Compositions and methods for treating disorders associated with glucopolysidylsphinolase beta 1

Abstract

The present disclosure relates to compositions and methods for delivering, inter alia, altering, e.g., enhancing, the content of GBA1 protein via the use of adeno-associated virus (AAV) capsid variants. The compositions and methods of the present disclosure are particularly useful for treating subjects suffering from, having been diagnosed with, or at risk of suffering from a GBA1-related disorder, such as Parkinson's disease (PD), Gaucher's disease (GD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), or Lewy body dementia (LBD).

Description

[0001] Related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application Serial No. 63 / 463,836, filed May 3, 2023; U.S. Provisional Application Serial No. 63 / 593,792, filed October 27, 2023; and U.S. Provisional Application Serial No. 63 / 564,462, 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_0081-00304_SL.xml, was created on April 10, 2024, and has a size of 5,682,716 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 glucosylsphingosine monophosphate β1 (GBA1) protein ("GBA1 protein") and peptides ("GBA1 peptide"), for the treatment of GBA1-related conditions, including Parkinson's disease (PD) and other GBA1-related conditions, including Gaucher disease, Parkinson's dementia (PDD), dementia with Lewy bodies (DLB), and Lewy body dementia (LBD). In some embodiments, the compositions described herein may be used to treat subjects in need, such as human subjects diagnosed with a GBA1-related condition or other conditions resulting from a deficiency in the quantity and / or function of the GBA1 protein.

[0006] Existing technology

[0007] Lysosomal acid glucosylceramidase, commonly known as glucosylcerebrosidase or GC enzyme, is a D-glucosyl-N-acylsphingosine glucohydrolase, a lysosomal membrane protein that plays an important role in glucose and lipid metabolism. This enzyme is encoded by the glucosylceramidase β (GBA1) gene (Ensembl gene ID ENSG00000177628). This enzyme, along with sphingolipid activator A (Saposin A) and sphingolipid activator C (Saposin C), catalyzes the hydrolysis of glucose-ceramide into ceramide and glucose. See Vaccaro, Anna Maria et al., Journal of Biological Chemistry 272.27 (1997): 16862-16867.

[0008] Mutations in GBA1 are known to cause disease in human subjects. Homozygous or compound heterozygous GBA1 mutations lead to Gaucher disease (“GD”). See Sardi, S. Pablo, Jesse M. Cedarbaum, and Patrik Brundin. Movement Disorders 33.5 (2018): 684-696. Gaucher disease is one of the most common lysosomal storage diseases, with a standardized birth incidence estimated at 0.4 to 5.8 per 100,000 subjects in the general population. Heterozygous GBA1 mutations may lead to PD. In fact, the mutation rate of GBA1 in all PD patients is 7%–10%, making GBA1 mutation the most important genetic risk factor for PD. PD-GBA patients have reduced levels of the lysosomal enzyme β-glucocerebrosidase (GC enzyme), leading to increased accumulation of glycosphingolipid glucosylceramide (GluCer), which is associated with increased α-synuclein aggregation and accompanying neurological symptoms. GD and PD, as well as other lysosomal storage diseases or Lewy body diseases, such as Lewy body dementia (LBD). See Sidransky, E. and Lopez, G. Lancet Neurol. November 2012; 11(11): 986-998.

[0009] To date, treatments for GBA1-related conditions such as Parkinson's disease (PD) are limited, and delivery to the adult central nervous system (CNS) remains a significant challenge in the development of new and effective therapies. Therefore, there is a long-standing need to develop pharmaceutical compositions and methods that can be delivered to the CNS to treat PD and other GBA1-related conditions and to improve the deficiency of GBA1 protein in subjects with GBA1-related conditions (e.g., human subjects).

[0010] 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). This disclosure provides improved pharmaceutical compositions and methods. In some embodiments, this disclosure provides a treatment method using an AAV capsid variant capable of delivering GBA1 to target cells or tissues (e.g., CNS cells or tissues). Summary of the Invention

[0011] This disclosure addresses these challenges by providing AAV-based compositions and methods containing AAV capsid variants for treating GC enzyme deficiency in subjects. This document discloses compositions and methods relating to AAV-based gene delivery of GC enzymes to improve loss of function and improve intracellular lipid migration. These compositions and methods are suitable for improving lysosomal glycolipid metabolism in subjects (e.g., subjects with at least one mutation in the GBA1 gene), and for slowing, halting, or reversing neurodegenerative and other symptoms of PD and other GBA1-related conditions (e.g., Lewy body dementia (DLB), Gaucher disease (GD)). Unless otherwise stated, GBA protein, GBA1 protein, and GC enzyme protein are synonymous and used interchangeably to refer to the protein encoded by the GBA1 gene. Unless otherwise stated, the nucleotide sequence encoding the GBA1 protein (i.e., the GBA1 coding sequence) refers to the nucleotide sequence of amino acids encoding the GBA1 protein and may also be referred to as the GBA1 protein coding sequence.

[0012] In some embodiments, this disclosure provides an AAV particle comprising a nucleotide sequence encoding a GBA1 protein (e.g., wild-type GBA1 protein) and an AAV capsid (e.g., an AAV capsid variant). In some embodiments, this disclosure provides an AAV particle comprising a nucleotide sequence encoding a wild-type GBA1 protein and an AAV capsid variant. In some embodiments, compared to a wild-type GBA1 coding sequence (e.g., a nucleotide sequence comprising SEQ ID NO: 1776 or 1777), the GBA1 coding nucleotide sequence comprises altered GC content and / or a reduced number of CpG motifs (e.g., lack of all CpG motifs), and wherein the AAV capsid variant is an AAV9 capsid variant.

[0013] In some embodiments, the AAV capsid variant is an AAV9 capsid variant that contains a peptide insert in the ring IV region. In some embodiments, the AAV capsid variant contains the amino acid sequence of SPH in the ring IV region. In some embodiments, the AAV capsid variant contains the amino acid sequence of SPH in the ring IV region, wherein the amino acid sequence (SPH) is present immediately after position 455 according to SEQ ID NO: 138.

[0014] In some embodiments, this disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant having an amino acid sequence of the formula [N1]-[N2]-[N3], wherein: optionally, [N1] comprises X1, X2, and X3, wherein at least one of X1, X2, or X3 is G; wherein [N2] comprises an amino acid sequence of SPH; and wherein [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid; wherein the AAV particle further comprises a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence. 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 implementations, [N2]-[N3] contains the amino acid sequence of SPHSKA (SEQ ID NO: 941).

[0015] In some embodiments, this disclosure provides an AAV particle comprising: a viral genome containing a GBA1 coding sequence 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 present immediately after the amino acid position corresponding to position 455 of SEQ ID NO: 4 or SEQ ID NO: 36.

[0016] 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).

[0017] In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing an amino acid sequence having at least 90% identity with SEQ ID NO: 4; a VP2 protein containing an amino acid sequence having at least 90% identity with positions 138-742 of SEQ ID NO: 4; and / or a VP3 protein containing an amino acid sequence having at least 90% identity with positions 203-742 of SEQ ID NO: 4. In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing an amino acid sequence having at least 95% identity with SEQ ID NO: 4; a VP2 protein containing an amino acid sequence having at least 95% identity with positions 138-742 of SEQ ID NO: 4; and / or a VP3 protein containing an amino acid sequence having at least 95% identity with positions 203-742 of SEQ ID NO: 4. In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing an amino acid sequence having at least 99% identity with SEQ ID NO: 4; a VP2 protein containing an amino acid sequence having at least 99% identity with positions 138-742 of SEQ ID NO: 4; and / or a VP3 protein containing an amino acid sequence having at least 99% identity with positions 203-742 of SEQ ID NO: 4. In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing the amino acid sequence of SEQ ID NO: 4; a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 4; and / or a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 4.

[0018] In some embodiments, the AAV9 capsid variant comprises the amino acid sequence of SPHSKA (SEQ ID NO: 941), wherein the amino acid sequence is present immediately following the amino acid position corresponding to position 455 of SEQ ID NO: 4; 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 no other modifications relative to wild-type AAV9.

[0019] In some embodiments, the AAV9 capsid variant 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 KTERVSGSPHSKAQNQQT (SEQ ID NO: 3589).

[0020] In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing an amino acid sequence having at least 90% identity with SEQ ID NO: 36; a VP2 protein containing an amino acid sequence having at least 90% identity with positions 138-742 of SEQ ID NO: 36; and / or a VP3 protein containing an amino acid sequence having at least 90% identity with positions 203-742 of SEQ ID NO: 36. In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing an amino acid sequence having at least 95% identity with SEQ ID NO: 36; a VP2 protein containing an amino acid sequence having at least 95% identity with positions 138-742 of SEQ ID NO: 36; and / or a VP3 protein containing an amino acid sequence having at least 95% identity with positions 203-742 of SEQ ID NO: 36. In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing an amino acid sequence having at least 99% identity with SEQ ID NO: 36; a VP2 protein containing an amino acid sequence having at least 99% identity with positions 138-742 of SEQ ID NO: 36; and / or a VP3 protein containing an amino acid sequence having at least 99% identity with positions 203-742 of SEQ ID NO: 36. In some embodiments, the AAV9 capsid variant comprises a VP1 protein containing the amino acid sequence of SEQ ID NO: 36; a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 36; and / or a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

[0021] In some embodiments, the AAV9 capsid variant comprises 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; 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 no other modifications relative to wild-type AAV9.

[0022] In some embodiments, the AAV capsid variant (e.g., the AAV9 capsid variant) comprises [N1]-[N2]-[N3] immediately following the position corresponding to amino acid position 452 of SEQ ID NO: 982, wherein the AAV capsid variant comprises an amino acid sequence that is at least 90% identical to, for example, 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, positions 203-742 of SEQ ID NO: 982. 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.

