Compositions and methods for treating conditions associated with synaptic fusion protein binding protein 1 deficiency

Abstract

The present disclosure relates to compositions and methods for altering, e.g., enhancing, the expression of the STXBP1 protein via delivery using adeno-associated virus (AAV) capsid variants. The compositions and methods of the present disclosure are useful for treating subjects diagnosed with or suspected of having an STXBP1 encephalopathy or another STXBP1-related disorder.

Description

[0001] Related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application Serial No. 63 / 499,925, filed May 3, 2023; U.S. Provisional Application Serial No. 63 / 593,828, filed October 27, 2023; and U.S. Provisional Application Serial No. 63 / 564,420, filed March 12, 2024, the contents of each of which are incorporated herein by reference in their entirety.

[0003] sequence list

[0004] This application is submitted together with the electronic sequence list. The sequence list file, named 14640_0085-00304_SL.xml, was created on March 26, 2024, and has a size of 5,536,190 bytes. The information in the electronic sequence list is incorporated herein by reference in its entirety. Technical Field

[0005] This document describes compositions and methods relating to adeno-associated virus (AAV) viral particles for delivering polynucleotides, such as polynucleotides encoding synaptic fusion protein-binding protein-1 (“STXBP1 protein”) and peptides (“STXBP1 peptide”), for the treatment of STXBP1 encephalopathy and other STXBP1-related conditions, including epileptic encephalopathy, Ōtahara syndrome, developmental encephalopathy, West syndrome, early myositis epileptic encephalopathy, Lennox-Gasto syndrome, autism (e.g., autism with an STXBP1 mutation and optionally other mutations), Dravet syndrome (not caused by mutations in SCN1A), and Rett syndrome phenotypes (not caused by mutations in MECP2 or CDKL5) (collectively, “STXBP1-related conditions”). In some embodiments, the compositions described herein may be used to treat subjects in need, such as human subjects diagnosed with STXBP1-related conditions or other conditions resulting from a deficiency in the quantity and / or function of the STXBP1 protein. Background Technology

[0006] Synaptic fusion protein-binding protein 1 (STXBP1), also known as Munc18-1, is part of the synaptic fusion system that enables vesicles to fuse with the plasma membrane. Other names for STXBP1 include P67, DEE4, NSEC1, UNC18, N-Sec1, RBSEC1, unc-18A, and unc18-1. STXBP1 regulates neurotransmitter transmission by interacting with the SNARE complex. The SNARE complex is primarily composed of SNAP-25, vesicle-associated membrane proteins, and synaptic fusion protein 1. SNAP-25 and synaptic fusion protein-1 form a targeting membrane vesicle protein (T-SNARE), which binds to synaptic vesicle protein (VAMP). STXBP1 has a complex, arched tertiary structure. The arched structure contains four tightly connected domains, namely 1, 2, 3a, and 3b. Domain 1 and domain 3a form an arched gap. STXBP1 primarily regulates vesicle fusion by interacting with synaptic fusion protein-1. STXBP1 domain 3a is in close contact with the Habc domain of synaptic fusion protein-1, and STXBP1 domain 1 binds to the N-terminal domain of synaptic fusion protein-1. STXBP1 regulates vesicle docking and fusion by interacting with the SNARE complex. STXBP1 influences released vesicles and participates in neurotransmitter transmission. STXBP1 is primarily involved in the early stages of neurotransmitter release.

[0007] STXBP1 is crucial for presynaptic vesicle release. Following neuronal depolarization, STXBP1 is rapidly phosphorylated by protein kinase C.

[0008] STXBP1 is encoded by the STXBP1 gene (Ensembl gene ID ENSG00000136854), located on chromosome 9. STXBP1 is expressed in the brain and spinal cord, and is highly enriched in axons. The highest expression levels of STXBP1 are observed in the retina and cerebellum. STXBP1 is also found outside the brain.

[0009] Mutations in the STXBP1 gene are known to cause disease in human subjects. Aberrant expression of STXBP1 plays a role in the pathogenesis of a variety of neurological disorders, including STXBP1 encephalopathy, epileptic encephalopathy, Ōtahara syndrome, developmental encephalopathy, West syndrome, early myositis epileptic encephalopathy, Lennox-Gasto syndrome, autism (e.g., autism with STXBP1 mutation and optionally other mutations), Draway syndrome (not caused by mutations in SCN1A), and Rett syndrome phenotype (not caused by mutations in MECP2 or CDKL5).

[0010] STXBP1 expression is also abnormal in STXBP1 encephalopathy. An estimated 750 known cases of STXBP1 encephalopathy exist worldwide, with an estimated incidence of 3.3–3.8 cases per 100,000 newborns.

[0011] Patients with STXBP1 mutations and / or STXBP1 encephalopathy typically present with epilepsy. Some patients with STXBP1 mutations express autistic features, including aggressive behavior, self-harm, hyperactivity, obsessive-compulsive symptoms, psychotic episodes, and / or auditory hallucinations. The phenotype ranges from severe neonatal epilepsy to infantile seizure-like epilepsy.

[0012] Many patients with STXBP1 mutations also exhibit non-epileptic motor disorders, including trunk and limb ataxia, generalized tremor, and dystonia. These patients often present with uninterrupted epileptic activity.

[0013] Patients with STXBP1 encephalopathy are dependent on caregivers for the duration of their lives. Furthermore, 40% of patients become immobile, and their life expectancy is significantly shortened to approximately 30 years.

[0014] STXBP1 encephalopathy is caused by haploinufficiency. Therefore, the disease can occur even when a single functional copy of the STXBP1 gene is mutated. Pathogenic mutations include missense, nonsense, frameshift, splice site, and whole gene deletion. There are approximately 135 known pathogenic variants of the STXBP1 gene.

[0015] Interneurons are more susceptible to haploinadequacy than excitatory neurons.

[0016] Studies have shown that, in addition to the moderate epileptic phenotype, heterozygous STXBP1 knockout mice also exhibit reduced glutamate and GABA transmission, increased anxiety, increased aggression, and reduced emotional learning.

[0017] Studies in mice have demonstrated that normalizing excitatory synaptic transmission in STXBP1 heterozygous knockout mice reduces aggression. This points to therapeutic options for controlling invasiveness in patients with STXBP1 mutations.

[0018] Current therapies target the symptoms of STXBP1 encephalopathy. Existing first-line treatments include antiepileptic drugs such as levetiracetam and phenobarbital. Existing second-line treatments include other antiepileptic drugs such as clobazam and topiramate. Existing third-line treatments include other antiepileptic drugs and / or interventions. Known interventions for existing third-line treatment include adrenocorticotropic hormone (ACTH), a ketogenic diet, and vagus nerve stimulation.

[0019] The lack of approved therapies targeting STXBP1 mutations is a potential reason. Driven by the high seizure rate and shortened lifespan in patients with STXBP1 mutations, the need for these treatments remains largely unmet.

[0020] Therefore, there remains a long-term need to develop pharmaceutical compositions and methods that can be delivered to the CNS to treat diseases associated with STXBP1 mutations. Specifically, there is a need for therapies that target neurons, including GABAergic and glutamatergic neurons.

[0021] Adeno-associated virus (AAV) has been extensively studied and utilized as a viral particle for delivering therapeutically effective peptides to mammalian cells. See, for example, Tratschin et al., Mol. Cell Biol., 5(11):3251-3260 (1985) and Grimm et al., Hum. Gene Ther., 10(15):2445-2450 (1999), each of which is incorporated herein by reference in its entirety.

[0022] There is still a need for effective treatments that can deliver STXBP1 to target cells or tissues, such as CNS cells or tissues, for AAV capsid variants. Summary of the Invention

[0023] In some embodiments, this disclosure provides 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 X1, X2, and X3, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises an 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 coding sequence for synaptic fusion protein-binding protein 1 (STXBP1). In some embodiments, the amino acid sequence [N1]-[N2]-[N3] is located in the hypervariable loop IV of the AAV capsid variant. In some embodiments, the AAV capsid variant is an AAV9 capsid variant. In some embodiments, [N1] comprises X1, X2, and X3, wherein at least one of X1, X2, or X3 is G. In some embodiments, [N2]-[N3] comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0024] In some embodiments, this disclosure provides an adeno-associated virus (AAV) particle comprising a viral genome containing a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) and an AAV9 capsid variant containing the amino acid sequence of SPHSKA (SEQ ID NO: 941). In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is located in the hypervariable loop IV of the AAV9 capsid variant. In some embodiments, the amino acid sequence of SPHSKA (SEQ ID NO: 941) is immediately following the amino acid position corresponding to position 455 of SEQ ID NO: 4 or SEQ ID NO: 36.

[0025] In some embodiments, the AAV9 capsid variant comprises one, two, or all of the following: N at the amino acid position corresponding to position 452 of SEQ ID NO: 4, E at the amino acid position corresponding to position 451 of SEQ ID NO: 4, and / or V at the amino acid position corresponding to position 453 of SEQ ID NO: 4. In some embodiments, the AAV9 capsid variant comprises the amino acid sequence KTENVSGSPHSKAQNQQT (SEQ ID NO: 3272).

[0026] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing an amino acid sequence having at least 90% identity with SEQ ID NO: 4; (ii) a VP2 protein containing an amino acid sequence having at least 90% identity with positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein containing an amino acid sequence having at least 90% identity with positions 203-742 of SEQ ID NO: 4.

[0027] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing an amino acid sequence having at least 95% identity with SEQ ID NO: 4; (ii) a VP2 protein containing an amino acid sequence having at least 95% identity with positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein containing an amino acid sequence having at least 95% identity with positions 203-742 of SEQ ID NO: 4.

[0028] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing an amino acid sequence having at least 99% identity with SEQ ID NO: 4; (ii) a VP2 protein containing an amino acid sequence having at least 99% identity with positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein containing an amino acid sequence having at least 99% identity with positions 203-742 of SEQ ID NO: 4.

[0029] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing the amino acid sequence of SEQ ID NO: 4; (ii) a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 4.

[0030] 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 after the amino acid position corresponding to position 455 of SEQ ID NO: 4; (ii) E at the amino acid position corresponding to position 451 of SEQ ID NO: 4 and V at the amino acid position corresponding to position 453 of SEQ ID NO: 4; and (iii) no other modifications relative to wild-type AAV9.

[0031] In some embodiments, the AAV9 capsid variant further comprises one, two, or all of the following: E ​​at the amino acid position corresponding to position 451 of SEQ ID NO: 36, R at the amino acid position corresponding to position 452 of SEQ ID NO: 36, and / or V at the 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).

[0032] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing an amino acid sequence having at least 90% identity with SEQ ID NO: 36; (ii) a VP2 protein containing an amino acid sequence having at least 90% identity with positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein containing an amino acid sequence having at least 90% identity with positions 203-742 of SEQ ID NO: 36.

[0033] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing an amino acid sequence having at least 95% identity with SEQ ID NO: 36; (ii) a VP2 protein containing an amino acid sequence having at least 95% identity with positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein containing an amino acid sequence having at least 95% identity with positions 203-742 of SEQ ID NO: 36.

[0034] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing an amino acid sequence having at least 99% identity with SEQ ID NO: 36; (ii) a VP2 protein containing an amino acid sequence having at least 99% identity with positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein containing an amino acid sequence having at least 99% identity with positions 203-742 of SEQ ID NO: 36.

[0035] In some embodiments, the AAV9 capsid variant comprises: (i) a VP1 protein containing the amino acid sequence of SEQ ID NO: 36; (ii) a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

[0036] 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 after the amino acid position corresponding to position 455 of SEQ ID NO: 36; (ii) E at the amino acid position corresponding to position 451 of SEQ ID NO: 36, R at the amino acid position corresponding to position 452 of SEQ ID NO: 36, and V at the amino acid position corresponding to position 453 of SEQ ID NO: 36; and (iii) no other modifications relative to wild-type AAV9.

[0037] In some embodiments, this disclosure provides an AAV particle comprising an AAV capsid variant comprising an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein [N1]-[N2]-[N3] is immediately following the position corresponding to amino acid position 452 of SEQ ID NO: 982; and wherein the AAV capsid variant comprises an amino acid sequence that is 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, for example, to positions 203-742 of SEQ ID NO: 982.

[0038] In some embodiments, [N1] comprises GHD. In some embodiments, [N1] comprises amino acid G at position 453 of SEQ ID NO: 138 or SEQ ID NO: 982, amino acid H at position 454 of SEQ ID NO: 138 or SEQ ID NO: 982, and amino acid D at position 455 of SEQ ID NO: 138 or SEQ ID NO: 982. In some embodiments, [N3] comprises KSG.

[0039] 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 with SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity with positions 138-742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity with positions 203-742 of SEQ ID NO: 982.

[0040] 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 with SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity with positions 138-742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity with positions 203-742 of SEQ ID NO: 982.

[0041] 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 with SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity with positions 138-742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 982 or an amino acid sequence having at least 99% identity with positions 203-742 of SEQ ID NO: 982.

[0042] In some embodiments, the AAV capsid variant comprises: (i) a VP1 protein containing the amino acid sequence of SEQ ID NO: 982; (ii) a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 982; or (iii) a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 982.

[0043] In some embodiments, this disclosure provides an AAV particle comprising a viral genome encoding a wild-type STXBP1 protein. In some embodiments, the viral genome encodes a human STXBP1 protein. In some embodiments, the STXBP1 protein comprises the amino acid sequence of SEQ ID NO: 6413.

[0044] In some embodiments, the STXBP1 coding sequence comprises a nucleotide sequence that is at least 90% identical to (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 STXBP1 coding sequence comprises a nucleotide sequence that is at least 95% identical to SEQ ID NO: 6414. In some embodiments, the STXBP1 coding sequence comprises a nucleotide sequence that is at least 99% identical to SEQ ID NO: 6414. In some embodiments, the STXBP1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 6414. In some embodiments, the STXBP1 coding sequence consists of the nucleotide sequence of SEQ ID NO: 6414.

[0045] In some embodiments, the viral genome contains a promoter that is efficiently linked to the STXBP1 coding sequence. In some embodiments, the promoter is a human elongation factor 1α-subunit (EF1α), a cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA), CAG, a CAG derivative, β-glucuronidase (GUSB) or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synaptic protein (Syn), synaptic protein 1 (Syn1), methyl-CpG-binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabolite receptor 2 (mGluR2), neurofilament light chain (NFL) or heavy chain (NFH), β-globin small gene nβ2, proenkephalinogen (PPE), enkephalin (Enk), and excitatory amino acid transporter 2. (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), cardiovascular promoters (e.g., αMHC, cTnT, and CMV-MLC2k), liver promoters (e.g., hAAT, TBG), skeletal muscle promoters (e.g., desmin, MCK, C512), or fragments thereof, such as truncated or functional variants.

[0046] In some embodiments, the viral genome further includes an inverted terminal repeat (ITR) sequence. In some embodiments, the viral genome includes an ITR sequence located at the 5' end relative to the STXBP1 coding sequence. In some embodiments, the viral genome includes an ITR sequence located at the 3' end relative to the STXBP1 coding sequence. In some embodiments, the viral genome includes both an ITR sequence located at the 5' end relative to the STXBP1 coding sequence and an ITR sequence located at the 3' end relative to the STXBP1 coding sequence.

[0047] In some embodiments, this disclosure provides an AAV particle comprising a viral genome containing a coding sequence for synaptic fusion protein binding protein 1 (STXBP1) 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.

[0048] In some embodiments, this disclosure provides an AAV particle comprising a viral genome containing a coding sequence for synaptic fusion protein binding protein 1 (STXBP1) 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.

[0049] In some embodiments, this disclosure provides a cell comprising the AAV particles disclosed herein. In some embodiments, the cell is a mammalian cell (e.g., HEK293 cell), an insect cell (e.g., Sf9 cell), or a bacterial cell.

[0050] In some embodiments, this disclosure provides a method for preparing the AAV particles disclosed herein, the method comprising: (i) providing a cell containing a viral genome, the viral genome containing an STXBP1 coding sequence and nucleic acid encoding an AAV capsid variant; and (ii) culturing the cell under conditions suitable for encapsulating the viral genome in an AAV capsid variant; thereby preparing AAV particles.

[0051] In some embodiments, the viral genome of the AAV particle contains the nucleotide sequence of SEQ ID NO: 6414 or 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%, or at least 99% identical); and the AAV capsid variant of the AAV particle contains: (i) a VP1 protein containing the amino acid sequence of SEQ ID NO: 4 or an amino 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) to SEQ ID NO: 4; and (ii) a VP2 protein containing the amino acid sequence at positions 138-742 of SEQ ID NO: 4 or an amino 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) to SEQ ID NO: 4. The amino acid sequence at positions 138-742 of SEQ ID NO: 4 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); or (iii) the VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 4 or 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) with the amino acid sequence at positions 203-742 of SEQ ID NO: 4.

[0052] In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence at positions 138-742 of SEQ ID NO: 4, and / or the amino acid sequence at positions 203-742 of SEQ ID NO: 4.

[0053] In some embodiments, the viral genome of the AAV particle contains the nucleotide sequence of SEQ ID NO: 6414 or 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%, or at least 99% identical) to it; and the AAV capsid variant of the AAV particle contains: (i) a VP1 protein containing the amino acid sequence of SEQ ID NO: 36 or an amino 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) to SEQ ID NO: 36; and (ii) a VP2 protein containing the amino acid sequence at positions 138-742 of SEQ ID NO: 36 or an amino 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) to SEQ ID NO: 36. The amino acid sequence at positions 138-742 of SEQ ID NO: 36 has 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); or (iii) the VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 36 or 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) with the amino acid sequence at positions 203-742 of SEQ ID NO: 36.

[0054] In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 36, the amino acid sequence at positions 138-742 of SEQ ID NO: 36, and / or the amino acid sequence at positions 203-742 of SEQ ID NO: 36.

[0055] In some embodiments, the viral genome of the AAV particle contains the nucleotide sequence of SEQ ID NO: 6414 or 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%, or at least 99% identical) to it; and the AAV capsid variant of the AAV particle contains: (i) a VP1 protein containing the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence that is at least 90% identical (e.g., at least 90%, 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) to SEQ ID NO: 982; and (ii) a VP2 protein containing the amino acid sequence at positions 138-742 of SEQ ID NO: 982 or an amino 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) to SEQ ID NO: 982. The amino acid sequence at positions 138-742 of SEQ ID NO: 982 has 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); or (iii) the VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 982 or 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) with the amino acid sequence at positions 203-742 of SEQ ID NO: 982.

[0056] In some embodiments, the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence at positions 138-742 of SEQ ID NO: 982, and / or the amino acid sequence at positions 203-742 of SEQ ID NO: 982.

[0057] In some embodiments, the preparation method further includes introducing a first nucleic acid molecule containing the viral genome into the cell prior to step (i).

[0058] In some embodiments, the cell contains a second nucleic acid molecule encoding an AAV capsid variant. In some embodiments, the preparation method further includes introducing the second nucleic acid molecule into the cell prior to step (i).

[0059] In some implementations, the cells comprise mammalian cells (e.g., HEK293 cells), insect cells (e.g., Sf9 cells), or bacterial cells.

[0060] In some embodiments, this disclosure provides a pharmaceutical composition comprising the AAV particles disclosed herein and pharmaceutically acceptable excipients.

[0061] In some embodiments, this disclosure provides a method for delivering AAV particles encoding the STXBP1 protein to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles disclosed herein.

[0062] In some embodiments, this disclosure provides a method of treating a subject who has or has been diagnosed with an STXBP1-related condition, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles disclosed herein. In some embodiments, the STXBP1-related condition is an STXBP1-related neurodegenerative disease or neuromuscular disease. In some embodiments, the STXBP1-related neurodegenerative disease or neuromuscular disease is STXBP1 encephalopathy, epileptic encephalopathy, Ōtahara syndrome, developmental encephalopathy, West syndrome, early myositis epileptic encephalopathy, Lennox-Gasto syndrome, autism (e.g., autism with an STXBP1 mutation and optionally other mutations), Drave syndrome (not caused by a mutation in SCN1A), or Rett syndrome phenotype (not caused by a mutation in MECP2 or CDKL5).

[0063] In some embodiments, this disclosure provides a method of treating a subject with or diagnosed with STXBP1 encephalopathy, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles disclosed herein.

[0064] In some implementations, the subject has one or more mutations in the STXBP1 gene.

[0065] In some implementations, the subject has a reduced level of STXBP1 activity compared to a reference level in subjects without STXBP1-related conditions.

[0066] In some embodiments, the treatment halts the progression of the condition in the subject. In some embodiments, the treatment improves the condition. In some embodiments, the treatment alters one or more biomarkers of the condition. In some embodiments, one or more biomarkers comprise STXBP1 activity or neurofilament light chains.

[0067] In some implementations, the treatment improves at least one symptom of the condition. In some implementations, the at least one symptom includes epilepsy, autism features, ataxia, generalized tremor, dystonia, or a combination thereof.

[0068] In some implementations, the subjects are humans.

[0069] In some embodiments, the AAV particle is delivered to cells, tissues, or regions of the CNS, such as regions of the brain or spinal cord, such as the parenchyma, cortex, substantia nigra, caudate cerebellum, striatum, corpus callosum, cerebellum, brainstem caudate-putamen, thalamus, superior colliculus, spinal cord, or combinations thereof, and / or delivered to neurons, such as GABAergic neurons, glutamatergic neurons, or combinations thereof.

[0070] In any of the foregoing embodiments, the method of delivery or treatment further includes assessment, such as measuring the STXBP1 expression level in the subject, for example, in the subject's cells, tissues, or body fluids, including STXBP1 gene expression level, STXBP1 mRNA expression level, and / or STXBP1 protein expression level. In some embodiments, the STXBP1 protein expression level is measured by ELISA, Western blot, or immunohistochemistry.

[0071] In some embodiments, STXBP1 expression levels are assessed before and after administration of AAV particles, optionally wherein pre-treatment STXBP1 expression levels are compared with post-administration STXBP1 expression levels. In some embodiments, STXBP1 expression levels are assessed in cells or tissues derived from the subject's central nervous system (e.g., parenchyma). In some embodiments, post-administration STXBP1 protein expression levels in the subject are increased relative to pre-administration levels.

[0072] In some embodiments, administration of the pharmaceutical composition or AAV particles described herein results in an increase in: (i) STXBP1 activity in the subject's cells, tissues (e.g., cells or tissues of the CNS, such as the cortex, striatum, thalamus, cerebellum, and / or brainstem) and / or body fluids (e.g., CSF and / or serum) relative to the STXBP1 activity in the subject prior to administration; (ii) the amount of viral genome (VG) per cell in the subject's CNS tissues (e.g., cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord) relative to the amount of viral genome (VG) per cell in the subject's peripheral tissues; and / or (iii) STXBP1 mRNA expression in the subject's cells or tissues (e.g., cells or tissues of the CNS, such as the cortex, thalamus, and / or brainstem) relative to the STXBP1 mRNA expression in the subject prior to administration.

[0073] In some embodiments, the treatment further includes administering to the subject an additional agent suitable for treating or preventing STXBP1-related conditions. In some embodiments, the additional agent comprises one or more antiepileptic drugs (e.g., levetiracetam, phenobarbital, clonazy, topiramate), adrenocorticotropic hormone, or a combination thereof. In some embodiments, the method further includes 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 eculizumab hydroxychloroquine.

[0074] In some embodiments, this disclosure provides pharmaceutical compositions or AAV particles described herein for the treatment of STXBP1-related conditions. In some embodiments, the STXBP1-related condition is STXBP1 encephalopathy, epileptic encephalopathy, Ōtahara syndrome, developmental encephalopathy, West syndrome, early myositis epileptic encephalopathy, Lennox-Gasto syndrome, autism (e.g., autism with an STXBP1 mutation and optionally other mutations), Dravey syndrome (not caused by a mutation in SCN1A), or Rett syndrome phenotype (not caused by a mutation in MECP2 or CDKL5).

[0075] In some embodiments, this disclosure provides the use of the pharmaceutical compositions or AAV particles described herein in the preparation of a medicament for treating STXBP1-related conditions. In some embodiments, the STXBP1-related condition is STXBP1 encephalopathy, epileptic encephalopathy, Ōtahara syndrome, developmental encephalopathy, West syndrome, early myositis epileptic encephalopathy, Lennox-Gasto syndrome, autism (e.g., autism with an STXBP1 mutation and optionally other mutations), Delaware syndrome (not caused by a mutation in SCN1A), or Rett syndrome phenotype (not caused by a mutation in MECP2 or CDKL5).

[0076] The listed implementation schemes

[0077] 1. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein: (i) Optionally, [N1] includes X1, X2 and X3, wherein at least one of X1, X2 or X3 is G; (ii) [N2] amino acid sequence containing SPH; and (iii) [N3] contains X4, X5 and X6, wherein at least one of X4, X5 or X6 is a basic amino acid, such as K or R.

[0078] 2. The AAV particle as described in implementation 1, wherein X4, X5, or both of [N3] are K.

[0079] 3. The AAV particle as described in implementation scheme 1 or 2, wherein X4, X5 or X6 of [N3] is R.

[0080] 4. The AAV particles as described in any one of implementation schemes 1 to 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, the AAV capsid variant comprises an amino acid modification, such as a conserved substitution, of any of the aforementioned amino acids in (a)-(c).

[0081] 5. AAV particles as described in any of embodiments 1 to 4, wherein [N3] includes 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.

[0082] 6. An AAV particle as described in any of embodiments 1 to 5, wherein [N3] is or includes 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, or RSG.

[0083] 7. AAV particles as described in any one of embodiments 1 to 6, wherein [N2]-[N3] comprise 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), SPHKF (SEQ ID NO: 4712), SPHKI (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), SPHKT (SEQ ID NO: 4719), SPHKT (SEQ ID NO: 4710), SPHKT (SEQ ID NO: 4711), SPHKT (SEQ ID NO: 4712), SPHKK (SEQ ID NO: 4713), SPHKL (SEQ ID NO: 4714), SPHKK (SEQ ID NO: 4715), SPHKT (SEQ ID NO: 4716), SPHKT (SEQ ID NO: 4717), SPHKT (SEQ ID NO: 4718), SPHKT (SEQ ID NO: 4719), SPHKT (SEQ ID NO: 4710), SPHKT (SEQ ID NO: 4711), SPHKT (SEQ ID NO: 4712), SPHKT (SEQ ID NO: 4713), SPHKT (SEQ ID NO: 4714), SPHKT (SEQ ID NO: 4715), SPHKT (SEQ ID NO: 4716), SPHKT ( 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).

[0084] 8. The AAV particle as described in any one of embodiments 1 to 7, wherein [N2]-[N3] is or includes: (i) SPHSKA (SEQ ID NO: 941)、SPHKSG (SEQ ID NO: 946)、SPHARM (SEQ IDNO: 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)、SPHKTY (SEQ ID NO: 965)、SPHKYG (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 ID NO: 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), SPHKHG (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) Any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0085] 9. An AAV particle as described in any one of embodiments 1 to 8, wherein the AAV capsid variant comprises an amino acid other than G (e.g., V, R, D, E, M, T, I, S, A, N, L, K, H, P, W, or C) at position 453 according to any one of SEQ ID NO: 36-59, 138, 981, or 982, an amino acid other than S (e.g., V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q) at position 454, and / or an amino acid other than G (e.g., C, L, D, E, Y, H, V, A, N, P, or S) at position 455.

[0086] 10. An AAV particle as described in any one of embodiments 1 to 8, wherein the AAV capsid variant comprises amino acid G at position 453, amino acid S at position 454, and amino acid G at position 455, as specified in SEQ ID NO: 138 or 981.

[0087] 11. An AAV particle as described in any one of embodiments 1 to 9, wherein the AAV capsid variant comprises amino acid G at position 453, amino acid H at position 454, and amino acid D at position 455, as specified in SEQ ID NO: 138 or 982.

