Compositions and methods for the treatment of disorders related to glucosylceramidase beta 1 deficiency

Abstract

The disclosure relates to compositions and methods for, inter alia, altering, e.g., enhancing, the level of GBA1 protein via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful, inter alia, for the treatment of subjects who have, have been diagnosed with having, or are at risk of having a GBA1-related disorder, e.g., Parkinson's Disease (PD), Gaucher Disease (GD), Dementia with Lewy Bodies (DLB), or Lewy Body Dementia (LBD).

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF DISORDERS RELATED TO GLUCOSYLCERAMIDASE BETA 1 DEFICIENCY RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to US Provisional Application Serial No. 63 / 519,956, filed August 16, 2023, the contents of which are incorporated herein by reference in their entirety. SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing file, entitled 14640_0091-00304_SL.xml, was created on June 21, 2024, and is 1,922,119 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE

[0003] Described herein are compositions and methods relating to adeno-associated virus (AAV) viral particles for the delivery of polynucleotides, e.g., polynucleotides encoding glucosylceramidase beta 1 (GBA1) proteins and peptides for use in the treatment of GBA1-related disorders, which include Parkinson’s Disease (PD) and other GBA1-related disorders, including Gaucher Disease, Parkinson’s Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), and Lewy Body Dementia (LBD). In some embodiments, compositions described herein may be used to treat a subject in need thereof, such as a human subject diagnosed with a GBA1-related disorder or other condition resulting from a deficiency in the quantity and / or function of GBA1 protein. BACKGROUND

[0004] Lysosomal acid glucosylceramidase, commonly called glucosylcerebrosidase or Gcase, a D- glucosyl-N-acylsphingosine glucohydrolase, is a lysosomal membrane protein important in glycolipid metabolism. The enzyme is encoded by the glucosylceramidase beta 1 (GBA1) gene (Ensembl Gene ID No. ENSG00000177628). This enzyme, together with Saposin A and Saposin C, catalyzes the hydrolysis of glucosylceramide to ceramide and glucose. See Vaccaro, Anna Maria, et al. Journal of Biological Chemistry 272.27 (1997): 16862-16867, the contents of which are incorporated herein by reference in their entirety.

[0005] Mutations in GBA 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, the contents of which are herein incorporated by reference in their entirety. Gaucher disease is one of the most prevalent lysosomal storage disorders, with an estimated standardized birth incidence in the general population of between 0.4 to 5.8 individuals per 100,000. Heterozygous GBA1 mutations can lead to PD. Indeed, GBA1 mutations occur in 7-10% of total PD patients, making GBA1 mutations the most important genetic risk factor ofPD. PD-GBA patients have reduced levels of the lysosomal enzyme beta-glucocerebrosidase (Gcase), which results in increased accumulations of glycosphingolipid glucosylceramide (GluCer), which in turn is correlated with exacerbated Į-Synuclein aggregation and concomitant neurological symptoms. GD and PD, as well as other lysosomal storage disorders or Lewy body diseases such as Lewy Body Dementia (LBD). See Sidransky, E. and Lopez, G. Lancet Neurol.2012 November; 11(11): 986–998, the contents of which are incorporated by reference in their entirety.

[0006] To date, there are limited available treatments for GBA1-related disorders such as PD, and delivery to the adult central nervous system (CNS) remains a significant challenge in the development of new and effective therapies. Thus, there remains a long-felt need to develop pharmaceutical compositions and methods that can be delivered to the CNS for the treatment of PD and other GBA1-related disorders and to ameliorate deficiencies of GBA1 protein in subjects, e.g., human subjects, afflicted with GBA1- related disorders.

[0007] Adeno-associated viruses (AAVs) have emerged as a widely studied and utilized viral particles for delivery of therapeutically effective polypeptides to mammalian cells. See, e.g., Tratschin et al., Mol. Cell Biol., 5(11):3251-3260 (1985) and Grimm et al., Hum. Gene Ther., 10(15):2445-2450 (1999), the contents of each of which are incorporated herein by reference in their entirety.

[0008] There remains a need for effective methods of treatment using AAV capsids that are capable of delivering GBA1 to a target cell or tissue, e.g., a CNS cell or tissue. SUMMARY

[0009] The present disclosure addresses these challenges by providing AAV-based compositions comprising AAV capsid variants and methods for treating Gcase deficiency in subjects. Disclosed herein are compositions and methods directed to AAV-based gene delivery of Gcase to ameliorate loss-of- function and to improve intracellular lipid trafficking. The compositions and methods are useful to improve lysosomal glycolipid metabolism, and to slow, halt, or reverse neurodegenerative and other symptoms of PD and other GBA1-related disorders (e.g., Lewy Body Dementia (LBD), Parkinson’s disease dementia (PDD), Gaucher disease (GD)) in a subject (e.g., a subject having at least one mutation in a GBA1 gene). Unless otherwise specified, GBA protein, GBA1 protein, and Gcase protein are synonymous terms and used interchangeably to refer to the protein encoded by the GBA1 gene.

[0010] In some embodiments, the present disclosure provides an AAV particle comprising a nucleotide sequence encoding a GBA1 protein, e.g., a wildtype GBA1 protein, and an AAV capsid, e.g., an AAV capsid variant. In some embodiments, the present disclosure provides an AAV particle comprising a nucleotide sequence encoding a wildtype GBA1 protein and an AAV capsid variant. In some embodiments, the GBA1-encoding nucleotide sequence comprises an altered GC-content, and / or a reduced number of CpG motifs (e.g., lacking all CpG motifs) as compared to a wildtype GBA1-encoding sequence (e.g., comprising the nucleotide sequence of SEQ ID NO: 1776 or 1777), and wherein the AAV capsid variant is an AAV5 capsid variant.

[0011] In some embodiments, the AAV capsid variant (e.g., an AAV5 capsid variant) comprises a peptide that has replaced amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant is an AAV5 capsid variant comprising a peptide comprising the amino acid sequence of VQK in loop VIII, wherein, optionally, the amino acid sequence of VQK has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) in loop VIII, or a peptide comprising one, two, or three—but no more than three—substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein, optionally, the amino acid sequence has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a peptide comprising the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) in loop VIII, wherein, optionally, the peptide has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138. In some embodiments, the peptide is present in a VP1 protein, a VP2 protein, and / or a VP3 protein of the AAV capsid variant. In some embodiments, the peptide is present in the VP1, VP2, and VP3 proteins of the AAV capsid variant.

[0012] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a ȕ- glucocerebrosidase 1 (GBA1)-encoding sequence and the AAV capsid variant comprises an amino acid sequence having the formula [N2]-[N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1 is Y, N, or C; (b) position X2 is P, K, T, or Q; (c) position X3 is A or P; (d) position X4is E, S, or A; and (e) position X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence VQK, EQK, VKK, VHK, VQQ, or LQK; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% identical thereto.

[0013] In some embodiments, [N2]-[N3] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, [N2]-[N3] is present immediately subsequent to an amino acid position 576 as numbered according to SEQ ID NO: 982.

[0014] In some embodiments, the AAV capsid variant is an AAV5 capsid variant comprising [N2]- [N3] in place of an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

[0015] In some embodiments, [N2] comprises the amino acid sequence YP, YPA, YPAE (SEQ ID NO: 21), or YPAEV (SEQ ID NO: 1). In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, [N2]-[N3] comprises the amino acid sequence AEVVQK (SEQ ID NO: 36) or PAEVVQK (SEQ ID NO: 20). In some embodiments, [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0016] In some embodiments, the AAV capsid variant further comprises [N1] comprising positions XD, XE, and XF, wherein: (a) position XDof [N1] is Q, T, S, A, I, L, or H; (b) position XEof [N1] is S, G, A, or R; and (c) position XFof [N1] is S, K, L, R, A, or T; wherein [N1] immediately precedes [N2]-[N3]. In some embodiments, [N1] comprises the amino acid sequence QS, SS, or QSS. In some embodiments, [N1]-[N2] comprises the amino acid sequence QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] comprises the amino acid sequence SSYPAEVVQ (SEQ ID NO: 121) or QSSYPAEVVQK (SEQ ID NO: 150).

[0017] In some embodiments, the AAV capsid variant further comprises [N0] comprising positions XA, XB, and XC, wherein: (a) position XA of [N0] is T, I, or N; (b) position XB of [N0] is N; and (c) position XCof [N0] is N, T, S, or K; wherein [N0] immediately precedes [N1]. In some embodiments, [N0] comprises the amino acid sequence TN, NN, or TNN. In some embodiments, [N0]-[N1] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183). In some embodiments, [N0]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0018] In some embodiments, the AAV capsid variant further comprises [N4] comprising positions XGand XH, wherein: (a) position XGof [N4] is T, P, or N; and (b) position XHof [N4] is A; wherein [N4] is present immediately subsequent to [N3]. In some embodiments, [N4] comprises the amino acid sequence TA. In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0019] In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, [N0] is present at amino acids corresponding to positions 571-573 of the amino acid sequence of SEQ ID NO: 982; [N1] is present at amino acids corresponding to positions 574-576 of the amino acid sequence of SEQ ID NO: 982; [N2] is present at amino acids corresponding to positions 577- 581 of the amino acid sequence of SEQ ID NO: 982; [N3] is present at amino acids corresponding to positions 582-584 of the amino acid sequence of SEQ ID NO: 982; and [N4] is present at amino acids corresponding to positions 585-586 of the amino acid sequence of SEQ ID NO: 982.

[0020] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises at least 4, 5, 6, 7, or 8 consecutive amino acids from the amino acid sequence YPAEVVQK (SEQ ID NO: 943). In some embodiments, (i) the at least 4 consecutive amino acids comprise the amino acid sequence YPAE (SEQ ID NO: 21), optionally present at amino acids corresponding to positions 577-580 of the amino acid sequence of SEQ ID NO: 982; (ii) the at least 5 consecutive amino acids comprise the amino acid sequence YPAEV (SEQ ID NO: 1), optionally present at amino acids corresponding to positions 577-581 of the amino acid sequence of SEQ ID NO: 982; (iii) the at least 6 consecutive amino acids comprise the amino acid sequence YPAEVV (SEQ ID NO: 725), optionally present at amino acids corresponding to positions 577-582 of the amino acid sequence of SEQ ID NO: 982; or (iv) the at least 7 consecutive amino acids comprise the amino acid sequence YPAEVVQ (SEQ ID NO: 726), optionally present atamino acids corresponding to positions 577-583 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) present at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982.

[0021] In some embodiments, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV capsid variant further comprises (i) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (ii) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0022] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a ȕ- glucocerebrosidase 1 (GBA1)-encoding sequence and wherein the AAV capsid variant comprises (i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0023] In some embodiments, the AAV capsid variant comprises (i) the amino acid sequence of SEQ ID NO: 982; (ii) the amino acid sequence of SEQ ID NO: 738; and / or (iii) the amino acid sequence of SEQ ID NO: 739.

[0024] In some embodiments, the viral genome encodes a GBA1 protein comprising the amino acid sequence of SEQ ID NO: 1775 or an amino acid sequence at least 90% identical thereto. In some embodiments, the viral genome encodes a wildtype GBA1 protein. In some embodiments, the viral genome encodes a human GBA1 protein, a dog GBA1 protein, or an equine GBA1 protein. In some embodiments, the viral genome encodes a wildtype human GBA1 protein.

[0025] In some embodiments, the viral genome does not encode a hemagglutinin (HA) tag.