[0023] In some embodiments, the AAV capsid variant comprises a VP1 protein containing an amino acid sequence having at least 90% identity with SEQ ID NO: 982; a VP2 protein containing an amino acid sequence having at least 90% identity with positions 138-742 of SEQ ID NO: 982; and / or a VP3 protein containing an amino acid sequence having at least 90% identity with positions 203-742 of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises a VP1 protein containing an amino acid sequence having at least 95% identity with SEQ ID NO: 982; a VP2 protein containing an amino acid sequence having at least 95% identity with positions 138-742 of SEQ ID NO: 982; and / or a VP3 protein containing an amino acid sequence having at least 95% identity with positions 203-742 of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises a VP1 protein containing an amino acid sequence having at least 99% identity with SEQ ID NO: 982; a VP2 protein containing an amino acid sequence having at least 99% identity with positions 138-742 of SEQ ID NO: 982; and / or a VP3 protein containing an amino acid sequence having at least 99% identity with positions 203-742 of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises a VP1 protein containing the amino acid sequence of SEQ ID NO: 982; a VP2 protein containing the amino acid sequence at positions 138-742 of SEQ ID NO: 982; and / or a VP3 protein containing the amino acid sequence at positions 203-742 of SEQ ID NO: 982.

[0024] In some embodiments, the viral genome of the AAV particle encodes the wild-type GBA1 protein. In some embodiments, the viral genome does not encode a hemagglutinin (HA) tag. In some embodiments, the viral genome encodes a human GBA1 protein, a canine GBA1 protein, or a horse GBA1 protein. In some embodiments, the viral genome encodes a human GBA1 protein. In some embodiments, the human GBA1 protein comprises the amino acid sequence of SEQ ID NO: 1775.

[0025] In some embodiments, the GBA1 coding sequence of the viral genome contains 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: 2002. In some embodiments, the GBA1 coding sequence contains a nucleotide sequence identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) to SEQ ID NO: 2002. In some embodiments, the GBA1 coding sequence contains the nucleotide sequence of SEQ ID NO: 2002.

[0026] In some embodiments, the GBA1 coding sequence encodes a signal sequence containing at least 90% of the same amino acid sequence as SEQ ID NO: 2005. In some embodiments, the signal sequence contains the amino acid sequence of SEQ ID NO: 2005.

[0027] In some embodiments, the GBA1 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: 2001. In some embodiments, the GBA1 coding sequence comprises SEQ ID NO: 2001.

[0028] In some implementations, the viral genome further includes a miRNA (miR) binding site that regulates the expression of the encoded GBA1 protein in cells or tissues of the DRG, liver, heart, hematopoietic lineage, or combinations thereof.

[0029] In some embodiments, the viral genome further includes a promoter efficiently linked to the GBA1 coding sequence. In some embodiments, the promoter is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1834 (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). In some embodiments, the promoter comprises the nucleotide sequence of SEQ ID NO: 1834.

[0030] In some embodiments, the viral genome further includes an enhancer. In some embodiments, the enhancer includes a CMV immediate early (CMVie) enhancer. In some embodiments, the CMVie enhancer is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1831 (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). In some embodiments, the CMVie enhancer contains the nucleotide sequence of SEQ ID NO: 1831.

[0031] In some embodiments, the viral genome further includes introns. In some embodiments, the introns are at least 90% identical to the nucleotide sequence of SEQ ID NO: 1842 (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). In some embodiments, the introns contain the nucleotide sequence of SEQ ID NO: 1842.

[0032] In some embodiments, the viral genome further includes a polyadenylated (polyadenylated) region. In some embodiments, this polyadenylated region is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1846 (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). In some embodiments, the polyadenylated region comprises the nucleotide sequence of SEQ ID NO: 1846.

[0033] In some embodiments, the viral genome further comprises inverted terminal repeats (ITRs). In some embodiments, the ITR is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830 (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). In some embodiments, the ITR contains the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830. In some embodiments, the viral genome comprises a 5' ITR and a 3' ITR, wherein the 5' ITR contains the nucleotide sequence of SEQ ID NO: 1829 and the 3' ITR contains the nucleotide sequence of SEQ ID NO: 1830.

[0034] In some embodiments, the viral genome further includes one or more miR183 binding sites. In some embodiments, the viral genome includes four miR183 binding sites. In some embodiments, each of the four miR183 binding sites contains at least 70% identity with the nucleotide sequence of SEQ ID NO: 1847. In some embodiments, each of the four miR183 binding sites contains the nucleotide sequence of SEQ ID NO: 1847.

[0035] In some embodiments, the viral genome further comprises a miR183 binding site series containing at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) of the nucleotide sequence of SEQ ID NO: 1849. In some embodiments, the miR183 binding site series comprises the nucleotide sequence of SEQ ID NO: 1849.

[0036] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a promoter; (iii) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; and (iv) a 3' ITR.

[0037] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a promoter; (iii) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; and (iv) a 3' ITR.

[0038] In some embodiments, the viral genome comprises: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a chicken β-actin (CBA) promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; and (v) The GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; and (vi) 3' ITR.

[0039] In some embodiments, the viral genome comprises: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1831 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iii) a CBA promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1842 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); and (v) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises SEQ ID NO: The nucleotide sequence of 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001, and (vi) 3' ITR.

[0040] In some embodiments, the viral genome comprises: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1831; (iii) a CBA promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1842 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); and (v) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence SEQ ID NO: 2002 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1834. 2002 is at least 90% identical (e.g., at least 93% identical) of the nucleotide sequence; (vi) a polyadenylated (polyadenylated) region containing the nucleotide sequence of SEQ ID NO: 1846 or at least 95% identical to the nucleotide sequence of SEQ ID NO: 1846; and (vii) 3' ITR.

[0041] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) The GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) a polyadenylate region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1846; and (vii) a 3' ITR.

[0042] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) a CMVie enhancer containing the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter containing the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; and (iv) an intron containing the nucleotide sequence of SEQ ID NO: 1834. (v) a nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to SEQ ID NO: 2002; (vi) a polyadenylated region that contains a nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to SEQ ID NO: 1846; and (vii) a 3' ITR that contains a nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1830.

[0043] In some embodiments, the viral genome comprises: (i) a 5' ITR containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) a CMVie enhancer containing the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter containing the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; and (iv) an intron containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834. (v) a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to SEQ ID NO: 2001; (vi) a polyadenylated region that contains the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to SEQ ID NO: 1846; and (vii) a 3' ITR that contains the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to SEQ ID NO: 1830.

[0044] In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence that is at least 90% identical (e.g., at least 97% identical) to SEQ ID NO: 2006. In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006. In some embodiments, the viral genome consists of the nucleotide sequence of SEQ ID NO: 2006.

[0045] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a promoter; (iii) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (iv) at least one miR183 binding site; and (v) a 3' ITR.

[0046] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a promoter; (iii) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (iv) at least one miR183 binding site; and (v) a 3' ITR.

[0047] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a promoter; (iii) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (iv) at least one miR183 binding site sequence comprising at least one miR183 binding site and at least one spacer sequence; and (v) a 3' ITR.

[0048] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a promoter; (iii) a GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (iv) at least one miR183 binding site sequence comprising at least one miR183 binding site and at least one spacer sequence; and (v) a 3' ITR.

[0049] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) The GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) at least one miR183 binding site; and (vii) 3' ITR.

[0050] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1842; and (v) a GBA1 coding sequence comprising the nucleotide sequence SEQ ID NO: 2001 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1842. (vi) at least 90% identical (e.g., at least 94% identical) nucleotide sequence; (vii) at least one miR183 binding site; and (vii) 3' ITR.

[0051] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) The GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence that is at least 90% identical to SEQ ID NO: 1849; and (vii) a 3' ITR.

[0052] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR; (ii) a CMVie enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter comprising the nucleotide sequence SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; (iv) an intron comprising the nucleotide sequence SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) (vi) A GBA1 coding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 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 SEQ ID NO: 1849; and (vii) a 3' ITR.

[0053] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) a CMVie enhancer containing the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter containing the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; and (iv) an intron containing the nucleotide sequence of SEQ ID NO: 1834. (v) A nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 2002; (vi) A GBA1 coding sequence comprising a nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) At least one miR183 binding site comprising a nucleotide sequence of SEQ ID NO: 1847; (vii) A polyadenylate region comprising a nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (viii) A 3' ITR comprising a nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; 1830 has at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) nucleotide sequences.

[0054] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) a CMVie enhancer containing the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter containing the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; and (iv) an intron containing the nucleotide sequence of SEQ ID NO: 1834. (v) A nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 2001; (vi) A GBA1 coding sequence comprising a nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) At least one miR183 binding site comprising a nucleotide sequence of SEQ ID NO: 1847; (vii) A polyadenylate region comprising a nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (viii) A 3' ITR comprising a nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; 1830 has at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) nucleotide sequences.

[0055] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) a CMVie enhancer containing the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter containing the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; and (iv) an intron containing the nucleotide sequence of SEQ ID NO: 1834. (v) A GBA1 coding sequence comprising the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to SEQ ID NO: 2002; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 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%) to SEQ ID NO: 1842; (vii) a polyadenylated region comprising the nucleotide sequence of SEQ ID NO: 1846 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%) to SEQ ID NO: 1842; 1846 is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) of a nucleotide sequence; and (viii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or the nucleotide sequence of SEQ ID NO: 1830 is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) of a nucleotide sequence.

[0056] In some embodiments, the viral genome comprises, in 5' to 3' order: (i) a 5' ITR containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) a CMVie enhancer containing the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) a CBA promoter containing the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1834; and (iv) an intron containing the nucleotide sequence of SEQ ID NO: 1834. (v) A GBA1 coding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to SEQ ID NO: 2001; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 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%) to SEQ ID NO: 1849; (vii) a polyadenylated region comprising the nucleotide sequence of SEQ ID NO: 1846 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%) to SEQ ID NO: 1842; 1846 is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) of a nucleotide sequence; and (viii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or the nucleotide sequence of SEQ ID NO: 1830 is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) of a nucleotide sequence.

[0057] In some embodiments, (i) the 5' ITR contains the nucleotide sequence of SEQ ID NO: 1829; (ii) the CMVie enhancer contains the nucleotide sequence of SEQ ID NO: 1831; (iii) the CBA promoter contains the nucleotide sequence of SEQ ID NO: 1834; (iv) the intron contains the nucleotide sequence of SEQ ID NO: 1842; (v) the GBA1 coding sequence contains the nucleotide sequence of SEQ ID NO: 2001; (vi) the miR183 binding site series contains the nucleotide sequence of SEQ ID NO: 1849; (vii) the polyadenylated nucleotide region contains the nucleotide sequence of SEQ ID NO: 1846; and (viii) the 3' ITR contains the nucleotide sequence of SEQ ID NO: 1830.