[0088] 12. An AAV particle as described in any one of embodiments 1 to 11, wherein [N1] comprises X1, X2 and X3, wherein at least one of X1, X2 or X3 is G.

[0089] 13. The AAV particles as described in any one of implementation schemes 1 to 12, wherein: (a) X1 of [N1] is: G, V, R, D, E, M, T, I, S, A, N, L, K, H, P, W or C; (b) X2 of [N1] is: S, V, L, N, D, H, R, P, G, T, I, A, E, Y, M, or Q; and / or (c) X3 of [N1] is: G, C, L, D, E, Y, H, V, A, N, P or S; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conserved substitution, of any of the aforementioned amino acids in (a)-(c).

[0090] 14. An AAV particle as described in any of embodiments 1 to 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, AI, 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.

[0091] 15. An AAV particle as described in any of embodiments 1 to 14, wherein [N1] is or includes 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.

[0092] 16. An AAV particle as described in any one of embodiments 1 to 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: 4762) 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) or HSSPH (SEQ ID NO:4783); (ii) Any part of the amino acid sequence in (i), such as any 2, 3 or 4 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0093] 17. An AAV particle as described in any one of embodiments 1 to 16, wherein [N1]-[N2] are or include: (i) GSGSPH (SEQ ID NO: 4695)、GHDSPH (SEQ ID NO: 4784)、GQDSPH (SEQ IDNO: 4785)、VSGSPH (SEQ ID NO: 4786)、CSGSPH (SEQ ID NO: 4787)、GRGSPH (SEQ IDNO: 4788)、CSHSPH (SEQ ID NO: 4789)、GQSSPH (SEQ ID NO: 4790)、GSHSPH (SEQ IDNO: 4791)、GDDSPH (SEQ ID NO: 4792)、GHESPH (SEQ ID NO: 4793)、GNYSPH (SEQ IDNO: 4794)、RVGSPH (SEQ ID NO: 4795)、GSCSPH (SEQ ID NO: 4796)、GLLSPH (SEQ IDNO: 4797)、MSGSPH (SEQ ID NO: 4798)、RNGSPH (SEQ ID NO: 4799)、TSGSPH (SEQ IDNO: 4800)、ISGSPH (SEQ ID NO: 4801)、GPGSPH (SEQ ID NO: 4802)、ESGSPH (SEQ IDNO: 4803)、SSGSPH (SEQ ID NO: 4804)、GNGSPH (SEQ ID NO: 4805)、ASGSPH (SEQ IDNO: 4806)、NSGSPH (SEQ ID NO: 4807)、LSGSPH (SEQ ID NO: 4808)、GGGSPH (SEQ IDNO: 4809)、KSGSPH (SEQ ID NO: 4810)、HSGSPH (SEQ ID NO: 4811)、GTGSPH (SEQ IDNO: 4812)、PSGSPH (SEQ ID NO: 4813)、GSVSPH (SEQ ID NO: 4814)、RSGSPH (SEQ IDNO: 4815)、GIGSPH (SEQ ID NO: 4816)、WSGSPH (SEQ ID NO: 4817)、DSGSPH (SEQ IDNO: 4818)、IDGSPH (SEQ ID NO: 4819)、GLGSPH (SEQ ID NO: 4820)、DAGSPH (SEQ IDNO: 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 IDNO: 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) Any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0094] 18. An AAV particle as described in any of embodiments 1 to 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: 4843) 4844). 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)、VGSPHSK (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 (SEQID NO: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), NDSPHKS (SEQ ID NO: 4891), QDSPHKI (SEQ ID NO: 4892), PDSPHKI (SEQ ID NO: 4893), PDSPHKS (SEQ ID NO: 4894), MGSPHSK (SEQ ID NO: 4895), HDSPHKH (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), HDSPHKL (SEQ ID NO: 4902), HPSPHWK (SEQ ID NO: 4903), HDSPHKM (SEQ ID NO: 4904) or HSSPHRS (SEQ ID NO: 4905); (ii) Any part of the amino acid sequence in (i), such as any 2, 3, 4, 5 or 6 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0095] 19. An AAV particle as described in any of embodiments 1 to 18, wherein [N1]-[N2]-[N3] are or include:(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: 4908) 4909). 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: 4925) 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) GHDSPHKSA (SEQ ID NO: 4940) GNYSPHKIG (SEQ ID NO: 4941) GHDSPHKSR (SEQ ID NO: 4942) GSGSPHSKL (SEQ ID NO: 4943) GSGSPHSRA (SEQ ID NO: 4944) GSGSPHSKR (SEQ ID NO: 4945) GSGSPHSLR (SEQ ID NO: 4946) GSGSPHSRG (SEQ ID NO: 4947) GSGSPHSSR (SEQ ID NO: 4948) RVGSPHSKA (SEQ ID NO: 4949) GSSCSPHRKA (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)、ISGSPHSKA (SEQ ID NO: 4960)、GPGSPHSKA (SEQ ID NO: 4961)、GSGSPHSKT (SEQID NO: 4962)、ESGSPHSKA (SEQ ID NO: 4963). 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 IDNO: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)、GHDSPHKTG (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), GPDSPHKIG (SEQ ID NO: 5008), GPDSPHKSG (SEQ IDNO: 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), GDDSPHKSV (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016), GGNSPHKRG (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: 5026); (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7 or 8 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0096] 20. An AAV particle as described in any of embodiments 1 to 19, wherein [N3] comprises SK, KA, KS or SG.

[0097] 21. An AAV particle as described in any of embodiments 1 to 20, wherein [N3] is or includes SKA, KSG or KYG.

[0098] 22. The AAV particles of any one of embodiments 1 to 21, wherein [N2]-[N3] comprise SPHSK (SEQ ID NO: 4701), SPHKS (SEQ ID NO: 4704), or SPHKY (SEQ ID NO: 4715).

[0099] 23. The AAV particle of any one of embodiments 1 to 22, wherein [N2]-[N3] is or contains SPHSKA (SEQ ID NO: 941).

[0100] 24. The AAV particle of any one of embodiments 1 to 22, wherein [N2]-[N3] is or contains SPHKSG (SEQ ID NO: 946).

[0101] 25. The AAV particles of any one of embodiments 1 to 22, wherein [N2]-[N3] are or contain SPHKYG (SEQ ID NO: 966).

[0102] 26. An AAV particle as described in any of embodiments 1 to 25, wherein [N1] comprises GS, SG, GH or HD.

[0103] 27. An AAV particle as described in any of embodiments 1 to 26, wherein [N1] is or contains GSG.

[0104] 28. An AAV particle as described in any of embodiments 1 to 26, wherein [N1] is or contains GHD.

[0105] 29. AAV particles as described in any one of embodiments 1 to 23 or 26 to 27, wherein [N1]-[N2]-[N3] contain SGSPHSK (SEQ ID NO: 4839).

[0106] 30. An AAV particle as described in any one of embodiments 1 to 22, 24, 26 or 28, wherein [N1]-[N2]-[N3] comprises HDSPHKS (SEQ ID NO: 4840).

[0107] 31. The AAV particles of any one of embodiments 1 to 22 or 25 to 27, wherein [N1]-[N2]-[N3] comprises SGSPHKYG (SEQ ID NO: 5027).

[0108] 32. AAV particles as described in any one of embodiments 1 to 8, 10, 12 to 23, 26 to 27 or 29, wherein [N1]-[N2]-[N3] is or contains GGSPHSKA (SEQ ID NO: 4697).

[0109] 33. An AAV particle as described in any one of embodiments 1 to 9, 11 to 22, 24, 26, 28 or 30, wherein [N1]-[N2]-[N3] is or contains GHDSPHKSG (SEQ ID NO: 4698).

[0110] 34. AAV particles as described in any one of embodiments 1 to 8, 10, 12 to 22, 25 to 27 or 31, wherein [N1]-[N2]-[N3] are or contain GSGSPHKYG (SEQ ID NO: 4927).

[0111] 35. The AAV particle of any one of embodiments 1 to 34, wherein [N1]-[N2]-[N3] replace positions 453-455 according to the numbering according to SEQ ID NO: 138.

[0112] 36. An AAV particle as described in any one of embodiments 1 to 35, wherein the AAV capsid variant comprises an amino acid other than Q at 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 at 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).

[0113] 37. An AAV particle as described in any one of embodiments 1 to 36, wherein the AAV capsid variant comprises, according to SEQ ID NO: Amino acids other than Q (e.g., W, K, R, G, L, V, S, P, H, K, I, M, A, E, or F) at position 462 (numbered 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56, or 57), amino acids other than N (e.g., Y, C, K, T, H, R, D, V, S, P, G, W, E, F, A, I, M, Q, or L) at position 463, amino acids other than Q (e.g., G, K, H, R, T, L, D, A, P, I, F, V, M, W, Y, S, E, N, or Y) at position 464, and / or amino acids other than Q (e.g., H, L, R, W, K, A, P, E, M, I, S, G, N, Y, C, V, T, D, or V) at position 465.

[0114] 38. An AAV particle as described in any one of embodiments 1 to 37, wherein the AAV capsid variant comprises: (a) Amino acid Q at position 456, amino acid N at position 457, amino acid Q at position 458, and / or amino acid Q at position 459, according to SEQ ID NO: 138; or (b) Amino acid Q at position 462, amino acid N at position 463, amino acid Q at position 464, and / or amino acid Q at position 465, according to SEQ ID NO: 981, 982, 36, 37, 39, 40, 42-46, 48, 49, 50, 52, 53, 56 or 57.

[0115] 39. An AAV particle as described in any one of embodiments 1 to 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, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(d), such as a conserved substitution.

[0116] 40. The AAV particles as described in implementation scheme 39, wherein: (a) X7 of [N4] is Q or R; (b) X8 of [N4] is N or R; (c) X9 of [N4] is Q or R; and (d) X10 of [N4] is Q, L or R.

[0117] 41. The AAV particle as described in 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 IDNO: 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 IDNO: 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 IDNO: 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 IDNO: 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)、QYIH (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 IDNO: 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 IDNO: 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 IDNO: 5115)、QIPP (SEQ ID NO: 5116)、QTQL (SEQ ID NO: 5117)、QAPS (SEQ IDNO: 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 IDNO: 5131)、QRTC (SEQ ID 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)、QNII (SEQ ID NO: 5142)、QGHH (SEQ ID NO: 5143)、QSKV (SEQ IDNO: 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 IDNO: 5157)、QVPA (SEQ ID NO: 5158)、HYQQ (SEQID 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 IDNO: 5170)、QVRN (SEQ ID NO: 5171)、PSNQ (SEQ ID NO: 5172)、QVGH (SEQ ID NO:5173)、QRDI (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 IDNO: 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)、QNKL (SEQ IDNO: 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 IDNO: 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 IDNO: 5222), QRQL (SEQ ID NO: 5223), QIIV (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 IDNO: 5235), QKQL (SEQ ID NO: 5236), RNQL (SEQ ID NO: 5237), ISIQ (SEQ ID NO:5238), QTVC (SEQ ID NO: 5239), QQIM (SEQ ID NO: 5240), LNHQ (SEQ ID NO: 5241), QNQA (SEQ ID NO: 5242), QMIH (SEQ ID NO: 5243), RNHQ (SEQ ID NO: 5244) or QKMN(SEQ ID NO: 5245); (ii) Any part of the amino acid sequence in (i), such as any two or three of its amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0118] 42. The AAV particle as described in any of embodiments 39 to 41, wherein [N1]-[N2]-[N3]-[N4] are or include: (i) The amino acid sequence of any one of SEQ ID NO: 1800-2241; (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0119] 43. The AAV particle of any one of embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is or contains GSGSPHSKAQNQQ (SEQ ID NO: 1801).

[0120] 44. The AAV particle of any one of embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is or contains GHDSPHKSGQNQQ (SEQ ID NO: 1800).

[0121] 45. The AAV particle of any one of embodiments 39 to 42, wherein [N1]-[N2]-[N3]-[N4] is or contains GSGSPHKYGQNQQT (SEQ ID NO: 910).

[0122] 46. ​​An AAV particle as described in any one of embodiments 1 to 45, wherein the AAV capsid variant comprises an amino acid other than T (e.g., S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G) at position 450, an amino acid other than I (e.g., M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L) at position 451, and / or an amino acid other than N (e.g., M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S) at position 452.

[0123] 47. An AAV particle as described in any one of embodiments 1 to 46, wherein the AAV capsid variant comprises amino acid T at position 450, amino acid I at position 451, and / or amino acid N at position 452, according to any one of SEQ ID NO: 138, 981, or 982.

[0124] 48. An AAV particle as described in any one of embodiments 1 to 47, wherein the AAV capsid variant further comprises [N0], wherein [N0] comprises X A X B and X C , and among them: (a) X A The options are: T, S, Y, M, A, C, I, R, L, D, F, V, Q, N, H, E, or G; (b) X B The following are the initials: I, M, P, E, N, D, S, A, T, G, Q, F, V, L, C, H, R, W, or L; and (c) X C For: N, M, E, G, Y, W, T, I, Q, F, V, A, L, I, P, K, R, H, S, D, or S; and Optionally, the AAV capsid variant comprises an amino acid modification, such as a conserved substitution, of any of the aforementioned amino acids in (a)-(c).

[0125] 49. The AAV particle of embodiment 48, wherein [NO] is or includes 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, MEF, 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, HDW, IEG, TII, TFP, TEK, EIN, TVN, TFN, SIN, TER, TSY, ELH, AIN, SVN, TDN, TFH, T VH, TEN, TSS, TID, TCN, NIN, TEH, AEM, AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TIY, TFS, TES, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, N AD, TIT, NCV, TIR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV , SDI, NSI, NSL, EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, NNL or any dipeptide thereof.

[0126] 50. The AAV particles of embodiment 48 or 49, wherein [N0]-[N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 2242-2886; (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0127] 51. The AAV particle of any one of embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains TINGSGSPHSKAQNQQ (SEQ ID NO: 2242).

[0128] 52. The AAV particle of any one of embodiments 48 to 50, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains TINGHDSPHKSGQNQQ (SEQ ID NO: 2243).

[0129] 53. The AAV particle of any one of embodiments 48 to 52, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains TINGSGSPHKYGQNQQT (SEQ ID NO: 5246).

[0130] 54. An AAV particle as described in any of embodiments 1 to 53, wherein [N1]-[N2]-[N3] are present in ring IV.

[0131] 55. An AAV particle as described in any of embodiments 48 to 54, wherein [N0] and [N4] are present in ring IV.

[0132] 56. The AAV particle of any one of embodiments 48 to 55, wherein [N0] is present immediately after position 449 according to the number SEQ ID NO:138.

[0133] 57. The AAV particle of any one of embodiments 48 to 56, wherein [N0] is present immediately after position 449 according to any one of the numbers in SEQ ID NO: 36-59, 981 or 982.

[0134] 58. AAV particles as described in any one of embodiments 48 to 57, wherein [N0] replaces positions 450, 451 and 452 numbered according to SEQ ID NO: 138 (e.g., T450, I451 and N452).

[0135] 59. The AAV particle as described in any one of embodiments 48 to 58, wherein [N0] replaces positions 450-452 (e.g., T450, I451, and N452) according to any one of the numbers in SEQ ID NO: 36-59, 981, or 982.

[0136] 60. The AAV particle of any one of embodiments 48 to 59, wherein [N0] corresponds to position 450-452 of any one of SEQ ID NO: 36-59, 138, 981 or 982.

[0137] 61. An AAV particle as described in any of embodiments 48 to 60, wherein [N0] is present immediately after position 449, and wherein [N0] replaces positions 450-452 (e.g., T450, I451, and N452), which are numbered according to SEQ ID NO: 138.

[0138] 62. An AAV particle as described in any of embodiments 48 to 61, wherein [N0] is present immediately after position 449, and wherein [N0] replaces positions 450-452 (e.g., T450, I451, and N452), which are numbered according to any one of SEQ ID NO: 36-59, 981, or 982.

[0139] 63. The AAV particle of any one of embodiments 1 to 62, wherein [N1] is present immediately after position 452 of the amino acid sequence number according to SEQ ID NO: 138.

[0140] 64. The AAV particle of any one of embodiments 1 to 63, wherein [N1] is present immediately after position 452 according to the number SEQ ID NO: 981 or 982.

[0141] 65. The AAV particle of any one of embodiments 1 to 61, wherein [N1] replaces positions 453-455 (e.g., G453, S454 and G455) numbered according to SEQ ID NO: 138.

[0142] 66. The AAV particle as described in any one of embodiments 1 to 64, wherein [N1] replaces position 453 (e.g., G453) according to the number SEQ ID NO: 138.

[0143] 67. The AAV particle of any one of embodiments 1 to 65, wherein [N1] replaces positions 453-455 (e.g., G453, S454 and G455) according to SEQ ID NO: 981.

[0144] 68. The AAV particle as described in any one of embodiments 1 to 65 or 67, wherein [N1] replaces positions 453-455 according to the number SEQ ID NO:982.

[0145] 69. An AAV particle as described in any one of embodiments 1 to 65, 67 or 68, wherein [N1] is present immediately after position 452, and wherein [N1] replaces positions 453-455 (e.g., G453, S454 and G455), which are numbered according to SEQ ID NO:138.

[0146] 70. An AAV particle as described in any one of embodiments 1 to 64 or 66, wherein [N1] is present immediately after position 452, and wherein [N1] replaces position 453 (e.g., G453), these positions being numbered according to SEQ ID NO: 138.

[0147] 71. An AAV particle as described in any one of embodiments 1 to 64, 66 or 70, wherein [N1] is present immediately after position 452, and wherein [N1] replaces positions 453-455, which are numbered according to SEQ ID NO: 4, 36, 981 or 982.

[0148] 72. The AAV particle of any one of embodiments 1 to 71, wherein [N1] corresponds to position 453-455 according to any one of the numbers SEQ ID NO: 4, 36-59, 981 or 982.

[0149] 73. An AAV particle as described in any one of embodiments 1 to 72, wherein the AAV capsid variant contains an amino acid other than S at position 454 and / or an amino acid other than G at position 455 according to SEQ ID NO: 138, 981 or 982.

[0150] 74. An AAV particle as described in any one of embodiments 1 to 73, wherein the AAV capsid variant comprises amino acid H at position 454 and amino acid D at position 455 according to SEQ ID NO: 138 or 982.

[0151] 75. An AAV particle as described in any one of embodiments 1 to 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) according to SEQ ID NO: 138.

[0152] 76. An AAV particle as described in any one of embodiments 1 to 75, wherein the AAV capsid variant comprises amino acid H at position 454 and amino acid D at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455, these positions being numbered according to SEQ ID NO: 138.

[0153] 77. An AAV particle as described in any one of embodiments 1 to 76, wherein the AAV capsid variant comprises amino acid H at position 454 and amino acid D at position 455 according to SEQ ID NO: 982.

[0154] 78. An AAV particle as described in any one of embodiments 1 to 77, wherein the AAV capsid variant comprises amino acid H at position 454 and amino acid D at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455, these positions being numbered according to SEQ ID NO: 982.

[0155] 79. An AAV particle as described in any one of embodiments 1 to 72, wherein the AAV capsid variant comprises amino acid S at position 454 and amino acid G at position 455 according to SEQ ID NO: 138.

[0156] 80. An AAV particle as described in any one of embodiments 1 to 72 or 79, wherein the AAV capsid variant comprises amino acid S at position 454 and amino acid G at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455, these positions being numbered according to SEQ ID NO: 138.

[0157] 81. An AAV particle as described in any one of embodiments 1 to 72, 79 or 80, wherein the AAV capsid variant comprises amino acid S at position 454 and amino acid G at position 455 according to SEQ ID NO: 981.

[0158] 82. An AAV particle as described in any one of embodiments 1 to 72 or 79 to 81, wherein the AAV capsid variant comprises amino acid S at position 454 and amino acid G at position 455, and further comprises the amino acid sequence SPHSKA (SEQ ID NO: 941) immediately following position 455, these positions being numbered according to SEQ ID NO: 981.

[0159] 83. The AAV particle of any one of embodiments 1 to 82, wherein [N2] is present immediately after position 455 according to the number SEQ ID NO: 138.

[0160] 84. The AAV particle of any one of embodiments 1 to 83, wherein [N2] corresponds to position 456-458 of SEQ ID NO: 981 or 982 (e.g., S456, P457, H458).

[0161] 85. The AAV particle of any one of embodiments 1 to 83, wherein [N2] corresponds to position 456-458 of any one of SEQ ID NO: 4 or 36-59 (e.g., S456, P457, H458).

[0162] 86. The AAV particles of any one of embodiments 1 to 85, wherein [N2]-[N3] are present immediately after position 455 according to the number SEQ ID NO: 138.

[0163] 87. An AAV particle as described in any of embodiments 1 to 86, wherein [N2] is present immediately after position 455 according to SEQ ID NO: 4, 36, 981 or 982.

[0164] 88. The AAV particles of any one of embodiments 1 to 87, wherein [N2]-[N3] are present immediately after position 455 according to SEQ ID NO: 4, 36, 981 or 982.

[0165] 89. AAV particles as described in any one of embodiments 1 to 88, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO:981 (e.g., S456, P457, H458, S459, K460, A461).

[0166] 90. The AAV particle of any one of embodiments 1 to 88, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO:982 (e.g., S456, P457, H458, K459, S460, G461).

[0167] 91. An AAV particle as described in any of embodiments 1-90, wherein [N2] is present immediately following [N1].

[0168] 92. An AAV particle as described in any one of embodiments 1 to 64, 66, 70 or 71, wherein [N3] is present immediately after [N2] and replaces positions 454 and 455 (e.g., S454 and G455), which are numbered according to SEQ ID NO: 138.

[0169] 93. An AAV particle as described in any one of embodiments 1 to 64, 66, 70, 71 or 92, wherein [N3] is present immediately following [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455), which are numbered according to SEQ ID NO: 138.

[0170] 94. The AAV particle of any one of embodiments 39 to 93, wherein [N4] is present immediately after position 455 according to the number SEQ ID NO:138.

[0171] 95. The AAV particles of any one of embodiments 39 to 94, wherein [N4] replaces positions 456-459 (e.g., Q456, N457, Q458 and Q459) according to SEQ ID NO: 138.

[0172] 96. The AAV particle of any one of embodiments 39 to 95, wherein [N4] corresponds to position 462-465 of SEQ ID NO: 4, 36, 981 or 982 (e.g., Q462, N463, Q464, Q465).

[0173] 97. The AAV particle of any one of embodiments 39 to 96, wherein [N2]-[N3]-[N4] replace positions 456-459 (e.g., Q456, N457, Q458 and Q459) according to SEQ ID NO: 138.

[0174] 98. An AAV particle as described in any of embodiments 39 to 97, wherein [N2]-[N3]-[N4] is present immediately after position 455, and wherein [N2]-[N3]-[N4] replaces positions 456-459 (e.g., Q456, N457, Q458, and Q459), which are numbered according to SEQ ID NO: 138.

[0175] 99. AAV particles as described in any one of embodiments 39 to 98, wherein [N2]-[N3]-[N4] correspond to positions 456-465 of SEQ ID NO: 981 (e.g., S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0176] 100. AAV particles as described in any one of embodiments 39 to 98, wherein [N2]-[N3]-[N4] correspond to positions 456-465 of SEQ ID NO: 982 (e.g., S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0177] 101. The AAV particle of any one of embodiments 39 to 98, wherein [N2]-[N3]-[N4] corresponds to position 456-465 of SEQ ID NO: 4 or any one of 36-59.

[0178] 102. The AAV particles of any one of embodiments 39 to 101, wherein [N1]-[N2]-[N3]-[N4] replace positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458 and Q459) according to the numbering according to SEQ ID NO: 138.

[0179] 103. An AAV particle as described in any of embodiments 39 to 102, wherein [N1]-[N2]-[N3]-[N4] is present immediately after position 452, and wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, and Q459), which are numbered according to SEQ ID NO: 138.

[0180] 104. AAV particles as described in any one of embodiments 39 to 99, 102 or 103, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-465 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0181] 105. AAV particles as described in any one of embodiments 39 to 98, 100, 102 or 103, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-465 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0182] 106. The AAV particles of any one of embodiments 39 to 98, 102 or 103, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-465 of any one of SEQ ID NO: 4 or 36-59.

[0183] 107. AAV particles as described in any one of embodiments 1 to 99 or 102 to 104, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0184] 108. AAV particles as described in any one of embodiments 1 to 98, 100, 102, 103 or 105, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461).

[0185] 109. The AAV particles of any one of embodiments 39 to 98, 102, 103 or 106, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of any one of SEQ ID NO: 36-59.

[0186] 110. AAV particles as described in any of embodiments 48 to 109, wherein [N0]-[N1]-[N2]-[N3]-[N4] replace positions 450-459 according to SEQ ID NO: 138 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458 and Q459).

[0187] 111. An AAV particle as described in any of embodiments 48 to 110, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately after position 449, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 450-459 (e.g., T450, I451, N452, G453, S454, G455, Q456, N457, Q458, and Q459), these positions being numbered according to SEQ ID NO:138.

[0188] 112. AAV particles as described in any one of embodiments 48 to 99, 102 to 104 or 106, wherein [N0]-[N1]-[N2]-[N3]-[N4] correspond to positions 450-465 of SEQ ID NO: 981 (e.g., T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465).

[0189] 113. AAV particles as described in any one of embodiments 48 to 98, 100, 102, 103, 105 or 108, wherein [N0]-[N1]-[N2]-[N3]-[N4] correspond to positions 450-465 of SEQ ID NO: 982 (e.g., T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465).

[0190] 114. The AAV particles of any one of embodiments 48 to 98, 102, 103, 106 or 109, wherein [N0]-[N1]-[N2]-[N3]-[N4] correspond to positions 450-465 of any one of SEQ ID NO: 36-59.

[0191] 115. The AAV particles of any one of embodiments 39 to 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.

[0192] 116. The AAV particle of any one of embodiments 39 to 115, wherein [N2]-[N3]-[N4] replace positions 462-465 (e.g., Q462, N463, Q464 and Q465) numbered according to SEQ ID NO: 4, 36, 981 or 982.

[0193] 117. An AAV particle as described in any of embodiments 39 to 116, wherein [N2]-[N3]-[N4] is present immediately after position 455, and wherein [N2]-[N3]-[N4] replaces positions 462-465 (e.g., Q462, N463, Q464, and Q465), which are numbered according to SEQ ID NO: 4, 36, 981, or 982.

[0194] 118. An AAV particle as described in any of embodiments 1 to 117, wherein [N3] is present immediately following [N2].

[0195] 119. An AAV particle as described in any one of embodiments 1 to 118, wherein the AAV capsid variant comprises [N2]-[N3] from the N-terminus to the C-terminus.

[0196] 120. An AAV particle as described in any one of embodiments 1 to 119, wherein the AAV capsid variant comprises [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0197] 121. An AAV particle as described in any of embodiments 48 to 120, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0198] 122. An AAV particle as described in any of embodiments 39 to 121, wherein the AAV capsid variant comprises [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0199] 123. An AAV particle as described in any of embodiments 48 to 122, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0200] 124. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant contains an amino acid other than T (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G or S) at position 460 according to SEQ ID NO: 138.

[0201] 125. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant comprises amino acid N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G or S at position 460 according to SEQ ID NO: 138.

[0202] 126. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant comprises an amino acid other than T (e.g., N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G, or S) at position 466 according to any of the numbers in SEQ ID NO: 36-59, 981, or 982.

[0203] 127. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant comprises amino acids N, I, C, H, R, L, D, Y, A, M, Q, I, E, K, P, G or S at position 466 according to any of the numbers in SEQ ID NO: 36-59, 981 or 982.