[0026] In some embodiments, the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0027] In some embodiments, the viral genome further comprises a signal sequence comprising the nucleotide sequence of SEQ ID NO: 2005 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0028] In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0029] In some embodiments, the viral genome encodes a GBA1 protein comprising the amino acid sequence of SEQ ID NO: 1774 or an amino acid sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0030] In some embodiments, the viral genome comprises a promoter operably linked to the GBA1- encoding sequence. In some embodiments, the promoter comprises a human elongation factor 1 alpha (EF-1a) promoter, a chicken ȕ-actin (CBA) promoter, a CAG promoter, a CAG derivative promoter, a CMV immediate-early enhancer and / or promoter, a CMV promoter, a ȕ glucuronidase (GUSB) promoter, a ubiquitin C (UBC) promoter, a neuron-specific enolase (NSE) promoter, a platelet-derived growth factor (PDGF) promoter, a platelet-derived growth factor B-chain (PDGF-ȕ) promoter, an intercellular adhesion molecule 2 (ICAM-2) promoter, a synapsin (Syn) promoter, a methyl-CpG binding protein 2 (MeCP2) promoter, a Ca2+ / calmodulin-dependent protein kinase II (CaMKII) promoter, a metabotropic glutamate receptor 2 (mGluR2) promoter, a neurofilament light (NFL) promoter, a heavy (NFH) promoter, a ȕ-globin minigene nȕ2 promoter, a preproenkephalin (PPE) promoter, an enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, a glial fibrillary acidic protein (GFAP) promoter, a myelin basic protein (MBP) promoter, a cardiovascular promoter (e.g., ĮMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512), or a fragment, e.g., a truncation, or a functional variant thereof. In some embodiments, the promoter comprises the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0031] In some embodiments, the viral genome further comprises an enhancer. In some embodiments, the enhancer comprises a CMV immediate-early (CMVie) enhancer; optionally wherein the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0032] In some embodiments, the viral genome further comprises an intron; optionally wherein the intron comprises the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0033] In some embodiments, the viral genome further comprises a polyadenylation (polyA) region; optionally wherein the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0034] In some embodiments, the viral genome further comprises an inverted terminal repeat (ITR); optionally wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, at 95%, 96%, 97%, 98%, or 99% identical) to the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830.

[0035] In some embodiments, the viral genome comprises a 5’ ITR and a 3’ ITR, wherein the 5’ ITR comprises the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto, and the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0036] In some embodiments, the viral genome further comprises one or more miR183 binding sites. In some embodiments, the viral genome comprises at least four miR183 binding sites. In some embodiments, each of the at least four miR183 binding sites is separated by a spacer. In some embodiments, each of the miR183 binding sites comprises the nucleotide sequence of SEQ ID NO: 1847 or a nucleotide sequence that has up to three modifications relative to SEQ ID NO: 1847. In some embodiments, the viral genome further comprises a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0037] In some embodiments the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter; (iii) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (iv) a 3’ ITR.

[0038] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (v) a 3’ ITR.

[0039] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) an intron; (v) the GBA1-encoding sequence, wherein the GBA1- encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vi) a 3’ ITR.

[0040] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO:1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vi) a 3’ ITR.

[0041] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vii) a 3’ ITR.

[0042] In some embodiments, the viral genome comprises: (i) a 5' inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1- encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0043] In some embodiments, (i) the 5' ITR comprises the nucleotide sequence of SEQ ID NO: 1829; (ii) the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831; (iii) the CBA promoter comprises the nucleotide sequence of SEQ ID NO: 1834; (iv) the intron comprises thenucleotide sequence of SEQ ID NO: 1842; (v) the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846; and (viii) the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830.

[0044] In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006.

[0045] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter; (iii) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) at least one miR183 binding site; and (v) a 3’ ITR.

[0046] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter; (iii) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (v) a 3’ ITR.

[0047] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vi) a 3’ ITR.

[0048] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) an intron; (v) the GBA1-encoding sequence, wherein the GBA1- encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vii) a 3’ ITR.

[0049] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) theGBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vii) a 3’ ITR.

[0050] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vii) a 3’ ITR.

[0051] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1- encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) at least one miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 1847; (vii) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0052] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95%identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1- encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vii) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto.

[0053] In some embodiments, (i) the 5’ ITR comprises the nucleotide sequence of SEQ ID NO: 1829; (ii) the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831; (iii) the CBA promoter comprises the nucleotide sequence of SEQ ID NO: 1834; (iv) the intron comprises the nucleotide sequence of SEQ ID NO: 1842; (v) the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001; (vi) the miR183 binding site series comprises the nucleotide sequence of SEQ ID NO: 1849; (vii) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846; and (viii) the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830.

[0054] In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. In some embodiments, the viral genome consists of the nucleotide sequence of SEQ ID NO: 2007.

[0055] In some aspects, the present disclosure provides a cell comprising an AAV particle disclosed herein, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

[0056] In some aspects, the present disclosure provides a method of making an AAV particle disclosed herein, the method comprising: (i) providing a cell comprising the viral genome comprising a GBA1-encoding sequence and a nucleic acid encoding the AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle.

[0057] In some embodiments of a method of making an AAV particle, the viral genome comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and wherein the AAV capsid variant comprises (i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); or (iii) the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0058] In some embodiments of a method of making an AAV particle, the viral genome comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO: 739.

[0059] In some embodiments of a method of making an AAV particle, the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006 or SEQ ID NO: 2007 and the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO: 739.

[0060] In some embodiments of a method of making an AAV particle, the method further comprises, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell. In some embodiments, the method further comprises, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell. In some embodiments, the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

[0061] In some aspects, the present disclosure provides a pharmaceutical composition comprising an AAV particle disclosed herein and a pharmaceutically acceptable excipient.

[0062] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a GBA1 protein to a cell, comprising administering an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the cell is in a subject. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having a GBA1-related disorder.

[0063] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a GBA1 protein to a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having a GBA1-related disorder.

[0064] In some aspects, the present disclosure provides a method of treating a subject having or diagnosed with having a GBA1-related disorder, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having a GBA1-related disorder. In some embodiments, the GBA1-related disorder is a GBA1-related neurodegenerative or neuromuscular disorder. In some embodiments, the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome. In some embodiments, the GBA1-related disorder is PD. In some embodiments, the GBA1-related disorder is LBD. In some embodiments, the GBA1-related disorder is DLB. In some embodiments, GBA1-related disorder is GD (e.g., GD type 1, GD type 2, or GD type 3).

[0065] In some aspects, the present disclosure provides a method of treating Parkinson’s Disease (PD) in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having PD.

[0066] In some aspects, the present disclosure provides a method of treating Lewy Body Dementia (LBD) in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having LBD.

[0067] In some aspects, the present disclosure provides a method of treating Dementia with Lewy Bodies (DLB) in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having DLB.

[0068] In some embodiments, the present disclosure provides a method of treating Gaucher Disease (GD) in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle disclosed herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having GD (e.g., GD type 1, GD type 2, or GD type 3). 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.

[0069] In some embodiments, the subject has one or more mutations in the GBA1 gene. In some embodiments, prior to the administration of the AAV particle or the pharmaceutical composition, the subject has lower GCase activity as compared to GCase activity in an individual who does not have a GBA1-related disorder, optionally wherein the level of GCase activity is measured by a 4-MUG assay or a SensoLyte Blue Glucocerebrosidase assay.

[0070] In some embodiments, the treating results in prevention of progression of the disorder in the subject. In some embodiments, the treating results in amelioration of at least one symptom of the disorder in the subject, e.g., as indicated by one or more biomarkers. In some embodiments, the one or more biomarkers comprises a GCase activity, a level of glucocerebroside and other glycolipids, (e.g., within immune cells such as macrophages), a level of synuclein aggregates (e.g., Lewy bodies), or a combination thereof. In some embodiments, the at least one symptom comprises developmental delay, progressive encephalopathy, progressive dementia, ataxia, myoclonus, oculomotor dysfunction, bulbar palsy, generalized weakness, trembling of a limb, depression, visual hallucinations, cognitive decline, or a combination thereof.

[0071] In some embodiments, the subject is a human.

[0072] In some embodiments, the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the central nervous system (CNS) in the subject. In some embodiments, the cell or tissue of the CNS is a cell or tissue of the spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum. In some embodiments, the AAV particle or the pharmaceutical composition is delivered to a peripheral cell or tissue in the subject. In some embodiments, the peripheral cell or tissue is a cell or tissue of the liver, heart, skeletal muscle, sympathetic ganglia, and / or plasma.

[0073] In some embodiments, the AAV particle or pharmaceutical composition is delivered to the subject via intravenous administration.

[0074] In some embodiments, the method of delivering or treating further comprises evaluating, e.g., measuring, the level of GBA1 expression (e.g., GBA1 gene expression, GBA1 mRNA expression, and / or GBA1 protein expression) in the subject, e.g., in a cell, tissue, or fluid of the subject. In some embodiments, the level of GBA1 protein expression is measured by an ELISA, a Western blot, or an immunohistochemistry assay. In some embodiments, evaluating the subject’s level of GBA1 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of GBA1 expression prior to administration is compared to the subject’s level of GBA1 expression subsequent to administration. In some embodiments, the method of delivering or treating further comprises evaluating the level of GBA1 expression in a cell or tissue of the central nervous system. In some embodiments, the subject’s level of GBA1 protein expression subsequent to administration is increased relative to the subject’s level of GBA1 protein expression prior to administration. In some embodiments, the method of delivering or treating further comprises evaluating, e.g., measuring, the level of GCase activity in the subject.

[0075] In some embodiments, administering the pharmaceutical composition or AAV particle to the subject results in an increase in: (i) GCase activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinjecell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum), and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or relative to GCase activity in a cell, tissue, or fluid of an individual with a GBA1-related disorder who has not been administered the pharmaceutical composition or AAV particle; (ii) the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or (iii) GBA1 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantial nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or relative to GBA1 mRNA expression in a cell or tissue of an individual with a GBA1-related disorder who has not been administered the pharmaceutical composition or AAV particle.

[0076] In some embodiments, the method of delivering or treating further comprises administering to the subject at least one additional therapeutic agent and / or therapy. In some embodiments, the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating the GBA1-related disorder. In some embodiments, the at least one additional therapeutic agent and / or therapy suitable for treating the GBA1-related disorder comprises enzyme replacement therapy (ERT) (e.g., imiglucerase, velaglucerase alfa, or taliglucerase alfa); substrate reduction therapy (SRT) (e.g., eliglustat or miglustat), levodopa, carbidopa, Safinamide, a dopamine agonist (e.g., pramipexole, rotigotine, or ropinirole), a dopamine antagonist (e.g., quetiapine, clozapine), an anticholinergic (e.g., benztropine or trihexyphenidyl), a cholinesterase inhibitor (e.g., rivastigmine, donepezil, or galantamine), an N-methyl-d-aspartate (NMDA) receptor antagonist (e.g., memantine), or a combination thereof. In some embodiments, the at least one additional therapeutic agent and / or therapy is suitable for treating Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden- Spatz Syndrome. In some embodiments, the GBA1-related disorder is PD, LBD, or GD, wherein, optionally, the GD is GD type 1, GD type 2, or GD type 3.

[0077] In some embodiments, the method of delivering or treating further comprises administering an immunosuppressant to the subject. In some embodiments, the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine. In some embodiments, the method of delivering or treating further comprises administering a blood transfusion to the subject.

[0078] In some aspects, the present disclosure provides a pharmaceutical composition or AAV particle disclosed herein for use in a method of treating a disorder disclosed herein.

[0079] In some aspects, the present disclosure provides a pharmaceutical composition or AAV particle disclosed herein for use in the treatment of a GBA1-related disorder in a subject. In some embodiments, the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome. In some embodiments, the GBA1- related disorder is PD. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having PD. In some embodiments, the GBA1-related disorder is LBD. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having LBD. In some embodiments, the GBA1-related disorder is DLB. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having DLB. In some embodiments, the GBA1-related disorder is GD (e.g., GD type 1, GD type 2, or GD type 3). In some embodiments, the subject has, has been diagnosed with having, or is at risk of having GD (e.g., GD type 1, GD type 2, or GD type 3).