[0058] In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence that is at least 90% identical (e.g., at least 97% identical) to SEQ ID NO: 2007. In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2007. In some embodiments, the viral genome is composed of the nucleotide sequence of SEQ ID NO: 2007.

[0059] In some embodiments, this disclosure provides an AAV particle comprising: a viral genome containing the nucleotide sequence of SEQ ID NO: 2001; an AAV capsid variant containing a VP1 protein containing the amino acid sequence of SEQ ID NO: 4; a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 4; and / or a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 4.

[0060] In some embodiments, this disclosure provides an AAV particle comprising: a viral genome containing the nucleotide sequence of SEQ ID NO: 2001; an AAV capsid variant containing a VP1 protein containing the amino acid sequence of SEQ ID NO: 36; a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 36; and / or a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

[0061] In some embodiments, this disclosure provides an AAV particle comprising: a viral genome containing the nucleotide sequence of SEQ ID NO: 2002; an AAV capsid variant containing a VP1 protein containing the amino acid sequence of SEQ ID NO: 4; a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 4; and / or a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 4.

[0062] In some embodiments, this disclosure provides an AAV particle comprising: a viral genome containing the nucleotide sequence of SEQ ID NO: 2002; an AAV capsid variant containing a VP1 protein containing the amino acid sequence of SEQ ID NO: 36; a VP2 protein containing the amino acid sequence of positions 138-742 of SEQ ID NO: 36; and / or a VP3 protein containing the amino acid sequence of positions 203-742 of SEQ ID NO: 36.

[0063] In some embodiments, this disclosure provides a cell comprising the AAV particles described 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.

[0064] In some embodiments, this disclosure provides a method for preparing the AAV particles described herein, the method comprising: providing a cell containing a viral genome, the viral genome containing a GBA1 coding sequence and nucleic acid encoding the AAV capsid variant; and culturing the cell under conditions suitable for encapsulating the viral genome in the AAV capsid variant; thereby preparing the AAV particles.

[0065] In some embodiments, this disclosure provides a method for preparing AAV particles, wherein the viral genome of the AAV particles comprises (a) the nucleotide sequence of SEQ ID NO: 2006 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; or (b) the nucleotide sequence of SEQ ID NO: 2007 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 the AAV capsid variant of the AAV particles comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is identical to SEQ ID NO: 2006. 4. An amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity); (ii) a VP2 protein comprising the amino acid sequence at positions 138-742 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 positions 138-742 of SEQ ID NO: 4; or (iii) a 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 positions 203-742 of SEQ ID NO: 4; Position 4, 203-742, has an amino acid sequence with 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).

[0066] In some embodiments, this disclosure provides a method for preparing AAV particles, wherein the viral genome of the AAV particles comprises (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence that is at least 90% identical to it (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); or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence that is at least 90% identical to it (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 particles 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.

[0067] In some embodiments, this disclosure provides a method for preparing AAV particles, wherein the viral genome of the AAV particles comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence that is at least 90% identical thereto (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); or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence that is at least 90% identical thereto (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto); and the AAV capsid variant of the AAV particles comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is identical to or identical to that of SEQ ID NO: 2007. 36 having an amino acid sequence with 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); (ii) VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 36 or having an amino acid sequence with 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); and / or (iii) VP3 protein comprising the amino acid sequence at positions 203 ...). Positions 203-742 of 36 have an amino acid sequence with 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).

[0068] In some embodiments, this disclosure provides a method for preparing AAV particles, wherein the viral genome of the AAV particles comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence that is at least 90% identical thereto (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); or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence that is at least 90% identical thereto (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto); and the AAV capsid variant of the AAV particles 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.

[0069] In some embodiments, this disclosure provides a method for preparing AAV particles, wherein the viral genome of the AAV particles comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence that is at least 90% identical thereto (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); or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence that is at least 90% identical thereto (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto); and the AAV capsid variant of the AAV particles comprises: (i) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence that is identical to or identical to that of SEQ ID NO: 2006. (i) an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) with SEQ ID NO: 982; (ii) a VP2 protein comprising the amino acid sequence at positions 138-742 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 SEQ ID NO: 982; and / or (iii) a VP3 protein comprising the amino acid sequence at positions 203 ... Positions 203-742 of 982 have an amino acid sequence with 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).

[0070] In some embodiments, this disclosure provides a method for preparing AAV particles, wherein the viral genome of the AAV particles comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence that is at least 90% identical thereto (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); or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence that is at least 90% identical thereto (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto); and the AAV capsid variant of the AAV particles 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.

[0071] In some embodiments, the method for preparing AAV particles further includes introducing a first nucleic acid molecule containing the viral genome into the cell prior to step (i). In some embodiments, the cell contains a second nucleic acid molecule encoding an AAV capsid variant. In some embodiments, the method for preparing AAV particles further includes introducing the second nucleic acid into the cell prior to step (i). In some embodiments, the cell comprises mammalian cells (e.g., HEK293 cells), insect cells (e.g., Sf9 cells), or bacterial cells.

[0072] In some embodiments, this disclosure provides a pharmaceutical composition comprising the AAV particles described herein and pharmaceutically acceptable excipients.

[0073] In some embodiments, this disclosure provides a method of delivering AAV particles encoding the GBA1 protein to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles described herein. In some embodiments, the subject has, has been diagnosed with, or is at risk of developing a GBA1-related condition. In some embodiments, the GBA1-related condition is a GBA1-related neurodegenerative or neuromuscular disease. In some embodiments, the GBA1-related condition is Parkinson's disease (PD), Parkinson's dementia (PDD), Gaucher disease (GD) (e.g., GD type 1, 2, or 3), Lewy body dementia (DLB), Lewy body dementia (LBD), multiple system atrophy (MSA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), isolated autonomic failure, brain iron deposition neurodegeneration type 1 (NBIA 1), or Hallewarden-Schpatrick syndrome. In some embodiments, the subject has, has been diagnosed with, or is at risk of developing PD.

[0074] In some embodiments, this disclosure provides a method of treating a subject who has or has been diagnosed with a GBA1-related condition, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles described herein. In some embodiments, the GBA1-related condition is a GBA1-related neurodegenerative disease or neuromuscular disease. In some embodiments, the GBA1-related condition is PD, PDD, GD (e.g., GD type 1, 2, or 3), DLB, LBD, MSA, AD, ALS, isolated autonomic failure, NBIA 1, or Hallewarden-Schpatrick syndrome. In some embodiments, the GBA1-related neurodegenerative disease or neuromuscular disease is PD. In some embodiments, the GBA1-related neurodegenerative disease or neuromuscular disease is GD (e.g., GD type 1, 2, or 3). In some embodiments, the GBA1-related neurodegenerative disease or neuromuscular disease is GD type 1. In some embodiments, the GBA1-related neurodegenerative disease or neuromuscular disease is GD type 2. In some embodiments, GBA1-related neurodegeneration or neuromuscular disease is GD type 3. In some embodiments, GBA1-related neurodegeneration or neuromuscular disease is DLB. In some embodiments, GBA1-related neurodegeneration or neuromuscular disease is LBD.

[0075] In some embodiments, this disclosure provides a method of treating a subject with PD or diagnosed with PD, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles described herein.

[0076] In some embodiments, this disclosure provides a method of treating a subject with or diagnosed with Graves' disease (GD) (e.g., GD type 1, 2, or 3), comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles described herein. In some embodiments, the GD is GD type 1. In some embodiments, the GD is GD type 2. In some embodiments, the GD is GD type 3.

[0077] In some embodiments, this disclosure provides a method of treating a subject with LBD, comprising administering to the subject an effective amount of the pharmaceutical composition or AAV particles described herein.

[0078] In some embodiments, this disclosure provides a method of treating a subject who has one or more mutations in the GBA1 gene. In some embodiments, the subject has lower GC enzyme activity compared to subjects without GBA1-related conditions. In some embodiments, the level of GC enzyme activity is measured by a 4-MUG assay or a SensoLyte blue glucocerebrosidase assay.

[0079] 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, the one or more biomarkers include GC enzyme activity, the levels of glucocerebroside and other glycolipids (e.g., in immune cells such as macrophages), the levels of synuclein aggregates (e.g., Lewy bodies), the levels of neurofilament light chains, or combinations thereof. In some embodiments, the treatment improves at least one symptom of the condition. In some embodiments, the at least one symptom includes developmental delay, progressive encephalopathy, progressive dementia, ataxia, myoclonus, oculomotor dysfunction, bulbar palsy, general weakness, limb tremor, depression, visual hallucinations, cognitive decline, or combinations thereof.

[0080] In some implementations, the subject is a human.

[0081] In some embodiments, the AAV particles are 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 nucleus, cerebellum, striatum, corpus callosum, cerebellum, brainstem caudate nucleus-putamen, thalamus, superior colliculus, spinal cord, or combinations thereof, wherein the AAV particles or a pharmaceutical composition containing the AAV particles are delivered via intravenous administration.

[0082] In some embodiments, this disclosure provides a method of treating a subject, further comprising assessing, for example, measuring the level of GBA1 expression in the subject's cells, tissues, or body fluids, such as GBA1 gene expression level, GBA1 mRNA expression level, and / or GBA1 protein expression level. In some embodiments, the GBA1 protein expression level is measured by ELISA, Western blot, or immunohistochemistry. In some embodiments, the assessment of GBA1 expression level is performed before and after administration of AAV. In some embodiments, the pre-administration GBA1 expression level is compared with the post-administration GBA1 expression level.

[0083] In some embodiments, the method of delivery or treatment includes assessing GBA1 expression levels in cells or tissues of the central nervous system (e.g., parenchyma). In some embodiments, the GBA1 protein expression level in a subject increases after administration relative to the subject's GBA1 protein expression level prior to administration.

[0084] In some implementations, the method further includes assessment, for example, measuring the level of GC enzyme activity in the subject.