[0204] 128. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant contains an amino acid other than K (e.g., E, N, or T) at position 449 according to any of the numbers in SEQ ID NO: 36-59, 138, 981, or 982.

[0205] 129. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant contains amino acid E, N or T at position 449 according to any of the numbers in SEQ ID NO: 36-59, 138, 981 or 982.

[0206] 130. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises [A][B] (SEQ ID NO: 4694), wherein: (i) [A] contains the amino acid sequence GSGSPH (SEQ ID NO: 4695); and (ii) [B] contains X1 X2 X3 X4 X5 X6 X7, where: (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 or F; (e) X5 is: N, Y, R, C, K, or L; (f) X6 is: Q, G, K, R, T, L, or Y; and (g) X7 is: Q, L, R or V; Optionally, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(g), such as a conserved substitution.

[0207] 131. The AAV particles as described in embodiment 130, wherein

[0208] (a) X1 is S; (b) X2 is K or L; (c) X3 is: A, R, or L; (d) X4 is either Q or R; (e) X5 is either N or R; (f) X6 is either Q or R; and (g) X7 is: Q, L or R.

[0209] 132. The AAV particle as described in implementation scheme 130 or 131, wherein [B] comprises: (i) SLLWNQQ (SEQ ID NO: 5247)、SKAQYYV (SEQ ID NO: 5248)、SKLRRQQ (SEQID NO: 5249)、SIWQNQQ (SEQ ID NO: 5250)、SKAGCGQ (SEQ ID NO: 5251)、SRAQNQQ (SEQID NO: 5252)、SKRLRQQ (SEQ ID NO: 5253)、SLRRNQQ (SEQ ID NO: 5254)、SRGRNQQ (SEQID NO: 5255)、SEIVNQQ (SEQ ID NO: 5256)、SSRRNQQ (SEQ ID NO: 5257)、CLLQNQQ (SEQID NO: 5258)、SKAFRLQ (SEQ ID NO: 5259)、CLAQNQQ (SEQ ID NO: 5260)、FLRQNQQ (SEQID NO: 5261)、SLRFNQQ (SEQ ID NO: 5262)、SYLRNQQ (SEQ ID NO: 5263)、CSLQNQQ (SEQID NO: 5264)、VLWQNQQ (SEQ ID NO: 5265)、SKWLLQQ (SEQ ID NO: 5266)、SLWSNQQ (SEQID NO: 5267)、SKRRLQQ (SEQ ID NO: 5268)、SVYLNQQ (SEQ ID NO: 5269)、SLWLNQQ (SEQID NO: 5270)、SKAQRKL (SEQ ID NO: 5271)、SKALRRQ (SEQ ID NO: 5272)、SKAQRLR (SEQID NO: 5273)、SKAQNQQ (SEQ ID NO: 5274)、SKAQRRL (SEQ ID NO: 5275)、SKARRQQ (SEQID NO: 5276)、SKARRLQ (SEQ ID NO: 5277)、SKSRRQQ (SEQ ID NO: 5278)、SKARLRQ (SEQID NO: 5279)、SKASKRQ (SEQ ID NO: 5280)、VRRQNQQ (SEQ ID NO: 5281)、SKAQLYR (SEQID NO: 5282)、SLFRNQQ (SEQ ID NO: 5283)、SKAQLTV (SEQ ID NO: 5284); (ii) Any part of the amino acid sequence in (i), such as any 2, 3, 4, 5 or 6 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0210] 133. An AAV particle as described in any of embodiments 130 to 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)、GSGSPHVLWQNQQ(SEQ ID NO: 5292)、GSGSPHSKWLLQQ (SEQ ID NO: 2072)、GSGSPHSLWSNQQ (SEQ ID (SEQ ID NO: 5293) GSGSPHSKRRLQQ (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), GGSPHSKSRRQQ (SEQ ID NO: 2080), GGSPHSKARLRQ (SEQ ID NO: 2082), GSGSPHSKASKRQ (SEQ ID NO: 2083), GGSSPSVRRQNQQ (SEQ ID NO: 2084), GGSSPHSKAQLYR (SEQ ID NO: 2085), GGSSPHSLFRNQQ (SEQ ID NO: 5296), GGSSPHSKAQLTV (SEQ ID NO: 2086); (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0211] 134. An AAV particle as described in any one of embodiments 130 to 133, wherein the AAV capsid variant further comprises one, two, or all of the amino acid other than T (e.g., S, Y, or G) at position 450, the amino acid other than I (e.g., M or L) at position 451, and / or the amino acid other than N (e.g., S) at position 452, as specified in SEQ ID NO: 138.

[0212] 135. An AAV particle as described in any one of embodiments 130 to 134, wherein the AAV capsid variant further comprises S at position 450 and M at position 451 according to SEQ ID NO: 138.

[0213] 136. An AAV particle as described in any one of embodiments 130 to 134, wherein the AAV capsid variant further comprises Y at position 450, L at position 451, and S at position 452, as specified in SEQ ID NO: 138.

[0214] 137. An AAV particle as described in any one of embodiments 130 to 134, wherein the AAV capsid variant further comprises G at position 450, L at position 451, and S at position 452, as numbered according to SEQ ID NO: 138.

[0215] 138. An AAV particle as described in any of embodiments 130 to 137, wherein [A][B] is present in ring IV.

[0216] 139. An AAV particle as described in any of embodiments 130 to 138, wherein [A] is present immediately following position 452 according to the number SEQ ID NO: 138.

[0217] 140. The AAV particle as described in any one of embodiments 130 to 139, wherein [A] replaces positions 453-455 (e.g., G453, S454, G455) according to the numbering in SEQ ID NO:138.

[0218] 141. An AAV particle as described in any of embodiments 130 to 140, wherein [A] is present immediately after position 452, and wherein [A] replaces positions 453-455 (e.g., G453, S454, G455), which are numbered according to SEQ ID NO: 138.

[0219] 142. An AAV particle as described in any of embodiments 130 to 141, wherein [B] exists immediately following [A].

[0220] 143. AAV particles as described in any one of embodiments 130 to 142, wherein [B] replaces positions 456-459 (e.g., Q456, N457, Q458, Q459) according to SEQ ID NO:138.

[0221] 144. AAV particles as described in any one of embodiments 130 to 143, wherein [A][B] replaces positions 453-459 according to the numbering according to SEQ ID NO:138 (e.g., G453, S454, G455, Q456, N457, Q458, Q459).

[0222] 145. An AAV particle as described in any of embodiments 130 to 144, wherein [A][B] is present immediately after position 452, and wherein [A][B] replaces positions 453-459 (e.g., G453, S454, G455, Q456, N457, Q458, Q459), which are numbered according to SEQ ID NO: 138.

[0223] 146. An AAV particle as described in any one of embodiments 130 to 145, wherein the AAV capsid variant comprises [A][B] from the N-terminus to the C-terminus.

[0224] 147. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises [A][B] (SEQ ID NO: 4699), wherein: (i) [A] contains X1 X2 X3 X4 X5 X6, where (a) X1 is T, M, A, C, I, 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 either D or R; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conserved substitution, of any of the aforementioned amino acids in (a)-(f); and (ii) [B] Contains SPHKSG (SEQ ID NO: 946).

[0225] 148. AAV particles as described in implementation scheme 147, wherein

[0226] (a) X1 is: T, M, A or I; (b) X2 is: E, I, or D; (c) X3 is: N, Q, Y, I, M or V; (d) X4 is G; (e) X5 is H; and (f) X6 is D.

[0227] 149. The AAV particle as described in implementation scheme 147 or 148, wherein [A] comprises: (i) TINGHD (SEQ ID NO: 5297)、MPEGHD (SEQ ID NO: 5298)、MEGGHD (SEQ IDNO: 5299)、MEYGHD (SEQ ID NO: 5300)、AEWGHD (SEQ ID NO: 5301)、CEWGHD (SEQ IDNO: 5302)、ANNGQD (SEQ ID NO: 5303)、IPEGHD (SEQ ID NO: 5304)、ADMGHD (SEQ IDNO: 5305)、IEYGHD (SEQ ID NO: 5306)、ADYGHD (SEQ ID NO: 5307)、IETGHD (SEQ IDNO: 5308)、MEWGHD (SEQ ID NO: 5309)、CEYGHD (SEQ ID NO: 5310)、RINGHD (SEQ IDNO: 5311)、MEIGHD (SEQ ID NO: 5312)、LEYGHD (SEQ ID NO: 5313)、ADWGHD (SEQ IDNO: 5314)、IEIGHD (SEQ ID NO: 5315)、TIKDND (SEQ ID NO: 5316)、DIMGHD (SEQ IDNO: 5317)、FEQGHD (SEQ ID NO: 5318)、MEFGHD (SEQ ID NO: 5319)、CDQGHD (SEQ IDNO: 5320)、LPEGHD (SEQ ID NO: 5321)、IENGHD (SEQ ID NO: 5322)、MESGHD (SEQ IDNO: 5323)、AEIGHD (SEQ ID NO: 5324)、VEYGHD (SEQ ID NO: 5325)、TSNGDD (SEQ IDNO: 5326)、IEVGHD (SEQ ID NO: 5327)、MEMGHD (SEQ ID NO: 5328)、AEVGHD (SEQ IDNO: 5329)、MDAGHD (SEQ ID NO: 5330)、VEWGHD (SEQ ID NO: 5331)、AEQGHD (SEQ IDNO: 5332)、LEWGHD (SEQ ID NO: 5333)、MELGHD (SEQ ID NO: 5334)、METGHD (SEQ IDNO: 5335)、MEAGHD (SEQ ID NO: 5336)、TINRQR(SEQ ID NO: 5337), IESGHD (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), NMNGHD (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) Any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0228] 150. An AAV particle as described in any of embodiments 147 to 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: 5374) 5375)、MEFGHDSPHKS (SEQ ID NO: 5376)、CDQGHDSPHKS (SEQ ID NO: 5377)、LPEGHDSPHKS (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), NNMNGHDSPHKS (SEQ ID NO: 5403), TPWEHDSPHKS (SEQ ID NO: 5404), IEMGHDSPHKS (SEQ ID NO: 5405), TANEHDSPHKS (SEQ ID NO: 5406), TINGHDSPHKS (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) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0229] 151. An AAV particle as described in any one of embodiments 147 to 150, wherein the AAV capsid variant further comprises one, two, three, four, or all of the following amino acids according to SEQ ID NO: 138: position 456 other than Q (e.g., R or L), position 457 other than N (e.g., H, K, or R), position 458 other than Q (e.g., R or T), position 459 other than Q (H), and / or position 460 other than T (N or S).

[0230] 152. An AAV particle as described in any one of embodiments 147 to 151, wherein the AAV capsid variant further comprises R at position 456 according to SEQ ID NO: 138.

[0231] 153. An AAV particle as described in any one of embodiments 147 to 151, wherein the AAV capsid variant further comprises L at position 456 according to SEQ ID NO: 138.

[0232] 154. An AAV particle as described in any one of embodiments 147 to 153, wherein the AAV capsid variant further comprises H at position 457 and R at position 458 according to SEQ ID NO: 138.

[0233] 155. An AAV particle as described in any one of embodiments 147 to 153, wherein the AAV capsid variant further comprises K at position 457 and N at position 460 according to SEQ ID NO: 138.

[0234] 156. An AAV particle as described in any one of embodiments 147 to 153, wherein the AAV capsid variant further comprises T at position 458, H at position 459, and S at position 460, as specified in SEQ ID NO: 138.

[0235] 157. An AAV particle as described in any one of embodiments 147 to 151, wherein the AAV capsid variant further comprises R at position 456, R at position 457 and R at position 458 according to SEQ ID NO: 138.

[0236] 158. An AAV particle as described in any of embodiments 147 to 157, wherein [A][B] is present in ring IV.

[0237] 159. An AAV particle as described in any of embodiments 147 to 158, wherein [A] is present immediately following position 449 according to SEQ ID NO: 138.

[0238] 160. AAV particles as described in any one of embodiments 147 to 159, wherein [A] replaces positions 450-453 (e.g., T450, I451, N452, G453) according to the numbering in SEQ ID NO:138.

[0239] 161. An AAV particle as described in any of embodiments 147 to 160, wherein [A] is present immediately after position 449, and wherein [A] replaces positions 450-453 (e.g., T450, I451, N452, G453), which are numbered according to SEQ ID NO:138.

[0240] 162. The AAV particles of any one of embodiments 147 to 161, wherein [A][B] replaces positions 450-455 according to the numbering according to SEQ ID NO:138 (e.g., T450, I451, N452, G453, S454, G455).

[0241] 163. An AAV particle as described in any of embodiments 147 to 162, wherein [A][B] is present immediately after position 449, and wherein [A][B] replaces positions 450-455 (e.g., T450, I451, N452, G453, S454, G455), which are numbered according to SEQ ID NO: 138.

[0242] 164. An AAV particle as described in any of embodiments 147 to 163, wherein [B] is present immediately following [A] and replaces positions 454 and 455 (e.g., S454 and G455), these positions being numbered according to SEQ ID NO: 138.

[0243] 165. An AAV particle as described in any of embodiments 147 to 164, wherein [B] is present immediately after position 455 according to SEQ ID NO: 4, 36, 981 or 982.

[0244] 166. An AAV particle as described in any of embodiments 147 to 165, wherein [B] exists immediately following [A].

[0245] 167. An AAV particle as described in any of embodiments 147 to 166, wherein the AAV capsid variant comprises [A][B] from the N-terminus to the C-terminus.

[0246] 168. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3] (SEQ ID NO: 6407), wherein: (i) [N1] contains X1, X2 and X3, where X2 is S and X3 is G; (ii) [N2] contains the amino acid sequence SPH; and (iii) [N3] contains X4, X5 and X6, where X5 is K.

[0247] 169. The AAV particles of implementation scheme 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, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (i) or (ii).

[0248] 170. The AAV particle as described in implementation scheme 168 or 169, wherein X4 is S and / or X5 is A.

[0249] 171. An AAV particle as described in any of embodiments 168 to 170, wherein [N3] comprises SK, TK, NK, AK, KA, KV, KT, KS, KG, KR, KL or KN.

[0250] 172. An AAV particle as described in any of embodiments 168 to 171, wherein [N3] is or includes SKA, SKV, SKT, SKS, SKG, SKR, TKA, NKA, SKL, SKN or AKA.

[0251] 173. An AAV particle as described in any of embodiments 168 to 172, wherein [N3] is or contains SKA.

[0252] 174. The AAV particles of any one of embodiments 168 to 173, wherein [N2]-[N3] comprise SPHSK (SEQ ID NO: 4701), SPHTK (SEQ ID NO: 4725), SPHNK (SEQ ID NO: 4726) or SPHAK (SEQ ID NO: 4727).

[0253] 175. An AAV particle as described in any of embodiments 168 to 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 SPHAKA (SEQ ID NO: 4736); (ii) Any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0254] 176. The AAV particles of any one of embodiments 168 to 175, wherein [N2]-[N3] are or contain SPHSKA (SEQ ID NO: 941).

[0255] 177. An AAV particle as described in any one of embodiments 168 to 176, wherein the AAV capsid variant contains an amino acid other than G (e.g., M, T, I, E, S, A, N, V, L, K, H, P, R, W, or D) at position 453 according to SEQ ID NO: 138 or 981.

[0256] 178. An AAV particle as described in any one of embodiments 168 to 177, wherein the AAV capsid variant contains amino acid G at position 453 according to SEQ ID NO: 138 or 981.

[0257] 179. An AAV particle as described in any of embodiments 168 to 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 of any of the aforementioned amino acids, such as a conservative substitution.

[0258] 180. An AAV particle as described in any of embodiments 168 to 179, wherein [N1] comprises SG, GS, MS, TS, IS, ES, SS, AS, NS, VS, LS, KS, HS, PS, RS, WS, or DS.

[0259] 181. An AAV particle as described in any one of embodiments 168 to 180, wherein [N1] is or includes: GSG, MSG, TSG, ISG, ESG, SSG, ASG, NSG, VSG, LSG, KSG, HSG, PSG, RSG, WSG, or DSG.

[0260] 182. An AAV particle as described in any of embodiments 168 to 181, wherein [N1] is or contains GSG.

[0261] 183. The AAV particles of any one of embodiments 168 to 182, wherein [N1]-[N2] comprises SGSPH (SEQ ID NO: 4752).

[0262] 184. An AAV particle as described in any of embodiments 168 to 183, wherein [N1]-[N2] are or include: (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), ASGSPH (SEQ ID NO: 4806), NSGSPH (SEQ ID NO: 4807), VSGSPH (SEQ ID NO: 4786), LSGSPH (SEQ ID NO: 4808), KSGSPH (SEQ ID NO: 4810), HSGSPH (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) Any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0263] 185. An AAV particle as described in any of embodiments 168 to 184, wherein [N1]-[N2]-[N3] are or include: (i) GSGSPHSKA (SEQ ID NO: 4697), GSGSPHSKV (SEQ ID NO: 4956), MSGSPHSKA (SEQ ID NO: 4957), TSGSPHSKA (SEQ ID NO: 4959), ISGSPHSKA (SEQ ID NO: 4960), GSGSPHSKT (SEQ ID NO: 4962), ESGSPHSKA (SEQ ID NO: 4963), SSGSPHSKA (SEQ ID NO: 4964), GGSSPHSKA (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), GGSSPHSKR (SEQ ID NO: 4945), HSGSPHSKA (SEQ ID NO: 4973), PSGSPHSKA (SEQ ID NO: 4975), RGSSPHSKA (SEQ ID NO: 4977), GGSSPHTKA (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) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8 or 9 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0264] 186. The AAV particles of any one of embodiments 168 to 185, wherein [N1]-[N2]-[N3] are or contain GGSPHSKA (SEQ ID NO: 4697).

[0265] 187. An AAV capsid variant of any one of embodiments 168 to 186, comprising an amino acid other than Q (e.g., R, P, H, L, K, I, G, S, M, or E) at position 456 according to SEQ ID NO: 138, an amino acid other than N (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M) at position 457, an amino acid other than Q (e.g., R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, or D) at position 458, an amino acid other than Q (e.g., H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G) at position 459, and / or an amino acid other than T (e.g., I, N, S, H, R, L, D, Y, A, or Q) at position 460.

[0266] 188. An AAV particle as described in any one of embodiments 168 to 187, wherein the AAV capsid variant comprises, according to SEQ ID NO: Amino acids other than Q (e.g., R, P, H, L, K, I, G, S, M, or E) at position 462 of number 981, amino acids other than N (e.g., D, V, S, P, T, G, Y, W, E, R, H, K, F, A, I, L, or M) at position 464, amino acids other than Q (e.g., R, L, A, P, H, T, I, F, K, V, M, G, W, Y, S, E, N, or D) at position 465, amino acids other than Q (e.g., H, K, A, L, P, E, M, I, S, N, R, Y, C, V, T, W, D, G) at position 466, and / or amino acids other than T (e.g., I, N, S, H, R, L, D, Y, A, or Q) at position 466.

[0267] 189. An AAV particle as described in any one of embodiments 168 to 188, wherein the AAV capsid variant comprises amino acid Q at position 456, amino acid N at position 457, amino acid Q at position 458, amino acid Q at position 459, and / or amino acid T at position 460, as specified in SEQ ID NO: 138.

[0268] 190. An AAV particle as described in any one of embodiments 168 to 189, wherein the AAV capsid variant comprises amino acid Q at position 462, amino acid N at position 463, amino acid Q at position 464, amino acid Q at position 465, and / or amino acid T at position 466, as specified in SEQ ID NO: 981.

[0269] 191. An AAV particle as described in any one of embodiments 168 to 190, wherein the AAV 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, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(e), such as a conserved substitution.

[0270] 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)、QYQQT (SEQ ID NO:5429)、QDQET (SEQ ID NO: 5430)、QNHQT (SEQ ID NO: 5431)、QDQQT (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)、QYIHT (SEQ ID NO:5441)、QKFET (SEQ ID NO: 5442)、QFPST (SEQ ID NO: 5443)、HNQQR (SEQ ID NO:5444)、QAIKT (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 IDNO: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)、QNLQA (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:5468) NO: 5469), QAMHT (SEQ ID NO: 5470), LNNQQT (SEQ ID NO: 5471), QHPST (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 IDNO: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)、IGKQT (SEQ ID NO: 5509)、QAIHT (SEQ ID NO:5510)、QHGLT (SEQ ID NO: 5511)、QFMCT (SEQ ID NO: 5512)、QHLQT (SEQ ID NO:5513)、QNHQN (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 ID NO: 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 IDNO: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) Any part of the amino acid sequence in (i), such as any 2, 3 or 4 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0271] 193. The AAV particles of embodiment 191 or 192, wherein [N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 200 or 2887-3076; (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acids thereon, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0272] 194. The AAV particle of any one of embodiments 191 to 193, wherein [N1]-[N2]-[N3]-[N4] is or contains GGSPHSKAQNQQT (SEQ ID NO: 200).

[0273] 195. An AAV particle as described in any one of embodiments 191 to 193, wherein [N1]-[N2]-[N3]-[N4] is or contains VSGSPHASKAQNQQT (SEQ ID NO: 903).

[0274] 196. An AAV particle as described in any one of embodiments 168 to 195, wherein the AAV capsid variant comprises an amino acid other than K (e.g., T, E, or N) at position 449, an amino acid other than T (e.g., S, E, A, N, V, Q, or G) at position 450, an amino acid other than I (e.g., F, E, V, L, D, S, C, T, A, N, H, R, G, or W) at position 451, and / or an amino acid other than N (e.g., I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G) at position 452.

[0275] 197. An AAV particle as described in any one of embodiments 168 to 196, wherein the AAV capsid variant comprises amino acid K at position 449, amino acid T at position 450, amino acid I at position 451, and / or amino acid N at position 452, as specified in SEQ ID NO: 138 or 981.

[0276] 198. An AAV particle as described in any one of embodiments 168 to 197, wherein the AAV capsid variant further comprises [N0], wherein [N0] comprises XA, X B X C and X D ,in: (a) X A It can be K, T, E, or N; (b) X B For T, S, E, A, N, V, Q, or G; (c) X C It is I, F, E, V, L, D, S, C, T, A, N, H, R, G, or W; and (d) X D For N, I, P, K, R, H, S, M, Q, D, T, L, A, Y, V, F, E, W, or G; Optionally, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(d), such as a conserved substitution.

[0277] 199. The AAV particle of embodiment 198, wherein [N0] 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 IDNO: 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 IDNO: 5590)、KTEI (SEQ ID NO: 5591)、KTID (SEQ ID NO: 5592)、KNTN (SEQ ID NO:5593)、KTET (SEQ ID NO: 5594)、KTEL (SEQ ID NO: 5595)、KNIN (SEQ ID NO: 5596)、KTEA (SEQ ID NO: 5597)、KTAN (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 IDNO: 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)、KTV ID NO: 5614)、KTVI (SEQ ID NO: 5615)、KAEH (SEQ IDNO: 5616)、KNCL (SEQ ID NO: 5617)、KTVK (SEQ ID NO: 5618)、KNAD (SEQ ID NO: 5619)、KNAD (SEQ ID NO: 5619)、K IDNO: 5620)、KNCV (SEQ ID NO: 5621)、KNAL (SEQ ID NO: 5622)、KVIN (SEQ ID NO: 5623)、KTEF (SEQ ID NO: 5624)、KTRE (SEQ ID NO: 5625)、KTRE (SEQ ID NO: 5625)、SEQ ID NO: 5625) 5626)、KSEK (SEQ ID NO: 5627)、KNVN (SEQ ID NO: 5628)、KGGE (SEQ IDNO: 5629)、KEFV (SEQ ID NO: 5630)、KSDK (SEQ ID NO: 5631) (SEQ ID NO: 5631) NO:5632)、KEVQ (SEQ ID NO: 5633)、KTEY (SEQ ID NO: 5634)、KNCW (SEQ ID NO: 5635)、KTDV (SEQ ID NO: 5636)、KSDI (SEQ ID NO: 5637)、KSDI (SEQ ID NO: 5637) (SEQ ID NO: 5637) 5638)、KNSL(SEQ ID NO: 5639)、KEVV (SEQ ID NO: 5640)、KTEP (SEQ ID NO: 5641)、KSEL (SEQ IDNO: 5642)、KTWQ (SEQ ID NO: 5643)、KTWQ (SEQ ID NO: 5643) (SEQ ID NO: 5643) 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)、KTGN (SEQ ID NO: 5649) (SEQ ID NO: 5649) 5650)、FABRIC (SEQ ID NO: 5651)、CLOTH(SEQ IDNO: 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 KTIH (SEQ ID NO: 5659); (ii) Any part of the amino acid sequence in (i), such as any two or three of its amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0278] 200. AAV particles as described in implementation scheme 198 or 199, wherein [N0]-[N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 3239-3526 or 3591-3605; (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0279] 201. The AAV particle of any one of embodiments 198 to 200, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTINGSGSPHSKAQNQQT (SEQ ID NO: 5660).

[0280] 202. The AAV particle of any one of embodiments 198 to 200, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589).

[0281] 203. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 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] contains X1, X2 and X3, wherein X2 is an amino acid other than S and X3 is an amino acid other than G; (ii) [N2] contains the amino acid sequence SPH; and (iii) [N3] contains X4, X5 and X6, where X4 is K.

[0282] 204. The AAV particles as described in implementation scheme 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, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (i) or (ii).

[0283] 205. AAV particles as described in implementation scheme 203 or 204, wherein X5 is S and / or X6 is G.

[0284] 206. An AAV particle as described in any of embodiments 203 to 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.

[0285] 207. An AAV particle as described in any of embodiments 203 to 206, wherein [N3] is or includes KSG, KIG, KTG, KRG, KSA, KSL, KSE, KSV, KSR, KSW, KSN, KHG, KYG, KSQ, KIV, KSK, KLW, KMG, or KMA.

[0286] 208. An AAV particle as described in any of embodiments 203 to 207, wherein [N3] is or contains KSG.

[0287] 209. The AAV particles of any one of embodiments 203 to 208, wherein [N2]-[N3] comprise 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).

[0288] 210. An AAV particle as described in any of embodiments 203 to 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), SPHKLW (SEQ ID (SEQ ID NO: 4748), SPHKMG (SEQ ID NO: 4750) or SPHKMA (SEQ ID NO: 4751); (ii) Any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0289] 211. The AAV particle of any one of embodiments 203 to 210, wherein [N2]-[N3] is or contains SPHKSG (SEQ ID NO: 946).

[0290] 212. An AAV particle as described in any one of embodiments 203 to 211, wherein the AAV capsid variant contains an amino acid other than G (e.g., A, K, W, R, L, I, M, N, T, E, Q, Y, H, F, or V) at position 453 according to SEQ ID NO: 138 or 981.

[0291] 213. An AAV particle as described in any one of embodiments 203 to 212, wherein the AAV capsid variant contains amino acid G at position 453 according to SEQ ID NO: 138 or 981.

[0292] 214. The AAV particle as described in any one of embodiments 203 to 214, wherein: (i) X1 of [N1] is G, A, K, W, R, L, I, M, N, T, E, Q, Y, H, F or V; (ii) X2 of [N1] is H, Y, R, Q, N, P or D; (iii) X3 of [N1] is D, E, G, V or N; Optionally, the AAV capsid variant comprises an amino acid modification, such as a conservative substitution, of any of the aforementioned amino acids in (i), (ii), or (iii).

[0293] 215. An AAV particle as described in any of embodiments 203 to 214, wherein X2 of [N1] is H and X3 of [N1] is D.

[0294] 216. An AAV particle as described in any of embodiments 203 to 215, wherein X1 of [N1] is G, X2 of [N1] is H, and X3 of [N1] is D.

