the CDKL5-related neurodegenerative or neuromuscular disorder is CDD, developmental and epileptic encephalopathy 2, or atypical Rett syndrome.

71. A method of treating a subject having CDKL5 deficiency disorder (CDD) or diagnosed with having CDD, comprising administering to the subject an effective amount of the pharmaceutical composition of any one of ciaims 58-61 or the AAV particle of any one of claims 1-46.

72. A method of treating a subject having CDKL5 deficiency disorder (CDD) or diagnosed with having CDKL5 deficiency disorder (CDD), comprising administering to the subject an effective amount of the pharmaceutical composition of claim 60 or the AAV particle of any one of claims 9-15 and 45.

73. A method of treating a subject having CDKL5 deficiency disorder (CDD) or diagnosed with having CDKL5 deficiency disorder (CDD), comprising administering to the subject an effective amount of the pharmaceutical composition of claim 61 or the AAV particle of any one of claims 16- 22. and 46.

74. A method of treating a subject having CDKL5 deficiency disorder (CDD ) or diagnosed with having CDKL5 deficiency disorder (CDD). comprising administering to the subject an effective amount of pharmaceutical composition of claim 59 or the AAV particle of any one of claims 5-22.

75. The method of any one of claims 32-38, wherein the subject has one or more mutations in the CDKL 5 gene.

76. The method of any one of claims 62-75, wherein the subject has a reduced level of CDKL5 activity as compared to a reference level in a subject who does not have a CDKL 5 -related disorder.

77. The method of any one of claims 65-76, wherein the administration results m prevention of progression of the disorder in the subject.

78. The method of any one of claims 65-77, wherein the administration results in amelioration of at least one symptom of the disorder and / or a change in one or more biomarkers of the disorder.

79. The method of claim 78, w'herein the one or more biomarkers comprises neurofilament light drain or a marker of CDKL5 activity, e.g., as measured by phosphorylation levels of substrate proteins, e.g.,MECP2, or as measured by mass spectrometry.

80. The method of any one of claims 65-77, wherein the treating results in amelioration of at least one symptom, optionally 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 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, 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.81 . The method of any one of claims 62-80, wherein the subject is a human.

82. The method of any one of claims 62-81, wherein the AAV particle is delivered to a cell, tissue, or region of the CNS, e.g., a region of the brain or spinal cord, e.g., the parenchyma, the cortex, substantia nigra, caudate cerebellum, striatum, corpus callosum, cerebellum, brain stem caudate- putamen, thalamus, superior colliculus, the spinal cord, or a combination thereof, and / or to neurons, or a combination thereof.

83. The method of any one of claims 62-82, 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 ceil, tissue, or fluid of the subject.

84. The method of claim 83, wherein the level of CDKL5 protein expression is measured by an ELISA, a Western blot, or an immunohistochemistry assay.

85. The method of claim 83 or claim 84, wherein evaluating the level of CDKL5 expression is perforated prior to and subsequent to administration of the AAV particle, optionally wherein the level of CDKL5 expression prior to adminis tration is compared to the level of CDKL5 expression subsequent to administration.

86. The method of any one of claims 83-85, comprising evaluating the level of CDKL5 expression in a cell or tissue of the central nervous system (e.g., parenchyma).

87. The method of any one of claims 83-86, wherein the subject’s level of CDKL5 protein expression subsequent to administration is increased relative to the subject’s level of CDKI.,5 protein expression prior to administration.

88. The method of any one of claims 62.-87, further comprising evaluating, e.g., measuring, the level of CDKL5 activity in tire subject, e.g., in a cell or tissue of the subject.

89. The method of any one of claims 65-88, wherein the administration results in an increase in:(i) CDKL5 activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., the cortex, striatum, thalamus, cerebellum, and / or brainstem), and / or fluid (e.g., CSF and / or serum) of the subject, relative to CDKL5 activity in the subject prior to the administration;(ii) viral genomes (VG) per cell level in a CNS tissue (e.g., the cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord) of the subject, relative to the subject’s VG per cell level in a peripheral tissue; and / or(iii) CDKL5 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., the cortex, thalamus, and / or brainstem) of the subject, as compared to CDKL5 mRNA expression in the subject prior to the administration.

90. The method of any one of claims 65-89, further comprising administering to the subject an additional agent suitable for treatment or prevention of a CDKL5-related disorder; optionally wherein the additional agent comprises one or more anti-epileptic drugs (e.g., valproate, levetiracetam, clobazam, lamotrigine, ganaxolone, topiramate, or a combination thereof).91 . The method of any one of claims 65-90, further comprising administering an immunosuppressant to the subject.

92. The method of claim 91, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin. mycopbenolate mofetil, tacrolimus, rituximab, and / or ecnlizumab hydroxychloroquine.

93. The pharmaceutical composition of any one of claims 58-61 or the AAV particle of any one of claims 1-46, for use in the treatment of a CDKL5-reiated disorder; optionally wherein the CDKL5- related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, or atypical Rett syndrome.

94. Use of the pharmaceutical composition of any one of claims 58-61 orthe AAV particle of any one of claims 1-46 in the manufacture of a medicament for the treatment of a CDKL5-related disorder; optionally wherein the CJDKL 5 -related disorder is CDKL5 deficiency disorder (CDD), developmental and epileptic encephalopathy 2, or atypical Rett syndrome.

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