[0085] In some embodiments, administration of the AAV particles or pharmaceutical composition described herein causes an increase in: (i) GC enzyme 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), optionally wherein the GC enzyme activity in the subject increases by at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold after administration relative to the GC enzyme 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), optionally wherein the amount of VG per cell in the subject's CNS tissues increases by more than 50 VG per cell relative to the amount of VG per cell in the subject's peripheral tissues; and / or (iii) the amount of GBA1 in the subject's cells or tissues (e.g., cells or tissues of the CNS, such as the cortex, thalamus, and / or brainstem). mRNA expression, optionally, wherein GBA1 mRNA expression in the subject increases by at least 100-1300-fold after administration compared to GBA1 mRNA expression in the subject before administration.

[0086] In some embodiments, this disclosure provides a method of treating a subject, which further includes administering to the subject an additional agent suitable for treating or preventing GBA1-related conditions. In some embodiments, the additional agent comprises enzyme replacement therapy (ERT) (e.g., imiglucerase, velaglucerase α, or taliglucerase). α); substrate reduction therapy (SRT) (e.g., eliglustat or miglustat), levodopa, carbidopa, safinamide, dopamine agonists (e.g., quetiapine, clozapine, pramipexole, rotigotine, or ropinirole), anticholinergics (e.g., benztropine or trihexyphenidyl), cholinesterase inhibitors (e.g., rivastigmine, donepezil, or galantamine), N-methyl-d-aspartate (NMDA) receptor antagonists (e.g., memantine) or combinations thereof. In some embodiments, the method further includes administering a blood transfusion to the subject. 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.

[0087] In some embodiments, this disclosure provides the pharmaceutical compositions or AAV particles described herein for the treatment of GBA1-related conditions. In some embodiments, the GBA1-related condition is PD, PDD, GD (e.g., GD type 1, 2, or 3), DLB, LBD, MSA, AD, ALS, isolated autonomic failure, NBIA 1, or Hallewarden-Schpatrick syndrome. In some embodiments, the GBA1-related condition is PD. In some embodiments, the GBA1-related condition is GD (e.g., GD type 1, 2, or 3). In some embodiments, GD is GD type 1. In some embodiments, GD is GD type 2. In some embodiments, GD is GD type 3. In some embodiments, the GBA1-related condition is DLB. In some embodiments, the GBA1-related condition is LBD.

[0088] In some embodiments, this disclosure provides use of the pharmaceutical composition or AAV particles described herein in the preparation of a medicament for treating GBA1-related conditions. In some embodiments, the GBA1-related condition is PD, PDD, GD (e.g., GD type 1, 2, or 3), DLB, LBD, MSA, AD, ALS, isolated autonomic failure, NBIA 1, or Hallewarden-Schpatrick syndrome. In some embodiments, the GBA1-related condition is PD. In some embodiments, the GBA1-related condition is GD (e.g., GD type 1, 2, or 3). In some embodiments, GD is GD type 1. In some embodiments, GD is GD type 2. In some embodiments, GD is GD type 3. In some embodiments, the GBA1-related condition is DLB. In some embodiments, the GBA1-related condition is LBD.

[0089] The listed implementation schemes

[0090] 1. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding the human GBA1 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.

[0091] 2. The AAV particle as described in implementation 1, wherein X4, X5, or both of [N3] are K.

[0092] 3. The AAV particle as described in implementation scheme 1 or 2, wherein X4, X5 or X6 of [N3] is R.

[0093] 4. 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).

[0094] 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.

[0095] 6. An AAV particle as described in any one 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.

[0096] 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).

[0097] 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).

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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).

[0103] 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.

[0104] 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.

[0105] 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).

[0106] 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).

[0107] 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).

[0108] 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).

[0109] 20. An AAV particle as described in any of embodiments 1 to 19, wherein [N3] comprises SK, KA, KS or SG.

[0110] 21. An AAV particle as described in any of embodiments 1 to 20, wherein [N3] is or includes SKA, KSG or KYG.

[0111] 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).

[0112] 23. The AAV particle of any one of embodiments 1 to 22, wherein [N2]-[N3] is or contains SPHSKA (SEQ ID NO: 941).

[0113] 24. The AAV particle of any one of embodiments 1 to 22, wherein [N2]-[N3] is or contains SPHKSG (SEQ ID NO: 946).

[0114] 25. The AAV particles of any one of embodiments 1 to 22, wherein [N2]-[N3] are or contain SPHKYG (SEQ ID NO: 966).

[0115] 26. An AAV particle as described in any of embodiments 1 to 25, wherein [N1] comprises GS, SG, GH or HD.

[0116] 27. An AAV particle as described in any of embodiments 1 to 26, wherein [N1] is or contains GSG.

[0117] 28. An AAV particle as described in any of embodiments 1 to 26, wherein [N1] is or contains GHD.

[0118] 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).

[0119] 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).

[0120] 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).

[0121] 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).

[0122] 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).

[0123] 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).

[0124] 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.

[0125] 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).

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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).

[0131] 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: 1800-1808, 1832, 1833, 1835-1841, 1843-1845, 1848, 1851, 1852, 1854-2000, 2003, 2004, 2008-2241, 6421-6441, 6443-6456; (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).

[0132] 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).

[0133] 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).

[0134] 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).

[0135] 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.

[0136] 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.

[0137] 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).

[0138] 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.

[0139] 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).

[0140] 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).

[0141] 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).

[0142] 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).

[0143] 54. An AAV particle as described in any of embodiments 1 to 53, wherein [N1]-[N2]-[N3] are present in ring IV.

[0144] 55. An AAV particle as described in any of embodiments 48 to 54, wherein [N0] and [N4] are present in ring IV.

[0145] 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.

[0146] 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.

[0147] 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).

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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).

[0174] 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).

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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).

[0179] 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).

[0180] 91. An AAV particle as described in any of embodiments 1-90, wherein [N2] is present immediately following [N1].

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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).

[0186] 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.

[0187] 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.

[0188] 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).

[0189] 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).

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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).

[0194] 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).

[0195] 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.

[0196] 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).

[0197] 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).

[0198] 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.

[0199] 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).

[0200] 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.

[0201] 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).

[0202] 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).

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 118. An AAV particle as described in any of embodiments 1 to 117, wherein [N3] is present immediately following [N2].

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 130. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0220] 131. The AAV particles as described in embodiment 130, wherein

[0221] (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.

[0222] 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).

[0223] 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).

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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 specified in SEQ ID NO: 138.

[0228] 138. An AAV particle as described in any of embodiments 130 to 137, wherein [A][B] is present in ring IV.

[0229] 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.

[0230] 140. AAV particles 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.

[0231] 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.

[0232] 142. An AAV particle as described in any of embodiments 130 to 141, wherein [B] exists immediately following [A].

[0233] 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.

[0234] 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).

[0235] 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.

[0236] 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.

[0237] 147. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, the viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding the human GBA1 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).

[0238] 148. AAV particles as described in implementation scheme 147, wherein

[0239] (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.

[0240] 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).

[0241] 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).

[0242] 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).

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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, as numbered according to SEQ ID NO: 138.

[0249] 158. An AAV particle as described in any of embodiments 147 to 157, wherein [A][B] is present in ring IV.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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).

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 166. An AAV particle as described in any of embodiments 147 to 165, wherein [B] exists immediately following [A].

[0258] 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.

[0259] 168. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0260] 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).

[0261] 170. The AAV particle as described in implementation scheme 168 or 169, wherein X4 is S and / or X5 is A.

[0262] 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.

[0263] 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.

[0264] 173. An AAV particle as described in any of embodiments 168 to 172, wherein [N3] is or contains SKA.

[0265] 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).

[0266] 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).

[0267] 176. The AAV particles of any one of embodiments 168 to 175, wherein [N2]-[N3] are or contain SPHSKA (SEQ ID NO: 941).

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 182. An AAV particle as described in any of embodiments 168 to 181, wherein [N1] is or contains GSG.

[0274] 183. The AAV particles of any one of embodiments 168 to 182, wherein [N1]-[N2] comprises SGSPH (SEQ ID NO: 4752).

[0275] 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).

[0276] 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).

[0277] 186. The AAV particles of any one of embodiments 168 to 185, wherein [N1]-[N2]-[N3] are or contain GGSPHSKA (SEQ ID NO: 4697).

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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).

[0284] 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).

[0285] 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).

[0286] 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).

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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)、KIT(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).

[0291] 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).

[0292] 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).

[0293] 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).

[0294] 203. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding the human GBA1 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.

[0295] 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).

[0296] 205. AAV particles as described in implementation scheme 203 or 204, wherein X5 is S and / or X6 is G.

[0297] 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.

[0298] 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.

[0299] 208. An AAV particle as described in any of embodiments 203 to 207, wherein [N3] is or contains KSG.

[0300] 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).

[0301] 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).

[0302] 211. The AAV particle of any one of embodiments 203 to 210, wherein [N2]-[N3] is or contains SPHKSG (SEQ ID NO: 946).

[0303] 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.

[0304] 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.

[0305] 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).

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 219. An AAV particle as described in any of embodiments 203 to 218, wherein [N1] is or contains GHD.

[0311] 220. An AAV particle as described in any one of embodiments 203 to 219, wherein [N1]-[N2] comprises HDSPH (SEQ ID NO: 4703).

[0312] 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).

[0313] 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).

[0314] 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).

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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).

[0321] 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).

[0322] 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).

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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).

[0327] 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).

[0328] 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).

[0329] 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).

[0330] 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).

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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).

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] 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).

[0344] 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).

[0345] 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.

[0346] 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).

[0347] 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).

[0348] 257. An AAV particle as described in any of embodiments 168 to 256, wherein [N2] is present immediately following [N1].

[0349] 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).

[0350] 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).

[0351] 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.

[0352] 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.

[0353] 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).

[0354] 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).

[0355] 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).

[0356] 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).

[0357] 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.

[0358] 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).

[0359] 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.

[0360] 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.

[0361] 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).

[0362] 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).

[0363] 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.

[0364] 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.

[0365] 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).

[0366] 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.

[0367] 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).

[0368] 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.

[0369] 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.

[0370] 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.

[0371] 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.

[0372] 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).

[0373] 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).

[0374] 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).

[0375] 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).

[0376] 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.

[0377] 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).

[0378] 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).

[0379] 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).

[0380] 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).

[0381] 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.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 300. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0392] 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.

[0393] 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、KALKAH、PRLCQLQ 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

[0394] 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).

[0395] 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).

[0396] 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).

[0397] 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).

[0398] 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.

[0399] 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.

[0400] 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.

[0401] 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.