[0295] 217. An AAV particle as described in any of embodiments 203 to 216, wherein [N1] comprises GH, HD, GY, GR, GQ, AH, GN, KH, GP, WH, 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.

[0296] 218. An AAV capsid variant as described in any of embodiments 203 to 217, wherein [N1] is or includes GHD, GYD, GHE, GRG, GQD, GRD, AHD, GND, KHD, GPD, WHD, RHD, LHD, GQV, IHD, MHD, GDD, GHN, NHD, THD, GNG, EHD, QHD, YHD, HHD, FHD, or VHD.

[0297] 219. An AAV particle as described in any of embodiments 203 to 218, wherein [N1] is or contains GHD.

[0298] 220. An AAV particle as described in any one of embodiments 203 to 219, wherein [N1]-[N2] comprises HDSPH (SEQ ID NO: 4703).

[0299] 221. An AAV particle as described in any of embodiments 203 to 220, wherein [N1]-[N2] are or include: (i) GHDSPH (SEQ ID NO: 4784), GYDSPH (SEQ ID NO: 4829), GHESPH (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) Any part of the amino acid sequence in (i), such as any 2, 3, 4 or 5 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0300] 222. An AAV particle as described in any of embodiments 203 to 221, wherein [N1]-[N2]-[N3] are or include: (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)、GHDSPHKSE (SEQ ID NO: 5003)、GRDSPHKSG (SEQ ID NO: 5004) AHDSPHKSG (SEQ ID NO: 5681) GNDSPHKSV (SEQ ID NO: 5005) AHDSPHKIG (SEQ ID NO: 5682) GHESPHKSA (SEQ ID NO: 4939) GQDSPHKIG (SEQ ID NO: 5006) GHDSPHKSV (SEQ ID NO: 5007) GHDSPHKSR (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 ID NO: 5688), GDDSPHKSV (SEQ ID NO: 5015), GHNSPHKSG (SEQ ID NO: 5016), NHDSPHKSG (SEQ ID NO: 5689), THDSPHKSG (SEQ ID NO:5690), GGNSPHKRG (SEQ ID NO: 5017), EHDSPHKSG (SEQ ID NO: 5691), GHDSPHKYG (SEQ ID NO: 5018), GHDSPHKSQ (SEQ ID NO: 5019), QHDSPHKSG (SEQ ID NO: 5692), RHDSPHKIV (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 GDDSPHKSG (SEQ ID NO: 4938); (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8 or 9 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0301] 223. An AAV particle as described in any one of embodiments 203 to 222, wherein [N1]-[N2]-[N3] is or contains GHDSPHKSG (SEQ ID NO: 4698).

[0302] 224. An AAV particle as described in any one of embodiments 203 to 223, wherein the AAV capsid variant comprises an amino acid other than Q (e.g., R, P, H, K, L, V, A, E, or I) at position 456 according to SEQ ID NO: 138, an amino acid other than N (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q, or M) at position 457, an amino acid other than Q (e.g., R, V, K, P, Y, H, L, I, E, or M) at position 458, an amino acid other than Q (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N) at position 459, and / or an amino acid other than T (e.g., A, E, K, S, I, P, G, or N) at position 460.

[0303] 225. An AAV particle as described in any one of embodiments 203 to 224, wherein the AAV capsid variant comprises an amino acid other than Q (e.g., R, P, H, K, L, V, A, E, or I) at position 462 according to SEQ ID NO: 982, an amino acid other than N (e.g., I, K, S, H, R, T, D, Y, L, W, F, A, Q, or M) at position 463, an amino acid other than Q (e.g., R, V, K, P, Y, H, L, I, E, or M) at position 464, an amino acid other than Q (e.g., H, L, E, P, W, D, I, V, S, K, R, C, M, or N) at position 465, and / or an amino acid other than T (e.g., A, E, K, S, I, P, G, or N) at position 466.

[0304] 226. An AAV particle as described in any one of embodiments 203 to 225, wherein the AAV capsid variant comprises amino acid Q at position 456, amino acid N at position 457, amino acid Q at position 458, amino acid Q at position 459, and / or amino acid T at position 460, as specified in SEQ ID NO: 138.

[0305] 227. An AAV particle as described in any one of embodiments 203 to 226, wherein the AAV capsid variant comprises amino acid Q at position 462, amino acid N at position 463, amino acid Q at position 464, amino acid Q at position 465, and / or amino acid T at position 466, as specified in SEQ ID NO: 138.

[0306] 228. An AAV particle as described in any one of embodiments 203 to 227, wherein the AAV 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, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(e), such as a conserved substitution.

[0307] 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)、QRQHT (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)、QTQQI (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 IDNO:5724)、QNLLT (SEQ ID NO: 5725)、QLVIT (SEQ ID NO: 5726)、RTQET (SEQ ID NO:5727)、QTHQT (SEQ ID NO: 5728)、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)、QNQHS (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)、QIIVT (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 ID NO: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)、QNHQI (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 IDNO: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), LNHQT (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) Any part of the amino acid sequence in (i), such as any 2, 3 or 4 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0308] 230. The AAV particles of embodiment 228 or 229, wherein [N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 201 or 3160-3237; (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acids thereon, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0309] 231. An AAV particle as described in any one of embodiments 228 to 230, wherein [N1]-[N2]-[N3]-[N4] is or contains GHDSPHKSGQNQQT (SEQ ID NO: 201).

[0310] 232. An AAV particle as described in any one of embodiments 203 to 231, wherein the AAV capsid variant comprises an amino acid other than K (e.g., T) at position 449, an amino acid other than T (e.g., A, S, I, V, N, E, Y, C, G, W, or Q) at position 450, an amino acid other than I (e.g., E, V, S, T, N, D, C, G, Q, L, P, A) at position 451, and / or an amino acid other than N (e.g., S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R) at position 452.

[0311] 233. An AAV particle as described in any one of embodiments 203 to 232, wherein the AAV capsid variant comprises amino acid K at position 449, amino acid T at position 450, amino acid I at position 451, and / or amino acid N at position 452, as specified in SEQ ID NO: 138 or 982.

[0312] 234. An AAV particle as described in any one of embodiments 203 to 233, wherein the AAV capsid variant further comprises [N0], wherein [N0] comprises X A X B X C and X D ,in: (a) X A For K or T; (b) X B The options are T, A, S, I, V, N, E, Y, C, G, W, or Q; (c) X C For I, E, V, S, T, N, D, C, G, Q, L, P, A; and (d) X D For N, S, Y, I, K, F, T, D, E, G, V, L, A, M, Q, H, P, or R; Optionally, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(d), such as a conserved substitution.

[0313] 235. The AAV particle of embodiment 234, wherein [N0] 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)、KIIN(SEQ ID NO: 5776)、KTIS (SEQ ID NO: 5606)、KAII (SEQ ID NO: 5777)、KTIK (SEQ IDNO: 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 IDNO: 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 IDNO: 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)、K IDC NO: 5794) 5795)、KASN (SEQ ID NO: 5796)、KTET (SEQ IDNO: 5594)、KTIG (SEQ ID NO: 5797)、KTDP (SEQ ID NO: 5798)、KELV (SEQ ID NO: 5799)、KELM (SEQ ID NO: 5799) (SEQ ID NO: 5801)、KTPN (SEQ ID NO: 5802)、KTDI (SEQ ID NO: 5803)、KTDQ (SEQ ID NO: 5805)、KGIN(SEQ ID NO: 5806)、KGIN(SEQ ID NO: 5806) 5807)、KSEK (SEQ ID NO: 5627)、KWSA (SEQ IDNO: 5808)、KELA (SEQ ID NO: 5809)、KQTQ (SEQ ID NO: 5810)、KGAD (SEQ ID NO: 5811)、KGAD (SEQ ID NO: 5811)、KGAD (SEQ ID NO: 5811) (SEQ ID NO: 5813)、KTDT (SEQ ID NO: 5814)、KTCI (SEQ ID NO: 5815)、KELR (SEQ ID NO: 5816)、KCQI (SEQ ID NO: 5817)、KGVM(SEQ ID NO: 5818) 5819)、KNEL (SEQ ID NO: 5820)、KAAE (SEQ IDNO: 5821)、KGQN (SEQ ID NO: 5822)、KNEF (SEQ ID NO: 5823)、KTSI (SEQ ID NO:5824)、KTSI (SEQ ID NO: 5824)、SEQ IDNO: 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)、K IDTPD(SEQ ID NO: 5573)NO: 5827), KTIH (SEQ ID NO: 5659) or KTEI (SEQ ID NO: 5591); (ii) Any part of the amino acid sequence in (i), such as any two or three of its amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0314] 236. The AAV particles of embodiment 234 or 235, wherein [N0]-[N1]-[N2]-[N3]-[N4] are or comprise: (i) The amino acid sequence of any one of SEQ ID NO: 3606-3836; (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0315] 237. An AAV particle as described in any of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTINGHDSPHKSGQNQQT (SEQ ID NO: 5828).

[0316] 238. An AAV particle as described in any of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754).

[0317] 239. The AAV particle of any one of embodiments 234 to 236, wherein [N0]-[N1]-[N2]-[N3]-[N4] is or contains KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241).

[0318] 240. An AAV particle as described in any of embodiments 168 to 239, wherein [N1]-[N2]-[N3] are present in ring IV, for example, according to SEQ ID NO: 4, 36, 138, 981 or 982.

[0319] 241. The AAV particles of any one of embodiments 198 to 202 or 234 to 240, wherein [N0] and [N4] are present, for example, in ring IV numbered according to SEQ ID NO: 4, 36, 138, 981 or 982.

[0320] 242. The AAV particle of any one of embodiments 198 to 202 or 234 to 241, wherein [NO] is present immediately after position 448 of the amino acid sequence number according to SEQ ID NO: 4, 36, 138, 981 or 982.

[0321] 243. The AAV particles of any one of embodiments 198 to 202 or 234 to 242, wherein [N0] replaces positions 449-452 (e.g., K449, T450, I451 and N452) numbered according to SEQ ID NO: 4, 36, 138, 981 or 982.

[0322] 244. An AAV particle as described in any one of embodiments 198 to 202 or 234 to 243, wherein [N0] is present immediately after position 448, and wherein [N0] replaces positions 449-452 (e.g., K449, T450, I451, and N452), which are numbered according to SEQ ID NO: 4, 36, 138, 981, or 982.

[0323] 245. AAV particles as described in any one of embodiments 198 to 202 or 234 to 244, wherein [N0] corresponds to position 449-452 of any one of SEQ ID NO: 4, 36, 138, 981 or 982 (e.g., K449, T450, I451 and N452).

[0324] 246. An AAV particle as described in any of embodiments 168 to 245, wherein [N1] is present immediately after position 452, which is numbered according to SEQ ID NO: 4, 36, 138, 981 or 982.

[0325] 247. The AAV particle as described in any one of embodiments 168 to 246, wherein [N1] replaces positions 453-455 (e.g., G453, S454, and G455) numbered according to SEQ ID NO: 4, 36, 138, 981, or 982.

[0326] 248. The AAV particle as described in any one of embodiments 168 to 246, wherein [N1] replaces position 453 (e.g., G453) numbered according to SEQ ID NO: 4, 36, 138, 981 or 982.

[0327] 249. AAV particles as described in any one of implementation schemes 168 to 177, 179 to 181, 183 to 185, 187 to 193, 195 to 200, 202 or 240 to 246, wherein: (i) X1 replacement position 453 of [N1] (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), (i), (ii) and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981.

[0328] 250. AAV particles as described in any one of embodiments 168 to 176, 178 to 201, or 240 to 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] corresponds to position 455 (e.g., G455); (i), (ii) and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 981.

[0329] 251. The AAV particle as described in any one of embodiments 203 to 248, wherein: (i) X1 of [N1] corresponds to position 453 (e.g., G453); (ii) The X2 replacement position of [N1] is 454 (e.g., S454); and (iii) Replacement position 455 of X3 in [N1] (e.g., G455), Wherein (i), (ii) and (iii) are numbered according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0330] 252. AAV particles as described in any one of embodiments 203 to 248 or 251, wherein [N1] corresponds to positions 453-455 of SEQ ID NO982 (e.g., G453, H454, D455).

[0331] 253. AAV particles as described in any one of embodiments 168 to 176, 178 to 201, 240 to 247 or 250, wherein [N1] corresponds to positions 453-455 of SEQ ID NO: 138 or 981 (e.g., G453, S454, G455).

[0332] 254. The AAV particle of any one of embodiments 168 to 253, wherein [N2] is present immediately after position 455 according to the numbering of SEQ ID NO: 4, 36, 138, 981 or 982.

[0333] 255. AAV particles as described in any one of embodiments 168 to 254, wherein [N2] corresponds to positions 456-458 of SEQ ID NO: 981 or 982 (e.g., S456, P457, and H458).

[0334] 256. AAV particles as described in any one of embodiments 168 to 254, wherein [N2] corresponds to position 456-458 of any one of SEQ ID NO: 4 or 36-59 (e.g., S456, P457, and H458).

[0335] 257. An AAV particle as described in any of embodiments 168 to 256, wherein [N2] is present immediately following [N1].

[0336] 258. AAV particles as described in any one of embodiments 168 to 202, 240 to 247 or 249 to 257, wherein [N3] corresponds to positions 459-460 of SEQ ID NO: 981 (e.g., S459, K460, A461).

[0337] 259. AAV particles as described in any one of embodiments 168 to 202, 240 to 247 or 249 to 257, wherein [N3] corresponds to positions 459-460 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 (e.g., S459, K460, A461).

[0338] 260. An AAV particle as described in any of embodiments 168 to 259, wherein [N2]-[N3] are present immediately after position 455 according to any of the numbers SEQ ID NO: 4, 36, 138, 981 or 982.

[0339] 261. The AAV particles of any one of embodiments 168 to 259, wherein [N2]-[N3] are present immediately after position 455 according to the number SEQ ID NO: 981.

[0340] 262. AAV particles as described in any one of embodiments 168 to 261, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 981 (e.g., S456, P457, H458, S459, K460, A461).

[0341] 263. The AAV particle of any one of embodiments 168 to 262, wherein [N2]-[N3] correspond to positions 456-461 of any one 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 (e.g., S456, P457, H458, S459, K460, A461).

[0342] 264. AAV particles as described in any one of embodiments 203 to 257 or 259 to 261, wherein [N3] corresponds to positions 459-460 of SEQ ID NO: 982 (e.g., K459, S460, G461).

[0343] 265. AAV particles as described in any one of embodiments 203 to 257 or 259 to 261, wherein [N3] corresponds to positions 459-460 of SEQ ID NO: 37 (e.g., K459, S460, G461).

[0344] 266. The AAV particles of any one of embodiments 203 to 265, wherein [N2]-[N3] are present immediately after position 455 according to the number SEQ ID NO: 982.

[0345] 267. The AAV particles of any one of embodiments 203 to 246, 248, 252, 255, 257, 260, 263 to 266, wherein [N3] replaces positions 454 and 455 according to SEQ ID NO: 138 (e.g., S454 and G455).

[0346] 268. An AAV particle as described in any one of embodiments 203 to 246, 248, 252, 255, 257, 260, 263 to 267, wherein [N3] is present immediately after [N2] and replaces positions 454 and 455 (e.g., S454 and G455), these positions being numbered according to SEQ ID NO: 138.

[0347] 269. An AAV particle as described in any one of embodiments 203 to 246, 248, 252, 255, 257, 260, 263 to 268, wherein [N3] is present immediately following [N1]-[N2] and replaces positions 454 and 455 (e.g., S454 and G455), these positions being numbered according to SEQ ID NO: 138.

[0348] 270. AAV particles as described in any one of embodiments 203 to 257, 260, 264 to 269, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 982 (e.g., S456, P457, H458, K459, S460, G461).

[0349] 271. AAV particles as described in any one of embodiments 203 to 257, 260, 264 to 270, wherein [N2]-[N3] correspond to positions 456-461 of SEQ ID NO: 37 (e.g., S456, P457, H458, K459, S460, G461).

[0350] 272. The AAV particles of any one of embodiments 191 to 202 or 228 to 271, wherein [N4] is present immediately after position 455 according to the number SEQ ID NO: 138.

[0351] 273. AAV particles as described in any one of embodiments 191 to 202 or 228 to 272, wherein [N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459 and T460) according to SEQ ID NO: 138.

[0352] 274. AAV particles as described in any one of embodiments 191 to 202 or 228 to 273, wherein [N4] corresponds to positions 462-466 ​​of SEQ ID NO: 981 or 982 (e.g., Q462, N463, Q464, Q465 and T466).

[0353] 275. The AAV particle of any one of embodiments 191 to 202 or 228 to 273, wherein [N4] corresponds to position 462-466 ​​of any one of SEQ ID NO: 4 or 36-59.

[0354] 276. AAV particles as described in any one of embodiments 191 to 202 or 228 to 274, wherein [N4] corresponds to positions 456-460 of SEQ ID NO: 138 (e.g., Q456, N457, Q458, Q459 and T460).

[0355] 277. AAV particles as described in any one of embodiments 191 to 202 or 228 to 276, wherein [N2]-[N3]-[N4] replace positions 456-460 (e.g., Q456, N457, Q458, Q459 and T460) according to SEQ ID NO: 138.

[0356] 278. An AAV particle as described in any one of embodiments 191 to 202 or 228 to 277, wherein [N2]-[N3]-[N4] is present immediately after position 455, and wherein [N2]-[N3]-[N4] replaces positions 456-460 (e.g., Q456, N457, Q458, Q459 and T460), which are numbered according to SEQ ID NO: 138.

[0357] 279. AAV particles as described in any one of embodiments 191 to 202 or 228 to 278, wherein [N1]-[N2]-[N3]-[N4] replace positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459 and T460) according to SEQ ID NO: 138.

[0358] 280. An AAV particle as described in any one of embodiments 191 to 202 or 228 to 279, wherein [N1]-[N2]-[N3]-[N4] is present immediately after position 452, and wherein [N1]-[N2]-[N3]-[N4] replaces positions 453-460 (e.g., G453, S454, G455, Q456, N457, Q458, Q459, and T460), which are numbered according to SEQ ID NO: 138.

[0359] 281. AAV particles as described in any one of embodiments 191 to 202, 240 to 247, 249, 250, 253 to 263, 266 or 272 to 280, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-466 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465 and T466).

[0360] 282. AAV particles as described in any one of embodiments 168 to 202, 240 to 247, 249, 250, 253 to 263, 266 or 272 to 280, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 981 (e.g., G453, S454, G455, S456, P457, H458, S459, K460, A461).

[0361] 283. AAV particles as described in any one of embodiments 228 to 257, 260, 261, 264 to 282, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-466 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466).

[0362] 284. AAV particles as described in any one of embodiments 203 to 257, 260, 261, 264 to 283, wherein [N1]-[N2]-[N3] correspond to positions 453-461 of SEQ ID NO: 982 (e.g., G453, H454, D455, S456, P457, H458, K459, S460, G461).

[0363] 285. The AAV particles of any one of embodiments 228 to 257, 260, 261, 264 to 282, wherein [N1]-[N2]-[N3]-[N4] correspond to positions 453-466 of any one of SEQ ID NO: 4 or 36-59.

[0364] 286. AAV particles as described in any one of embodiments 198 to 202 or 234 to 286, wherein [N0]-[N1]-[N2]-[N3]-[N4] replace positions 449-460 according to SEQ ID NO: 138 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459 and T460).

[0365] 287. An AAV particle as described in any one of embodiments 198 to 202 or 234 to 286, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately after position 448, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 449-460 numbered according to SEQ ID NO: 138 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459 and T460).

[0366] 288. AAV particles as described in any one of embodiments 198 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286 or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] correspond to positions 449-466 of SEQ ID NO: 981 (e.g., K449, T450, I451, N452, G453, S454, G455, S456, P457, H458, S459, K460, A461, Q462, N463, Q464, Q465, T466).

[0367] 289. AAV particles as described in any one of embodiments 234 to 257, 260, 261, 264 to 284, 286 or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 449-466 of SEQ ID NO: 982 (e.g., K449, T450, I451, N452, G453, H454, D455, S456, P457, H458, K459, S460, G461, Q462, N463, Q464, Q465, T466).

[0368] 290. The AAV particles of any one of embodiments 234 to 257, 260, 261, 264 to 284, 286 or 287, wherein [N0]-[N1]-[N2]-[N3]-[N4] correspond to positions 449-466 of any one of SEQ ID NO: 4 or 36-59.

[0369] 291. The AAV particles of any one of embodiments 191 to 202 or 228 to 290, wherein [N4] is present immediately after position 461 according to SEQ ID NO: 4, 36, 981 or 982.

[0370] 292. The AAV particles of any one of embodiments 191 to 202 or 228 to 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.

[0371] 293. The AAV particles of any one of embodiments 191 to 202 or 228 to 292, wherein [N2]-[N3]-[N4] replace positions 462-466 ​​(e.g., Q462, N463, Q464, Q465 and T466) numbered according to SEQ ID NO: 4, 36, 981 or 982.

[0372] 294. An AAV particle as described in any one of embodiments 191 to 202 or 228 to 293, wherein [N2]-[N3]-[N4] is present immediately after position 455, and wherein [N2]-[N3]-[N4] replaces positions 462-466 ​​(e.g., Q462, N463, Q464, Q465, and T466), which are numbered according to SEQ ID NO: 4, 36, 981, or 982.

[0373] 295. An AAV particle as described in any of embodiments 168 to 294, wherein the AAV capsid variant comprises [N2]-[N3] from the N-terminus to the C-terminus.

[0374] 296. An AAV particle as described in any of embodiments 168 to 295, wherein the AAV capsid variant comprises [N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0375] 297. An AAV particle as described in any of embodiments 168 to 296, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3] from the N-terminus to the C-terminus.

[0376] 298. An AAV particle as described in any of embodiments 168 to 297, wherein the AAV capsid variant comprises [N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0377] 299. An AAV particle as described in any one of embodiments 168 to 298, wherein the AAV capsid variant comprises [N0]-[N1]-[N2]-[N3]-[N4] from the N-terminus to the C-terminus.

[0378] 300. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises formula [A]-[B] (SEQ ID NO: 4696), wherein: (i) [A] contains GSGSPH (SEQ ID NO: 4695); and (ii) [B] includes X1, X2, X3, X4, and X5, where: (a) X1 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, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(e), such as a conserved substitution.

[0379] 301. The AAV particles as described in implementation scheme 300, wherein: (a) X1 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, the AAV capsid variant comprises an amino acid modification of any of the aforementioned amino acids in (a)-(e), such as a conserved substitution.

[0380] 302. An AAV particle according to embodiment 300 or 301, wherein [B] comprises SKA, SMY, SKL, SKR, SKW, SRC, SFT, SKF, IVW, 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, RVV, GQN, YSN, QSN, AKG, CTS, FEN, AKK, KAQ, MYM, KAF, KLK, KRH, KWR, RCR, FTC, KFF, VWQ, KYF, KAR, CHQ, PWQ, KIR, YYQ, LYW, KPK, RFW, RMR, VKK, WAP, LWK, 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, KRQ, KCF, VPQ, FWS, KFK, KAP, KAPFR Y、KMI、RWQ、PTQ、KWK、YMR、KAA、LCQ、CCQ、CVQ、KLT、KLC、YLV、AFQ、KWG、KIL、FQI、KAL、KAH、PRLCQ CPQ, VRY, VRC, KMP, KKT, LPY, YHQ, YTR, VYQ, RYQ, WLK, PAQ, MCT, PPD, WTQ, RKQ, KCS, FVQ, KLP, KVA Q、LYQ、KVR、ALQ、SCT、KNS、KRK、CTQ、TCL、YAR、KQR、KRV、SGQ、YYS、LTC、CQS、KAK、KPQ、KPFQ、VCT

[0381] 303. An AAV particle as in any one of embodiments 300 to 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), SKYF (SEQ IDNO: 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 IDNO: 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 IDNO: 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 (SEQID 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 IDNO: 5878)、SKGC (SEQ ID NO: 5879)、VPWQ (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 IDNO: 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 IDNO: 5904)、QGCQ (SEQ ID NO: 5905)、MAFQ (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 IDNO: 5917)、SKMP (SEQ ID NO: 5918)、SKKT (SEQ ID NO: 5919)、SLPY (SEQ ID NO:5920)、VYHQ (SEQ ID NO: 5921)、SYTR (SEQ ID NO: 5922)、LVYQ (SEQ ID NO: 5923)、YRYQ (SEQ ID NO: 5924)、SWLK (SEQ ID NO: 5925)、CPAQ (SEQ ID NO: 5926)、SMCT(SEQ ID NO: 5927)、SPPD (SEQ ID NO: 5928)、SKRN (SEQ ID NO: 5929)、RWTQ (SEQ IDNO: 5930)、PRKQ (SEQ ID NO: 5931)、SKCS (SEQ ID NO: 5932)、PFVQ (SEQ ID NO:5933)、SKLP (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 IDNO: 5943)、STCL (SEQ ID NO: 5944)、SYAR (SEQ ID NO: 5945)、SKQR (SEQ ID NO:5946)、SKRV (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 IDNO: 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)、KAQK (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 IDNO: 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 IDNO: 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 IDNO: 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 IDNO: 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 IDNO: 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 IDNO: 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)、YMRN (SEQ IDNO: 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 (SEQID NO: 6046)、FQIN (SEQ IDNO: 6047)、KACI (SEQ ID NO: 6048)、KALR (SEQ ID NO: 6049)、KAHA (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 IDNO: 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)、MCTN (SEQ ID NO: 6069)、PPDN(SEQ ID NO: 6070)、KRNY (SEQ ID NO: 6071)、WTQN (SEQ ID NO: 6072)、KACR (SEQ IDNO: 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 IDNO: 6086)、CTQN (SEQ ID NO: 6087)、TCLN (SEQ ID NO: 6088)、YARN (SEQ ID NO:6089)、KQRP (SEQID NO: 6090), KRVV (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).