[0080] In some aspects, the present disclosure provides a use of a pharmaceutical composition or AAV particle disclosed herein in the manufacture of a medicament for the treatment of a GBA1-related disorder in a subject. In some embodiments, the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome. In some embodiments, the GBA1-related disorder is PD. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having PD. In some embodiments, the GBA1-related disorder is GD. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having GD. 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. In some embodiments, the GBA1-related disorder is LBD. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having LBD. In some embodiments, the GBA1-related disorder is DLB. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having DLB. Enumerated Embodiments 1. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises the formula [N2]-[N3], wherein:(i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1 is Y, N, C, or T; (b) position X2 is P, E, K, T, or Q; (c) position X3is A or P; (d) position X4is E, S, D, or A; and (e) position X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK. 2. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises the formula [N2]-[N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1is Y, N, or C; (b) position X2is P, K, T, or Q; (c) position X3is A or P; (d) position X4is E, S, or A; and (e) position X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK. 3. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [N0] comprising TNN, TNT, INN, TNS, NNN, or TNK; (ii) an [N1] comprising QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS; (iii) an [N2] comprising YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID(iv) an [N3] comprising VQK, EQK, VKK, VHK, VQQ, or LQK; and (v) an [N4] comprising TA, PA, or NA. 4. The AAV particle of embodiment 1 or 2, wherein: (a) position X1 is Y or N;(b) position X2 is P, T or Q; (c) position X3 is A; (d) position X4 is E or S; and / or (e) position X5is V or L. 5. The AAV particle of any one of embodiments 1, 2, and 4, wherein [N2] comprises YP, NK, YT, YQ, NP, CP, TH, AE, PS, AA, AS, PA, PP, KA, TA, QA, TP, HA, EV, SL, EE, AV, or SH. 6. The AAV particle any one of embodiments 1, 2, 4, and 5, wherein [N2] comprises YPA, YPP, NKA, YTA, YQA, YTP, NPA, CPA, THA, PAE, PPS, KAE, TAE, QAE, TPS, PAA, HAS, AEV, PSL, AEE, or AAV. 7. The AAV particle of any one of embodiments 1, 2, 4, and 6, wherein [N2] comprises YPAE (SEQ ID NO: 21), YPPS (SEQ ID NO: 22), NKAE (SEQ ID NO: 23), YTAE (SEQ ID NO: 24), YQAE (SEQ ID NO: 25), YTPS (SEQ ID NO: 26), YPAA (SEQ ID NO: 27), NPAE (SEQ ID NO: 28), CPAE (SEQ ID NO: 29), THAS (SEQ ID NO: 30), PAEV (SEQ ID NO: 17), PPSL (SEQ ID NO: 31), KAEV (SEQ ID NO: 32), TAEV (SEQ ID NO: 16), PAEE (SEQ ID NO: 18), QAEV (SEQ ID NO: 15), TPSL (SEQ ID NO: 33), PAAV (SEQ ID NO: 34), or QAEE (SEQ ID NO: 35). 8. The AAV particle of any one of embodiments 1-7, wherein [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11). 9. The AAV particle of any one of embodiments 1, 2, 4, and 8, wherein [N3] comprises the amino acid sequence of VQK, EQK, or VKK. 10. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises VQK. 11. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises EQK. 12. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-9, wherein [N3] comprises VKK.13. The AAV particle of any one of embodiments 1-12, wherein [N2] is or comprises the amino acid sequence of YPAEV (SEQ ID NO: 1) and [N3] is or comprises the amino acid sequence of VQK. 14. The AAV particle of any one of embodiments 1-12, wherein: (i) [N2] is or comprises the amino acid sequence of YTPSL (SEQ ID NO: 7) and [N3] is or comprises the amino acid sequence of VQK; (ii) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of VQK; (iii) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of EQK; or (iv) [N2] is or comprises the amino acid sequence of YPPSL (SEQ ID NO: 2) and [N3] is or comprises the amino acid sequence of VKK. 15. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-14, wherein [N2]-[N3] comprises: (i) AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 16. The AAV particle of embodiment 1 or 2 or any one of embodiments 4-15, wherein [N2]-[N3] comprises: (i) PAEVVQK (SEQ ID NO: 20), PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48), TAEVVQK (SEQ ID NO: 49), PAEVEQK (SEQ ID NO: 50), PAEEVQK (SEQ ID NO: 51), QAEVVQK (SEQ ID NO: 52), TPSLVQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61), or QAEEVQK (SEQ ID NO: 62); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 17. The AAV particle of any one of embodiments 1-16, wherein [N2]-[N3] is or comprises: (i) YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948), YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSLVKK (SEQ ID NO: 954), YPAEVVKK (SEQ ID NO: 955), YPAEVVHK (SEQ ID NO: 956), YPAAVVQK (SEQ ID NO: 957), NPAEVVQK (SEQ ID NO: 958), YPAEVVQQ (SEQ ID NO: 959), CPAEVVQK (SEQ ID NO: 960), YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 18. The AAV particle of any one of embodiments 1-17, which further comprises one, two, three or all of an amino acid other than Q at position 574 (e.g., T, S, A, I, L, or H), an amino acid other than S at position 575 (e.g., G, A, or R), and / or an amino acid other than S at position 576 (e.g., K, L, R, A, or T), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 19. The AAV particle of any one of embodiments 1-17, which further comprises: (i) a Q at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) a T at position 574, an S at position 575, and / or a L at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) an S at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) a Q at position 574, an S at position 575, and / or an R at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982;(v) a Q at position 574, an S at position 575, and / or a K at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (vi) an A at position 574, a G at position 575, and / or an A at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (vii) an I at position 574, a G at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (viii) a Q at position 574, an A at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ix) an A at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (x) an L at position 574, a G at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xi) a Q at position 574, an S at position 575, and / or a T at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xii) an H at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (xiii) an L at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or (xiv) a Q at position 574, an R at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 20. The AAV particle of any one of embodiments 1-19, which further comprises [N1], wherein [N1] comprises positions XD, XE, and XF, wherein: (a) position XDis Q, T, S, A, I, L, or H; (b) position XEis S, G, A, or R; and (c) position XFis S, K, L, R, A, or T; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 21. The AAV particle of embodiment 20, wherein [N1] comprises SK, SL, SS, SR, GA, GS, AS, ST, RS, QS, TS, AG, IG, QA, LG, HS, LS, or QR. 22. The AAV particle of any one of embodiments 3, 20, and 21, wherein [N1] is or comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS. 23. The AAV particle of any one of embodiments 20-22, wherein [N1]-[N2] comprises:(i) SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64), SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68), GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70), STNKA (SEQ ID NO: 71), SSYTA (SEQ ID NO: 72), SSYQA (SEQ ID NO: 73), SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77), or SSTHA (SEQ ID NO: 78); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 24. The AAV particle of any one of embodiments 20-23, wherein [N1]-[N2] comprises: (i) SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81), SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84), GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 25. The AAV particle of embodiment 3 or any one of embodiments 20-24, wherein [N1]-[N2] is or comprises: (i) QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), HSSYPAAV (SEQ ID NO: 115), QSSNPAEV (SEQ ID NO: 116),), or(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 26. The AAV particle of any one of embodiments 20-25, wherein [N1]-[N2]-[N3] comprises: (i) SSYPAEVVQ (SEQ ID NO: 121), SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125), GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127), ASYPAEVVQ (SEQ ID NO: 128), STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO: 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVVQ (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134), SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140), SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145), RSYTAEVVQ (SEQ ID NO: 146), SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 27. The AAV particle of embodiment 3 or any one of embodiments 20-26, wherein [N1]-[N2]-[N3] is or comprises: (i) QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 28. The AAV particle of any one of embodiments 1-27, which further comprises [N0], wherein [N0] comprises positions XA, XB, and XC, wherein: (a) position XAis T, I, or N; (b) position XB is N; (c) position XCis N, T, S, or K; and optionally, wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 29. The AAV particle of embodiment 28, wherein [N0] comprises TN, IN, NN, NT, NS, or NK. 30. The AAV particle of embodiment 3, 28, or 29, wherein [N0] is or comprises TNN, TNT, INN, TNS, NNN, or TNK. 31. The AAV particle of embodiment 3 or any one of embodiments 28-30, wherein [N0]-[N1] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR(SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 32. The AAV particle of embodiment 3 or any one of embodiments 28-31, wherein [N0]-[N1]-[N2]-[N3] is or comprises: (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524), TNNHSSYPAEVVQK (SEQ ID NO: 525), TNNSSSYTAEVVQK (SEQ ID NO: 526), TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 551), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557), TNNQSSYTAEVVKK (SEQ ID NO: 558), TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562), or TNKQASYPAEVVQK (SEQ ID NO: 563); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 33. The AAV particle of embodiment 3 or 32, wherein [N0]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 34. The AAV particle of embodiment 3 or 32, wherein [N0]-[N1]-[N2]-[N3] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), or INNQSSYPAEVVQK (SEQ ID NO: 543). 35. The AAV particle of any one of embodiments 1-34, which further comprises [N4], wherein [N4] comprises positions XGand XH, wherein: (a) position XGis T, P, or N; and (b) position XH is A; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 36. The AAV particle of embodiment 35, wherein [N4] is or comprises TA, PA, or NA. 37. The AAV particle of any one of embodiments 3, 35, and 36, wherein [N3]-[N4] is or comprises: (i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 38. The AAV particle of embodiment 3 or any one of embodiments 35-37, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises:(i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583), TNTASSYQAEVVQKTA (SEQ ID NO: 1584), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEVVQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), TNNQRSYTAEVVQKTA (SEQ ID NO: 1604), TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), , TNKQASYPAEVVQKTA (SEQ ID NO: 1587); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 39. The AAV particle of embodiment 3 or any one of embodiments 35-38, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533). 40. The AAV particle of embodiment 3 or any one of embodiments 35-38, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024).41. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises the formula [B]-[C] (SEQ ID NO: 2159), wherein: (i) [B] comprises positions X1, X2, and X3, wherein: (a) position X1is Q, T, S, A, I, L, or H; (b) position X2is S, G, or A; and (c) position X3is S, K, L, R, or A; and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943. 42. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [A], wherein [A] comprises the amino acid sequence of TNN, TNT, INN, NNN, TNS, or TNK; (ii) a [B], wherein [B] comprises the amino acid sequence of QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS; (iii) a [C], wherein [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943); and (iv) a [D], wherein [D] comprises the amino acid sequence of TA or PA; and wherein, optionally, [C] replaces position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 43. The AAV particle of embodiment 41, wherein: (a) position X1is Q, T, S, A, or H; (b) position X2is S or G; and (c) position X3is S, K, L, or R. 44. The AAV particle of embodiment 41 or 43, wherein [B] comprises QS, TS, SS, AG, IG, QA, AS, LG, HS, SK, SL, SR, GA, or GS. 45. The AAV particle of any one of embodiments 41-44, wherein [B] is or comprises QSS, TSL, SSS, QSR, QSK, AGA, IGS, QAS, ASS, LGS, or HSS.46. The AAV particle of embodiment 41 or any one of embodiments 43-45, wherein [B]-[C] comprises: (i) SSYPAEVVQK (SEQ ID NO: 572), SKYPAEVVQK (SEQ ID NO: 573), SLYPAEVVQK (SEQ ID NO: 574), SRYPAEVVQK (SEQ ID NO: 575), GAYPAEVVQK (SEQ ID NO: 576), GSYPAEVVQK (SEQ ID NO: 580), or ASYPAEVVQK (SEQ ID NO: 582); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 47. The AAV particle of any one of embodiments 41-46, wherein [B]-[C] is or comprises: (i) QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), or HSSYPAEVVQK (SEQ ID NO: 162); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 48. The AAV particle of any one of embodiments 41-47, wherein [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150). 49. The AAV particle of any one of embodiments embodiment 41-47, wherein [B]-[C] is or comprises AGAYPAEVVQK (SEQ ID NO: 156), TSLYPAEVVQK (SEQ ID NO: 152), QSKYPAEVVQK (SEQ ID NO: 151), or QSRYPAEVVQK (SEQ ID NO: 154). 50. The AAV particle of any one of embodiments 1-49, which further comprises one or both of an amino acid other than T at position 571 (e.g., I or N), and / or an amino acid other than N at position 573 (e.g., T, S, or K), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.51. The AAV particle of any one of embodiments 1-49, which further comprises: (i) a T at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) a T at position 571, an N at position 572, and / or a T at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) an I at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) a T at position 571, an N at position 572, and / or an S at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (v) an N at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or (vi) a T at position 571, an N at position 572, and / or a K at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 52. The AAV particle of any one of embodiments 41-51, which further comprises [A], wherein [A] comprises positions XA, XB, and XC, wherein: (a) position XAis T, I, or N; (b) position XBis N; and (c) position XC is N, T, S, or K; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 53. The AAV particle of embodiment 52, wherein [A] comprises TN, IN, NN, NT, NS, or NK. 54. The AAV particle of any one of embodiments 42, 52, and 53, wherein [A] is or comprises TNN, TNT, INN, NNN, TNS, or TNK. 55. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNHSS (SEQ ID NO: 194), INNQSS (SEQ ID NO: 196), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), or TNKQAS (SEQ ID NO: 201); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 56. The AAV particle of embodiment 42 or any one of embodiments 52-55, wherein [A]-[B]-[C] is or comprises: (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNHSSYPAEVVQK (SEQ ID NO: 525), INNQSSYPAEVVQK (SEQ ID NO: 543), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNSTSLYPAEVVQK (SEQ ID NO: 556), or TNKQASYPAEVVQK (SEQ ID NO: 563); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 57. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 58. The AAV particle of embodiment 42 or any one of embodiments 52-54, wherein [A]-[B]-[C] is or comprises TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNQSRYPAEVVQK (SEQ ID NO: 510), or INNQSSYPAEVVQK (SEQ ID NO: 543). 59. The AAV particle of any one of embodiments 1-58, which further comprises: (i) an amino acid other than T at position 578 (e.g., P or N), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (ii) an amino acid other than T at position 585 (e.g., P or N), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.60. The AAV particle of any one of embodiments 1-58, which further comprises: (i) a T at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or a T at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982; (ii) a P at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or a P at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982; or (iii) an N at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or an N at position 585 and / or an A at position 586 relative to a reference sequence numbered according to SEQ ID NO: 982. 61. The AAV particle of any one of embodiments 41-60, which further comprises [D], wherein [D] comprises positions X4and X5, wherein: (a) position X4is T or N; and (b) position X5is A. 62. The AAV particle of embodiment 42 or 61, wherein [D] is or comprises TA or PA. 63. The AAV particle of any one of embodiments 42, 61, and 62, wherein [C]-[D] is or comprises: (i) YPAEVVQKTA (SEQ ID NO: 584) or YPAEVVQKPA (SEQ ID NO: 586); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 64. The AAV particle of embodiment 42 or any one of embodiments 61-63, wherein [A]-[B]-[C]-[D] is or comprises: (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112), TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142),INNQSSYPAEVVQKTA (SEQ ID NO: 1024), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 65. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533). 66. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024). 67. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises an amino sequence comprising the formula [N2]- [N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1 is Y or T; (b) position X2 is Q, T, P, or E; (c) position X3 is A; (d) position X4 is E or D; and (e) position X5 is V or E; and (ii) [N3] comprises the amino acid sequence of VQK or VQN. 68. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [N0] comprising TNN, TNS, TNT, or TNK; (ii) an [N1] comprising QSS, SLS, SLY, SAT, or QTS;(iii) an [N2] comprising YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13); (iv) an [N3] comprising VQK or VQN; and (v) an [N4] comprising TA, PA, TD, NA, or PA. 69. The AAV particle of embodiment 1 or 67, wherein [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV, AE, or AD. 70. The AAV particle of any one of embodiments 1, 67, and 69, wherein [N2] comprises^YPA, YQA, YTA, TEA, QAE, TAE, PAE, EAE, PAD, AEV, AEE, or ADV. 71. The AAV particle of any one of embodiments 1, 67, 69, and 70, wherein [N2] comprises YPAE (SEQ ID NO: 21), YQAE (SEQ ID NO: 25), YTAE (SEQ ID NO: 24), TEAE (SEQ ID NO: 587), YPAD (SEQ ID NO: 588), QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), EAEV (SEQ ID NO: 590), or PADV (SEQ ID NO: 19). 72. The AAV particle of embodiment 1 or any one of embodiments 67-71, wherein [N2] is or comprises YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13). 73. The AAV particle of embodiment 1 or any one of embodiments 67-72, wherein [N3] comprises the amino acid sequence of VQK. 74. The AAV particle of embodiment 1 or 67 or any one of embodiments 69-73, wherein [N2]-[N3] comprises: (i) AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 75. The AAV particle of embodiment 1 or 67 or any one of embodiments 69-74, wherein [N2]-[N3] comprises:(i) PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 76. The AAV particle of embodiment 1 or any one of embodiments 57-75, wherein [N2]-[N3] is or comprises: (i) YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 77. The AAV particle of embodiment 1 or any one of embodiments 67-76, wherein [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943). 78. The AAV particle of any one of embodiments 1-77, wherein [N2]-[N3] replaces position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 79. The AAV particle of embodiment 1 or any one of embodiments 67-78, which further comprises one, two, three or all of an amino acid other than Q at position 574 (e.g., S), an amino acid other than S at position 575 (e.g., L, A, or T), and / or an amino acid other than S at position 576 (e.g., Y or T), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 80. The AAV particle of embodiment 1 or any one of embodiments 67-78, which further comprises:(i) a Q at position 574, an S at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (ii) an S at position 574, an L at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iii) an S at position 574, an L at position 575, and / or a Y at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; (iv) an S at position 574, an A at position 575, and / or a T at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; or (v) a Q at position 574, a T at position 575, and / or an S at position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 81. The AAV particle of embodiment 1 or any one of embodiments 67-80, which further comprises [N1], wherein [N1] comprises positions XD, XE, and XF, wherein: (a) position XDis Q or S; (b) position XEis S, L, A, or T; and (c) position XFis S, Y, or T;^and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 82. The AAV particle of embodiment 81, wherein [N1] comprises QS, SL, SA, QT, LS, LY, AT, TS, or SS. 83. The AAV particle of any one of embodiments 68, 81, and 82, wherein [N1] is or comprises QSS, SLS, SLY, SAT, or QTS. 84. The AAV particle of any one of embodiments 81-83, wherein [N1]-[N2] comprises: (i) SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603), or TSTEA (SEQ ID NO: 605); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i).85. The AAV particle of any one of embodiments 81-84, wherein [N1]-[N2] comprises: (i) SSYPAE (SEQ ID NO: 79), LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), ATYPAE (SEQ ID NO: 613), LSYPAE (SEQ ID NO: 616), TSTEAE (SEQ ID NO: 619), or LSYPAD (SEQ ID NO: 621); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 86. The AAV particle of embodiment 68 or any one of embodiments 81-85, wherein [N1]-[N2] is or comprises: (i)^QSSYPAEV (SEQ ID NO: 96), SLSYQAEV (SEQ ID NO: 622), SLSYTAEV (SEQ ID NO: 623), SLYYPAEV (SEQ ID NO: 624), SATYPAEV (SEQ ID NO: 625), SLSYPAEV (SEQ ID NO: 629), SLSYPAEE (SEQ ID NO: 632), QTSTEAEV (SEQ ID NO: 633), or SLSYPADV (SEQ ID NO: 634); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 87. The AAV particle of embodiment 68 or any one of embodiments 81-86, wherein [N1]-[N2]-[N3] is or comprises: (i) QSSYPAEVVQK (SEQ ID NO: 150), SLSYQAEVVQK (SEQ ID NO: 635), SLSYTAEVVQK (SEQ ID NO: 637), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), SLSYPAEVVQK (SEQ ID NO: 642), SLSYPAEEVQK (SEQ ID NO: 643), SLSYPAEVVQN (SEQ ID NO: 644), QTSTEAEVVQK (SEQ ID NO: 645), or SLSYPADVVQK (SEQ ID NO: 646); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 88. The AAV particle of embodiment 68 or any one of embodiments 81-87, wherein [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150). 89. The AAV particle of embodiment 1 or any one of embodiments 67-88, which further comprises [N0], wherein [N0] comprises positions XA, XB, and XC, wherein: (a) position XAis T; (b) position XBis N; and (c) position XCis N, T, S, or K; and optionally wherein the AAV capsid comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 90. The AAV particle of embodiment 89, wherein [N0]: (i) comprises TN, NS, NT, NN, or NK; and / or (ii) is or comprises TNS, TNT, TNN, or TNK. 91. The AAV particle of any one of embodiments 68, 89, and 90, wherein [N0]-[N1] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNSSLS (SEQ ID NO: 647), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNNQTS (SEQ ID NO: 650), or TNKSAT (SEQ ID NO: 651; (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 92. The AAV particle of embodiment 68 or any one of embodiments 89-91, wherein [N0]-[N1]-[N2]- [N3] is or comprises: (i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657),TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), TNNQTSTEAEVVQK (SEQ ID NO: 662), TNKSATYPAEVVQK (SEQ ID NO: 663), or TNSSLSYPADVVQK (SEQ ID NO: 665); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 93. The AAV particle of embodiment 68 or any one of embodiments 89-92, wherein [N0]-[N1]-[N2]- [N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 94. The AAV particle of embodiment 1 or any one of embodiments 67-93, which further comprises [N4], wherein [N4] comprises positions XGand XH, wherein: (a) position XG is T, P, or N; and (b) position XHis A or D; and optionally wherein the AAV capsid variant comprise an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 95. The AAV particle of embodiment 94, wherein [N4] is or comprises TA, TD, PA, or NA. 96. The AAV particle of embodiment 68, 94, and 95, wherein [N3]-[N4] is or comprises: (i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 97. The AAV particle of embodiment 68 or any one of embodiments 94-96, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises:(i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), TNNQTSTEAEVVQKTA (SEQ ID NO: 2074), TNKSATYPAEVVQKTA (SEQ ID NO: 2075), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 98. The AAV particle of embodiment 68 or any one of embodiments 94-97, wherein [N0]-[N1]-[N2]- [N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533). 99. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises the formula [K1]-[K2], wherein: (i) [K1] comprises LSY or LYY; and (ii) [K2] comprises positions X1, X2, X3, and X4, wherein: (a) position X1 is Q, T, or P; (b) position X2 is A; (c) position X3 is E or D; and (d) position X4 is V or E. 100. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [K0], which comprises TNNS (SEQ ID NO: 14); (ii) an [K1], which comprises LSY or LYY; (iii) an [K2], which comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19);(iv) an [K3], which comprise VQK or VQN; and (v) an [K4], which comprises TA, TD, NA, or PA. 101. The AAV particle of embodiment 99 or 100, wherein [K1] comprises LSY. 102. The AAV particle of embodiment 99 or 101, wherein [K2] comprises QA, TA, PA, EV, EE, DV, AE, or AD. 103. The AAV particle of any one of embodiments 99, 101, and 102, wherein [K2] comprises QAE, TAE, PAE, PAD, AEV, AEE, or ADV. 104. The AAV particle of any one of embodiments 99-103, wherein [K2] is or comprises QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), or PADV (SEQ ID NO: 19). 105. The AAV particle of embodiment 99 or any one of embodiments 101-104, wherein [K1]-[K2] comprises LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), or LSYPA (SEQ ID NO: 603). 106. The AAV particle of embodiment 99 or any one of embodiments 101-105, wherein [K1]-[K2] comprises: (i) LSYQAE (SEQ ID NO: 607), LSYTAE (SEQ ID NO: 610), LYYPAE (SEQ ID NO: 611), LSYPAE (SEQ ID NO: 616), or LSYPAD (SEQ ID NO: 621); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 107. The AAV particle of any one of embodiments 99-106, wherein [K1]-[K2] is or comprises: (i) LSYQAEV (SEQ ID NO: 667), LSYTAEV (SEQ ID NO: 668), LYYPAEV (SEQ ID NO: 669), LSYPAEV (SEQ ID NO: 671), LSYPAEE (SEQ ID NO: 673), or LSYPADV (SEQ ID NO: 674); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 108. The AAV particle of any one of embodiments 99-107, which further comprises an amino acid other than Q at position 574 (e.g., S), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 109. The AAV particle of any one of embodiments 99-108, which further comprises S at position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 110. The AAV particle of any one of embodiments 99-109, which further comprises [K0], wherein [K0] is or comprises TNNS (SEQ ID NO: 14); an amino acid sequence comprising any portion of an amino acid sequence, e.g., any 2 or 3 amino acids, e.g., consecutive amino acids, thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of TNNS (SEQ ID NO: 14); or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of TNNS (SEQ ID NO: 14). 111. The AAV particle of embodiment 110, wherein [K0]-[K1] comprises: (i) TNSSLS (SEQ ID NO: 647) or TNSSLY (SEQ ID NO: 648); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 112. The AAV particle of any one of embodiments 100, 110, and 111, wherein [K0]-[K1] is or comprises: (i) TNSSLSY (SEQ ID NO: 676) or TNSSLYY (SEQ ID NO: 678); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 113. The AAV particle of any one of embodiments 110-112, wherein [K0]-[K1]-[K2] comprises: (i) TNSSLSYQA (SEQ ID NO: 679), TNSSLSYTA (SEQ ID NO: 681), TNSSLYYPA (SEQ ID NO: 682), or TNSSLSYPA (SEQ ID NO: 683); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, or 8 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 114. The AAV particle of any one of embodiments 110-113, wherein [K0]-[K1]-[K2] comprises: (i) TNSSLSYQAE (SEQ ID NO: 684), TNSSLSYTAE (SEQ ID NO: 685), TNSSLYYPAE (SEQ ID NO: 686), TNSSLSYPAE (SEQ ID NO: 687), or TNSSLSYPAD (SEQ ID NO: 689); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 115. The AAV particle of embodiment 100 or any one of embodiments 110-114, wherein [K0]-[K1]- [K2] is or comprises: (i) TNSSLSYQAEV (SEQ ID NO: 692), TNSSLSYTAEV (SEQ ID NO: 693), TNSSLYYPAEV (SEQ ID NO: 696), TNSSLSYPAEV (SEQ ID NO: 697), TNSSLSYPAEE (SEQ ID NO: 698), or TNSSLSYPADV (SEQ ID NO: 699); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 116. The AAV particle of any one of embodiments 99-115, which further comprises [K3], wherein [K3] comprises positions XA, XB, and XC, wherein: (a) position XAis V; (b) position XBis Q; and (c) position XCis K or N; and optionally wherein the AAV capsid comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 117. The AAV particle of embodiment 116, wherein [K3]: (i) comprises VQ, QK, or QN; (ii) is or comprises VQK or VQN. 118. The AAV particle of embodiment 100, 116, or 117, wherein [K2]-[K3] is or comprises: (i) QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), PAEVVQN (SEQ ID NO: 594), or PADVVQK (SEQ ID NO: 596); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, or 6 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 119. The AAV particle of embodiment 100 or any one of embodiments 116-118, wherein [K1]-[K2]- [K3] is or comprises: (i) LSYQAEVVQK (SEQ ID NO: 700), LSYTAEVVQK (SEQ ID NO: 701), LYYPAEVVQK (SEQ ID NO: 702), LSYPAEVVQK (SEQ ID NO: 703), LSYPAEEVQK (SEQ ID NO: 704), LSYPAEVVQN (SEQ ID NO: 706), or LSYPADVVQK (SEQ ID NO: 708); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof;(iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 120. The AAV particle of embodiment 100 or any one of embodiments 116-119, wherein [K0]-[K1]- [K2]-[K3] is or comprises: (i) TNSSLSYQAEVVQK (SEQ ID NO: 652), TNSSLSYTAEVVQK (SEQ ID NO: 654), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNSSLSYPAEVVQK (SEQ ID NO: 657), TNSSLSYPAEEVQK (SEQ ID NO: 658), TNSSLSYPAEVVQN (SEQ ID NO: 660), or TNSSLSYPADVVQK (SEQ ID NO: 665); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 121. The AAV particle of any one of embodiments 99-120, which further comprises [K4], wherein [K4] comprises positions XDand XE, wherein: (a) position XDis T, P, or N; and (b) position XEis A or D; and optionally wherein the AAV capsid variant comprise an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 122. The AAV particle of embodiment 100 or 121, wherein [K4] is or comprises TA, TD, PA, or NA. 123. The AAV particle of embodiment 100, 121, or 122, wherein [K3]-[K4] is or comprises: (i) VQKTA (SEQ ID NO: 564), VQKTD (SEQ ID NO: 714), VQNTA (SEQ ID NO: 715), VQKNA (SEQ ID NO: 570), or VQKPA (SEQ ID NO: 567); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or(iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 124. The AAV particle of embodiments 100 or any one of embodiments 121-123, wherein [K0]-[K1]- [K2]-[K3]-[K4] is or comprises: (i) TNSSLSYQAEVVQKTA (SEQ ID NO: 2064), TNSSLSYTAEVVQKTA (SEQ ID NO: 2065), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEEVQKTA (SEQ ID NO: 2069), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQNTA (SEQ ID NO: 2071), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNSSLSYPADVVQKTA (SEQ ID NO: 2076); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 125. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises [B]-[C] (SEQ ID NO: 2160), wherein: (i) [B] comprises positions X1, X2, and X3, wherein: (a) position X1is Q or S; (b) position X2is S, L, or A; and (c) position X3is S, Y, or T; and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 126. An AAV particle comprising an AAV capsid variant (e.g., an AAV5 capsid variant) and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [A] comprising TNN, TNS, TNT, or TNK; (ii) a [B] comprising QSS, SLY, SAT, or SLS; (iii) a [C] comprising YPAEVVQK (SEQ ID NO: 943); and (iv) a [D] comprising TA, TD, NA, or PA;wherein, optionally, [C] replaces position 577 relative to reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 127. The AAV particle of embodiment 125, comprising wherein [B] comprises QS, SL, SA, LY, AT, LS, or SS. 128. The AAV particle of any one of embodiments 125-127, comprising wherein [B] is or comprises QSS, SLY, SAT, or SLS. 129. The AAV particle of any one of embodiments 125, 127, and 128, wherein [B]-[C] comprises: (i) SSYPAEVVQK (SEQ ID NO: 572), LYYPAEVVQK (SEQ ID NO: 702), ATYPAEVVQK (SEQ ID NO: 718), or LSYPAEVVQK (SEQ ID NO: 703); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 130. The AAV particle of any one of embodiments 125-129, wherein [B]-[C] is or comprises: (i) QSSYPAEVVQK (SEQ ID NO: 150), SLYYPAEVVQK (SEQ ID NO: 639), SATYPAEVVQK (SEQ ID NO: 641), or SLSYPAEVVQK (SEQ ID NO: 642); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 131. The AAV particle of embodiment 126 or 130, wherein [B]-[C] is or comprises QSSYPAEVVQK (SEQ ID NO: 150). 132. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-131, which further comprises an amino acid other than N at position 573 (e.g., T, S, or K), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.133. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-131, which further comprises: (i) a T at position 571, an N at position 572, and / or an N at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (ii) a T at position 571, an N at position 572, and / or a T at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (iii) a T at position 571, an N at position 572, and / or a S at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (iv) a T at position 571, an N at position 572, and / or a K at position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 134. The AAV particle of any one of embodiments 125-133, which further comprises [A], wherein [A] comprises positions XA, XB, and XC, wherein: (a) position XAis T; (b) position XBis N; and (c) position XC is N, T, S, or K; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 135. The AAV particle of embodiment 126 or 134, wherein [A]: (i) comprises TN, NS, NT, NK, or NN; (ii) is or comprises TNN, TNS, TNT, or TNK. 136. The AAV particle of any one of embodiments 126, 134, and 135, wherein [A]-[B] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNSSLS (SEQ ID NO: 647), or TNKSAT (SEQ ID NO: 651); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 137. The AAV particle of embodiment 126 or any one of embodiments 134-136, wherein [A]-[B]-[C] is or comprises:(i) TNNQSSYPAEVVQK (SEQ ID NO: 500), TNSSLYYPAEVVQK (SEQ ID NO: 655), TNTSATYPAEVVQK (SEQ ID NO: 656), TNSSLSYPAEVVQK (SEQ ID NO: 657), or TNKSATYPAEVVQK (SEQ ID NO: 663); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 138. The AAV particle of embodiment 126 or any one of embodiments 134-137, wherein [A]-[B]-[C] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500). 139. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-138, which further comprises one or both of an amino acid other than T at position 578 (e.g., P or N) and / or an amino acid other than A at position 579 (e.g., D), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 140. The AAV particle of any one of embodiments 67-98 or any one of embodiments 125-138, which further comprises: (i) a T at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (ii) a T at position 578 and / or a D at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; (iii) a P at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138; or (iv) an N at position 578 and / or an A at position 579, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 141. The AAV particle of any one of embodiments 125-140, which further comprises [D], wherein [D] comprises positions X4 and X5, wherein: (a) position X4 is T, N, or P; and (b) position X5 is A or D; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b).142. The AAV particle of embodiment 141, wherein [D] is or comprises TA, TD, NA, or PA. 143. The AAV particle of embodiment 126, 141, or 142, wherein [C]-[D] is or comprises: (i) YPAEVVQKTA (SEQ ID NO: 584), YPAEVVQKTD (SEQ ID NO: 719), YPAEVVQKNA (SEQ ID NO: 724), or YPAEVVQKPA (SEQ ID NO: 586); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 144. The AAV particle of embodiment 126 or any one of embodiments 141-143, wherein [A]-[B]-[C]- [D] is or comprises: (i) TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNSSLYYPAEVVQKTA (SEQ ID NO: 2066), TNTSATYPAEVVQKTA (SEQ ID NO: 2067), TNSSLSYPAEVVQKTA (SEQ ID NO: 2068), TNSSLSYPAEVVQKTD (SEQ ID NO: 2070), TNSSLSYPAEVVQKNA (SEQ ID NO: 2072), TNSSLSYPAEVVQKPA (SEQ ID NO: 2073), or TNKSATYPAEVVQKTA (SEQ ID NO: 2075); (ii) (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences in (i). 145. The AAV particle of embodiment 126 or any one of embodiments 141-144, wherein [A]-[B]-[C]- [D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533). 146. The AAV particle of any one of the embodiments 1-40, 59, 60, 67-98, 139, and 140, wherein [N2]- [N3] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 147. The AAV particle of any one of embodiments 2, 15-40, 59, 60, 68, 79-98, 139, 137, and 146 wherein [N0], [N1], and / or [N4] is present in loop VIII, optionally wherein loop VIII comprises positions571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 148. The AAV particle of any one of embodiments 2, 15-40, 59, 60, 68, 79-98, 139, 140, 146, and 147, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 149. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-148, wherein [N2] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 150. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-149, wherein [N2] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 151. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-150, wherein [N2] is present immediately subsequent to position 576, and wherein [N2] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 152. The AAV particle of any one of 1-40, 59, 60, 67-98, 139, 140, and 146-151, wherein [N2] corresponds to positions 577-581 (e.g., Y577, P578, A579, E580, V581) of SEQ ID NO: 982. 153. The AAV particle of any one of embodiments 1-152, wherein the capsid variant comprises an amino acid other than T at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 154. The AAV particle of any one of embodiments 1-153, wherein the capsid variant comprises a Y at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 155. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-154, wherein X1of [N2] is present at position 577 (e.g., T577), and positions X2-X5of [N2] are present immediately subsequent to position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.156. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-155, wherein X1 of [N2] corresponds to position 577 (e.g., Y577), X2 of [N2] corresponds to position 578 (e.g., P588), X3 of [N2] corresponds to position 579 (e.g., A579), X4 of [N2] corresponds to position 580 (e.g., E580), and X5 of [N2] corresponds to position 581 (e.g., V581) of SEQ ID NO: 982. 157. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-156, wherein [N2]-[N3] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 158. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-157, wherein [N2]-[N3] replaces position 577 relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 159. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-158, wherein [N2]-[N3] is present immediately subsequent to position 576, and wherein [N2]-[N3] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 160. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-159, wherein [N2]-[N3] corresponds to positions 577-584 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584) of SEQ ID NO: 982. 161. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-160, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 162. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-161, wherein [N2]-[N3]-[N4] replaces positions 577-579 (e.g., T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 163. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-162, wherein [N2]-[N3]-[N4] is present immediately subsequent to position 576, and wherein [N2]-[N3]-[N4] replaces positions 577-579 (e.g., T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.164. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-163, wherein [N2]-[N3]-[N4] corresponds to positions 577-586 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 165. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-164, wherein [N1] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 166. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-165, wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 167. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-166, wherein [N1] is present immediately subsequent to position 573, and wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 168. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-167, wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 169. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-168, wherein [N1] is present immediately subsequent to position 573, and wherein [N1] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 170. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-169, wherein [N1] corresponds to positions 574-576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982. 171. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-170, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 172. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-171, wherein [N1]-[N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.173. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-171, wherein [N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 573, and wherein [N1]- [N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 174. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-173, wherein [N1]-[N2]-[N3]-[N4] corresponds to positions 574-586 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 175. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-174 wherein [N0] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 176. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-175, wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 177. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-176, wherein [N0] is present immediately subsequent to position 570, and wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 178. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-177 wherein [N0] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 179. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-178, wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 180. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-179, wherein [N0] is present immediately subsequent to position 570, and wherein [N0] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.181. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-181, wherein [N0] corresponds to positions 571-573 (e.g., T571, N572, and N573) of SEQ ID NO: 982. 182. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-181, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 183. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-182, wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 184. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-183, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present immediately subsequent to position 570, and wherein [N0]-[N1]-[N2]-[N3]-[N4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 185. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-184, wherein [N0]-[N1]-[N2]-[N3]-[N4] corresponds to positions 571-586 (e.g., T571, N572, N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586), of SEQ ID NO: 982. 186. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-185, wherein [N4] is present immediately subsequent to position 584, numbered according to SEQ ID NO: 982. 187. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-186, wherein [N4] replaces position 578 and 579, numbered according to SEQ ID NO: 138; or positions 585 and 586 numbered according to SEQ ID NO: 982. 188. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-187, wherein [N4] is present immediately subsequent to position 584 and replaces positions 585 and 586 numbered according to SEQ ID NO: 982. 189. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-188, wherein: (i) XAof [N0] is present at position 571, XBof [N0] is present at position 572, and XCof [N0] is present at position 573, numbered according to SEQ ID NO: 982;(ii) XDof [N1] is present at position 574, XEof [N1] is present at position 575, and XFof [N1] is present at position 576, numbered according to SEQ ID NO: 982; (iii) X1of [N2] is present at position 577, X2of [N2] is present at position 578, X3of [N2] is present at position 579, X4of [N2] is present at position 580, and X5of [N2] is present at position 581, numbered according to SEQ ID NO: 982; (iv) [N3] is present at positions 582-584, numbered according to SEQ ID NO: 982; and / or (v) XGof [N4] is present at position 585 and XHof [N4] is present at position 586, numbered according to SEQ ID NO: 982. 190. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-189, wherein: (i) [N0] is present at positions 571-573, numbered according to SEQ ID NO: 982; (ii) [N1] is present at positions 574-576, numbered according to SEQ ID NO: 982; (iii) [N2] is present at positions 577-581, numbered according to SEQ ID NO: 982; (iv) [N3] is present at positions 582-584, numbered according to SEQ ID NO: 982; (v) [N4] is present at positions 585-586, numbered according to SEQ ID NO: 982; (vi) [N2]-[N3] is present at positions 577-584, numbered according to SEQ ID NO: 982; and / or (vii) [N0]-[N1]-[N2]-[N3]-[N4] is present at positions 571-586, numbered according to SEQ ID NO: 982. 191. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-190, wherein [N3] is present immediately subsequent to [N2]. 192. The AAV particle of any one of embodiments 3, 31-40, 68, 94-98, 139, 140, and 146-191, wherein [N4] is present immediately subsequent to [N3]. 193. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-192, wherein the capsid variant comprises from N-terminus to C-terminus [N2]-[N3]. 194. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-193, wherein the capsid variant comprises from N-terminus to C-terminus [N1]-[N2]-[N3]. 195. The AAV particle of any one of embodiments 3, 18, 19, 28-40, 59, 60, 68, 89-98, 139, 140, and 146-194, wherein the capsid variant comprises from N-terminus to C-terminus [N0]-[N1]-[N2]-[N3]. 196. The AAV particle of any one of embodiments 3, 18-40, 59, 60, 68, 79-98, 139, 140, and 146-195, wherein the capsid variant comprises from N-terminus to C-terminus [N1]-[N2]-[N3]-[N4].197. The AAV particle of any one of embodiments 3, 18, 19, 28-40, 59, 60, 68, 89-98, 139, 140, and 146-196, wherein the capsid variant comprises from N-terminus to C-terminus [N0]-[N1]-[N2]-[N3]- [N4]. 198. The AAV particle of any one of embodiments 41-66 or any one of embodiments 125-145, wherein [B]-[C] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 199. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198, wherein [A] and / or [D] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 200. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, 198, and 199, wherein [A]- [B]-[C]-[D] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 201. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-200, wherein [B] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 202. The AAV particle of any one of embodiments 41-66, 125-145, and 198-201, wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 203. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-202, wherein [B] is present immediately subsequent to position 573, and wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 204. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-203, wherein [B] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982.205. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-204, wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 206. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-205, wherein [B] is present immediately subsequent to position 573, and wherein [B] replaces positions 574-576 (e.g., Q574, S575, and S576), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 207. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-206, wherein [B] corresponds to positions 574-576 (e.g., Q574, S575, and S576) of SEQ ID NO: 982. 208. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-207, wherein [B]-[C] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 209. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-208, wherein [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 210. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-209, wherein [B]-[C] is present immediately subsequent to position 573, and wherein [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 211. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-210, wherein [B]-[C] corresponds to positions 574-584 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584) of SEQ ID NO: 982. 212. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-211, wherein [B]-[C]-[D] is present immediately subsequent to position 573, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.213. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-212, wherein [B]-[C]-[D] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 214. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-213, wherein [B]-[C]-[D] is present immediately subsequent to position 573, and wherein [B]-[C]-[D] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 215. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-214, wherein [B]-[C]-[D] corresponds to positions 574-586 (e.g., Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 216. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-215, wherein [C] is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 217. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-216, wherein [C] replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 218. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-217, wherein [C] is present immediately subsequent to position 576, and wherein [C] replaces 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 219. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-218, wherein [C] corresponds to positions 577-584 (e.g., Y577, P578, A579, E580, V581, V582, Q583, K584) of SEQ ID NO: 982. 220. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-219, wherein [A] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.221. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-220, wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 222. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-221, wherein [A] is present immediately subsequent to position 570, and wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 223. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-222, wherein [A] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 224. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-223, wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 225. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-224, wherein [A] is present immediately subsequent to position 570, and wherein [A] replaces positions 571-573 (e.g., T571, N572, and N573), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 982. 226. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-225, wherein [A] corresponds to positions 571-573 (e.g., T571, N572, and N573) of SEQ ID NO: 982. 227. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-226, wherein [D] is present immediately subsequent to position 584, numbered according to SEQ ID NO: 982. 228. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-227, wherein [D] replaces positions 578 and 579 numbered according to SEQ ID NO: 138; or positions 585 and 586, numbered according to SEQ ID NO: 982. 229. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-228, wherein [D] is present immediately subsequent to position 584 and replaces positions 585 and 586, numbered according to SEQ ID NO: 982.230. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-229, wherein [A]- [B]-[C]-[D] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 231. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-230, wherein [A]- [B]-[C]-[D] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 232. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-231, wherein [A]- [B]-[C]-[D] is present immediately subsequent to position 570, and wherein [A]-[B]-[C]-[D] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 233. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-232, wherein [A]- [B]-[C]-[D] corresponds to positions 571-586 (e.g., T571, N572, N573, Q574, S575, S576, Y577, P578, A579, E580, V581, V582, Q583, K584, T585, A586) of SEQ ID NO: 982. 234. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-233, wherein: (i) XA of [A] is present at position 571, XB of [A] is present at position 572, and XC of [A] is present at position 573, numbered according to SEQ ID NO: 982; (ii) X1of [B] is present at position 574, X2of [B] is present at position 575, and X3of [B] is present at position 576, numbered according to SEQ ID NO: 982; (iii) [C] is present at positions 577-584, numbered according to SEQ ID NO: 982; and / or (iv) X4 of [D] is present at position 585 and position X5 of [D] is present at position 586, numbered according to SEQ ID NO: 982. 235. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-234, wherein: (i) [A] is present at positions 571-573, numbered according to SEQ ID NO: 982; (ii) [B] is present at positions 574-576, numbered according to SEQ ID NO: 982; (iii) [C] is present at positions 577-584, numbered according to SEQ ID NO: 982; (iv) [D] is present at positions 585-586, numbered according to SEQ ID NO: 982; and / or (v) [A]-[B]-[C]-[D] is present at positions 571-586, numbered according to SEQ ID NO: 982. 236. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-235, wherein [C] is present immediately subsequent to [B].237. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-236 wherein [D] is present immediately subsequent to [C]. 238. The AAV particle of any one of embodiments 41-66, any one of embodiments 125-145, or any one of embodiments 198-237, wherein the capsid variant comprises from N-terminus to C-terminus [B]-[C]. 239. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-238, wherein the AAV capsid variant comprises from N-terminus to C-terminus [A]-[B]-[C]. 240. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-239, wherein the AAV capsid variant comprises from N-terminus to C-terminus [B]-[C]-[D]. 241. The AAV particle of any one of embodiments 42, 61-66, 126, 141-145, and 198-240, wherein the AAV capsid variant comprises from N-terminus to C-terminus [A]-[B]-[C]-[D]. 242. The AAV particle of any one of the embodiments 99-124, wherein [K1]-[K2] is present in loop VIII. 243. The AAV particle of any one of embodiments 92-124 or embodiment 242, wherein [K0], [K3], and / or [K4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 244. The AAV particle of any one of embodiments 92-124 embodiment 242, or embodiment 243, wherein [K0]-[K1]-[K2]-[K3]-[K4] is present in loop VIII, optionally wherein loop VIII comprises positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to SEQ ID NO: 138, or positions 571-599, numbered according to SEQ ID NO: 982. 245. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-244, wherein [K1] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 246. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-245, wherein [K1] replaces positions 575-577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.247. The AAV particle of any one of embodiments 99-124 or any one of embodiments 242-246, wherein [K1] is present immediately subsequent to position 574, and wherein [K1] replaces positions 575-577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 248. The AAV particle of any one of embodiments 100, 116-124, and 242-247, wherein [K1]-[K2]-[K3] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 249. The AAV particle of any one of embodiments 100, 116-124, and 242-248, wherein [K1]-[K2]-[K3] replaces positions 575-577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 250. The AAV particle of any one of embodiments 100, 116-124, and 242-249, wherein [K1]-[K2]-[K3] is present immediately subsequent to position 574, and wherein [K1]-[K2]-[K3] replaces positions 575- 577 (e.g., S575, S576, and T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 251. The AAV particle of any one of embodiments 100, 121-124, and 242-250, wherein [K1]-[K2]-[K3]- [K4] is present immediately subsequent to position 574, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 252. The AAV particle of any one of embodiments 100, 121-124, and 242-251, wherein [K1]-[K2]-[K3]- [K4] replaces positions 575-579 (e.g., S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 253. The AAV particle of any one of embodiments 100, 121-124, and 242-252, wherein [K1]-[K2]-[K3]- [K4] is present immediately subsequent to position 574, and wherein [K1]-[K2]-[K3]-[K4] replaces positions 575-579 (e.g., S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 254. The AAV particle of any one of embodiments 100, 110-124, and 242-253, wherein [K0] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.255. The AAV particle of any one of embodiments 100, 110-124, and 242-254, wherein [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 256. The AAV particle of any one of embodiments 100, 110-124, and 242-255, wherein [K0] is present immediately subsequent to position 570, and wherein [K0] replaces positions 571 to 574 (e.g., T571, N572, N573, and Q574), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 257. The AAV particle of any one of embodiments 100, 121-124, and 242-256, wherein [K0]-[K1]-[K2]- [K3]-[K4] is present immediately subsequent to position 570, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 258. The AAV particle of any one of embodiments 100, 121-124, and 242-257, wherein [K0]-[K1]-[K2]- [K3]-[K4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 259. The AAV particle of any one of embodiments 100, 121-124, and 242-258, wherein [K0]-[K1]-[K2]- [K3]-[K4] is present immediately subsequent to position 570, and wherein [K0]-[K1]-[K2]-[K3]-[K4] replaces positions 571-579 (e.g., T571, N572, N573, Q574, S575, S576, T577, T578, and A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 260. The AAV particle of any one of embodiments 100, 116-124, and 242-259, wherein [K3] is present immediately subsequent [K2]. 261. The AAV particle of any one of embodiments 100, 121-124, and 242-260, wherein [K4] is present immediately subsequent [K3]. 262. The AAV particle of any one of embodiments 100, 121-124, and 242-261, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2]. 263. The AAV particle of any one of embodiments 100, 116-124, and 242-262, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2]-[K3]. 264. The AAV particle of any one of embodiments 100, 116-124, and 242-263, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K0]-[K1]-[K2]-[K3].265. The AAV particle of any one of embodiments 100, 121-124, and 242-264, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K1]-[K2]-[K3]-[K4]. 266. The AAV particle of any one of embodiments 100, 121-124, and 242-265, wherein the AAV capsid variant comprises from N-terminus to C-terminus [K0]-[K1]-[K2]-[K3]-[K4]. 267. An AAV particle comprising a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 23-28; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 23-28; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 23-28; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any one of the amino acid sequences provided in Tables 1, 2A, 2B, 11, or 23-28. 268. An AAV particle comprising a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, and 1610-1624; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591- 1593, 1598-1608, and 1610-1624; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583- 1587, 1590, 1591-1593, 1598-1608, and 1610-1624; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, and 1610-1624.269. An AAV particle comprising a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080. 