[0402] 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.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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).

[0408] 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).

[0409] 318. An AAV particle as described in any of embodiments 300 to 317, wherein [A]-[B] are present in ring IV.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 322. An AAV particle as described in any of embodiments 300 to 321, wherein [B] exists immediately following [A].

[0414] 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.

[0415] 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.

[0416] 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.

[0417] 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.

[0418] 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.

[0419] 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.

[0420] 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.

[0421] 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.

[0422] 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).

[0423] 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).

[0424] 333. An AAV particle as described in any of embodiments 327 to 332, wherein the charged amino acid residue is D.

[0425] 334. An AAV particle as described in any one of embodiments 327 to 333, wherein the charged amino acid residue is E.

[0426] 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).

[0427] 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).

[0428] 337. An AAV particle as described in any one of embodiments 327 to 336, wherein the charged amino acid residue is H.

[0429] 338. An AAV particle as described in any one of embodiments 327 to 337, wherein the charged amino acid residue is R.

[0430] 339. An AAV particle as described in any of embodiments 327 to 338, wherein the charged amino acid residue is K.

[0431] 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).

[0432] 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.

[0433] 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).

[0434] 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] 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.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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 relative to SEQ ID NO: 138, or at positions 462-466 ​​according to any one of SEQ ID NO: 36-59, 981, or 982.

[0445] 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).

[0446] 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).

[0447] 356. An AAV particle as described in any one of embodiments 350 to 355, wherein the charged amino acid residue is R.

[0448] 357. An AAV particle as described in any one of embodiments 350 to 355, wherein the charged amino acid residue is K.

[0449] 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.

[0450] 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).

[0451] 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.

[0452] 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.

[0453] 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.

[0454] 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.

[0455] 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.

[0456] 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 AAV capsid of 138 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.

[0457] 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.

[0458] 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).

[0459] 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).

[0460] 369. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0461] 370. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0462] 371. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0463] 372. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0464] 373. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0465] 374. An adeno-associated virus (AAV) particle comprising an AAV capsid variant (e.g., an AAV9 capsid variant) and a viral genome containing a β-glucocerebrosidase 1 (GBA1) coding sequence (e.g., encoding a human GBA1 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.

[0466] 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.

[0467] 376. An AAV particle as described in any one of embodiments 369 to 374, wherein at least three consecutive amino acids contain SPH.

[0468] 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).

[0469] 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).

[0470] 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).

[0471] 380. The AAV particles of embodiments 369 to 371, wherein at least three consecutive amino acids contain HDS.

[0472] 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).

[0473] 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).

[0474] 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).

[0475] 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).

[0476] 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.

[0477] 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).

[0478] 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).

[0479] 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).

[0480] 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.

[0481] 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.

[0482] 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).

[0483] 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.

[0484] 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).

[0485] 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).

[0486] 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.

[0487] 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.

[0488] 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.

[0489] 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.

[0490] 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.

[0491] 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.

[0492] 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.

[0493] 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.

[0494] 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.

[0495] 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.

[0496] 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.

[0497] 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, 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, or 395, wherein the AAV capsid variant comprises an amino acid sequence encoded by the following: 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.

[0498] 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.

[0499] 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, 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, 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.

[0500] 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.

[0501] 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.

[0502] 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.

[0503] 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).

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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.

[0508] 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.

[0509] 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.

[0510] 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.

[0511] 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 of any of the numbers in SEQ ID NO: 36, 138 or 981 (at amino acids 456-461 of SEQ ID NO: 36 or 981).

[0512] 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.

[0513] 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.

[0514] 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.

[0515] 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.

[0516] 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.

[0517] 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.

[0518] 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.

[0519] 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.

[0520] 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.

[0521] 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.

[0522] 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.

[0523] 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.

[0524] 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.

[0525] 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.

[0526] 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.

[0527] 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.

[0528] 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 relative to SEQ ID NO: 138.

[0529] 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.

[0530] 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.

[0531] 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.

[0532] 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.

[0533] 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.

[0534] 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 β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 protein).

[0535] 444. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 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.

[0536] 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 β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 protein).

[0537] 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 β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 protein).

[0538] 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.

[0539] 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).

[0540] 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.

[0541] 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.

[0542] 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.

[0543] 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.

[0544] 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.

[0545] 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.

[0546] 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.

[0547] 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.

[0548] 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.

[0549] 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.

[0550] 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).

[0551] 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.

[0552] 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).

[0553] 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.

[0554] 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.

[0555] 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).

[0556] 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.

[0557] 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).

[0558] 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.

[0559] 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.

[0560] 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.

[0561] 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).

[0562] 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.

[0563] 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.

[0564] 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).

[0565] 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.

[0566] 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.

[0567] 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).

[0568] 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.

[0569] 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.

[0570] 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.

[0571] 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.

[0572] 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.

[0573] 482. The AAV particle of any of the foregoing embodiments, wherein the nucleotide sequence encoding the capsid variant is codon-optimized.

[0574] 483. 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, 02, 240 to 247, 249, 250, 253 to 263, 266, 272 to 281, 286, 288, Adeno-associated virus (AAV) particles of any one of 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.

[0575] 484. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 protein), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 981.

[0576] 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.

[0577] 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.

[0578] 487. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 protein), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982.

[0579] 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.

[0580] 489. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 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.

[0581] 490. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 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.

[0582] 491. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and nucleic acid encoding a β-glucocerebrosidase 1 (GBA1) protein (e.g., human GBA1 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.

[0583] 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.

[0584] 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.

[0585] 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.

[0586] 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.

[0587] 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.

[0588] 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.

[0589] 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)).

[0590] 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.

[0591] 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).

[0592] 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.

[0593] 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.

[0594] 503. An AAV particle as described in any one of embodiments 1 to 129, 168 to 299, 369 to 371, or 375 to 500, which, when measured by means of an assay, such as qRT-PCR or qPCR assay (e.g., as described in embodiment 2 or 8), delivers an increased level of payload to a brain region, optionally wherein the level of payload 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.

[0595] 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.

[0596] 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.

[0597] 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.

[0598] 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).

[0599] 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.

[0600] 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.

[0601] 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.

[0602] 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).

[0603] 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).

[0604] 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.

[0605] 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.

[0606] 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.

[0607] 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.

[0608] 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.

[0609] 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.

[0610] 519. The AAV particles of any of the foregoing embodiments, which are separated and / or recombined.

[0611] [Implementation plans 520 to 585 are intentionally nonexistent.]

[0612] 586. An AAV particle as described in any of the foregoing embodiments, wherein the viral genome contains a promoter effectively linked to a GBA coding sequence.

[0613] 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, 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), methyl-CpG-binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabolite glutamate 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 (e.g., truncated) or functional variants.

[0614] [Implementation plans 588 and 589 are intentionally nonexistent.]

[0615] 590. An AAV particle as described in any one of embodiments 586 to 589, wherein the viral genome further comprises a polyadenylated (polyadenylated) sequence.

[0616] 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.

[0617] 592. An AAV particle as described in any of embodiments 586 to 591, wherein the viral genome contains an ITR sequence positioned at the 5' relative to the nucleotide sequence encoding a GBA1 protein (e.g., human GBA1 protein).

[0618] 593. An AAV particle as described in any of embodiments 586 to 592, wherein the viral genome contains an ITR sequence located at the 3' of a nucleotide sequence encoding a GBA1 protein (e.g., human GBA1 protein).

[0619] 594. An AAV particle as described in any of embodiments 586 to 593, wherein the viral genome comprises an ITR sequence located at the 5' of the nucleotide sequence encoding a GBA1 protein (e.g., human GBA1 protein) and an ITR sequence located at the 3' of the nucleotide sequence encoding a GBA1 protein (e.g., human GBA1 protein).

[0620] 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.

[0621] 596. An AAV particle as described in any one of embodiments 586 to 594, wherein the viral genome further comprises a nucleotide sequence encoding a miR binding site, for example, a nucleotide sequence that regulates (e.g., reduces) the expression of the GBA1 protein encoded by the viral genome in cells or tissues expressing the corresponding miRNA.

[0622] 597. The AAV particle of embodiment 596, wherein the encoded miRNA binding site is fully or partially complementary to a miRNA expressed in cells or tissues of the DRG, liver, heart, hematopoietic lineage or a combination thereof.

[0623] 598. AAV particles as described in embodiments 596 or 597, wherein the encoded miR binding site is regulated, for example, to reduce the expression of the encoded GBA1 protein in cells or tissues of the DRG, liver, heart, hematopoietic lineage, or combinations thereof.

[0624] 599. An AAV particle as described in any one of embodiments 586 to 598, wherein the viral genome contains at least 1 to 5 copies of a miR binding site encoded, for example at least 1, at least 2, at least 3, at least 4, or at least 5 copies.

[0625] 600. An AAV particle as described in any one of embodiments 586 to 599, wherein the viral genome contains at least three copies of a miR binding site encoded therein, optionally wherein all three copies contain the same miR binding site, or at least one, at least two, at least three, or all of these copies contain different miR binding sites.

[0626] 601. An AAV particle as described in embodiment 600, wherein the three copies of the encoded miR binding site are consecutive (e.g., not separated by spacers) or separated by spacers, optionally wherein the spacers contain a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, at least two, or at least three modifications (e.g., substitutions (e.g., conserved substitutions)) but no more than four modifications (e.g., substitutions (e.g., conserved substitutions)) relative to the nucleotide sequence of GATAGTTA.

[0627] 602. An AAV particle as described in any one of embodiments 586 to 601, wherein the viral genome contains at least four copies of a miR binding site encoded therein, optionally wherein all four copies contain the same miR binding site, or at least one, at least two, at least three, or all of these copies contain different miR binding sites.

[0628] 603. The AAV particle of embodiment 602, wherein at least four copies of the encoded miR binding site are consecutive (i.e., not separated by spacers).

[0629] 603a. An AAV particle as described in embodiment 602, wherein at least four copies of the encoded miR binding site are separated by spacers.

[0630] 604. An AAV particle as described in any of embodiments 596 to 603a, wherein the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-1 binding site, a miR-142-3p or a combination thereof, optionally wherein: The encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 1847 or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, or at least 99% sequence identity); or a nucleotide sequence having at least one, at least two, at least three, at least four, at least five, at least six, or at least seven modifications (e.g., substitutions (e.g., conservative substitutions)) but no more than ten modifications (e.g., substitutions (e.g., conservative substitutions)) relative to SEQ ID NO: 1847.