[0382] 304. An AAV particle as described in any of embodiments 300 to 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: 6121)、SKPKR (SEQ ID NO:6122)、SKAFS (SEQ ID NO: 6123)、SRFWN (SEQ ID NO: 6124)、SKAQC (SEQ ID NO:6125)、SRMRN (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 IDNO: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)、VPWQN (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)、SKMIC (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 IDNO:6185)、SKIRG (SEQ ID NO: 6186)、SYLVN (SEQ ID NO: 6187)、QGCQN (SEQ ID NO:6188)、MAFQN (SEQ ID NO: 6189)、SKACQ (SEQ ID NO: 6190)、SKWGL (SEQ ID NO:6191)、SKILR (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: 6201)、SKAQF (SEQ ID NO: 6202)、SVRYN (SEQ ID NO:6203)、SVRCN (SEQ ID NO: 6204)、SKMPC (SEQ ID NO: 6205)、SKKTS (SEQ ID NO:6206)、SLPYN (SEQ ID NO: 6207)、VYHQN (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 IDNO: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), SVFEN (SEQ ID NO: 6247), SKAKK (SEQ ID NO: 6248) or GRYQN (SEQ ID NO: 6249); (ii) Any part of the amino acid sequence in (i), such as any 2, 3 or 4 amino acids therein, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0383] 305. An AAV particle as described in any one of embodiments 300 to 304, wherein [A]-[B] are or include: (i) GSGSPHSKAQA (SEQ ID NO: 6250)、GSGSPHSKAQN (SEQ ID NO: 6251)、GSGSPHSMYMN (SEQ ID NO: 6252)、GSGSPHSKAFY (SEQ ID NO: 6253)、GSGSPHSKLKR (SEQ ID NO: 6254)、GSGSPHSKRHR (SEQ ID NO: 6255)、GSGSPHSKAQK (SEQ ID NO: 6256)、GSGSPHSKWRL (SEQ ID NO: 6257)、GSGSPHSRCRN (SEQ ID NO: 6258)、GSGSPHSFTCN (SEQ ID NO: 6259)、GSGSPHSKFFI (SEQ ID NO: 6260)、GSGSPHSKAQY (SEQ ID NO: 6261)、GSGSPHIVWQN (SEQ ID NO: 6262)、GSGSPHSKYFM (SEQ ID NO: 6263)、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 (SEQID NO: 6274)、GSGSPHSVKKN (SEQ ID NO: 6275)、GSGSPHSWAPN (SEQ ID NO: 6276)、GSGSPHSLWKN (SEQ ID NO: 6277)、GSGSPHSKARW (SEQ ID NO: 6278)、GSGSPHSFRPN (SEQID NO: 6279)、GSGSPHSKKVF (SEQ ID NO: 6280)、GSGSPHSYAFN (SEQ ID NO: 6281)、GSGSPHSKACS (SEQ ID NO: 6282)、GSGSPHSKRLW(SEQ ID NO: 6283)、GSGSPHSCSRN (SEQID NO: 6284)、GSGSPHSRCPN (SEQ ID NO: 6285)、GSGSPHSGACN (SEQ ID NO: 6286)、GSGSPHSKFRQ (SEQ ID NO: 6287)、GSGSPHSFPFN (SEQ ID NO: 6288)、GSGSPHSFFGN (SEQID NO: 6289)、GSGSPHSMCQN (SEQ ID NO: 6290)、GSGSPHSKLFW (SEQ ID NO: 6291)、GSGSPHSKTRK (SEQ ID NO: 6292)、GSGSPHSGKRN (SEQ ID NO: 6293)、GSGSPHFYRQN (SEQID NO: 6294)、GSGSPHCRVQN (SEQ ID NO: 6295)、GSGSPHYGIQN (SEQ ID NO: 6296)、GSGSPHSKAQR (SEQ ID NO: 6297)、GSGSPHVNCQN (SEQ ID NO: 6298)、GSGSPHSKPFR (SEQID NO: 6299)、GSGSPHSLAWN (SEQ ID NO: 6300)、GSGSPHSKRSY (SEQ ID NO: 6301)、GSGSPHWSYQN (SEQ ID NO: 6302)、GSGSPHRWLQN (SEQ ID NO: 6303)、GSGSPHPSCQN (SEQID 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:6316)、GSGSPHWVPQN (SEQ ID NO: 6317)、GSGSPHSFWSN (SEQ ID NO: 6318)、GSGSPHSKFKN (SEQ ID NO: 6319)、GSGSPHRIKQN (SEQ ID NO: 6320)、GSGSPHSKAPR (SEQ ID NO: 6321)、GSGSPHSFRYN (SEQ ID NO: 6322)、GSGSPHSKMIC (SEQ ID NO: 6323)、GSGSPHLRWQN (SEQ ID NO: 6324)、GSGSPHLPTQN (SEQ ID NO: 6325)、GSGSPHSKWKS (SEQ ID NO: 6326)、GSGSPHSYMRN (SEQ ID NO: 6327). 6332). 6337)、GSGSPHSKACQ (SEQ ID NO: 6338)、GSGSPHSKWGL (SEQID NO: 6339)、GSGSPHSKILR (SEQ ID NO: 6340)、GSGSPHSFQIN (SEQ ID NO: 6341)、GSGSPHSKACI (SEQ ID NO: 6342)、GSGSPHSKALR (SEQ ID NO: 6343)、GSGSPHSKAHA (SEQID NO: 6344)、GSGSPHSLCLN (SEQ ID NO: 6345)、GSGSPHSKAFV (SEQ ID NO: 6346)、GSGSPHRPWQN (SEQ ID NO: 6347)、GSGSPHRPRQN (SEQ ID NO: 6348)、GSGSPHSCPQN (SEQID NO: 6349)、GSGSPHSKAQF(SEQ ID NO: 6350)、GSGSPHSVRYN (SEQ ID NO: 6351)、GSGSPHSVRCN (SEQ ID NO: 6352)、GSGSPHSKMPC (SEQ ID NO: 6353)、GSGSPHSKKTS (SEQID NO: 6354)、GSGSPHSLPYN (SEQ ID NO: 6355)、GSGSPHVYHQN (SEQ ID NO: 6356)、GSGSPHSKAQS (SEQ ID NO: 6357)、GSGSPHSYTRN (SEQ ID NO: 6358)、GSGSPHLVYQN (SEQID NO: 6359)、GSGSPHYRYQN (SEQ ID NO: 6360)、GSGSPHSWLKN (SEQ ID NO: 6361)、GSGSPHSKAQM (SEQ ID NO: 6362)、GSGSPHCPAQN (SEQ ID NO: 6363)、GSGSPHSMCTN (SEQID NO: 6364)、GSGSPHSPPDN (SEQ ID NO: 6365)、GSGSPHSKRNY (SEQ ID NO: 6366)、GSGSPHRWTQN (SEQ ID NO: 6367)、GSGSPHSKACR (SEQ ID NO: 6368)、GSGSPHPRKQN (SEQID NO: 6369)、GSGSPHSKCSV (SEQ ID NO: 6370)、GSGSPHSKARI (SEQ ID NO: 6371)、GSGSPHPFVQN (SEQ ID NO: 6372)、GSGSPHSKLPK (SEQ ID NO: 6373)、GSGSPHSKSEQ (SEQID NO: 6374)、GSGSPHWVAQN (SEQ ID NO: 6375)、GSGSPHSLYQN (SEQ ID NO: 6376)、GSGSPHSKVRM (SEQ ID NO: 6377)、GSGSPHCALQN (SEQ ID NO: 6378)、GSGSPHSSCTN (SEQID NO: 6379)、GSGSPHSKNSR (SEQ ID NO: 6380)、GSGSPHSKRKR (SEQ ID NO: 6381)、GSGSPHLCTQN (SEQ ID NO: 6382)、GSGSPHSTCLN (SEQ ID NO:6383), GGSPHSYARN (SEQ ID NO: 6384), GSGSPHSKQRP (SEQ ID NO: 6385), GGSSPHSKRVV (SEQ ID NO: 6386), GGSSPHKSGQN (SEQ ID NO: 6387), GSGSPHSYYSN (SEQ ID NO: 6388), GGSSPHSLTCN (SEQ ID NO: 6389), GGSPHSCQSN (SEQ ID NO: 6390), GGSSPHSKAKG (SEQ ID NO: 6391), GGSSPHSKPQN (SEQ ID NO: 6392), GGSPHSFPFQN (SEQ ID NO: 6393), GGSPHSKCTS (SEQ ID NO: 6394), GGSSPHSVFEN (SEQ ID NO: 6395), GGSSPHSKAKK (SEQ ID NO: 6396) or GGSSPHGRYQN (SEQ ID NO: 6397); (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0384] 306. An AAV particle as described in any one of embodiments 300 to 305, wherein [A]-[B] does not contain the amino acid sequence of GGSPHSKAQN (SEQ ID NO: 6251).

[0385] 307. An AAV particle as described in any one of embodiments 300 to 306, wherein the AAV capsid variant comprises one, two, or all of the amino acids other than Q (e.g., R, C, S, W, L, F, Y, H, I, V, A, or P) at position 458 according to SEQ ID NO: 138, the amino acid other than Q (e.g., K, I, R, L, or S) at position 459, and / or the amino acid other than T (e.g., R) at position 460.

[0386] 308. An AAV particle as described in any one of embodiments 300 to 307, wherein the AAV capsid variant comprises: (i) Amino acid R at position 458; (ii) Amino acid W at position 458; (iii) Amino acid Y at position 458; (iv) Amino acid F at position 458; (v) Amino acid S at position 458; (vi) Amino acid C at position 458; (vii) Amino acid I at position 458; (viii) Amino acid L at position 458; (ix) Amino acid P at position 458; (x) Amino acid I at position 459; (xi) The amino acid H at position 458; or (xii) Amino acid V at position 458; Where (i)-(xii) are numbered according to SEQ ID NO: 138.

[0387] 309. An AAV particle as described in any one of embodiments 300 to 307, wherein the AAV capsid variant comprises: (i) Amino acid R at position 458 and amino acid K at position 459; (ii) Amino acid C at position 458 and amino acid I at position 459; (iii) Amino acid S at position 458 and amino acid R at position 459; (iv) Amino acid L at position 458 and amino acid K at position 459; (v) Amino acid F at position 458 and amino acid K at position 459; (vi) Amino acid C at position 458 and amino acid R at position 459; (vii) Amino acid H at position 458 and amino acid R at position 459; (viii) Amino acid I at position 458 and amino acid L at position 459; (ix) Amino acid V at position 458 and amino acid R at position 459; (x) Amino acid A at position 458 and amino acid K at position 459; (xi) Amino acid I at position 458 and amino acid K at position 459; (xii) Amino acid C at position 458 and amino acid S at position 459; or (xiii) Amino acid C at position 458 and amino acid L at position 459 Where (i)-(xiii) are numbered according to SEQ ID NO: 138.

[0388] 310. An AAV particle as described in any one of embodiments 300 to 307, wherein the AAV capsid variant comprises amino acid F at position 458, amino acid K at position 459, and amino acid R at position 460, as specified in SEQ ID NO: 138.

[0389] 311. An AAV particle as described in any one of embodiments 300 to 310, wherein the AAV capsid variant comprises one, two, or all of the amino acids other than T (e.g., Y, P, W, R, K, S, or F) at position 450 according to SEQ ID NO: 138, the amino acids other than I (e.g., R, S, Y, L, V, H, P, A, or F) at position 451, and / or the amino acids other than N (e.g., V, W, A, T, F, Y, L, R, H, S, or M) at position 452.

[0390] 312. An AAV particle as described in any one of embodiments 300 to 311, wherein the AAV capsid variant contains amino acid V at position 452 according to SEQ ID NO: 138.

[0391] 313. An AAV particle as described in any one of embodiments 300 to 312, wherein the AAV capsid variant comprises amino acid Y at position 450 and amino acid V at position 452 according to SEQ ID NO: 138.

[0392] 314. An AAV particle as described in any one of embodiments 300 to 312, wherein the AAV capsid variant comprises amino acid R at position 450 and amino acid Y at position 451 according to SEQ ID NO: 138.

[0393] 315. An AAV particle as described in any one of embodiments 300 to 311, wherein the AAV capsid variant comprises: (i) Amino acid P at position 450, amino acid R at position 451 and amino acid W at position 452; (ii) Amino acid Y at position 450, amino acid S at position 451, and amino acid A at position 452; (iii) Amino acid Y at position 450, amino acid Y at position 451, and amino acid T at position 452; (iv) Amino acid P at position 450, amino acid R at position 451 and amino acid F at position 452; (v) Amino acid W at position 450, amino acid L at position 451, and amino acid T at position 452; (vi) Amino acid R at position 450, amino acid S at position 451, and amino acid Y at position 452; (vii) Amino acid Y at position 450, amino acid V at position 451, and amino acid F at position 452; (viii) Amino acid K at position 450, amino acid H at position 451, and amino acid L at position 452; (ix) Amino acid P at position 450, amino acid P at position 451, and amino acid L at position 452; (x) Amino acid P at position 450, amino acid A at position 451, and amino acid R at position 452; (xi) Amino acid S at position 450, amino acid R at position 451, and amino acid R at position 452; (xii) Amino acid F at position 450, amino acid F at position 451, and amino acid H at position 452; (xiii) Amino acid R at position 450, amino acid F at position 451, and amino acid S at position 452; (xiv) Amino acid Y at position 450, amino acid S at position 451, and amino acid M at position 452; or (xv) Amino acid P at position 450, amino acid F at position 451, and amino acid L at position 452; Where (i)-(xv) are numbered according to SEQ ID NO: 138.

[0394] 316. An AAV particle as described in any one of embodiments 300 to 315, wherein the AAV capsid variant comprises: (i) The amino acid sequence of any one of SEQ ID NO: 3849-3982, 2984-4010, 4681-4693; (ii) Contains any part of the amino acid sequence in (i), such as any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 amino acids, such as an amino acid sequence of consecutive amino acids; (iii) A sequence containing one, two, or three, but no more than four modified amino acid sequences relative to any one of the amino acid sequences in (i); or (iv) An amino acid sequence containing one, two, or three, but not more than four different amino acids, relative to any one of the amino acid sequences in (i).

[0395] 317. An AAV particle as described in any one of embodiments 300 to 316, wherein the AAV capsid variant does not contain the amino acid sequence of GSGSPHSKAQNQQ (SEQ ID NO: 1801) or GSGSPHSKAQNQQT (SEQ ID NO: 200).

[0396] 318. An AAV particle as described in any of embodiments 300 to 317, wherein [A]-[B] are present in ring IV.

[0397] 319. The AAV particle of any one of embodiments 300 to 318, wherein [A] is present immediately after position 452 according to the number SEQ ID NO: 138 or 981.

[0398] 320. AAV particles as described in any one of embodiments 300 to 319, wherein [A] replaces positions 453-455 (e.g., G453, S454, G455) according to SEQ ID NO:138 or 981.

[0399] 321. An AAV particle as described in any of embodiments 300 to 320, wherein [A] is present immediately after position 452, and wherein [A] replaces positions 453-455 (e.g., G453, S454, G455), which are numbered according to SEQ ID NO: 138 or 981.

[0400] 322. An AAV particle as described in any of embodiments 300 to 321, wherein [B] exists immediately following [A].

[0401] 323. The AAV particles of any one of embodiments 300 to 322, wherein [B] replaces positions 456 and 457 (e.g., Q456, N457) according to SEQ ID NO:138.

[0402] 324. AAV particles as described in any one of embodiments 300 to 323, wherein [A]-[B] replace positions 453-457 (e.g., G453, S454, G455, Q456, N457) according to the numbering according to SEQ ID NO: 138.

[0403] 325. An AAV particle as described in any of embodiments 300 to 324, wherein [A]-[B] is present immediately after position 452, and wherein [A]-[B] replaces positions 453-457 (e.g., G453, S454, G455, Q456, N457), which are numbered according to SEQ ID NO: 138.

[0404] 326. An AAV particle as described in any one of embodiments 300 to 325, wherein the AAV capsid variant comprises [A][B] from the N-terminus to the C-terminus.

[0405] 327. An AAV particle as described in any 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., 1-4 to 1-5) charged amino acid residues (e.g., acidic and / or basic amino acid residues) relative to SEQ ID NO: 138, present at the N-terminus of the amino acid sequence of SPH (e.g., within 1, 2, 3, 4, 5, or 6 amino acids from the beginning of the amino acid sequence of SPH (e.g., within positions 450-455 according to SEQ ID NO: 138)), optionally, wherein the amino acid sequence of SPH is present at positions 456-458 according to any one of SEQ ID NO: 36-59, 981, or 982.

[0406] 328. The AAV particle of embodiment 327, wherein the amino acid sequence of SPH is present at positions 456-458 according to any one of the numbers in SEQ ID NO: 36-59, 981 or 982.

[0407] 329. The AAV particle of embodiment 327 or 328, wherein the AAV capsid variant comprises fewer than four, fewer than three, fewer 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.

[0408] 330. An AAV particle as described in any one of embodiments 327 to 329, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., an acidic or basic amino acid residue) relative to SEQ ID NO: 138, optionally located at any one of positions 450-455 relative to SEQ ID NO: 138.

[0409] 331. An AAV particle as described in any one of embodiments 327 to 330, wherein the charged amino acid residue is an acidic amino acid (e.g., D or E).

[0410] 332. An AAV particle as described in any one of embodiments 327 to 331, wherein the charged amino acid residues are negatively charged amino acids (e.g., D or E).

[0411] 333. An AAV particle as described in any of embodiments 327 to 332, wherein the charged amino acid residue is D.

[0412] 334. An AAV particle as described in any one of embodiments 327 to 333, wherein the charged amino acid residue is E.

[0413] 335. An AAV particle as described in any one of embodiments 327 to 334, wherein the charged amino acid residues are basic amino acids (e.g., K, R, or H).

[0414] 336. An AAV particle as described in any one of embodiments 327 to 335, wherein the charged amino acid residues are positively charged amino acids (e.g., K, R, or H).

[0415] 337. An AAV particle as described in any one of embodiments 327 to 336, wherein the charged amino acid residue is H.

[0416] 338. An AAV particle as described in any one of embodiments 327 to 337, wherein the charged amino acid residue is R.

[0417] 339. An AAV particle as described in any of embodiments 327 to 338, wherein the charged amino acid residue is K.

[0418] 340. An AAV particle as described in any one of embodiments 327 to 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).

[0419] 341. An AAV particle as described in any one of embodiments 327 to 340, wherein at least one, two, three or four charged amino acid residues are present in 1, 2, 3, 4, 5 or 6 (e.g. 1-6) amino acids starting from the SPH amino acid sequence.

[0420] 342. An AAV particle as described in any one of embodiments 327 to 341, wherein the AAV capsid variant comprises two charged amino acid residues immediately preceding the amino acid sequence of SPH (e.g., at positions 454 and 455 according to SEQ ID NO: 138 or SEQ ID NO: 982).

[0421] 343. An AAV particle as described in any one of embodiments 327 to 342, wherein the AAV capsid variant comprises charged amino acid residues (e.g., E) within 1, 2, 3, 4, 5 (e.g., 5) amino acids starting from the SPH amino acid sequence.

[0422] 344. An AAV particle as described in any one of embodiments 327 to 343, wherein the AAV capsid variant contains a charged amino acid residue (e.g., E) at position 451 according to any one of SEQ ID NO: 138, 981 or 982.

[0423] 345. An AAV particle as described in any one of embodiments 327 to 344, wherein the AAV capsid variant contains E at position 451 according to any one of the numbering SEQ ID NO: 138, 981 or 982.

[0424] 346. An AAV particle as described in any one of embodiments 327 to 345, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., R or K) at position 452 according to any one of SEQ ID NO: 138, 981 or 982.

[0425] 347. An AAV particle as described in any one of embodiments 327 to 346, wherein the AAV capsid variant contains R at position 452 according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0426] 348. An AAV particle as described in any one of embodiments 327 to 347, wherein the AAV capsid variant comprises E at position 451 and R at position 452 according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0427] 349. An AAV particle as described in any one of embodiments 327 to 348, wherein the AAV capsid variant has a reduced tropism to hepatocytes or tissues relative to the tropism of an AAV capsid containing the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981.

[0428] 350. An AAV particle as described in any 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., 1-4 to 1-5) charged amino acid residues (e.g., basic amino acid residues) relative to SEQ ID NO: 138, present at the C-terminus of the amino acid sequence of SPH (e.g., within 1, 2, 3, 4, 5, 6, or 7 amino acids from the end of the amino acid sequence of SPH (e.g., within positions 459-465 according to any one of the numbers in SEQ ID NO: 36-59 or 981)), optionally, wherein the amino acid sequence of SPH is present at positions 456-458 according to any one of the numbers in SEQ ID NO: 36-59, 981, or 982.

[0429] 351. The AAV particle of embodiment 350, wherein the amino acid sequence of SPH is present at positions 456-458 according to any one of the numbers in SEQ ID NO: 36-59, 981 or 982.

[0430] 352. The AAV particle as described in embodiment 350 or 351, wherein the AAV capsid variant contains fewer than four, fewer than three, fewer than two (e.g., two or one) charged amino acid residues (e.g., basic amino acid residues) relative to SEQ ID NO: 138.

[0431] 353. An AAV particle as described in any one of embodiments 350 to 352, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., a basic amino acid residue) relative to SEQ ID NO: 138, optionally at any one of positions 456-460 according to SEQ ID NO: 138, or at positions 462-466 ​​according to any one of SEQ ID NO: 36-59, 981, or 982.

[0432] 354. An AAV particle as described in any one of embodiments 350 to 353, wherein the charged amino acid residues are basic amino acids (e.g., R or K).

[0433] 355. An AAV particle as described in any one of embodiments 350 to 354, wherein the charged amino acid residues are positively charged amino acids (e.g., R or K).

[0434] 356. An AAV particle as described in any one of embodiments 350 to 355, wherein the charged amino acid residue is R.

[0435] 357. An AAV particle as described in any one of embodiments 350 to 355, wherein the charged amino acid residue is K.

[0436] 358. An AAV particle as described in any one of embodiments 350 to 357, wherein at least one, two, three or four charged amino acid residues are present in 1, 2, 3, 4, 5, 6, or 7 (e.g., 1-7) amino acids from the end of the SPH amino acid sequence.

[0437] 359. An AAV particle as described in any one of embodiments 350 to 358, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., K or R) immediately following the SPH sequence (e.g., at position 459 according to SEQ ID NO: 981).

[0438] 360. An AAV particle as described in any one of embodiments 350 to 359, wherein the AAV capsid variant comprises a charged amino acid residue (e.g., K or R) at position 459 according to SEQ ID NO: 138 or SEQ ID NO: 982.

[0439] 361. An AAV particle as described in any one of embodiments 350 to 360, wherein the AAV capsid variant contains K at position 459 according to SEQ ID NO: 981.

[0440] 362. An AAV particle as described in any one of embodiments 350 to 360, wherein the AAV capsid variant contains R at position 459 according to SEQ ID NO: 981.

[0441] 363. An AAV particle as described in any one of embodiments 350 to 362, wherein the AAV capsid variant comprises one, two, three, four, five, or all of the charged amino acid residues (e.g., R or K) at positions 460, 461, 462, 463, 464, and / or 465 as numbered according to SEQ ID NO: 138 or 981.

[0442] 364. An AAV particle as described in any one of embodiments 300 to 326 or 350 to 363, wherein the AAV capsid variant has increased tropism toward liver cells or tissues relative to the tropism of an AAV capsid containing the amino acid sequence of SEQ ID NO: 138.

[0443] 365. AAV particles as described in any one of embodiments 300 to 326 or 350 to 364, wherein, for example, when measured by means of the analysis described in Example 4, the AAV capsid variant is enriched in the liver as containing SEQ ID NO: The amino acid sequence of 138 has an AAV capsid that is at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, at least 100 times, at least 105 times, at least 110 times, at least 115 times, at least 120 times, at least 125 times, at least 130 times, at least 135 times, at least 140 times, at least 150 times, at least 160 times, at least 170 times, at least 180 times, at least 190 times, or at least 200 times stronger.

[0444] 366. An AAV particle as described in any one of embodiments 300 to 326, 364 or 365, wherein the AAV capsid variant has a reduced tropism to CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells or spinal cord tissue, relative to the tropism of the AAV capsid containing the amino acid sequence of SEQ ID NO: 138.

[0445] 367. An AAV particle as described in any one of embodiments 300 to 326 or 364 to 366, wherein the AAV capsid variant exhibits preferential transduction in the liver region relative to transduction in the brain and / or dorsal root ganglion (DRG).

[0446] 368. An AAV particle as described in any one of embodiments 300 to 326 or 364 to 367, wherein the AAV capsid variant exhibits preferential transduction in the liver region relative to transduction in the heart and / or muscle (e.g., quadriceps femoris).

[0447] 369. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises: (a) The amino acid sequence of any one of the sequences provided in Table 1, Table 2A, Table 2B or Tables 20-26; (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 of the sequences provided in Tables 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 distinct amino acids, relative to any one of the sequences provided in Tables 1, 2A, 2B, or 20-26; or (d) An amino acid sequence that contains at least one, at least two, or at least three but no more than four modified amino acid sequences relative to any of the sequences provided in Tables 1, 2A, 2B, or 20-26.

[0448] 370. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises: (a) The amino acid sequence of any one of SEQ ID NO: 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 NO: 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 any one of SEQ ID NO: 945-980 or 985-986; (d) The amino acid sequence relative to any one of SEQ ID NO: 945-980 or 985-986 contains at least one, at least two, or at least three but no more than four modified amino acid sequences.

[0449] 371. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises: (a) The amino acid sequence of any one of SEQ ID NO: 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 NO: 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 distinct amino acids relative to any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909; or (d) The amino acid sequence relative to any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909 contains at least one, at least two or at least three but no more than four modified amino acid sequences.

[0450] 372. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises: (a) The amino acid sequence of any one of SEQ ID NO: 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 NO: 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 distinct amino acids relative to any one of SEQ ID NO: 3849-4051 or 4681-4693; or (d) The amino acid sequence relative to any one of SEQ ID NO: 3849-4051 or 4681-4693 contains at least one, at least two, or at least three but no more than four modified amino acid sequences.

[0451] 373. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises: (a) The amino acid sequence of any one of SEQ ID NO: 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 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 NO: 4052-4092; (c) An amino acid sequence comprising at least one, at least two, or at least three but no more than four distinct amino acids relative to any one of SEQ ID NO: 4052-4092; or (d) The amino acid sequence relative to any one of SEQ ID NO: 4052-4092 contains at least one, at least two, or at least three but no more than four modified amino acid sequences.

[0452] 374. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome, the viral genome comprising a coding sequence for synaptic fusion protein-binding protein 1 (STXBP1) (e.g., encoding the human STXBP1 protein), wherein the AAV capsid variant comprises: (a) The amino acid sequence of any one of SEQ ID NO: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090 or 4095-4097; (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 NO: 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 not more than four distinct amino acids relative to any one of SEQ ID NO: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090, or 4095-4097; or (d) The amino acid sequence relative to any one of SEQ ID NO: 4056, 4058, 4059, 4062-4064, 4066, 4067, 4080, 4084, 4090 or 4095-4097 contains at least one, at least two or at least three but no more than four modified amino acid sequences.

[0453] 375. The AAV particle of embodiment 369 or 371, wherein the AAV capsid variant comprises an amino acid sequence containing 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 NO: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0454] 376. An AAV particle as described in any one of embodiments 369 to 374, wherein at least three consecutive amino acids contain SPH.

[0455] 377. An AAV particle as described in any one of embodiments 369 to 371 or 376, wherein at least four consecutive amino acids comprise SPHS (SEQ ID NO: 4700).

[0456] 378. An AAV particle as described in any one of embodiments 369 to 371, 376 or 377, wherein at least 5 consecutive amino acids comprise SPHSK (SEQ ID NO: 4701).

[0457] 379. An AAV particle as described in any one of embodiments 369 to 371 or 376 to 378, wherein at least six consecutive amino acids comprise SPHSKA (SEQ ID NO: 941).

[0458] 380. The AAV particles of embodiments 369 to 371, wherein at least three consecutive amino acids contain HDS.

[0459] 381. An AAV particle as described in any one of embodiments 369 to 371 or 380, wherein at least four consecutive amino acids comprise HDSP (SEQ ID NO: 4702).

[0460] 382. An AAV particle as described in any one of embodiments 369 to 371, 380 or 381, wherein at least 5 consecutive amino acids comprise HDSPH (SEQ ID NO: 4703).

[0461] 383. An AAV particle as described in any one of embodiments 369 to 371 or 380 to 382, ​​wherein at least six consecutive amino acids comprise HDSPHK (SEQ ID NO: 2).

[0462] 384. The AAV particle as described in any one of implementation schemes 369 to 371, wherein: (i) At least three consecutive amino acids contain SPH; (ii) At least four consecutive amino acids contain SPHK (SEQ ID NO: 6398); (iii) At least five consecutive amino acids contain SPHKY (SEQ ID NO: 4715); and / or (iv) At least 6 consecutive amino acids contain SPHKYG (SEQ ID NO: 966).

[0463] 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 any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0464] 386. An AAV particle as described in 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).

[0465] 387. An AAV particle as described in 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 HDSPHK (SEQ ID NO: 2).

[0466] 388. An AAV particle as described in any one of embodiments 369 to 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).