270. An AAV particle comprising a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591. 271. The AAV particle of any one of embodiments 267-270, wherein the AAV capsid variant comprises at least 3, 4, 5, 6, or 7 consecutive amino acids from SEQ ID NO: 943 or any one of SEQ ID NOs: 946- 966. 272. The AAV particle of embodiment 271, wherein the at least 3 consecutive amino acids comprise YPA. 273. The AAV particle of embodiment 271, wherein the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21).274. The AAV particle of embodiment 271, wherein the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1). 275. The AAV particle of embodiment 271, wherein the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725). 276. The AAV particle of embodiment 271, wherein the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726). 277. The AAV particle of embodiment 271, wherein the amino acid sequence comprises YPAEVVQK (SEQ ID NO: 943). 278. The AAV particle of any one of embodiments 267, 268, and 270, wherein the AAV capsid variant comprises: (i) YTP; (ii) YTPS (SEQ ID NO: 26); (iii) YTPSL (SEQ ID NO: 7); (iv) YTPSLV (SEQ ID NO: 727); (v) YTPSLVQ (SEQ ID NO: 728); and / or (vi) YTPSLVQK (SEQ ID NO: 952). 279. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein: (i) the 3 consecutive amino acids comprise YPP; (ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the 7 consecutive amino acids comprise YPPSLVQ (SEQ ID NO: 732); and / or (vi) the amino acid sequence comprises YPPSLVQK (SEQ ID NO: 946). 280. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein: (i) the 3 consecutive amino acids comprise YPP; (ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 consecutive amino acids comprise YPPSLE (SEQ ID NO: 733); (v) the 7 consecutive amino acids comprise YPPSLEQ (SEQ ID NO: 734); and / or (vi) the amino acid sequence comprises YPPSLEQK (SEQ ID NO: 953).281. The AAV capsid variant of any one of embodiments 267, 268, and 270, wherein: (i) the 3 consecutive amino acids comprise YPP; (ii) the 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the 7 consecutive amino acids comprise YPPSLVK (SEQ ID NO: 735); and / or (vi) the amino acid sequence comprises YPPSLVKK (SEQ ID NO: 954). 282. The AAV particle of any one of embodiments 267-277, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 283. The AAV particle of any one of embodiments 267, 268, 270, and 278-281, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591. 284. The AAV particle of any one of embodiments 267, 268, 270, and 378-281, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any of SEQ ID NOs: 946, 952, 953, and 954. 285. The AAV particle of any one of embodiments 267-277 or embodiment 282, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 286. The AAV particle of any one of embodiments 267, 268, 270, 278-281, and 283, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591. 287. The AAV particle of any one of embodiments 267, 268, 270, 278-281, and 284, wherein the AAV capsid variant comprises an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 946, 952, 953, and 954.288. The AAV particle of any prior embodiment, e.g., any one of embodiments 267-277, 282, and 285, wherein the AAV capsid variant comprises an amino acid sequence encoded by: (i) a nucleotide sequence comprising SEQ ID NO: 944 or a nucleotide sequence that comprises at least one, two, three, four, five, six, seven, eight, nine, or ten modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; or (ii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, eight, nine, or ten, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944. 289. The AAV particle of any one of embodiments 267-277, 282, 285, and 289, wherein the AAV capsid variant is encoded by: (i) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions, but no more than ten modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NO: 944; or (ii) a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 944. 290. The AAV particle of embodiment 267, wherein the capsid variant comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 2024-2063; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 2024-2063; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063. 291. The AAV particle of embodiment 267 or 290, wherein the different amino acids of the amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 2024-2063, are present at one or more of the following positions: (i) position 1, wherein the different amino acid is T or L; (ii) position 2, wherein the different amino acid is N, L, K, A, T, or P; (iii) position 3, wherein the different amino acid is N, K, L, A, Y, or S; (iv) position 4, wherein the different amino acid is Q, L, T, S, F, Y, K, or A; (v) position 5, wherein the different amino acid is S, H, A, M, Q, T, V, or F; (vi) position 6, wherein the different amino acid is S, P, V, A, Q, L, T, N, or M;(vii) position 7, wherein the different amino acid is Y, H, S, V, A, L, or T; (viii) position 8, wherein the different amino acid is D, P, A, Q, F, L, S, H, or M; (ix) position 9, wherein the different amino acid is F, A, L, D, or Q; (x) position 10, wherein the different amino acid is T, E, I, or S; (xi) position 11, wherein the different amino acid is V, A, N, or S; (xii) position 12, wherein the different amino acid is V, L, or P; (xiii) position 13, wherein the different amino acid is Q, E, or P; (xiv) position 14, wherein the different amino acid is K, N, S, or L; (xv) position 15, wherein the different amino acid is T, V, M, or L; and / or (xvi) position 16, wherein the different amino acid is A, G, or R. 292. The AAV particle of embodiment 267, wherein the capsid variant comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 1632-1739, 1750-1758, 1784-1808, 1832, 1833, 1835-1841, 1843-1845, 1848, 1851, 1852, 1854-1869, 1871-2000, 2003, 2004, 2008-2023, and 2088-2158; (b) an amino acid sequence comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids from any one of SEQ ID NOs: 1632-1739, 1750-1758, 1784-1808, 1832, 1833, 1835-1841, 1843-1845, 1848, 1851, 1852, 1854-1869, 1871-2000, 2003, 2004, 2008-2023, and 2088- 2158; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-1739, 1750-1758, 1784- 1808, 1832, 1833, 1835-1841, 1843-1845, 1848, 1851, 1852, 1854-1869, 1871-2000, 2003, 2004, 2008- 2023, and 2088-2158; or (d) an amino sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-1739, 1750-1758, 1784-1808, 1832, 1833, 1835-1841, 1843- 1845, 1848, 1851, 1852, 1854-1869, 1871-2000, 2003, 2004, 2008-2023, and 2088-2158. 293. The AAV particle of embodiment 268 or 292, wherein the different amino acids of the amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of any one of SEQ ID NOs: 1632-1739, 1750-1758, 1784-1808, 1832, 1833, 1835-1841, 1843-1845, 1848, 1851, 1852, 1854-1869, 1871-2000, 2003, 2004, 2008-2023, and 2088-2158, are present at one or more of the following positions: (i) position 1, wherein the different amino acid is T, G, N, S, E, L, Y, V, or I; (ii) position 2, wherein the different amino acid is D, N, K, E, V, G, R, L, H, F, P, T, A, S, I, or Y;(iii) position 3, wherein the different amino acid is Y, N, K, T, W, Q, M, V, C, A, L, F, H, G, R, S, or P; (iv) position 4, wherein the different amino acid is H, Q, P, E, R, K, A, S, V, L, T, D, I, G, M, or N; (v) position 5, wherein the different amino acid is R, S, K, N, H, G, W, A, P, V, Q, Y, L, or F; (vi) position 6, wherein the different amino acid is G, S, F, R, W, H, I, C, M, A, Y, K, N, Q, V, P, E, D, T, or L; (vii) position 7, wherein the different amino acid is D, Y, S, I, H, F, P, K, R, G, L, Q, A, M, T, N, V, W, C, or E; (viii) position 8, wherein the different amino acid is P, L, Q, T, W, V, G, K, I, Y, N, H, R, D, S, M, A, F, or E; (ix) position 9, wherein the different amino acid is A, R, T, Q, S, M, L, E, K, V, G, D, N, H, F, P, or I; (x) position 10, wherein the different amino acid is K, E, Q, H, V, G, R, S, P, I, N, M, A, L, D, or T; (xi) position 11, wherein the different amino acid is V, A, E, N, R, L, M, T, Q, S, K, C, G, D, Y, P, H, F, or I; (xii) position 12, wherein the different amino acid is V, P, L, S, T, N, A, G, K, R, I, H, E, Q, or M; (xiii) position 13, wherein the different amino acid is Q, K, N, A, H, R, T, V, E, I, P, G, S, or L; (xiv) position 14, wherein the different amino acid is K, E, I, Y, Q, R, G, D, L, N, or S; (xv) position 15, wherein the different amino acid is S, T, N, Q, I, P, E, G, K, M, or H; and / or (xvi) position 16, wherein the different amino acid is A, D, L, Y, Q, or T. 294. The AAV particle of any one of embodiments 267-293, wherein the amino acid sequence is present in loop VIII of the AAV capsid variant. 295. The AAV particle of any one of embodiments 267-294, wherein the amino acid sequence is present immediately subsequent to position 570, 571, 572, 573, 574, 575, or 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 296. The AAV particle of any one of embodiments 267-295, wherein the amino acid sequence replaces one, two, three, four, five or all of positions 571, 572, 573, 574, 575, and / or 576 (e.g., positions T571, N572, N573, Q574, S575, S576, T577, T578, and / or A579), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138.297. The AAV particle of any one of embodiments 267-296, wherein the amino acid sequence is present immediately subsequent to position 576, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 298. The AAV particle of any one of embodiments 267-297, wherein the AAV capsid variant comprises an amino acid residue other than T at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 299. The AAV particle of any one of embodiments 267-298, wherein the AAV capsid variant comprises the amino acid Y at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 300. The AAV particle of any one of embodiments 267-299, wherein the AAV capsid variant comprises the substitution T577Y, numbered according to SEQ ID NO: 138. 300. The AAV particle of any one of embodiments 267-299, wherein the AAV capsid variant comprises the substitution T577Y, numbered according to SEQ ID NO: 138. 301. The AAV particle of embodiment 298 or 299, wherein the amino acid sequence is or comprises YPAEVVQK (SEQ ID NO: 943), and starts at position 577, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138 or 982. 302. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-301, wherein the AAV capsid variant comprises an amino acid other than T at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered relative to SEQ ID NO: 138. 303. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-302, wherein the AAV capsid variant comprises the amino acid Y at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered relative to SEQ ID NO: 138. 304. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-303, wherein the AAV capsid variant comprises the amino acid Y at position 577, and further comprises the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577 (e.g., at positions 578-584), numbered relative to SEQ ID NO: 982.305. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-304, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the amino acid sequence replaces position 577 (e.g., T577), relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. 306. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-305, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the amino acid sequence: (i) is present immediately subsequent to position 576; and (ii) replaces position 577 (e.g., T577), wherein in (i) and (ii) are numbered relative to SEQ ID NO: 138. 307. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-306, wherein the AAV capsid variant further comprises an amino acid other than T at position 571 (e.g., I), numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982. 308. The AAV particle of any one of embodiments 267-277, 272, 275, 278, 289, and 294-307, wherein the AAV capsid variant further comprises I at position 571, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982. 309. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-308, wherein the AAV capsid variant further comprises one, two, or all of an amino acid other than Q at position 574 (e.g., A or T), S at position 575 (e.g., G), and / or S (e.g., A, L, K, or R) at position 576, numbered relative to SEQ ID NO: 138 or SEQ ID NO: 982. 310. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-309, wherein the AAV capsid variant further comprises: (i) A at position 574, G at position 575, and A at position 576, numbered relative to SEQ ID NO: 138 or 982; or (ii) T at position 574 and L at position 576, numbered relative to SEQ ID NO: 138 or 982. 311. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-309, wherein the AAV capsid variant further comprises: (i) K at position 576, numbered relative to SEQ ID NO: 138 or 982; or (ii) R at position 576, numbered relative to SEQ ID NO: 138 or 982.312. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-310, wherein the capsid variant comprises: (i) A at position 574, G at position 575, A at position 576, and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 313. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-310, wherein the AAV capsid variant comprises: (i) T at position 574, L at position 576, and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 314. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-309, and 311, wherein the AAV capsid variant comprises: (i) K at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 315. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 295-309, and 311, wherein the AAV capsid variant comprises: (i) R at position 576 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 316. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, and 294-308, wherein the AAV capsid variant comprises: (i) I at position 571 and Y at position 577, numbered relative to SEQ ID NO: 138 or 982; and (ii) the amino acid sequence of PAEVVQK (SEQ ID NO: 20), which is present immediately subsequent to position 577, numbered according to SEQ ID NO: 138 or 982. 317. The AAV particle of any one of embodiments 267, 268, 270, 278, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence TPSLVQK (SEQ ID NO: 53), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982.318. The AAV particle of any one of embodiments 267, 268, 270, 279, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLVQK (SEQ ID NO: 47), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982. 319. The AAV particle of any one of embodiments 267, 268, 270, 280, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLEQK (SEQ ID NO: 54), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982. 320. The AAV particle of any one of embodiments 267, 268, 270, 281, 283, 284, 286, and 287, wherein the AAV capsid variant comprises Y at position 577 and the amino acid sequence PPSLVKK (SEQ ID NO: 55), which is present immediately subsequent to position 577, all numbered according to SEQ ID NO: 138 or 982. 321. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant further comprises a modification, e.g., an insertion, substitution (e.g., conservative substitution), and / or deletion, in loop I, II, IV, and / or VI. 322. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NO: 138. 323. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three, but no more than 30, 20 or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 138. 