[0631] [Implementation plans 605-608 are intentionally nonexistent.]

[0632] 609. An AAV particle as described in any one of embodiments 586 to 604, wherein the viral genome contains a miR183 binding site encoded.

[0633] 610. An AAV particle as described in any one of embodiments 586 to 609, wherein the viral genome contains at least 1 to 5 copies, such as 1, 2 or 3 copies, of the miR183 binding site, optionally wherein the copies are consecutive (i.e. not separated by spacers) or the copies are separated by spacers, optionally wherein the spacers contain a nucleotide sequence of GATAGTTA or a nucleotide sequence having at least one, at least two or at least three modifications (e.g., substitutions (e.g., conserved substitutions)) but no more than four modifications (e.g., substitutions (e.g., conserved substitutions)) relative to the nucleotide sequence of GATAGTTA.

[0634] 611. The AAV particle of embodiment 609 or 610, wherein the encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 1847 or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, or at least 99% sequence identity); or a nucleotide sequence having at least one, at least two, at least three, at least four, at least five, at least six, or at least seven modifications (e.g., substitutions (e.g., conservative substitutions)) but no more than ten modifications (e.g., substitutions (e.g., conservative substitutions)) relative to SEQ ID NO: 1847.

[0635] 612. An AAV particle as described in any one of embodiments 586 to 611, wherein the viral genome comprises: (A)(i) A first encoded miR183 bind...

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 beta-glucocerebrosidase 1 (GBA1) coding sequence.

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

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

4. The AAV particle of any one of claims 1 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 beta-glucocerebrosidase 1 (GBA1) 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 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 K T E N V S G S P H S K A Q N Q Q T (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 as claimed in any one of claims 23 to 27, wherein the AAV capsid variant comprises: (i) 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) 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) 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.

29. The AAV particle as claimed in any one of claims 23 to 28, wherein the AAV capsid variant comprises: (i) 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) 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) 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.

30. The AAV particle of any one of claims 23 to 29, wherein the AAV capsid variant comprises: (i) VP1 protein, which contains the amino acid sequence of SEQ ID NO: 982; (ii) VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 982; or (iii) VP3 protein, which contains the amino acid sequence at positions 203-742 of SEQ ID NO:

982.

31. The AAV particle according to any one of claims 1 to 30, wherein the viral genome encodes the wild-type GBA1 protein.

32. The AAV particle according to any one of claims 1 to 31, wherein the viral genome does not encode a hemagglutinin (HA) tag.

33. The AAV particle according to any one of claims 1 to 32, wherein the viral genome encodes a human GBA1 protein, a canine GBA1 protein, or a horse GBA1 protein.

34. The AAV particle of claim 33, wherein the viral genome encodes a human GBA1 protein, optionally wherein the human GBA1 protein comprises the amino acid sequence of SEQ ID NO: 1775.

35. The AAV particle according to any one of claims 1 to 34, wherein the GBA1 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:2002.

36. The AAV particle according to any one of claims 1 to 35, wherein the GBA1 coding sequence comprises at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) of the same nucleotide sequence as SEQ ID NO: 2002.

37. The AAV particle according to any one of claims 1 to 36, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO:2002.

38. The AAV particle according to any one of claims 1 to 37, wherein the GBA1 encoding sequence encodes a signal sequence comprising at least 90% of the same amino acid sequence as SEQ ID NO: 2005.

39. The AAV particle of claim 38, wherein the signal sequence comprises the amino acid sequence of SEQ ID NO: 2005.

40. The AAV particle according to any one of claims 1 to 39, wherein the GBA1 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: 2001.

41. The AAV particle of claim 40, wherein the GBA1 encoding sequence comprises SEQ ID NO: 2001.

42. The AAV particle according to any one of claims 1 to 41, wherein the viral genome further comprises a miRNA (miR) binding site that regulates the expression of the encoded GBA1 protein in cells or tissues of the DRG, liver, heart, hematopoietic lineage, or combinations thereof.

43. The AAV particle of any one of claims 1 to 42, wherein the viral genome further comprises a promoter effectively linked to the GBA1 coding sequence.

44. The AAV particle of claim 43, wherein the promoter is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1834 (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).

45. The AAV particle of claim 43, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 1834.

46. ​​The AAV particle according to any one of claims 1 to 45, wherein the viral genome further comprises an enhancer.

47. The AAV particle of claim 46, wherein the enhancer comprises a CMV immediate early (CMVie) enhancer.

48. The AAV particle of claim 47, wherein the CMVie enhancer is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1831 (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).

49. The AAV particle of claim 47, wherein the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831.

50. The AAV particle according to any one of claims 1 to 49, wherein the viral genome further comprises introns.

51. The AAV particle of claim 50, wherein the intron is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1842 (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).

52. The AAV particle of claim 50, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 1842.

53. The AAV particle according to any one of claims 1 to 52, wherein the viral genome further comprises a polyadenylated (polyadenylated) region.

54. The AAV particle of claim 53, wherein the polyadenylated region is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1846 (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).

55. The AAV particle of claim 53, wherein the polyadenylate region comprises the nucleotide sequence of SEQ ID NO: 1846.

56. The AAV particle according to any one of claims 1 to 55, wherein the viral genome further comprises inverted terminal repeats (ITRs).

57. The AAV particle of claim 56, wherein the ITR is at least 90% identical to the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830 (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).

58. The AAV particle of claim 56, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830.

59. The AAV particle of claim 56, wherein the viral genome comprises a 5' ITR and a 3' ITR, wherein the 5' ITR comprises the nucleotide sequence of SEQ ID NO: 1829 and the 3' ITR comprises the nucleotide sequence of SEQ ID NO: 1830.

60. The AAV particle of any one of claims 1 to 59, wherein the viral genome further comprises one or more miR183 binding sites.

61. The AAV particle of claim 60, wherein the viral genome contains four miR183 binding sites.

62. The AAV particle of claim 61, wherein each of the four miR183 binding sites comprises a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO: 1847, optionally, wherein each of the four miR183 binding sites comprises the nucleotide sequence of SEQ ID NO: 1847.

63. The AAV particle according to any one of claims 1 to 60, wherein the viral genome further comprises a series of miR183 binding sites, which contain at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) of the nucleotide sequence of SEQ ID NO: 1849.

64. The AAV particle of claim 63, wherein the miR183 binding site series comprises the nucleotide sequence of SEQ ID NO: 1849.

65. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' reverse terminal repeat (ITR); (ii) Promoter; (iii) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; and (iv) 3' ITR.

66. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) Promoter; (iii) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; and (iv) 3' ITR.

67. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises: (i) 5' Inverted Terminal Repeat (ITR); (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; and (vi) 3' ITR.

68. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises: (i) 5' Inverted Terminal Repeat (ITR); (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; and (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001, and (vi) 3' ITR.

69. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises: (i) 5' Inverted Terminal Repeat (ITR); (ii) A CMV immediate early (CMVie) enhancer comprising the nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1846; and (vii) 3' ITR.

70. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical to SEQ ID NO: 1846; and (vii) 3' ITR.

71. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' inverted terminal repeat (ITR) containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (vii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1830.

72. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises: (i) 5' inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (vii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1830.

73. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO:2006 or a nucleotide sequence that is at least 90% identical (e.g., at least 97% identical) to SEQ ID NO:2006.

74. The AAV particle of claim 73, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006.

75. The AAV particle of claim 74, wherein the viral genome consists of the nucleotide sequence of SEQ ID NO: 2006.

76. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) Promoter; (iii) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (iv) at least one miR183 binding site; and (v) 3' ITR.

77. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) Promoter; (iii) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (iv) at least one miR183 binding site; and (v) 3' ITR.

78. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) Promoter; (iii) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (iv) At least one miR183 binding site sequence comprising at least one miR183 binding site and at least one spacer subsequence; and (v) 3' ITR.

79. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) Promoter; (iii) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (iv) At least one miR183 binding site sequence comprising at least one miR183 binding site and at least one spacer subsequence; and (v) 3' ITR.

80. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) At least one miR183 binding site; and (vii) 3' ITR.

81. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) At least one miR183 binding site; and (vii) 3' ITR.

82. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) a series of miR183 binding sites comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence that is at least 90% identical to SEQ ID NO: 1849; and (vii) 3' ITR.

83. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' Inverted Terminal Repeat (ITR); (ii) CMV immediate early (CMVie) enhancer comprising a nucleotide sequence SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1831; (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) a series of miR183 binding sites comprising the nucleotide sequence of SEQ ID NO: 1849 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 SEQ ID NO: 1849; and (vii) 3' ITR.

84. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' inverted terminal repeat (ITR) containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) CMV immediate early (CMVie) enhancer, which contains the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1831 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) At least one miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 1847; (vii) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (viii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1830.

85. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' inverted terminal repeat (ITR) containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) CMV immediate early (CMVie) enhancer, which contains the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1831 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) At least one miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 1847; (vii) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (viii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1830.

86. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' inverted terminal repeat (ITR) containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) CMV immediate early (CMVie) enhancer, which contains the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1831 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical (e.g., at least 93% identical) to SEQ ID NO: 2002; (vi) miR183 binding site series, which contains the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence that is at least 90% identical to SEQ ID NO: 1849 (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); (vii) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (viii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1830.

87. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises, in a 5' to 3' order: (i) 5' inverted terminal repeat (ITR) containing the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1829; (ii) CMV immediate early (CMVie) enhancer, which contains the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1831 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iii) Chicken β-actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence that is at least 95% identical to SEQ ID NO: 1834 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical); (iv) Introns containing the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1842; (v) A GBA1 coding sequence, wherein the GBA1 coding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence that is at least 90% identical (e.g., at least 94% identical) to SEQ ID NO: 2001; (vi) miR183 binding site series, which contains the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence that is at least 90% identical to SEQ ID NO: 1849 (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); (vii) A polyadenylated (polyadenylated) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1846; and (viii) 3' ITR, which contains the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence that is at least 95% identical (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1830.