[0467] 389. The AAV particle of embodiment 370, wherein the AAV capsid variant comprises: (i) The amino acid sequence relative to KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589) contains at least one, at least two, or at least three but no more than four modified amino acid sequences; (ii) An amino acid sequence containing at least one, at least two, or at least three but no more than four modified amino acid sequences relative to the amino acid sequence of KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754). (iii) The amino acid sequence containing at least one, at least two, or at least three but no more than four modified amino acid sequences relative to the amino acid sequence of KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241); (iv) The amino acid sequence relative to KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100) contains at least one, at least two, or at least three but no more than four modified amino acid sequences; or (v) The amino acid sequence of KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062) contains at least one, at least two, or at least three but no more than four modified amino acid sequences.

[0468] 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 distinct amino acids relative to any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404, or 903-909.

[0469] 391. An AAV particle as described in 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).

[0470] 392. An AAV particle as described in 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 (SEQ ID NO: 2) of HDSPHK.

[0471] 393. An AAV particle as described in any one of embodiments 369, 371, 384 or 390, wherein the AAV capsid variant comprises an amino acid sequence containing 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 SPHKYG (SEQ ID NO: 966).

[0472] 394. The AAV particle of embodiment 369, wherein the AAV capsid variant comprises: (i) An amino acid sequence containing 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 KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589); (ii) An amino acid sequence containing 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 containing 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 amino acid sequence containing at least one, at least two, or at least three but no more than four distinct amino acids relative to the amino acid sequence of KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100); or (v) An amino acid sequence containing 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).

[0473] 395. An AAV particle as described in any one of embodiments 1 to 129, 269, 271, 375 to 388 or 390 to 394, wherein the AAV capsid variant comprises an amino acid sequence of any one of SEQ ID NO: 2, 200, 201, 941, 943, 204, 208, 404 or 903-909.

[0474] 396. An AAV particle as described in any one of embodiments 295 to 297, 301 to 305, 313, 314, 318, 319 or 323, wherein the AAV capsid variant comprises the amino acid sequence of ERVGSPHSKA (SEQ ID NO: 6399), optionally wherein the amino acid sequence is present immediately after position 450 and replaces positions 451-455 (e.g., I451, N542, G453, S454, G455), these positions being numbered according to SEQ ID NO: 138.

[0475] 397. An AAV particle as described in any one of embodiments 369 to 371, 375 to 379, 385, 386, 389 to 391, or 394 to 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 after position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), these positions being numbered according to SEQ ID NO: 138.

[0476] 398. An AAV particle as described in any one of embodiments 269 to 371, 375, 380 to 383, 385, 387, 389, 390, 393 or 394, wherein the AAV capsid variant comprises the amino acid sequence AEIGHDSPHKSG (SEQ ID NO: 6400), optionally wherein the amino acid sequence is present immediately after position 449 and replaces positions 450-455 (e.g., T450, I451, N452, G453, S454, G455), these positions being numbered according to SEQ ID NO: 138.

[0477] 399. An AAV particle as described in any one of embodiments 369 to 371, 375, 380 to 383, 385, 387, 389, 390, 393, 394 or 398, wherein the AAV capsid variant comprises the amino acid sequence KAEIGHDSPHKSGQNQQT (SEQ ID NO: 1754), optionally wherein the amino acid sequence is present immediately after position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), these positions being numbered according to SEQ ID NO: 138.

[0478] 400. An AAV particle as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, wherein the AAV capsid variant comprises the amino acid sequence of EKMSGSPHSKA (SEQ ID NO: 6401), optionally wherein the amino acid sequence is present immediately after position 450 and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455), these positions being numbered according to SEQ ID NO: 138.

[0479] 401. An AAV particle as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, wherein the AAV capsid variant comprises the amino acid sequence KTEKMSGSPHSKAQNQQT (SEQ ID NO: 3241), optionally wherein the amino acid sequence is present immediately after position 448 and replaces positions 449-460 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), these positions being numbered according to SEQ ID NO: 138.

[0480] 402. An AAV particle as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, wherein the AAV capsid variant comprises the amino acid sequence HDSPHSKAQNL (SEQ ID NO: 6402), optionally wherein the amino acid sequence is present immediately after position 453 and replaces positions 456-458 (e.g., Q456, N457, Q458), which are numbered according to SEQ ID NO: 138.

[0481] 403. An AAV particle as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, wherein the AAV capsid variant comprises the amino acid sequence KTINGHDSPHSKAQNLQT (SEQ ID NO: 4100), optionally wherein the amino acid sequence is present immediately after position 448 and replaces positions 449-460 (e.g. K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), these positions being numbered according to SEQ ID NO: 138.

[0482] 404. An AAV particle as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, wherein the AAV capsid variant comprises the amino acid sequence of VNGHDSPHSKA (SEQ ID NO: 6403), optionally wherein the amino acid sequence is present immediately after position 450 and replaces positions 451-455 (e.g., I451, N452, G453, S454, G455), these positions being numbered according to SEQ ID NO: 138.

[0483] 405. An AAV particle as described in any one of embodiments 369 to 371, 375 to 379, 390, 391 or 395, wherein the AAV capsid variant comprises the amino acid sequence KTVNGHDSPHSKAQNQQT (SEQ ID NO: 4062), optionally wherein the amino acid sequence is present immediately after position 448 and replaces positions 449-460 (e.g. K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459, T460), these positions being numbered according to SEQ ID NO: 138.

[0484] 406. An AAV particle as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, or 395, wherein the AAV capsid variant comprises an amino acid sequence encoded by: nucleotide sequence of SEQ ID NO: 942; comprising relative to SEQ ID NO: The nucleotide sequence of SEQ ID NO: 942 contains at least one, at least two, at least three, at least four, at least five, at least six or at least seven modifications, such as substitutions (e.g., conserved substitutions), but not more than ten modifications, such as substitutions (e.g., conserved substitutions); or a nucleotide sequence containing at least one, at least two, at least three, at least four, at least five, at least six or at least seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942.

[0485] 407. An AAV particle as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, or 395, wherein the AAV capsid variant comprises an amino acid sequence encoded by: the nucleotide sequence of SEQ ID NO: 3; comprising relative to SEQ ID NO: The nucleotide sequence of SEQ ID NO: 3 has at least one, at least two, at least three, at least four, at least five, at least six or at least seven modifications, such as substitutions (e.g., conserved substitutions), but not more than ten modifications, such as substitutions (e.g., conserved substitutions); or a nucleotide sequence containing at least one, at least two, at least three, at least four, at least five, at least six or at least seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3.

[0486] 408. An AAV particle as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 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; comprising relative to SEQ ID NO: The nucleotide sequence of SEQ ID NO: 942 contains at least one, at least two, at least three, at least four, at least five, at least six or at least seven modifications, such as substitutions (e.g., conserved substitutions), but not more than ten modifications, such as substitutions (e.g., conserved substitutions); or a nucleotide sequence containing at least one, at least two, at least three, at least four, at least five, at least six or at least seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 942.

[0487] 409. An AAV particle as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 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; comprising relative to SEQ ID NO: The nucleotide sequence of SEQ ID NO: 3 has at least one, at least two, at least three, at least four, at least five, at least six or at least seven modifications, such as substitutions (e.g., conserved substitutions), but not more than ten modifications, such as substitutions (e.g., conserved substitutions); or a nucleotide sequence containing at least one, at least two, at least three, at least four, at least five, at least six or at least seven but not more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 3.

[0488] 410. An AAV particle as described in any one of embodiments 369 to 409, wherein, for example, the amino acid sequence is present in ring IV relative to the amino acid sequence of SEQ ID NO: 138.

[0489] 411. An AAV particle as described in any one of embodiments 369 to 410, wherein the amino acid sequence is present immediately following the position 448, 449, 450, 451, 452, 453, 454 or 455 as numbered according to SEQ ID NO: 138.

[0490] 412. An AAV particle as described in any one of embodiments 369 to 411, wherein the amino acid sequence is replaced by amino acids 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459 and / or 460 as numbered according to SEQ ID NO: 138 (e.g., K449, T450, I451, N452, G453, S454, G455, Q456, N457, Q458, Q459 and / or T460).

[0491] 413. An AAV particle as described in any one of embodiments 369 to 412, wherein the amino acid sequence is present immediately following position 455 according to SEQ ID NO: 138.

[0492] 414. An AAV particle as described in any one of embodiments 369 to 413, wherein the amino acid sequence is present immediately following position 453 according to SEQ ID NO: 138.

[0493] 415. An AAV particle as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, or 410 to 413, wherein the AAV capsid variant contains the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately after position 455 according to SEQ ID NO: 138.

[0494] 416. An AAV particle as described in any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413 or 415, wherein the AAV capsid variant contains the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately after position 455 according to SEQ ID NO: 981.

[0495] 417. 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 an amino acid other than G at position 453, according to any of the numbers in SEQ ID NO: 36, 138, or 981.

[0496] 418. An AAV particle as described in any one of embodiments 415 to 417, wherein the AAV capsid variant further comprises E at position 451, R at position 452, and V at position 453, according to any one of the numbers in SEQ ID NO: 36, 138, or 981.

[0497] 419. An AAV particle as described in any one of embodiments 415 to 418, wherein the AAV capsid variant further comprises substituted I451E, N452R, and G453V according to any one of SEQ ID NO: 36, 138, or 981.

[0498] 420. An AAV particle as described in any one of embodiments 415 to 419, wherein the AAV capsid variant comprises: (i) According to any one of the numbers in SEQ ID NO: 36, 138 or 981, position 451 is E, position 452 is R and position 453 is V; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately after position 455 according to any one of the numbers in SEQ ID NO: 36, 138 or 981.

[0499] 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, as specified in SEQ ID NO: 39 or 138.

[0500] 422. An AAV particle as described in 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, as numbered according to SEQ ID NO: 138 or 39.

[0501] 423. An AAV particle as described in any one of embodiments 415, 416, 421 or 422, wherein the AAV capsid variant further comprises substituted I451E, N452K and G453M according to SEQ ID NO: 39 or 138.

[0502] 424. An AAV particle as described in any one of embodiments 415, 416, or 421 to 423, wherein the AAV capsid variant comprises: (i) According to SEQ ID NO: 39 or 138, position 451 is E, position 452 is K and position 453 is M; and (ii) The amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately after position 455 according to SEQ ID NO: 39 or 138.

[0503] 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 according to SEQ ID NO: 138.

[0504] 426. An AAV particle as described in 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 according to SEQ ID NO: 138.

[0505] 427. An AAV particle as described in any one of embodiments 415, 416, 425 or 426, wherein the AAV capsid variant further comprises the substitutions S454H, G455D and Q458L as numbered according to SEQ ID NO: 138.

[0506] 428. An AAV particle as described in any one of embodiments 415, 416, or 425 to 427, wherein the AAV capsid variant comprises: (i) H at position 454, D at position 455, and / or L at position 458 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 after position 455 according to SEQ ID NO: 138.

[0507] 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, as specified in SEQ ID NO: 52 or 138.

[0508] 430. An AAV particle as described in 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 according to SEQ ID NO: 52 or 138.

[0509] 431. An AAV particle as described in any one of embodiments 415, 416, 429 or 430, wherein the AAV capsid variant further comprises substituted I451V, S454H and / or G455D according to SEQ ID NO: 52 or 138.

[0510] 432. An AAV particle as described in any one of embodiments 415, 416, or 429 to 431, wherein the AAV capsid variant comprises: (i) V at position 451, H at position 454, and / or D at position 455 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 after position 455 according to SEQ ID NO: 52 or 138.

[0511] 433. An AAV particle as described in any one of embodiments 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412 or 414, wherein the AAV capsid variant contains the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately after position 453 of the amino acid sequence number according to SEQ ID NO: 138.

[0512] 434. AAV particles according to any one of implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, or 433, wherein the AAV capsid variant contains the amino acid sequence of HDSPHK (SEQ ID NO: 2), wherein the amino acid sequence is present immediately after position 453 of the amino acid sequence number according to SEQ ID NO: 982.

[0513] 435. AAV particles according to any one of implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 or 434, wherein the AAV capsid variant contains the amino acid sequence of SPHKSG (SEQ ID NO). ID NO: 946), wherein the amino acid sequence is present immediately after position 455 of the amino acid sequence number according to SEQ ID NO: 982.

[0514] 436. An AAV particle as described in any one of embodiments 369 to 435, wherein the AAV capsid variant comprises: (i) The amino acid sequence of HDSPHSKA (SEQ ID NO: 4486), which is present immediately after position 453; and (ii) Deletion of amino acid SG at positions 454 and 455; Wherein (i) and (ii) are numbered according to SEQ ID NO: 138.

[0515] 437. An AAV particle as described in any one of embodiments 369 to 436, wherein the AAV capsid variant comprises amino acid HD at positions 454 and 455 and further comprises an amino acid sequence of SPHSKA (SEQ ID NO: 941) immediately following position 455, these positions being numbered according to SEQ ID NO: 138.

[0516] 438. An AAV particle as described in any one of embodiments 433 to 435, wherein the AAV capsid variant further comprises an amino acid other than T at position 450, an amino acid other than I at position 451, and an amino acid other than N at position 452, as specified in SEQ ID NO: 138 or 982.

[0517] 439. An AAV particle as described in any one of embodiments 433 to 435 or 438, wherein the AAV capsid variant further comprises A at position 450, E at position 451, and I at position 452, as numbered according to SEQ ID NO: 138 or 982.

[0518] 440. An AAV particle as described in any one of embodiments 433 to 435, 438 or 439, wherein the AAV capsid variant further comprises substituted T450A, I451E and N452I according to SEQ ID NO: 138 or 982.

[0519] 441. An AAV particle as described in any one of embodiments 433, 434, or 438 to 440, wherein the AAV capsid variant comprises: (i) According to SEQ ID NO: 138 or 982, position 450 is A, position 451 is E, and position 452 is I; and (ii) The amino acid sequence of HDSPHK (SEQ ID NO: 2), which is present immediately after position 453 according to SEQ ID NO: 138 or 982.

[0520] 442. An AAV particle as described in any one of embodiments 1 to 22, 25 to 27, 31, 34 to 42, 45 to 50, 53 to 63, 69, 79, 83 to 86, 91 to 98, 102, 103, 110, 111, 118 to 129, 369 to 371, 384, 385, 390, 393, 395, 410 to 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 after position 455 of the amino acid sequence number according to SEQ ID NO: 138.

[0521] 443. An adeno-associated virus (AAV) particle comprising an AAV capsid variant containing the amino acid sequence HDSPHK (SEQ ID NO:2), wherein the amino acid sequence is present immediately following position 453 of the amino acid sequence number according to SEQ ID NO: 982, wherein the AAV particle further comprises nucleic acid encoding a synaptic fusion protein binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein).

[0522] 444. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a synaptic fusion protein-binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein), wherein the AAV capsid variant comprises the amino acid sequence SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately following position 455 of the amino acid sequence number according to SEQ ID NO: 981.

[0523] 445. An adeno-associated virus (AAV) particle comprising an AAV capsid variant containing the amino acid sequence HDSPHK (SEQ ID NO:2), wherein the amino acid sequence is present immediately following position 453 of the amino acid sequence number according to SEQ ID NO: 37, and optionally further comprising: (i) One, two, or all of the amino acids other than T at position 450, the amino acid other than I at position 541, and / or the amino acid other than N at position 452, according to SEQ ID NO: 138 or 37; (ii) One, two, or all of the following according to SEQ ID NO: 138 or 37: A at position 450, E at position 451, and / or I at position 452; The AAV particle further contains nucleic acid encoding synaptic fusion protein-binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein).

[0524] 446. An adeno-associated virus (AAV) particle comprising an AAV capsid variant containing an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately following position 455 of an amino acid sequence number according to any one of SEQ ID NO: 36, 38-55, 57 or 59, wherein the AAV particle further comprises nucleic acid encoding a synaptic fusion protein binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein).

[0525] 447. The AAV particle as described in any of the foregoing embodiments, wherein the AAV capsid variant further comprises: (i) Modifications in rings I, II, VI and / or VIII; and / or (ii) Substitution at position K449 according to SEQ ID NO: 138, for example, K449R substitution.

[0526] 448. An AAV particle as described in any of the foregoing embodiments, wherein the AAV capsid variant comprises an amino acid sequence containing at least one, at least two, or at least three modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 138, but not more than 30, 20, or 10 modifications, such as substitutions (e.g., conservative substitutions).

[0527] 449. The AAV particle of any of the foregoing 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, no more than 20, or no more than 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 138.

[0528] 450. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant comprises an amino acid sequence having 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 with SEQ ID NO: 138.

[0529] 451. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant comprises an amino acid sequence having at least 98% identity with SEQ ID NO: 138.

[0530] 452. The AAV particle of any of the foregoing embodiments, wherein the AAV capsid variant comprises an amino acid sequence encoded by a sequence having 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 with SEQ ID NO: 137.

[0531] 453. The AAV particle of any of the foregoing embodiments, wherein the nucleotide sequence encoding the capsid variant comprises a sequence having 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 with SEQ ID NO: 137.

[0532] 454. The AAV particle as described in any of the foregoing embodiments, wherein the AAV capsid variant comprises VP1 protein, VP2 protein, VP3 protein, or a combination thereof.

[0533] 455. An AAV particle as described in any one of embodiments 1 to 454, wherein the AAV capsid variant comprises an amino acid sequence corresponding to positions 138-742 (e.g., VP2) of SEQ ID NO: 981, 982, 36 or 4, or a sequence having 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 with it.

[0534] 456. An AAV particle as described in any one of embodiments 1 to 455, wherein the AAV capsid variant comprises an amino acid sequence corresponding to positions 203-742 (e.g., VP3) of SEQ ID NO: 981, 982, 36 or 4, or a sequence having 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 with it.

[0535] 457. An AAV particle as described in any one of embodiments 1 to 456, wherein the AAV capsid variant comprises an amino acid sequence having 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 with SEQ ID NO: 138.

[0536] 458. An AAV particle as described in any one of embodiments 1 to 457, wherein the AAV capsid variant comprises an amino acid sequence having 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 with SEQ ID NO: 138.

[0537] 459. As per implementation plans 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 2 AAV particles of any one of 99, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 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 SPHSKA amino acid sequence (SEQ ID NO: 941), wherein: (i) At least three consecutive amino acids contain SPH; (ii) At least four consecutive amino acids contain SPHS (SEQ ID NO: 4700); (iii) At least 5 consecutive amino acids contain SPHSK (SEQ ID NO: 4701); or (iv) At least six consecutive amino acids contain SPHSKA (SEQ ID NO: 941); The AAV capsid variant comprises: (a) a VP1 protein containing the amino acid sequence of SEQ ID NO: 981; (b) a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 981; (c) a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 981; or (d) an amino acid sequence having 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 with any of the amino acid sequences in (a)-(c).

[0538] 460. As per implementation schemes 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 2 AAV particles of any one of 99, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 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 SPHSKA amino acid sequence (SEQ ID NO: 941), wherein: (i) At least three consecutive amino acids contain SPH; (ii) At least four consecutive amino acids contain SPHS (SEQ ID NO: 4700); (iii) At least 5 consecutive amino acids contain SPHSK (SEQ ID NO: 4701); or (iv) At least six consecutive amino acids contain SPHSKA (SEQ ID NO: 941); The AAV capsid variant contains at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the amino acid sequence that is identical to that of SEQ ID NO: 981.

[0539] 461. AAV particles according to any one of embodiments 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 460, wherein the AAV capsid variant comprises an amino acid sequence relative to SPHSKA (SEQ ID NO: 941) has one or two, but no more than three, substitutions, wherein the AAV capsid variant comprises: (a) VP1 protein, comprising the amino acid sequence of SEQ ID NO: 981; (b) VP2 protein, comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 981; (c) VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 981; or (d) An amino acid sequence that has 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 with any of the amino acid sequences in (a)-(c).

[0540] 462. AAV particles according to any one of implementation schemes 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, or 446 to 461, wherein the AAV capsid variant comprises an amino acid sequence relative to SPHSKA (SEQ ID NO: (941) One or two but no more than three substitutions, wherein the AAV capsid variant contains at least 90% (e.g. at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) of the amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 981.

[0541] 463. An AAV particle as described in any one of embodiments 459 to 462, wherein the amino acid sequence is present immediately following position 455 according to SEQ ID NO: 138 or 981.

[0542] 464. As per implementation plans 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299 AAV particles of any one of 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, or 447 to 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 (SEQ ID NO: 2) of HDSPHK, wherein: (i) At least three consecutive amino acids contain HDS; (ii) At least four consecutive amino acids contain HDSP (SEQ ID NO: 4702); (iii) At least five consecutive amino acids contain HDSPH (SEQ ID NO: 4703); or (iv) At least six consecutive amino acids contain HDSPHK (SEQ ID NO: 2); The AAV capsid variant comprises: (a) a VP1 protein containing the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 982; (c) a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 982; or (d) an amino acid sequence having 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 with any of the amino acid sequences in (a)-(c).

[0543] 465. As per implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 3 AAV particles of any one of 27 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 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 (SEQ ID NO: 2) of HDSPHK, wherein: (i) At least three consecutive amino acids contain HDS; (ii) At least four consecutive amino acids contain HDSP (SEQ ID NO: 4702); (iii) At least five consecutive amino acids contain HDSPH (SEQ ID NO: 4703); or (iv) At least six consecutive amino acids contain HDSPHK (SEQ ID NO: 2); The AAV capsid variant contains at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of the same amino acid sequence as SEQ ID NO: 982.

[0544] 466. Implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to AAV particles of any one of 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 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 (SEQ ID NO: 2) of HDSPHK, wherein the AAV capsid variant comprises: (a) VP1 protein, comprising the amino acid sequence of SEQ ID NO: 982; (b) VP2 protein, comprising the amino acid sequence from position 138 to 742 of SEQ ID NO: 982; (c) VP3 protein comprising the amino acid sequence at positions 203 to 742 of SEQ ID NO: 982; or (d) An amino acid sequence that has 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 with any of the amino acid sequences in (a) through (c).

[0545] 467. As per implementation plans 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to AAV particles of any one of 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, or 464 to 466, 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 an amino acid sequence that is 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.

[0546] 468. An AAV particle as described in any one of embodiments 464 to 468, wherein the amino acid sequence is present immediately following position 453 according to SEQ ID NO: 138 or 982.

[0547] 469. An AAV particle as described in any one of embodiments 1 to 468, wherein the AAV capsid variant comprises an amino acid sequence of SEQ ID NO: 981 or 982 or an amino acid sequence having 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 with it.

[0548] 470. An AAV particle as described in any one of embodiments 1 to 469, wherein the AAV capsid variant comprises an amino acid sequence containing at least one, at least two, or at least three modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 981 or 982, but not more than 30, not more than 20, or not more than 10 modifications, such as substitutions (e.g., conservative substitutions).

[0549] 471. An AAV particle as described in any one of embodiments 1 to 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.

[0550] 472. AAV particles according to any one of implementation schemes 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, or 469 to 471, wherein the AAV capsid variant contains SEQ ID NO: The amino acid sequence of 981 or an amino acid sequence having 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 with it.

[0551] 473. As per implementation schemes 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 AAV particles of any one of SEQ ID NO: 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463 or 469 to 472, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, at least two or at least three modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 981, but not more than 30, not more than 20 or not more than 10 modifications, such as substitutions (e.g., conservative substitutions).

[0552] 474. As per implementation plans 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, 291 AAV particles of any one of SEQ ID NO: 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463 or 469 to 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.

[0553] 475. As per implementation plans 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to AAV particles of any one of 287, 289 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, or 464 to 471, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having 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 with it.

[0554] 476. As per implementation plans 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299 AAV particles of any one of SEQ ID NO: 982, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 471 or 475, wherein the AAV capsid variant comprises an amino acid sequence containing at least one, at least two or at least three modifications, such as substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 982, but not more than 30, not more than 20 or not more than 10 modifications, such as substitutions (e.g., conservative substitutions).

[0555] 477. Implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 289 to 299, 3 AAV particles of any one of 27 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 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.

[0556] 478. An AAV particle as described in any one of embodiments 1 to 477, wherein the AAV capsid variant comprises an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 983 or 984 or a nucleotide sequence having 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 with it.

[0557] 479. An AAV particle as described in any one of embodiments 1 to 478, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 983 or 984, or a nucleotide sequence having 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 with it.

[0558] 480. As per implementation plans 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288 AAV particles of any one of SEQ ID NO: 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, 469 to 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 having 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 with it.

[0559] 481. As per implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 28 AAV particles of any one of 9 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 471 or 475 to 479, wherein the nucleotide sequence encoding the capsid variant comprises the nucleotide sequence of SEQ ID NO: 984 or a nucleotide sequence having 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 with it.

[0560] 482. The AAV particle of any of the foregoing embodiments, wherein the nucleotide sequence encoding the capsid variant is codon-optimized.

[0561] 483. As per implementation plans 1 to 23, 26 to 29, 32, 35 to 43, 46 to 51, 54 to 72, 69 to 89, 91, 94 to 99, 102 to 104, 107, 110 to 112, 115 to 129, 168 to 202, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, AAV particles of any one of 288, 291 to 299, 327 to 363, 369 to 371, 375 to 379, 385, 386, 390, 391, 395, 406, 408, 410 to 413, 415 to 432, 444, 446 to 463, 469 to 474, 478 to 480 or 482, and further comprising an amino acid sequence that is at least 95% identical to that of SEQ ID NO: 981.

[0562] 484. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a synaptic fusion protein-binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981.

[0563] 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 is at least 90%, at least 95%, or at least 99% identical thereto.

[0564] 486. As per implementation schemes 1 to 9, 11, 12 to 22, 24, 26, 28, 30, 33, 35 to 42, 44, 46 to 50, 52, 54 to 77, 83 to 88, 90 to 97, 100 to 103, 105, 110, 111, 113 to 129, 203 to 248, 251, 252, 254 to 257, 260, 261, 264 to 280, 283 to 287, 2 AAV particles of any one of 89 to 299, 327 to 363, 369, 369, 371, 380 to 383, 385, 386, 390, 392, 395, 407, 409 to 412, 414, 433 to 435, 438 to 441, 443, 445, 447 to 458, 464 to 471, 475 to 479, 481 or 482, and further comprising an amino acid sequence that is at least 95% identical to that of SEQ ID NO: 982.

[0565] 487. An AAV particle comprising an AAV capsid variant and nucleic acid encoding a synaptic fusion protein-binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.

[0566] 488. The AAV particle of embodiment 486 or 487, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984 or a nucleotide sequence that is at least 90%, at least 95%, or at least 99% identical thereto.

[0567] 489. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a synaptic fusion protein-binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein), wherein the AAV capsid variant comprises an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 983 or 984 or a nucleotide sequence that is at least 95% identical thereto.

[0568] 490. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a synaptic fusion protein-binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein), wherein the AAV capsid variant comprises an amino acid sequence of any one of SEQ ID NO: 4 or 36 to 59, optionally wherein the AAV capsid variant comprises an amino acid sequence of SEQ ID NO: 4 or 36.

[0569] 491. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a synaptic fusion protein binding protein 1 (STXBP1) protein (e.g., human STXBP1 protein), wherein the AAV capsid variant comprises an amino acid sequence encoded by a nucleotide sequence of any one of SEQ ID NO: 12-35 or a nucleotide sequence that is at least 95% identical thereto.

[0570] 492. The AAV particle of embodiment 490 or 491, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of any one of SEQ ID NO: 12-35 or is at least 95% identical to it.

[0571] 493. The AAV particle of any one of embodiments 1 to 299, 369 to 371 or 375 to 492, having increased tropism to CNS cells or tissues, such as brain cells, brain tissue, spinal cord cells or spinal cord tissue, relative to the tropism of AAV particles comprising a capsid containing the amino acid sequence of SEQ ID NO: 138.

[0572] 494. AAV particles as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 493, which transduce brain regions, such as midbrain regions (e.g., hippocampus or thalamus) or brainstem, optionally wherein, when measured by means of assays, such as immunohistochemistry or qPCR, such as as described in Example 2, the transduction level is at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times or at least 65 times that of AAV particles containing the capsid of SEQ ID NO: 138.

[0573] 495. AAV particles of any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 494, which transduce brain regions, such as midbrain regions (e.g., hippocampus or thalamus) or brainstem, optionally wherein, for example when measured by means of an assay, such as immunohistochemistry or qPCR, such as as described in Example 2, the transduction level is at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times or at least 65 times that of AAV particles containing the capsid of SEQ ID NO: 138.

[0574] 496. AAV particles as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 495, for example, when measured by means of the determination described in Example 1, are enriched in the brain by at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times or at least 10 times the amount of AAV particles containing the capsid of SEQ ID NO: 138.

[0575] 497. AAV particles as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 496, for example, when measured by means of the determination described in Example 1, are enriched in the brain at at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times or at least 85 times.

[0576] 498. AAV particles as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371 or 375 to 497, for example, compared to AAV particles containing the capsid of SEQ ID NO: 138, are enriched in the brains of at least two to at least three species (e.g., non-human primates and rodents (e.g., mice)).

[0577] 499. AAV particles as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, or 375 to 498, which, when measured by means of the assay described in Example 1 or 5, are enriched in the brains of at least two to at least three species (e.g., non-human primates and rodents (e.g., mice)) containing SEQ ID NO: The AAV particles with a capsid of 138 are at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, at least 100 times, at least 105 times, at least 115 times, at least 120 times, at least 125 times, at least 130 times, at least 135 times, at least 140 times, at least 145 times, at least 150 times, at least 155 times, at least 160 times, at least 165 times, at least 170 times, at least 175 times, at least 180 times, at least 190 times, at least 200 times, at least 205 times, or at least 210 times more potent than those with a capsid of 138.

[0578] 500. AAV particles as described in embodiment 498 or 499, wherein at least two to at least three species are cynomolgus monkeys (Macaca fascicularis), green monkeys (Chlorocebus sabaeus), common marmosets (Callithrix jacchus) and / or mice (e.g., BALB / c mice, C57Bl / 6 mice and / or CD-1 distantly related hybrid mice).

[0579] 501. AAV particles as described in any one of embodiments 130 to 146, 369, 410 to 414, 447 to 454, 457, 458, 482, or 493, when measured by means of the determination described in Example 3, wherein the AAV particles are enriched in the brain at at least 2 times, at least 2.5 times, at least 3 times, at least 3.5 times, at least 4 times, at least 4.5 times, at least 5 times, at least 5.5 times, at least 6 times, at least 6.5 times, at least 7 times, at least 7.5 times, or at least 8 times.

[0580] 502. AAV particles as described in any one of embodiments 147 to 167, 369, 410 to 414, 447 to 454, 457, 458, 482 or 493, for example, when measured by means of the determination described in Example 3, are enriched in the brain at at least 2 times, at least 2.5 times, at least 3 times, at least 3.5 times, at least 4 times, at least 4.5 times, at least 5 times or at least 5.5 times the amount of AAV particles containing the capsid of SEQ ID NO: 982.

[0581] 503. An AAV particle, as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, or 375 to 500, delivers an increased level of STXBP1 to a brain region, for example, when measured by assay, such as qRT-PCR or qPCR assay (e.g., as described in Embodiment 2 or 8), optionally wherein the level of STXBP1 is increased by at least 10-fold, at least 12-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 55-fold, at least 60-fold, at least 65-fold, or at least 70-fold compared to an AAV particle containing the capsid of SEQ ID NO: 138.

[0582] 504. An AAV particle as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503, when measured by assay, such as qRT-PCR or qPCR assay (e.g., as described in Embodiment 2 or 8), delivers an increased level of viral genome to a brain region, optionally wherein the level of viral genome is increased by at least 5-fold, at least 10-fold, at least 15-fold, at least 17-fold, at least 18-fold, at least 19-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold or at least 50-fold compared to an AAV particle containing the capsid of SEQ ID NO: 138.

[0583] 505. AAV particles as described in implementation scheme 503 or 504, wherein the brain region is a midbrain region (e.g., hippocampus or thalamus), frontal cortex, temporal cortex, motor cortex, cerebral cortex, caudate nucleus, putamen, dentate nucleus, substantia nigra, or brainstem.

[0584] 506. AAV particles as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 505, when measured by means of the determination described in Example 1 or 8, are enriched in the spinal cord at at least 4 times, at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times or at least 35 times the amount of AAV particles containing the capsid of SEQ ID NO: 138, optionally wherein the region of the spinal cord is the thoracic spinal cord region, the cervical spinal cord region, the C5 ventral horn region, the lumbar spinal cord region or the L5 ventral horn region.

[0585] 507. AAV particles as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 506, which show preferential transduction in a brain region relative to transduction in the dorsal root ganglion (DRG).

[0586] 508. AAV particles of any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 507, which show preferential transduction in brain regions relative to the liver.

[0587] 509. AAV particles of any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 508, which show preferential transduction in brain regions relative to transduction in the heart.

[0588] 510. AAV particles of any one of embodiments 1 to 129, 168 to 299, 369 to 371, 375 to 500 or 503 to 509, which show preferential transduction in brain regions relative to transduction in the dorsal root ganglion (DRG) and the heart.

[0589] 511. The AAV particles of any of the foregoing embodiments are capable of transducing non-neuronal cells, such as glial cells (e.g., oligodendrocytes or astrocytes).

[0590] 512. The AAV particles of embodiment 511, wherein the non-neuronal cells comprise glial cells, oligodendrocytes (e.g., Olig2-positive oligodendrocytes), or astrocytes (e.g., Olig2-positive astrocytes).

[0591] 513. The AAV particles of any of the foregoing embodiments are capable of transducing Olig2-positive cells, such as Olig2-positive astrocytes or Olig2-positive oligodendrocytes.

[0592] 514. The AAV particle of any one of embodiments 369, 373, 447 to 454, 457, 458 or 482, having increased tropism toward cardiac cells or tissues, such as ventricles or atria, relative to the tropism of AAV particles containing the capsid of SEQ ID NO: 138.

[0593] 515. AAV particles as described in any one of embodiments 369, 373, 447 to 454, 457, 458, 482 or 514, when measured by means of the determination described in Example 4, are enriched in the heart by at least 4 times, at least 5 times, at least 8 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 24 times, at least 25 times, at least 27 times, at least 31 times, at least 33 times or at least 34 times.

[0594] 516. The AAV particle of any one of embodiments 369, 374, 447 to 454, 457, 458, 482, having increased tropism to muscle cells or tissues (e.g., quadriceps femoris cells or quadriceps femoris tissue) relative to the tropism of AAV particles comprising a capsid containing the amino acid sequence of SEQ ID NO: 138.

[0595] 517. AAV particles as described in any one of embodiments 369, 374, 447 to 454, 457, 458, 482, when measured by means of the determination described in Example 4, are enriched in muscle at least 4 times, at least 5 times, at least 8 times, at least 12 times, at least 17 times, at least 18 times, at least 20 times, at least 26 times, at least 27 times, at least 28 times, at least 30 times, or at least 36 times.

[0596] 518. AAV particles as described in embodiments 516 or 517, wherein the muscle cells or tissues are cardiac muscle (e.g., ventricle or atrium or both), quadriceps or both.

[0597] 519. The AAV particles of any of the foregoing embodiments, which are separated and / or recombined.

[0598] [Implementation plans 520 to 585 are intentionally nonexistent.]

[0599] 586. An AAV particle as described in any of the foregoing embodiments, wherein the viral genome contains a promoter effectively linked to the STXBP1 coding sequence.

[0600] 587. An AAV particle as described in embodiment 586, wherein the promoter is a human elongation factor 1α-subunit (EF1α), a cytomegalovirus (CMV) immediate early enhancer and / or promoter, a chicken β-actin (CBA) promoter, a CAG promoter, a CAG derivative promoter, a β-glucuronidase (GUSB) promoter or a ubiquitin C (UBC) promoter, a neuron-specific enolase (NSE) promoter, a platelet-derived growth factor (PDGF) promoter, a platelet-derived growth factor B chain (PDGF-β) promoter, an intercellular adhesion molecule 2 (ICAM-2) promoter, a synaptic protein (Syn) promoter, a methyl-CpG-binding protein 2 (MeCP2) promoter, or a Ca2+ / calmodulin-dependent protein kinase II. (CaMKII), metabolized glutamate receptor 2 (mGluR2) promoter, neurofilament light chain (NFL) or heavy chain (NFH) promoter, β-globin small gene nβ2, proenkephalinogen (PPE) promoter, enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, glial fibrillary acidic protein (GFAP) promoter, myelin basic protein (MBP) promoter, cardiovascular promoters (e.g., αMHC, cTnT and CMV-MLC2k), liver promoters (e.g., hAAT, TBG), skeletal muscle promoters (e.g., desmin, MCK, C512) or fragments thereof (e.g. truncated) or functional variants.

[0601] [Implementation plans 588 and 589 are intentionally nonexistent.]

[0602] 590. An AAV particle as described in any one of embodiments 586 to 589, wherein the viral genome further comprises a polyadenylate sequence.

[0603] 591. An AAV particle as described in any one of embodiments 586 to 590, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.

[0604] 592. An AAV particle as described in any one of embodiments 586 to 591, wherein the viral genome contains an ITR sequence located at the 5' position relative to the STXBP1 coding sequence (e.g., encoding the human STXBP1 protein).

[0605] 593. An AAV particle as described in any one of embodiments 586 to 592, wherein the viral genome contains an ITR sequence located at the 3' position relative to the STXBP1 coding sequence (e.g., encoding the human STXBP1 protein).

[0606] 594. An AAV particle as described in any one of embodiments 586 to 593, wherein the viral genome comprises an ITR sequence located at 5' relative to the STXBP1 coding sequence (e.g., encoding human STXBP1 protein) and an ITR sequence located at 3' relative to the STXBP1 coding sequence (e.g., encoding human STXBP1 protein).

[0607] 595. An AAV particle as described in any one of embodiments 586 to 594, wherein the viral genome further comprises enhancers, Kozak sequences, intron regions and / or exon regions.

[0608] [Implementation plans 596 to 615 are intentionally nonexistent.]

[0609] 616. An AAV particle as described in any one of embodiments 586 to 595, wherein the viral genome further comprises a nucleotide sequence encoding a Rep protein, such as a non-structural protein, wherein the Rep protein comprises Rep78 protein, Rep68 protein, Rep52 protein and / or Rep40 protein (e.g., Rep78 and Rep52 proteins).

[0610] 617. An AAV particle as described in embodiment 616, wherein the AAV particle further comprises a nucleotide sequence encoding a Rep protein, such as a non-structural protein, wherein the Rep protein comprises Rep78 protein, Rep68 protein, Rep52 protein and / or Rep40 protein (e.g., Rep78 and Rep52 proteins).

[0611] 618. The AAV particle of embodiment 616 or 617, wherein the Rep78 protein, Rep68 protein, Rep52 protein and / or Rep40 protein are encoded by at least one Rep gene.

[0612] 619. An AAV particle as described in any one of embodiments 586 to 618, wherein the viral genome further comprises a nucleic acid sequence encoding an AAV capsid variant of an AAV particle as described in any one of embodiments 1 to 519, 566 or 574.

[0613] 620. The AAV particles of any one of embodiments 575 to 619, wherein the AAV particles are separated and / or recombined AAV particles.

[0614] [Implementation plan 621 is intentionally nonexistent.]

[0615] 622. A cell, such as a host cell, comprising AAV particles as described in any of the foregoing embodiments.

[0616] 623. The cell of embodiment 622, wherein the cell is a mammalian cell or an insect cell.

[0617] 624. Cells as described in embodiments 622 or 623, wherein the cells are cells of a brain region or spinal cord region, optionally cells of the brainstem, hippocampus, or thalamus.

[0618] 625. A cell as described in any one of embodiments 622 to 624, wherein the cell is a neuron, sensory neuron, motor neuron, astrocyte, glial cell, oligodendrocyte, or muscle cell (e.g., cells of the heart, diaphragm, or quadriceps femoris muscle).

[0619] [Implementation plan 626 is intentionally nonexistent.]

[0620] 627. A method for preparing adeno-associated virus (AAV) particles, comprising:

[0621] (i) Providing a host cell containing a viral genome, the viral genome containing the STXBP1 coding sequence; and

[0622] (ii) The host cell is cultured under conditions suitable for encapsulating the viral genome in an AAV capsid variant as described in any of embodiments 1 to 620; The AAV particles were prepared in this way.

[0623] 628. The method of embodiment 627 further includes introducing a first nucleic acid molecule containing the viral genome into the host cell prior to step (i).

[0624] 629. The method of embodiment 628, wherein the host cell contains a second nucleic acid encoding a capsid variant.

[0625] 630. The method of embodiment 629, wherein the second nucleic acid molecule is introduced into the host cell before, simultaneously with, or after the first nucleic acid molecule.

[0626] 631. A pharmaceutical composition comprising AAV particles as described in any one of embodiments 1 to 620 and a pharmaceutically acceptable excipient.

[0627] 632. A method of delivering a payload to cells or tissues (e.g., CNS cells or CNS tissues), comprising administering an effective amount of a pharmaceutical composition as described in embodiment 631 or AAV particles as described in any one of embodiments 1 to 620.

[0628] 633. The method of embodiment 632, wherein the cell is a cell of a brain region or spinal cord region, optionally a cell of the frontal cortex, sensory cortex, motor cortex, caudate nucleus, cerebellar cortex, cerebral cortex, brainstem, hippocampus or thalamus.

[0629] 634. The method of embodiment 632 or 633, wherein the cell is a neuron, sensory neuron, motor neuron, astrocyte, glial cell or oligodendrocyte.

[0630] [Implementation Plan 635 is intentionally nonexistent.]

[0631] 636. The method of any one of embodiments 632 to 634, wherein the cell or tissue is within the subject.

[0632] 637. The method of implementation scheme 636, wherein the subject has a genetic condition, has been diagnosed with a genetic condition, such as a monogenic or polygenic genetic condition, or is at risk of developing a genetic condition, such as a monogenic or polygenic genetic condition.

[0633] 638. The method of implementation 636 or 637, wherein the subject has, has been diagnosed with, a neurological disorder, such as a neurodegenerative disease, or is at risk of developing a neurological disorder, such as a neurodegenerative disease.

[0634] [Implementation plan 639 is intentionally nonexistent.]

[0635] 640. The method of implementation 636 or 637, wherein the subject has, has been diagnosed with, a myopathy or neuromuscular disorder, or is at risk of developing a myopathy or neuromuscular disorder.

[0636] 641. A method of treating a subject who has or has been diagnosed with a genetic condition, such as a single-gene or polygenic genetic disease, comprising administering to the subject an effective amount of a pharmaceutical composition as described in embodiment 631 or AAV particles as described in any one of embodiments 1 to 620.

[0637] 642. A method of treating a subject who has or has been diagnosed with a neurological disorder, such as a neurodegenerative disorder, comprising administering to the subject an effective amount of a pharmaceutical composition as described in embodiment 631 or AAV particles as described in any one of embodiments 1 to 620.

[0638] 643. A method of treating a subject suffering from or diagnosed with a muscle disease or neuromuscular disease, comprising administering to the subject an effective amount of a pharmaceutical composition as described in embodiment 631 or AAV particles as described in any one of embodiments 1 to 620.

[0639] [Implementation plan 644 is intentionally nonexistent.]

[0640] 645. The method of any one of embodiments 637 to 643, wherein the genetic condition, neurological condition, neurodegenerative condition, myopathy, or neuromuscular condition is STXBP1 encephalopathy, epileptic encephalopathy, Ōtahara syndrome, developmental encephalopathy, West syndrome, early myositis epileptic encephalopathy, Lennox-Gasto syndrome, autism (e.g., autism with an STXBP1 mutation and optionally other mutations), Draway syndrome (not caused by a mutation in SCN1A), or Rett syndrome phenotype (not caused by a mutation in MECP2 or CDKL5).

[0641] 646. The method of any one of embodiments 641 to 645, wherein the treatment includes preventing the progression of the subject's condition.

[0642] 647. The method as described in embodiments 636 to 646, wherein the subject is a human.

[0643] 648. The method of any one of embodiments 636 to 647, wherein the AAV particles are administered to the subject intravenously, via intracisional injection (ICM), intracerebral, intrathecal, intraventricular, via intraparenchymal, intra-arterial, or intramuscularly.

[0644] 649. The method of any one of embodiments 636 to 648, wherein the AAV particles are administered to the subject via focused ultrasound (FUS), such as intravenous administration of FUS combined with microbubbles (FUS-MB), or MRI-guided FUS combined with intravenous administration.

[0645] 650. The method of any one of embodiments 636 to 649, wherein the AAV particles are administered to the subject intravenously.

[0646] 651. The method of any one of embodiments 636 to 650, wherein the AAV particles are administered to the subject via intra-pool injection (ICM).

[0647] 652. The method of any one of embodiments 636 to 651, wherein the AAV particles are administered to the subject intra-arterially.

[0648] [Implementation plan 653 is intentionally nonexistent.]

[0649] 654. The method of any one of embodiments 648 to 652, wherein the administration of the AAV particle causes an increase in the presence, content and / or activity of the STXBP1 gene, mRNA, protein or a combination thereof.

[0650] 655. A pharmaceutical composition as described in embodiment 631 or AAV particles as described in any one of embodiments 1 to 620, used in a method for delivering the STXBP1 coding sequence to cells or tissues.

[0651] 656. The pharmaceutical composition of embodiment 631 or the AAV particles of any one of embodiments 1 to 620, used in the method of treating genetic diseases, neurological diseases, neurodegenerative diseases, myopathy or neuromuscular diseases.

[0652] 657. The pharmaceutical composition of embodiment 631 or the AAV particles of any one of embodiments 1 to 620, used in the manufacture of a pharmaceutical product.

[0653] 658. Use of the pharmaceutical composition of embodiment 631 or AAV particles of any one of embodiments 1 to 620 in the preparation of a medicament.

[0654] 659. Use of the pharmaceutical composition of embodiment 631 or AAV particles of any one of embodiments 1 to 620 in the preparation of a medicament for treating genetic diseases, neurological diseases or neurodegenerative diseases, muscle diseases or neuromuscular diseases.

[0655] 660. An AAV particle comprising an AAV capsid variant as described in any one of embodiments 1 to 519, such as any one of embodiments 507 to 510, and a viral genome comprising a nucleotide sequence encoding a synaptic fusion protein binding protein 1 (STXBP1) protein (i.e., the STXBP1 coding sequence), wherein the nucleotide sequence is at least 90% (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 the nucleotide sequence of SEQ ID NO: 6414.

[0656] 661. The AAV particle of embodiment 660, wherein the nucleotide sequence encoding the STXBP1 protein (i.e., the STXBP1 coding sequence) comprises at least 90% the same nucleotide sequence as SEQ ID NO: 6414.

[0657] 662. The AAV particle of embodiment 660 or embodiment 661, wherein the nucleotide sequence encoding the STXBP1 protein (i.e., the STXBP1 coding sequence) comprises at least 95% the same nucleotide sequence as SEQ ID NO: 6414.

[0658] 663. An AAV particle as described in any one of embodiments 660 to 662, wherein the nucleotide sequence encoding the STXBP1 protein (i.e., the STXBP1 coding sequence) comprises the nucleotide sequence of SEQ ID NO: 6414.

[0659] [Implementation plan 664 is intentionally nonexistent.]

[0660] 665. An AAV particle as described in any one of embodiments 660 to 663, 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; or (c) a VP3 protein comprising the amino acid sequence of positions 203-742 of SEQ ID NO: 982; or wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 984 or a 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).

[0661] 666. An AAV particle as described in any one of embodiments 660 to 663, wherein the AAV capsid variant comprises no more than three amino acid substitutions relative to the amino acid sequence (SEQ ID NO: 2) of HDSPHK, wherein the AAV capsid variant comprises an amino acid sequence that is at least 99% identical to that of SEQ ID NO: 982.

[0662] [Implementation plans 667 to 668 are intentionally nonexistent.]

[0663] 669. An AAV particle as described in any one of embodiments 660 to 666, wherein the encoded STXBP1 protein comprises the amino acid sequence of SEQ ID NO: 6413 or an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, 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 to it.

[0664] 670. The AAV particle of embodiment 669, wherein the nucleotide sequence encoding the STXBP1 protein (i.e., the STXBP1 coding sequence) comprises the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence that is at least 90% (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 to it.

[0665] 671. The AAV particle of embodiment 669 or 670, wherein the nucleotide sequence encoding the STXBP1 protein (i.e., the STXBP1 coding sequence) comprises the nucleotide sequence of SEQ ID NO: 6414.

[0666] 672. An AAV particle as described in any one of embodiments 660 to 671, wherein the viral genome further comprises a nucleotide sequence encoding a signal sequence.

[0667] [Implementation plan 673 does not exist intentionally].

[0668] 674. An AAV particle as described in embodiment 672, wherein the nucleotide sequence encoding the signal sequence is positioned relative to the 5' of the STXBP1 coding sequence.

[0669] 675. An AAV particle as described in embodiment 674, wherein the STXBP1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence that is at least 97% (e.g., at least 97%, at least 98%, or at least 99%) identical to it.

[0670] 676. The AAV particle of embodiment 675, wherein the STXBP1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 6414.

[0671] 677. The AAV particle of embodiment 675, wherein the STXBP1 coding sequence consists of the nucleotide sequence of SEQ ID NO: 6414.

[0672] 678. An AAV particle as described in any one of embodiments 660 to 677, wherein the viral genome further comprises a promoter effectively linked to the STXBP1 coding sequence.

[0673] 679. An AAV particle as described in any one of embodiments 660 to 678, wherein the viral genome further includes an enhancer.

[0674] [Implementation plans 680 to 681 are intentionally nonexistent.]

[0675] 682. The AAV particles of embodiment 678 or 679, wherein the promoter comprises a tissue-specific promoter.

[0676] 683. The AAV particle as described in embodiment 678 or 679, wherein the promoter comprises a universally present promoter.

[0677] 684. An AAV particle as described in any one of embodiments 678 to 683, wherein the promoter comprises: EF-1a promoter, CB promoter, chicken β-actin (CBA) promoter or its derivatives, CAG promoter or its derivatives, CMV immediate early enhancer and / or promoter, β-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-β) promoter, intercellular adhesion molecule 2 (ICAM-2) promoter, synaptic protein (Syn) promoter, synaptic protein 1 promoter (Syn1), methyl-CpG binding protein 2 (MeCP2) promoter, Ca2+ / calmodulin-dependent protein kinase II (CaMKII) promoter, metabolite glutamate receptor 2 (mGluR2) promoter, neurofilament light chain (NFL) or heavy chain (NFH) promoter, β-globin small gene nβ2 promoter, proenkephalinogen (PPE) promoter, enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, glial fibrillary acidic protein (GFAP) promoter, myelin basic protein (MBP) promoter, cardiovascular promoters (e.g., αMHC, cTnT and CMV-MLC2k), liver promoters (e.g., hAAT, TBG), skeletal muscle promoters (e.g., desmin, MCK, C512) or fragments thereof (e.g. truncated) or functional variants.

[0678] [Implementation plans 685 to 712 are intentionally nonexistent.]

[0679] 713. An AAV particle as described in any one of embodiments 660 to 684, wherein the viral genome further comprises an inverted terminal repeat (ITR) sequence.

[0680] 714. An AAV particle as described in embodiment 713, wherein the ITR sequence is positioned relative to the 5' position of the STXBP1 coding sequence.

[0681] 715. An AAV particle as described in embodiment 713 or 714, wherein the ITR sequence is positioned relative to the 3' location of the STXBP1 coding sequence.

[0682] 716. An AAV particle as described in any one of embodiments 713 to 715, wherein the viral genome contains an ITR located at the 5' position relative to the STXBP1 coding sequence and an ITR located at the 3' position relative to the STXBP1 coding sequence.

[0683] 722. An AAV particle as described in any one of embodiments 660 to 721, wherein the viral genome further comprises a polyadenylated (polyadenylated) region.

[0684] 724. An AAV particle as described in any one of embodiments 660 to 723, wherein the viral genome further comprises introns.

[0685] 727. An AAV particle as described in any one of embodiments 660 to 726, wherein the viral genome further comprises exons, such as at least one, at least two, or at least three exons.

[0686] 728. An AAV particle as described in any one of embodiments 660 to 727, wherein the viral genome further comprises a Kozak sequence.

[0687] [Implementation plans 729 to 761 are intentionally nonexistent.]

[0688] 762. An AAV particle as described in any one of embodiments 660 to 728, further comprising a nucleic acid encoding a Rep protein, wherein the Rep protein comprises Rep78 protein, Rep68 protein, Rep52 protein and / or Rep40 protein.

[0689] 763. The AAV particle of embodiment 762, wherein the Rep78 protein, Rep68 protein, Rep52 protein and / or Rep40 protein are encoded by at least one Rep gene.

[0690] 764. A carrier that encodes AAV particles as described in any one of embodiments 660 to 763.

[0691] 765. A cell comprising AAV particles as described in any one of embodiments 660 to 763 or a carrier as described in embodiment 764.

[0692] 766. The cells of embodiment 765 are mammalian cells (e.g., HEK293 cells), insect cells (e.g., Sf9 cells), or bacterial cells.

[0693] 767. A method for preparing recombinant adeno-associated virus (AAV) particles, the method comprising:

[0694] (i) Providing a host cell containing a viral genome comprising the nucleotide sequence of SEQ ID NO: 6414 or a sequence identical thereto by at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) the viral genome; and

[0695] (ii) The host cells were cultured under conditions suitable for enclosing the viral genome in a capsid variant containing the amino acid sequence of SEQ ID NO: 982; The recombinant AAV particles were prepared in this way.

[0696] 768. The method of embodiment 767 further includes introducing a first nucleic acid molecule containing the viral genome into the host cell prior to step (i).

[0697] 769. The method of embodiment 767 or embodiment 768, wherein the host cell contains a second nucleic acid encoding a capsid variant.

[0698] 770. The method of embodiment 769 further includes introducing the second nucleic acid into the cell.

[0699] 771. The method of embodiment 769 or embodiment 770, wherein the second nucleic acid molecule is introduced into the host cell before, simultaneously with, or after the first nucleic acid molecule.

[0700] 772. The method of any one of embodiments 767 to 772, wherein the host cell comprises mammalian cells (e.g., HEK293 cells), insect cells (e.g., Sf9 cells) or bacterial cells.

[0701] 773. A pharmaceutical composition comprising AAV particles as described in any one of embodiments 660 to 763 and a pharmaceutically acceptable excipient.

[0702] 774. A method of delivering STXBP1 protein to a subject, comprising administering to the subject an effective amount of a pharmaceutical composition as described in embodiment 773 or AAV particles as described in any one of embodiments 660 to 763, thereby delivering to the subject nucleic acid encoding the STXBP1 protein (i.e., the STXBP1 coding sequence).

[0703] 775. The method of implementation scheme 774, wherein the subject has, has been diagnosed with, or is at risk of developing STXBP1-related conditions.

[0704] 776. The method of implementation scheme 774 or implementation scheme 775, wherein the subject has, has been diagnosed with, a neurodegenerative disease or neuromuscular disease, or is at risk of developing a neurodegenerative disease or neuromuscular disease.

[0705] 777. A method of treating a subject who has or has been diagnosed with STXBP1-related conditions, comprising administering to the subject an effective amount of a pharmaceutical composition as described in embodiment 773 or AAV particles as described in any one of embodiments 660 to 763, thereby treating the subject's STXBP1-related conditions.