88. The AAV particles as described in claim 87, wherein: (i) The 5' ITR contains the nucleotide sequence of SEQ ID NO: 1829; (ii) The CMVie enhancer contains the nucleotide sequence of SEQ ID NO: 1831; (iii) The CBA promoter contains the nucleotide sequence of SEQ ID NO: 1834; (iv) The intron contains the nucleotide sequence of SEQ ID NO: 1842; (v) The GBA1 coding sequence contains the nucleotide sequence of SEQ ID NO: 2001; (vi) This miR183 binding site series contains the nucleotide sequence of SEQ ID NO: 1849; (vii) The polyadenylated region contains the nucleotide sequence of SEQ ID NO: 1846; and (viii) The 3' ITR contains the nucleotide sequence of SEQ ID NO: 1830.

89. The AAV particle according to any one of claims 1 to 34, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO:2007 or a nucleotide sequence that is at least 90% identical (e.g., at least 97% identical) to SEQ ID NO:2007.

90. The AAV particle of claim 89, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2007.

91. The AAV particle of claim 90, wherein the viral genome consists of the nucleotide sequence of SEQ ID NO: 2007.

92. An adeno-associated virus (AAV) particle comprising a viral genome containing the nucleotide sequence of SEQ ID NO: 2001 and an AAV capsid variant comprising the following: (i) VP1 protein, which contains the amino acid sequence of SEQ ID NO: 4; (ii) VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 4; and / or (iii) VP3 protein, which contains the amino acid sequence at positions 203-742 of SEQ ID NO:

4.

93. An adeno-associated virus (AAV) particle comprising a viral genome containing the nucleotide sequence of SEQ ID NO: 2001 and an AAV capsid variant comprising the following: (i) VP1 protein, which contains the amino acid sequence of SEQ ID NO: 36; (ii) VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 36; and / or (iii) VP3 protein, which contains the amino acid sequence at positions 203-742 of SEQ ID NO:

36.

94. An adeno-associated virus (AAV) particle comprising a viral genome containing the nucleotide sequence of SEQ ID NO: 2002 and an AAV capsid variant comprising the following: (i) VP1 protein, which contains the amino acid sequence of SEQ ID NO: 4; (ii) VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 4; and / or (iii) VP3 protein, which contains the amino acid sequence at positions 203-742 of SEQ ID NO:

4.

95. An adeno-associated virus (AAV) particle comprising a viral genome containing the nucleotide sequence of SEQ ID NO: 2002 and an AAV capsid variant comprising the following: (i) VP1 protein, which contains the amino acid sequence of SEQ ID NO: 36; (ii) VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 36; and / or (iii) VP3 protein, which contains the amino acid sequence at positions 203-742 of SEQ ID NO:

36.

96. A cell comprising AAV particles as claimed in any one of claims 1 to 95, optionally wherein the cell is a mammalian cell (e.g., HEK293 cell), an insect cell (e.g., Sf9 cell), or a bacterial cell.

97. A method for preparing AAV particles as described in any one of claims 1 to 95, the method comprising: (i) Provide a cell containing the viral genome, the viral genome containing the GBA1 coding sequence and nucleic acid encoding the AAV capsid variant; as well as (ii) The cells were cultured under conditions suitable for encapsulating the viral genome within the AAV capsid variant; The AAV particles were prepared in this way.

98. The method of claim 97, wherein the viral genome comprises (a) The nucleotide sequence of SEQ ID NO: 2006 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); or (b) The nucleotide sequence of SEQ ID NO: 2007 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 This AAV capsid variant includes: (i) VP1 protein comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity with SEQ ID NO: 4 (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); (ii) VP2 protein comprising the amino acid sequence at positions 138-742 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 positions 138-742 of SEQ ID NO: 4; or (iii) VP3 protein comprising the amino acid sequence at position 203-742 of SEQ ID NO: 4 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with position 203-742 of SEQ ID NO:

4.

99. The method of claim 97, wherein the viral genome comprises (a) The nucleotide sequence of SEQ ID NO: 2006 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); or (b) The nucleotide sequence of SEQ ID NO: 2007 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 contains 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.

100. The method of claim 97, wherein the viral genome comprises: (a) The nucleotide sequence of SEQ ID NO: 2006 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); or (b) The nucleotide sequence of SEQ ID NO: 2007 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 This AAV capsid variant includes: (i) VP1 protein comprising the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity with SEQ ID NO: 36 (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); (ii) VP2 protein comprising the amino acid sequence at positions 138-742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) with positions 138-742 of SEQ ID NO: 36; and / or (iii) VP3 protein comprising the amino acid sequence at positions 203-742 of SEQ ID NO: 36 or an amino acid sequence having at least 90% identity (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity) with positions 203-742 of SEQ ID NO:

36.

101. The method of claim 97, wherein the viral genome comprises: (a) The nucleotide sequence of SEQ ID NO: 2006 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); or (b) The nucleotide sequence of SEQ ID NO: 2007 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 contains 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.

102. The method of claim 97, wherein the viral genome comprises: (a) The nucleotide sequence of SEQ ID NO: 2006 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); or (b) The nucleotide sequence of SEQ ID NO: 2007 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 This AAV capsid variant includes: (i) 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 (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); (ii) 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 (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 positions 138-742 of SEQ ID NO: 982; and / or (iii) 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 positions 203-742 of SEQ ID NO:

982.

103. The method of claim 97, wherein the viral genome comprises: (a) The nucleotide sequence of SEQ ID NO: 2006 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); or (b) The nucleotide sequence of SEQ ID NO: 2007 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 contains 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.

104. The method of any one of claims 97 to 103, further comprising introducing a first nucleic acid molecule containing the viral genome into the cell prior to step (i).

105. The method of any one of claims 97 to 104, wherein the cell contains a second nucleic acid molecule encoding the AAV capsid variant.

106. The method of claim 105, further comprising introducing the second nucleic acid into the cell prior to step (i).

107. The method of any one of claims 97 to 106, wherein the cell comprises mammalian cells (e.g., HEK293 cells), insect cells (e.g., Sf9 cells), or bacterial cells.

108. A pharmaceutical composition comprising AAV particles as described in any one of claims 1 to 95 and a pharmaceutically acceptable excipient.

109. A pharmaceutical composition comprising AAV particles as described in any one of claims 5 to 22 and a pharmaceutically acceptable excipient.

110. A pharmaceutical composition comprising AAV particles as described in any one of claims 9 to 15, 92 and 94 and a pharmaceutically acceptable excipient.

111. A pharmaceutical composition comprising AAV particles as described in any one of claims 16 to 22, 93 and 95 and a pharmaceutically acceptable excipient.

112. A method of delivering AAV particles encoding GBA1 protein to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition as described in any one of claims 108 to 111 or the AAV particles as described in any one of claims 1 to 95.

113. The method of claim 112, wherein the subject has, has been diagnosed with, or is at risk of developing a GBA1-related condition, optionally wherein the GBA1-related condition is a GBA1-related neurodegenerative or neuromuscular disease, further optionally wherein the GBA1-related condition is Parkinson's disease (PD), Parkinson's dementia (PDD), Gaucher disease (GD) (e.g., GD type 1, 2, or 3), Lewy body dementia (DLB), Lewy body dementia (LBD), multiple system atrophy (MSA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), isolated autonomic failure, brain iron deposition neurodegeneration type 1 (NBIA 1), or Hallewarden-Schpattz syndrome.

114. The method of claim 112 or claim 113, wherein the subject has, has been diagnosed with, or is at risk of developing Parkinson's disease (PD).

115. A method of treating a subject who has or has been diagnosed with GBA1-related conditions, comprising administering to the subject an effective amount of a pharmaceutical composition as described in any one of claims 108 to 111 or AAV particles as described in any one of claims 1 to 95.

116. A method of treating a subject who has or has been diagnosed with GBA1-related conditions, comprising administering to the subject an effective amount of a pharmaceutical composition as described in any one of claims 109 to 111 or AAV particles as described in any one of claims 5 to 22.

117. A method of treating a subject who has or has been diagnosed with GBA1-related conditions, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 110 or AAV particles of any one of claims 9 to 15, 92 and 94.

118. A method of treating a subject who has or has been diagnosed with GBA1-related conditions, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 111 or AAV particles of any one of claims 16 to 22, 93 and 95.

119. The method of any one of claims 115 to 118, wherein the GBA1-related condition is a GBA1-related neurodegenerative or neuromuscular disease, optionally wherein the GBA1-related condition is Parkinson's disease (PD), Parkinson's dementia (PDD), Gaucher disease (GD) (e.g., GD type 1, 2, or 3), dementia with Lewy bodies (DLB), Lewy body dementia (LBD), multiple system atrophy (MSA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), isolated autonomic failure, brain iron deposition neurodegeneration type 1 (NBIA 1), or Hallewarden-Scpatz syndrome.

120. The method of claim 119, wherein the GBA1-related neurodegenerative or neuromuscular disorder is Parkinson's disease (PD).

121. The method of claim 119, wherein the GBA1-related neurodegenerative disease or neuromuscular disorder is Gaucher disease (GD) (e.g., GD type 1, 2, or 3).

122. The method of claim 121, wherein the GBA1-related neurodegeneration or neuromuscular disease is GD type 1.

123. The method of claim 121, wherein the GBA1-related neurodegeneration or neuromuscular disease is GD type 2.

124. The method of claim 121, wherein the GBA1-related neurodegeneration or neuromuscular disease is GD type 3.

125. The method of claim 119, wherein the GBA1-related neurodegeneration or neuromuscular disorder is dementia with Lewy bodies (DLB).

126. The method of claim 119, wherein the GBA1-related neurodegeneration or neuromuscular disorder is Lewy body dementia (LBD).

127. A method of treating a subject suffering from Parkinson's disease (PD) or diagnosed with PD, comprising administering to the subject an effective amount of a pharmaceutical composition as described in any one of claims 108 to 111 or AAV particles as described in any one of claims 1 to 95.

128. A method of treating a subject suffering from Parkinson's disease (PD) or diagnosed with PD, comprising administering to the subject an effective amount of a pharmaceutical composition as described in any one of claims 109 to 111 or AAV particles as described in any one of claims 5 to 22.

129. A method of treating a subject with Parkinson's disease (PD) or diagnosed with PD, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 110 or AAV particles of any one of claims 9 to 15, 92 and 94.