[0706] 778. A method of treating a subject suffering from or diagnosed with a neurodegenerative disease or neuromuscular disorder, comprising administering to the subject an effective amount of a pharmaceutical composition as described in embodiment 773 or AAV particles as described in any one of embodiments 660 to 763, thereby treating the subject's neurodegenerative disease or neuromuscular disorder.

[0707] 779. The method of any one of embodiments 774 to 778, wherein the STXBP1-related disorder or neurodegenerative or neuromuscular disorder includes STXBP1 encephalopathy, epileptic encephalopathy, Ōtahara syndrome, developmental encephalopathy, West syndrome, early myositis epileptic encephalopathy, Lennox-Gasto syndrome, autism (e.g., autism with an STXBP1 mutation and optionally other mutations), Draway syndrome (not caused by a mutation in SCN1A), and Rett syndrome phenotype (not caused by a mutation in MECP2 or CDKL5).

[0708] 780. A method of treating a subject suffering from or diagnosed with STXBP1 encephalopathy, comprising administering an effective amount of a pharmaceutical composition as described in embodiment 773 or AAV particles as described in any one of embodiments 660 to 763, thereby treating the subject with STXBP1 encephalopathy.

[0709] 781. The method of embodiment 779 or embodiment 780, wherein the subject has one or more mutations in STXBP1.

[0710] 784. A method of treating a subject suffering from or diagnosed with STXBP1 encephalopathy, comprising administering an effective amount of a pharmaceutical composition as described in embodiment 773 or AAV particles as described in any one of embodiments 660 to 763, thereby treating the subject with STXBP1 encephalopathy.

[0711] [Implementation plans 785 to 788 are intentionally nonexistent.]

[0712] 789. The method of any one of embodiments 774 to 784, wherein the subject has a reduced STXBP1 activity level compared to a reference level.

[0713] 790. The method of embodiment 789, wherein the reference level includes the STXBP1 activity level in subjects who do not have STXBP1-related conditions, neuromuscular diseases, and / or neurodegenerative diseases.

[0714] 791. The method of any one of embodiments 777 to 790, wherein the treatment results in improvement of at least one symptom of the subject’s STXBP1-related condition, neurodegenerative condition, and / or neuromuscular condition.

[0715] 792. The method of embodiment 791, wherein at least one symptom of an STXBP1-related disorder, a neurodegenerative disorder, and / or a neuromuscular disorder includes decreased STXBP1 activity, accumulation of glucocerebrosides and other glycolipids (e.g., in immune cells (e.g., macrophages)), accumulation of synuclein aggregates (e.g., Lewy bodies), developmental delay, progressive encephalopathy, progressive dementia, ataxia, myoclonus, oculomotor dysfunction, bulbar palsy, general weakness, limb tremor, depression, visual hallucinations, cognitive decline, dystonia, or a combination thereof.

[0716] 793. The method of any one of embodiments 774 to 792, wherein the subject is a human.

[0717] 794. The method of any one of embodiments 774 to 793, wherein the subject is an adolescent, for example, between the ages of 6 and 20.

[0718] 795. The method of any one of embodiments 774 to 793, wherein the subject is an adult, for example, aged 20 or older.

[0719] 796. The method of any one of embodiments 774 to 795, wherein the subject has one or more mutations in the STXBP1 gene, STXBP1 mRNA and / or STXBP1 protein.

[0720] 797. The method of any one of embodiments 774 to 796, wherein the AAV particles are administered to the subject via intravenous; intracerebral; intrathalamic (ITH); intramuscular; intrathecal; intraventricular; intraparenchymal; via focused ultrasound (FUS), such as intravenous administration of FUS combined with microbubbles (FUS-MB), or MRI-guided FUS combined with intravenous administration; or via intracisternal injection (ICM).

[0721] 798. The method of any one of embodiments 774 to 796, wherein the AAV particles are administered intravenously.

[0722] 799. The method of any one of embodiments 774 to 796, wherein the AAV particles are administered via intravenous injection, optionally wherein the intravenous injection is performed via focused ultrasound (FUS), such as intravenous administration of FUS combined with microbubbles (FUS-MB) or MRI-guided FUS combined with intravenous administration.

[0723] 800. The method of any one of embodiments 774 to 799, wherein the AAV particle is applied to cells, tissues or regions of the CNS, such as regions of the brain or spinal cord, such as parenchyma, cortex, substantia nigra, caudate nucleus, cerebellum, striatum, corpus callosum, cerebellum, brainstem caudate nucleus-putamen, thalamus, epithalamus, spinal cord or combinations thereof.

[0724] 801. The method of any one of embodiments 774 to 800, wherein the AAV particles are applied to at least two tissues or regions of the CNS, for example, bilateral application.

[0725] 802. The method of any one of embodiments 774 to 799, wherein the AAV particles are administered to cerebrospinal fluid, serum, or a combination thereof.

[0726] 803. The method of any one of embodiments 774 to 802, further comprising performing a blood test, performing an imaging test, collecting CNS biopsy samples, collecting tissue biopsy (e.g., biopsy of the lung, liver or spleen), collecting blood or serum samples or collecting aqueous cerebrospinal fluid biopsy.

[0727] 804. The method of any one of embodiments 774 to 803, further comprising assessing, for example, measuring the expression level of STXBP1 in the subject, such as in the subject's cells, tissues or body fluids, including the expression levels of the STXBP1 gene, STXBP1 mRNA and / or STXBP1 protein, optionally wherein the content of STXBP1 protein is measured by means of assays described herein, such as ELISA, Western blotting or immunohistochemistry.

[0728] 805. The method of embodiment 804, wherein the STXBP1 expression level is measured before, during or after treatment with the AAV particles.

[0729] 806. The method of embodiment 804 or embodiment 805, 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., liver, heart and / or spleen).

[0730] 807. The method of any one of embodiments 774 to 806, wherein, relative to a reference content, for example, in a subject who has not yet received treatment, such as in a subject who has not yet been administered the AAV particles, the administration results in an increase in the expression level of the STXBP1 protein in the subject's cells or tissues.

[0731] 808. The method of any one of embodiments 774 to 807, further comprising, for example, assessing, measuring, the level of STXBP1 activity in the subject, such as in the subject's cells or tissues, optionally wherein the level of STXBP1 activity is measured by means of the assay described herein.

[0732] 809. The method of any one of embodiments 774 to 808, wherein the application causes at least one, at least two, or all of the following to increase: (i) The level of STXBP1 activity in the subject’s cells, tissues (e.g., cells or tissues of the CNS, such as the cortex, striatum, thalamus, cerebellum and / or brainstem) and / or body fluids (e.g., CSF and / or serum) compared to a reference level (e.g., subjects who have not received treatment (e.g., subjects who have not been administered AAV particles). (ii) The viral genome (VG) content per cell in the subject's CNS tissues (e.g., cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord) compared to peripheral tissues, wherein the VG content per cell in the peripheral tissues is at least 1 / 4 to at least 1 / 10 of the content in the CNS tissues, as measured, for example, by means of the assays described herein; and / or (iii) The level of STXBP1 mRNA expression in cells or tissues (e.g., cells or tissues of the CNS, such as the cortex, thalamus and / or brainstem) measured, compared to a reference level (e.g., subjects who have not received treatment (e.g., have not been administered AAV particles)) or endogenous STXBP1 mRNA levels, as described herein.

[0733] 810. The method of any one of embodiments 774 to 809, further comprising administering additional therapeutic agents and / or therapies suitable for treating or preventing diseases, neurodegenerative diseases and / or neuromuscular diseases associated with STXBP1 expression.

[0734] 811. The method of embodiment 810, wherein the additional therapeutic agent and / or therapy comprises an antiepileptic drug (e.g., levetiracetam, phenobarbital, clonazepam, topiramate), an adrenocorticotropic hormone, or a combination thereof.

[0735] 812. The pharmaceutical composition of embodiment 773 or the AAV particles of any one of embodiments 660 to 763, for the treatment of STXBP1-related conditions, neuromuscular conditions and / or neurodegenerative conditions.

[0736] 813. Use of an effective amount of the pharmaceutical composition of embodiment 773 or AAV particles of any one of embodiments 660 to 763 in the preparation of a medicament for treating STXBP1-related conditions, neuromuscular diseases and / or neurodegenerative diseases.

[0737] Details of various aspects or embodiments of this disclosure are set forth below. Other features, objectives, and advantages of this disclosure will be apparent from the description and claims. In the description, the singular form includes the plural form unless the context clearly requires otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art of this disclosure. In the event of any conflict, this specification shall prevail.

[0738] Brief description of the attached figures

[0739] Figure 1 Biodistribution (VG / cell) in the motor cortex, frontal cortex, putamen, substantia nigra, dentate nucleus, ventral horn of cervical spinal cord, DRG, liver, and heart of cynomolgus monkeys at 28 days after IV injection of TTM-002.GBA_VG17-HA, AAV9.GBA_VG17-HA, or the mediator control.

[0740] Figure 2 The mRNA expression of the GBA1 transgene in the motor cortex, frontal cortex, putamen, substantia nigra, dentate nucleus, ventral horn of the cervical spinal cord, DRG, liver, and heart of cynomolgus monkeys was depicted 28 days after IV injection of TTM-002.GBA_VG17-HA, AAV9.GBA_VG17-HA, or the mediator control.

[0741] Figure 3A A graph showing the percentage of HA-positive cells (the percentage of cells transduced by the specified capsid variant) in the cortex of mice 28 days after intravenous administration of AAV particles containing the TTM-002 or TTM-027 AAV capsid variant at specified doses (listed on the X-axis) (from highest to lowest dose: 1e14 vg / kg, 3.2e13 vg / kg, 1e13 vg / kg, 3.2e12 vg / kg, or 1e12 vg / kg) (listed on the Y-axis). Figure 3BTo illustrate the graph of mRNA transgene expression relative to the housekeeping gene in the mouse brain 28 days after intravenous administration of AAV particles containing the TTM-002 or TTM-027 AAV capsid variant at specified doses (listed on the X-axis) (from highest to lowest dose: 1e14 vg / kg, 3.2e13 vg / kg, 1e13 vg / kg, 3.2e12 vg / kg, or 1e12 vg / kg).

[0742] Figure 4A To illustrate the percentage (HA+ cells%) of transduced cells with HA+ nuclei, measured by nuclear H2B-HA staining and hematoxylin co-localization in designated brain regions (temporal cortex, caudate nucleus, thalamus, or hippocampus) of African green monkeys. Measurements were taken on day 28 following intravenous administration of AAV particles containing a TTM-002 capsid variant or an AAV9 capsid control and a self-complementary genome encoding a histone 2B protein tagged with HA. Figure 4B This diagram illustrates the percentage of HA+ cells among those positive for specified markers (NeuN+ neurons, SMI311+ neurons, GFAP+ astrocytes, or Sox9+ astrocytes) in designated brain regions (temporal cortex, caudate nucleus, thalamus, or hippocampus) in African green monkeys. Measurements were taken on day 28 following intravenous administration of AAV particles containing the TTM-002 capsid variant and a self-complementary genome encoding histone 2B protein tagged with HA. Figures 4A-4B The data plotted in the figure represent one slice per monkey (n=2). Quantitative image analysis was performed on cells ranging from 1e3 to 1e5 based on region size. All p-values ​​are derived from unpaired two-tailed t-tests.

[0743] Figures 5A-5D To illustrate a series of graphs showing the tropism of TTM-001 and TTM-002 in the brain and liver relative to the AAV9 control 28 days after intravenous administration in mice at a dose of 1e13 VG / kg. Figure 5A Display viral genomes (VG) / diploid genomes (DG) in the brain of AAV9 control, TTM-001, or TTM-002; Figure 5B Display brain RNA (multiples of AAV9 control, TTM-001, or TTM-002 relative to AAV9); Figure 5C Demonstrates VG / DG in the liver for AAV9 control, TTM-001, or TTM-002; and Figure 5DLiver RNA (fold relative to AAV9) from AAV9 control, TTM-001, or TTM-002 is displayed. Each data point represents an individual mouse, and all plotted values ​​represent mean ± SD (n=3). P-values ​​are derived from unpaired two-tailed t-tests.

[0744] Detailed Implementation Plan

[0745] Overview

[0746] This document particularly describes compositions comprising an AAV capsid variant containing a sequence encoding an STXBP1 protein, such as wild-type STXBP1 protein, such as wild-type human STXBP1 protein. In some embodiments, this disclosure provides a method for delivering an AAV capsid variant containing a sequence encoding an STXBP1 protein to the cells or tissues of a subject. In some embodiments, this disclosure provides a method for delivering an AAV capsid variant, thereby providing an STXBP1 protein, such as wild-type STXBP1 protein, such as wild-type human STXBP1 protein, to the cells or tissues of a subject. In some embodiments, the AAV capsid variants described herein exhibit enhanced CNS tropism compared to other cells or tissues in vivo (e.g., liver and / or DRG).

[0747] AAV has proven suitable as a biological tool due to its relatively simple structure, its ability to infect a wide range of cells (including quiescent and dividing cells) without integrating into the host genome and without replication, and its relatively benign immunogenic profile. Engineered adeno-associated virus (AAV) capsids with improved brain-specificity represent an attractive solution to limitations in CNS delivery. AAV-derived vectors are promising tools for clinical gene transfer due to their nonpathogenic properties, low immunogenicity profile, low integration rate into the host genome, and long-term transgenic expression in non-dividing cells. However, the transduction efficiency of naturally occurring AAV in certain organs is too low for clinical application, and the neutralizing effect of pre-existing neutralizing antibodies on the capsid may hinder treatment in a large proportion of patients. For these reasons, considerable effort has been devoted to obtaining capsid variants with enhanced properties. Of the many methods tested to date, significant progress has ...

Claims

1. An adeno-associated virus (AAV) particle comprising: a) an AAV capsid variant comprising an amino acid sequence having the formula: [N1]-[N2]-[N3], wherein: (i) optionally, [N1] 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 syntaxin binding protein 1 (STXBP1) coding sequence.

2. The AAV particle of claim 1, wherein the amino acid sequence [N1]-[N2]-[N3] is located 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 to 3, wherein [N1] comprises X1, X2, and X3, wherein at least one of X1, X2, or X3 is G.

5. The AAV particle of any one of claims 1 to 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 syntaxin binding protein 1 (STXBP1) coding 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 located 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 after the amino 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 to 8, wherein the AAV9 capsid variant further comprises one, two, or all of: N at the amino acid position corresponding to position 452 of SEQ ID NO: 4, E at the amino acid position corresponding to position 451 of SEQ ID NO: 4, and / or V at the amino acid position corresponding to position 453 of SEQ ID NO:

4.

10. The AAV particle of any one of claims 6 to 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 to 10, wherein the AAV9 capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 4; (ii) a VP2 protein comprising an amino acid sequence that is at least 90% identical to positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence that is at least 90% identical 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 VP1 protein comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 4; (ii) a VP2 protein comprising an amino acid sequence that is at least 95% identical to positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence that is at least 95% identical 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 that is at least 99% identical to SEQ ID NO: 4; (ii) a VP2 protein comprising an amino acid sequence that is at least 99% identical to positions 138-742 of SEQ ID NO: 4; and / or (iii) a VP3 protein comprising an amino acid sequence that is at least 99% identical to positions 203-742 of SEQ ID NO:

4.

14. The AAV 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) an amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately after the amino acid position corresponding to position 455 of SEQ ID NO: 4; (ii) an E at the amino acid position corresponding to position 451 of SEQ ID NO: 4 and a V at the 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: E at the amino acid position corresponding to position 451 of SEQ ID NO: 36, R at the amino acid position corresponding to position 452 of SEQ ID NO: 36, and / or V at the 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 AAV9 capsid variant comprises the amino acid sequence of KTERVSGSPHSKAQNQQT (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 that is at least 90% identical to SEQ ID NO: 36; (ii) a VP2 protein comprising an amino acid sequence that is at least 90% identical to positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence that is at least 90% identical 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 that is at least 95% identical to SEQ ID NO: 36; (ii) a VP2 protein comprising an amino acid sequence that is at least 95% identical to positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence that is at least 95% identical 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 that is at least 99% identical to SEQ ID NO: 36; (ii) a VP2 protein comprising an amino acid sequence that is at least 99% identical to positions 138-742 of SEQ ID NO: 36; and / or (iii) a VP3 protein comprising an amino acid sequence that is at least 99% identical 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 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. (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 after the amino acid position corresponding to position 455 of SEQ ID NO: 36; (ii) E at the amino acid position corresponding to position 451 of SEQ ID NO: 36, R at the amino acid position corresponding to position 452 of SEQ ID NO: 36, and V at the 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 after the position corresponding to amino acid position 452 of SEQ ID NO: 982; and wherein the AAV capsid variant comprises an amino acid sequence that is 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 [N1] comprises GHD.

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

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

27. The AAV 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 that is at least 90% identical 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 that is at least 90% identical to 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 or an amino acid sequence that is at least 90% identical 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 VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence at least 95% identical 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 at least 95% identical to 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 or an amino acid sequence at least 95% identical 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 VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence at least 99% identical 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 at least 99% identical to 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 or an amino acid sequence at least 99% identical 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 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.

31. The AAV particle of any one of claims 1-30, wherein the viral genome encodes a wild-type STXBP1 protein.

32. The AAV particle of any one of claims 1-31, wherein the viral genome encodes a human STXBP1 protein.

33. The AAV particle of claim 31 or claim 32, wherein the STXBP1 protein comprises the amino acid sequence of SEQ ID NO: 6413.

34. The AAV particle of any one of claims 1 to 33, wherein the STXBP1 coding 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.

35. The AAV particle of claim 34, wherein the STXBP1 coding 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 STXBP1 coding 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 STXBP1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 6414.

38. The AAV particle of claim 36, wherein the STXBP1 coding sequence consists of the nucleotide sequence of SEQ ID NO: 6414.

39. The AAV particle of any one of claims 1 to 38, wherein the viral genome comprises a promoter operably linked to the STXBP1 coding sequence.

40. The AAV particle of claim 39, wherein the promoter is human elongation factor 1 alpha-subunit (EF1a), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken beta-actin (CBA), CAG, CAG derivatives, beta glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-beta), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), synapsin 1 (Synl), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or heavy chain (NFH), beta-globin minigene nB2, preproenkephalin (PPE), enkephalin (Enk), and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), cardiovascular promoters (e.g., aMHC, cTnT, and CMV-MLC2k), liver promoters (e.g., hAAT, TBG), skeletal muscle promoters (e.g., desmin, MCK, C512), or fragments thereof, e.g., truncations or functional variants.

41. The AAV particle of any one of claims 1 to 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 5’ relative to the STXBP1 coding sequence.

43. The AAV particle of claim 41 or claim 42, wherein the viral genome comprises an ITR sequence 3’ relative to the STXBP1 coding sequence.

44. The AAV particle of any one of claims 41 to 43, wherein the viral genome comprises an ITR sequence 5’ relative to the STXBP1 coding sequence, and an ITR sequence 3’ relative to the STXBP1 coding sequence.

45. An adeno-associated virus (AAV) particle comprising a viral genome comprising a Syntaxin Binding Protein 1 (STXBP1) coding sequence, and an AAV capsid variant, the 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 Syntaxin Binding Protein 1 (STXBP1) coding sequence, and an AAV capsid variant, the 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 to 46, optionally wherein the cell is a mammalian cell (e.g., a HEK293 cell), an insect cell (e.g., a Sf9 cell), or a bacterial cell.

48. A method of making the AAV particle of any one of claims 1 to 46, the method comprising: (i) providing a cell comprising a viral genome comprising a STXBP1 coding sequence and a nucleic acid encoding the AAV capsid variant; and (ii) incubating the cell under conditions suitable for encapsidation of 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 the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence 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: 4 or an amino acid sequence 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) 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 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) to positions 138-742 of 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 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) 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 the nucleotide sequence of SEQ ID NO: 6414 or a nucleotide sequence 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 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) 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 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) to positions 138-742 of 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 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) to positions 203-742 of SEQ ID NO:

36. (iii) a VP3 protein comprising an amino acid sequence of positions 203-742 of SEQ ID NO: 36 or an amino 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) to positions 203-742 of SEQ ID NO:

36.

52. The method of claim 51, wherein the AAV capsid variant comprises an amino acid sequence of SEQ ID NO: 36, an amino acid sequence of positions 138-742 of SEQ ID NO: 36, and / or an 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 nucleotide sequence of SEQ ID NO: 6414 or 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%, or at least 99% identical) thereto; and (b) the AAV capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence of SEQ ID NO: 982 or an amino 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) to SEQ ID NO: 982; (ii) a VP2 protein comprising an amino acid sequence of positions 138-742 of SEQ ID NO: 982 or an amino 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) to positions 138-742 of SEQ ID NO: 982; or (iii) a VP3 protein comprising an amino acid sequence of positions 203-742 of SEQ ID NO: 982 or an amino 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) to positions 203-742 of SEQ ID NO:

982.

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

982.

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

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 introducing the second nucleic acid molecule into the cell prior to step (i).

57. The method of any one of claims 48-56, wherein the cell comprises a mammalian cell (e.g., a HEK293 cell), an insect cell (e.g., a 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 a STXBP1 protein to a subject, comprising administering to the subject an effective amount of the 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, or is at risk of developing a STXBP1 -related disorder, optionally wherein the STXBP1 -related disorder is a STXBP1 -related neurodegenerative or neuromuscular disorder.

64. The method of claim 62 or claim 63, wherein the subject has, has been diagnosed with, or is at risk of developing STXBP1 encephalopathy, epileptic encephalopathy, Odaigahara syndrome, developmental encephalopathy, West syndrome, early myoclonic epileptic encephalopathy, Lennox-Gastaut syndrome, autism (e.g., autism with a STXBP1 mutation and optionally other mutations), Dravet syndrome (not caused by mutations in SCN1A), or Rett syndrome phenotype (not caused by mutations in MECP2 or CDKL5).

65. A method of treating a subject having or diagnosed with a STXBP1 -related disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 58-61 or the AAV particle of any one of claims 1-46.

66. A method of treating a subject having or diagnosed with a STXBP1 -related disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 59 or the AAV particle of any one of claims 5-22.

67. A method of treating a subject having or diagnosed with a STXBP1 -associated 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.

68. A method of treating a subject having or diagnosed with a STXBP1 -associated disorder, 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.

69. The method of any one of claims 65-68, wherein the STXBP1 -associated disorder is a STXBP1 -associated neurodegenerative or neuromuscular disorder.

70. The method of claim 69, wherein the STXBP1 -associated neurodegenerative or neuromuscular disorder is STXBP1 encephalopathy, epileptic encephalopathy, Ohtahara syndrome, developmental encephalopathy, West syndrome, early myoclonic epileptic encephalopathy, Lennox-Gastaut syndrome, autism (e.g., autism with a STXBP1 mutation and optionally other mutations), Dravet syndrome (not caused by mutations in SCN1A), or Rett syndrome phenotype (not caused by mutations in MECP2 or CDKL5).

71. A method of treating a subject having STXBP1 encephalopathy or diagnosed with STXBP1 encephalopathy, comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 58-61 or the AAV particle of any one of claims 1-46.

72. A method of treating a subject having STXBP1 encephalopathy or diagnosed with STXBP1 encephalopathy, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 59 or the AAV particle of any one of claims 5-22.

73. A method of treating a subject having STXBP1 encephalopathy or diagnosed with STXBP1 encephalopathy, 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.

74. A method of treating a subject having STXBP1 encephalopathy or diagnosed with STXBP1 encephalopathy, 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.

75. The method of any one of claims 62-74, wherein the subject has one or more mutations in the STXBP1 gene.

76. The method of any one of claims 62-75, wherein the subject has a reduced level of STXBP1 activity compared to a reference level in a subject not having a STXBP1 -associated disorder.

77. The method of any one of claims 65-76, wherein the treatment halts progression of the subject’s disorder.

78. The method of any one of claims 65-77, wherein the treatment improves at least one symptom of the disorder and / or alters one or more biomarkers of the disorder.

79. The method of claim 78, wherein the one or more biomarkers comprises STXBP1 activity or neurofilament light chain.

80. The method of claim 78, wherein the at least one symptom comprises seizures, autism features, ataxia, general tremor, dystonia, 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 cells, tissues, or regions of the CNS, e.g., regions of the brain or spinal cord, e.g., parenchyma, cortex, substantia nigra, caudal putamen cerebellum, striatum, corpus callosum, cerebellum, brainstem caudal putamen-putamen, thalamus, superior colliculus, spinal cord, or a combination thereof, and / or to neurons, e.g., GABAergic neurons, glutamatergic neurons, or a combination thereof.

83. The method of any one of claims 62-82, further comprising assessing, e.g., measuring, STXBP1 expression levels, e.g., STXBP1 gene expression levels, STXBP1 mRNA expression levels, and / or STXBP1 protein expression levels, in the subject, e.g., in cells, tissues, or bodily fluids of the subject.

84. The method of claim 83, wherein the STXBP1 protein expression levels are measured by ELISA, Western blot, or immunohistochemical assay.

85. The method of claim 83 or claim 84, wherein assessing the STXBP1 expression levels is performed before and after administration of the AAV particle, optionally wherein the STXBP1 expression levels before treatment are compared to the STXBP1 expression levels after administration.

86. The method of any one of claims 83-85, comprising assessing the STXBP1 expression levels in cells or tissues of the central nervous system, e.g., parenchyma.

87. The method of any one of claims 83-86, wherein the STXBP1 protein expression levels in the subject after administration are increased relative to the STXBP1 protein expression levels in the subject before administration.

88. The method of any one of claims 62-87, further comprising assessing, e.g., measuring, STXBP1 activity levels in the subject, e.g., in cells or tissues of the subject.

89. The method of any one of claims 62-88, wherein the administration results in an increase in: (i) STXBP1 activity in cells, tissues (e.g., cells or tissues of the CNS, e.g., cortex, striatum, thalamus, cerebellum, and / or brainstem) and / or bodily fluids (e.g., CSF and / or serum) of the subject relative to STXBP1 activity in the subject prior to the administration; (ii) the level of viral genome (VG) per cell in CNS tissue (e.g., cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord) of the subject relative to the level of VG per cell in peripheral tissue of the subject; and / or (iii) STXBP1 mRNA expression in cells or tissues of the subject (e.g., cells or tissues of the CNS, e.g., cortex, thalamus, and / or brainstem) as compared to STXBP1 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 adapted to treat or prevent a STXBP1 -associated disorder; optionally, wherein the additional agent comprises one or more anti-epileptic drugs (e.g., levetiracetam, phenobarbital, clobazam, topiramate), adrenocorticotropic hormone, or a combination thereof.

91. The method of any one of claims 65-90, further comprising administering to the subject an immunosuppressant.

92. The method of claim 91, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab 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 treating a STXBP1 -associated disorder; optionally, wherein the STXBP1 -associated disorder is STXBP1 encephalopathy, epileptic encephalopathy, Takayasu syndrome, developmental encephalopathy, West syndrome, early myoclonic epileptic encephalopathy, Lennox-Gastaut syndrome, autism (e.g., autism with a STXBP1 mutation and optionally other mutations), Dravet syndrome (not caused by a mutation in SCN1A), or Rett syndrome phenotype (not caused by a mutation in MECP2 or CDKL5).

94. Use of the pharmaceutical composition of any one of claims 58-61 or the AAV particle of any one of claims 1-46 in the manufacture of a medicament for treating a STXBP1 -associated disorder; optionally, wherein the STXBP1 -associated disorder is STXBP1 encephalopathy, epileptic encephalopathy, Takayasu syndrome, developmental encephalopathy, West syndrome, early myoclonic epileptic encephalopathy, Lennox-Gastaut syndrome, autism (e.g., autism with a STXBP1 mutation and optionally other mutations), Dravet syndrome (not caused by a mutation in SCN1A), or Rett syndrome phenotype (not caused by a mutation in MECP2 or CDKL5).

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