130. A method of treating a subject with Parkinson's disease (PD) or diagnosed with PD, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 111 or AAV particles of any one of claims 16 to 22, 93 and 95.

131. A method of treating a subject suffering from or diagnosed with Gaucher disease (GD) (e.g., GD type 1, 2, or 3) or Gaucher disease (GD) (e.g., GD type 1, 2, or 3), comprising administering to the subject an effective amount of the pharmaceutical composition as described in any one of claims 108 to 111 or AAV particles as described in any one of claims 1 to 95.

132. A method of treating a subject suffering from or diagnosed with Gaucher disease (GD) (e.g., GD type 1, 2, or 3) or Gaucher disease (GD) (e.g., GD type 1, 2, or 3), comprising administering to the subject an effective amount of the pharmaceutical composition as claimed in claims 109 to 111 or AAV particles as claimed in any one of claims 5 to 22.

133. A method of treating a subject with Gaucher disease (GD) (e.g., GD type 1, 2, or 3) or diagnosed with Gaucher disease (GD) (e.g., GD type 1, 2, or 3), comprising administering to the subject an effective amount of the pharmaceutical composition of claim 110 or AAV particles as described in any one of claims 9 to 15, 92, and 94.

134. A method of treating a subject with Gaucher disease (GD) (e.g., GD type 1, 2, or 3) or diagnosed with Gaucher disease (GD) (e.g., GD type 1, 2, or 3), comprising administering to the subject an effective amount of the pharmaceutical composition of claim 111 or AAV particles of any one of claims 16 to 22, 93, and 95.

135. The method of any one of claims 131 to 134, wherein the GD is of type GD 1.

136. The method of any one of claims 131 to 134, wherein the GD is of type GD 2.

137. The method of any one of claims 131 to 134, wherein the GD is of type GD 3.

138. A method of treating a subject with Lewy body dementia (LBD), comprising administering to the subject an effective amount of a pharmaceutical composition as described in any one of claims 108 to 111 or AAV particles as described in any one of claims 1 to 95.

139. A method of treating a subject with Lewy body dementia (LBD), comprising administering to the subject an effective amount of the pharmaceutical composition as claimed in claims 109 to 111 or AAV particles as claimed in any one of claims 5 to 22.

140. A method of treating a subject with Lewy body dementia (LBD) comprising administering to the subject an effective amount of the pharmaceutical composition as claimed in claim 111 or AAV particles as claimed in any one of claims 9 to 15, 92 and 94.

141. A method of treating a subject with Lewy body dementia (LBD) comprising administering to the subject an effective amount of the pharmaceutical composition as claimed in claim 111 or AAV particles as claimed in any one of claims 16 to 22, 93 and 95.

142. A method of treating a subject with dementia having Lewy bodies (DLB), comprising administering to the subject an effective amount of a pharmaceutical composition as described in any one of claims 108 to 111 or AAV particles as described in any one of claims 1 to 95.

143. A method of treating a subject with dementia having Lewy bodies (DLB), comprising administering to the subject an effective amount of the pharmaceutical composition as claimed in claims 109 to 111 or AAV particles as claimed in any one of claims 5 to 22.

144. A method of treating a subject with dementia having Lewy bodies (DLB), comprising administering to the subject an effective amount of the pharmaceutical composition as claimed in claim 111 or AAV particles as claimed in any one of claims 9 to 15, 92 and 94.

145. A method of treating a subject with dementia having Lewy bodies (DLB), comprising administering to the subject an effective amount of the pharmaceutical composition as claimed in claim 111 or AAV particles as claimed in any one of claims 16 to 22, 93 and 95.

146. The method of any one of claims 112 to 145, wherein the subject has one or more mutations in the GBA1 gene.

147. The method of any one of claims 112 to 146, wherein the subject has lower GC enzyme activity compared to the subject without GBA1-related disease, optionally wherein the level of GC enzyme activity is measured by a 4-MUG assay or a SensoLyte blue glucocerebrosidase assay.

148. The method of any one of claims 115 to 147, wherein the treatment prevents the progression of the disease in the subject.

149. The method of any one of claims 115 to 148, wherein the treatment improves at least one symptom of the condition and / or alters one or more biomarkers of the condition.

150. The method of claim 149, wherein the one or more biomarkers comprise GC enzyme activity, levels of glucocerebroside and other glycolipids (e.g., in immune cells, such as macrophages), levels of synuclein aggregates (e.g., Lewy bodies), levels of neurofilament light chains, or combinations thereof.

151. The method of claim 149, wherein the at least one symptom comprises developmental delay, progressive encephalopathy, progressive dementia, ataxia, myoclonus, oculomotor dysfunction, bulbar palsy, general weakness, limb tremor, depression, visual hallucinations, cognitive decline, or a combination thereof.

152. The method of any one of claims 112 to 151, wherein the subject is a human.

153. The method of any one of claims 112 to 152, wherein the AAV particles are 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 nucleus, cerebellum, striatum, corpus callosum, cerebellum, brainstem caudate nucleus-putamen, thalamus, superior colliculus, spinal cord, or combinations thereof, wherein the AAV particles or pharmaceutical composition are delivered via intravenous administration.

154. The method of any one of claims 112 to 153, further comprising assessing, for example, measuring the level of GBA1 expression in the subject, such as the level of GBA1 gene expression, the level of GBA1 mRNA expression, and / or the level of GBA1 protein expression in the subject's cells, tissues, or body fluids.

155. The method of any one of claims 112 to 154, wherein the expression level of the GBA1 protein is measured by ELISA, Western blotting, or immunohistochemistry.

156. The method of claim 154 or claim 155, wherein the assessment of the GBA1 expression level is performed before and after administration of the AAV, optionally wherein the GBA1 expression level before administration is compared with the GBA1 expression level after administration.

157. The method of any one of claims 154 to 156, comprising assessing the expression level of GBA1 in cells or tissues of the central nervous system (e.g., parenchyma).

158. The method of claim 156 or claim 157, wherein the subject's GBA1 protein expression level increases after administration relative to the subject's GBA1 protein expression level prior to administration.

159. The method of any one of claims 112 to 158, further comprising, for example, evaluating, a measure of the GC enzyme activity level in the subject.

160. The method of any one of claims 112 to 159, wherein the application results in the following increase: (i) GC enzyme 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), optionally, wherein the GC enzyme activity in the subject increases by at least 2, at least 3, at least 4, or at least 5 times after the administration relative to the GC enzyme activity in the subject before the administration; (ii) The level of viral genome (VG) in each cell of the subject's CNS tissue (e.g., the cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord), optionally wherein the level of VG in each cell of the subject's CNS tissue is increased by more than 50 VG per cell relative to the level of VG in each cell of the subject's peripheral tissue; and / or (iii) GBA1 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), optionally wherein GBA1 mRNA expression in the subject increases by at least 100-1300 times after administration compared to GBA1 mRNA expression in the subject before administration.

161. The method of any one of claims 115 to 160, further comprising administering to the subject an additional agent suitable for treating or preventing the GBA1-related condition; Optionally, the additional agent comprises enzyme replacement therapy (ERT) (e.g., imiglucerase, veralucerase α, or taliglucerase α); substrate reduction therapy (SRT) (e.g., elixstat or miglustat), levodopa, carbidopa, safenamide, dopamine agonists (e.g., quetiapine, clozapine, pramipexole, rotigotine, or ropinirole), anticholinergics (e.g., benzalkonium chloride or trihexyphenidyl), cholinesterase inhibitors (e.g., rivastigmine, donepezil, or galantamine), N-methyl-d-aspartate (NMDA) receptor antagonists (e.g., memantine), or combinations thereof.

162. The method of any one of claims 112 to 161, further comprising administering a blood transfusion to the subject.

163. The method of any one of claims 112 to 161, further comprising administering an immunosuppressant to the subject.

164. The method of claim 162, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or ikuzumab hydroxychloroquine.

165. The pharmaceutical composition of any one of claims 108 to 111 or the AAV particles of any one of claims 1 to 95, for the treatment of GBA1-related conditions; optionally, wherein the GBA1-related condition is Parkinson's disease (PD), Parkinson's dementia (PDD), Gaucher disease (GD) (e.g., GD type 1, 2, or 3), Lewy body dementia (LBD), Lewy body dementia (LBD), multiple system atrophy (MSA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), isolated autonomic failure, brain iron deposition neurodegeneration type 1 (NBIA 1), or Hallewarden-Scpatz syndrome.

166. The pharmaceutical composition or AAV particles of claim 165, wherein the GBA1-related condition is Gaucher disease (GD) (e.g., GD type 1, 2, or 3).

167. The pharmaceutical composition or AAV particles of claim 166, wherein the GD is GD type 1.

168. The pharmaceutical composition or AAV particles of claim 166, wherein the GD is GD type 2.

169. The pharmaceutical composition or AAV particles of claim 166, wherein the GD is GD type 3.

170. The pharmaceutical composition or AAV particles of claim 165, wherein the GBA1-related condition is Parkinson's disease (PD).

171. The pharmaceutical composition or AAV particles of claim 165, wherein the GBA1-related condition is LBD.

172. The pharmaceutical composition or AAV particles of claim 165, wherein the GBA1-related condition is DLB.

173. Use of a pharmaceutical composition as described in any one of claims 108 to 111 or AAV particles as described in any one of claims 1 to 95 in the preparation of a medicament for treating GBA1-related conditions; optionally, wherein the GBA1-related condition is Parkinson's disease (PD), Parkinson's dementia (PDD), Gaucher disease (GD) (e.g., GD type 1, 2, or 3), dementia with Lewy bodies (DLB), Lewy body dementia (LBD), multiple system atrophy (MSA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), isolated autonomic failure, brain iron deposition neurodegeneration type 1 (NBIA 1), or Hallewarden-Scpatz syndrome.

174. The use as described in claim 173, wherein the GBA1-related condition is PD.

175. The use as described in claim 173, wherein the GBA1-related condition is Gaucher disease (GD) (e.g., GD type 1, 2, or 3).

176. The use as described in claim 175, wherein the GD is type GD 1.

177. The use as described in claim 175, wherein the GD is type GD 2.

178. The use as described in claim 175, wherein the GD is type GD 3.

179. The use as described in claim 173, wherein the GBA1-related condition is LBD.

180. The use as described in claim 173, wherein the GBA1-related condition is DLB.

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