324. The AAV particle of any one of the embodiments provided herein, wherein the AAV capsid variant comprises an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity to SEQ ID NO: 138. [Embodiments 325-327 are intentionally absent.] 328. The AAV particle of any one of the embodiments provided herein, wherein the capsid variant comprises a VP1 protein, a VP2 protein, a VP3 protein, or a combination thereof.329. The AAV particle of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, and 321-328, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 137-731, e.g., a VP2, of SEQ ID NO: 982, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 330. The AAV particle of any one of embodiments 1-98, 125-242, 267-277, 282, 285, 288, 289, 294-306, and 321-329, wherein the AAV capsid variant comprises the amino acid sequence corresponding to positions 193-731, e.g., a VP3, of SEQ ID NO: 982, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 331. The AAV particle of any one of embodiments 1-321, wherein the AAV capsid variant comprises a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity to the amino acid sequence corresponding to positions 137-724, e.g., a VP2, of SEQ ID NO: 138. 332. The AAV particle of any one of embodiments 1-321, wherein the AAV capsid variant comprises a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity to the amino acid sequence corresponding to positions 193-724, e.g., a VP3, of SEQ ID NO: 138. 333. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, and 321-328, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein: (i) the at least 3 consecutive amino acids comprise YPA; (ii) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725); or (v) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726); wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 739. 334. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333, wherein the AAV capsid variant comprises an amino acid sequence comprising at least 3, 4, 5, or 6 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein: (i) the 3 consecutive amino acids comprise YPA; (ii) the 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725); or(v) the 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137- 731 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193-731 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). 335. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 334, wherein the AAV capsid variant comprises one, two, or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137-731 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193-731 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c). 336. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-335, comprising one, two, or three but no more than four different amino acids, relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739; or an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 739. 337. The AAV particle of any one of embodiments 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-336, comprising one or two, but no more than three substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein the AAV capsid variant comprises an amino acid sequence at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 982. 338. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-337, wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, or an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.339. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-338, wherein the capsid variant comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 95% identity thereto. 340. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-339, wherein the capsid variant comprises the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence with at least 98% identity thereto. 341. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, or 333-340, wherein the AAV capsid variant comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of SEQ ID NO: 982. 342. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-341, wherein the capsid variant comprises an amino acid sequence comprising at least one, two or three, but not more than 30, 20 or 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 982. 343. The AAV particle of any one of embodiments 1-98, 125-241, 267-277, 282, 285, 288, 289, 294-306, 321-328, and 333-342, wherein the nucleotide sequence encoding the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 984, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. 344. The AAV particle of any one of the embodiments provided herein, wherein the nucleotide sequence encoding the AAV capsid variant is codon-optimized. [Embodiments 345-349 are intentionally absent.] 350. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138. 351. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cordcell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982. 352. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 139. 353. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which transduces a brain region, e.g., a temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum, optionally wherein the level of transduction is at least 1.5, 2.2, 2.4, 2.5, 2.6, 2.7, 3.0, 3.2, 3.5, 3.7, 4.0, 4.2, 4.5, 4.7, 4.9, 5, 10, 15, 20, 25, 30, 35-fold greater as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 2. 354. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 353, which is enriched at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65-fold in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1. 355. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 354, which is enriched at least about 10, 12, 15, 17, 20, 25, 30, 35, 40, 45, 50, 55, 60, 61, 62, 63, 64, or 65-fold in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1. 356. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 355, which is enriched in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), e.g., as compared to a reference sequence of SEQ ID NO: 138. 357. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 356, which is enriched at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, 30, 35, 40, 45-fold in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Examples 1, 2, 4, and 5.358. The AAV particle of embodiment 356 or 357, wherein the at least two to three species are Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, rat, and / or mouse (e.g., BALB / c mice). 359. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 358, which is enriched at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 125, 150, 175, 200, or 225-fold, in the brain compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 360. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 359, which delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 20, 25, 30, or 35-fold, as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2). 361. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 360, which delivers an increased number and / or level of viral genomes to a brain region, optionally wherein the number and / or level of viral genomes is increased by at least 1.5, 2.2, 2.4, 2.5, 2.6, 2.7, 3.0, 3.2, 3.5, 3.7, 4.0, 4.2, 4.5, 4.7, 4.9, or 5-fold as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2). 362. The AAV particle of any one of embodiments 350-361, wherein the brain region is a temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, cerebellum, or a combination thereof. 363. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 362, which is enriched at least about 3, 3.5, 4.0, 4.5, 5, 5.0, 6.0, or 6.5-fold in a spinal cord region compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay as described in Example 2. 364. The AAV particle of any one of embodiments 363, wherein the spinal cord region is a cervical region, a lumbar region, a thoracic region, or a combination thereof. 365. The AAV particle of any one of the embodiments provided herein, which shows preferential transduction in a brain region relative to transduction in the dorsal root ganglia (DRG). 366. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 365, which is capable of transducing neuronal cells.367. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 366, which is capable of transducing non-neuronal cells, e.g., glial cells (e.g., oligodendrocytes). 368. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 367, which shows preferential transduction in a brain region relative to transduction in the liver. 369. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, and 321-349, which has an increased tropism for a heart cell or heart tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138. 370. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369, which has an increased tropism for a heart cell or tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 139. 371. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, 369, and 370, which delivers an increased level of a payload to a heart region, optionally wherein the level of the payload is increased by at least 1.5, 2, or 2.5-fold, as compared to a reference sequence of SEQ ID NO: 139, e.g., when measured by an assay, e.g., an IHC assay or a RT-ddPCR assay (e.g., as described in Example 2). 372. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369-371, which has an increased tropism for a heart cell or tissue, e.g., a heart ventricle or heart atrium, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982. 373. The AAV particle of any one of embodiments 67-267, 269, 271-277, 282, 285, 288, 289, 294-306, 321-349, and 369-372, which is enriched at least about 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50-fold in the heart compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 374. The AAV particle of any one of embodiments 267, 290, 291, 321-328, 331, 332, and 344, which has an increased tropism for a muscle cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982.375. The AAV particle of any one of embodiments 267, 290, 291, 321-328, 331, 332, 344, and 374, which is enriched at least about 2, 3, 4, 5, 10, 15, 20, 25, 30, or 35-fold in the muscle compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 376.^The AAV particle of embodiment 374 or 375, wherein the muscle cell or tissue is a heart muscle (e.g., a heart ventricle or a heart atrium, or both), a quadriceps muscle, or both. 377. The AAV particle of any one of embodiments 267, 292, 293, 321-328, 331, 332, and 344, which has an increased tropism for a liver cell or tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 982. 378. The AAV particle of any one of embodiments 267, 292, 293, 321-328, 331, 332, 344, and 377, which is enriched at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 130, 140, 150, 160, 170, 180, 185, or 190-fold in the liver compared to a reference sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4. 379. The AAV particle of any one of embodiments 1-378, wherein the AAV particle comprises a viral genome comprising a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 and a Rep52 protein). 380. The AAV particle of any one of the embodiments provided herein, wherein the AAV particle comprises a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 and a Rep52 protein). 381. The AAV particle of embodiment 379 or 380, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene. [Embodiments 382-445 are intentionally absent.] 446. A cell, e.g., a host cell, comprising the AAV particle of any one of embodiments 1-381. 447. The cell of embodiment 446, wherein the cell is a mammalian cell or an insect cell. 448. The cell of embodiment 446 or 447, wherein the cell is a cell of the CNS and / or the spinal cord.449. The cell of any one of embodiments 446-448, wherein the cell is a cell of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum. 450. A method of making an AAV particle of embodiment 381, comprising: (i) providing a host cell comprising a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle. 451. The method of embodiment 450, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the host cell. 452. The method of embodiment 450 or 451, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell. 453. The method of embodiment 452, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule. 454. A pharmaceutical composition comprising the AAV particle of any one of embodiments 1-381, and a pharmaceutically acceptable excipient. 455. A method of delivering to a subject a GBA1 protein, comprising administering an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381. 456. The method of embodiment 455, wherein the GBA1 protein is delivered to a cell or tissue of the central nervous system (CNS). 457. The method of embodiment 456, wherein the cell or tissue of the CNS is a cell or tissue of a brain or spinal cord region. 458. The method of embodiment 456 or embodiment 457, wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, or cerebellum.459. The method of any one of embodiments 456-458, wherein the cell or tissue of the CNS comprises a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, or an oligodendrocyte. 460. The method of any one of embodiments 455-459, wherein the subject is a human. 461. The method of embodiment 460, wherein the subject has, has been diagnosed with having, or is at risk of having a genetic disorder. 462. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having a neurological (e.g., a neurodegenerative disorder) or a neuromuscular disorder. 463. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having GBA1-related disorder. 464. The method of any one of embodiments 460-463, wherein the subject has, has been diagnosed with having, or is at risk of having Parkinson’s Disease (PD), Gaucher Disease (GD), Dementia with Lewy Bodies (DLB), or Lewy Body Dementia (LBD). 465. A method of treating a GBA1-related disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, optionally wherein the subject has, has been diagnosed with having, or is at risk of having the GBA1-related disorder. 466. A method of treating a neurological disorder, e.g., a neurodegenerative disorder, in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, optionally wherein the subject has, has been diagnosed with having, or is at risk of having the neurological disorder. 467. A method of treating a muscular disorder or a neuromuscular disorder in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, optionally wherein the subject has, has been diagnosed with having, or is at risk of having the muscular disorder or the neuromuscular disorder. 468. The method of any one of embodiments 465-467, wherein the genetic disorder, neurological disorder, neurodegenerative disorder, muscular disorder, or neuromuscular disorder is PD, GD, or LBD.469. The method of any one of embodiments 465-468, wherein the treatment comprises prevention of progression of the disease or disorder in the subject. 470. The method of any one of embodiments 460-469, wherein the subject is a human. 471. The method of any one of embodiments 465-470, wherein the AAV particle is administered to the subject intravenously, via intra-cisterna magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly. 472. The method of any one of embodiments 465-471, wherein the AAV particle is administered to the subject via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration. 473. The method of any one of embodiments 465-471, wherein the AAV particle is administered to the subject intravenously. 474. The method of any one of embodiments 455-473, wherein the subject has lower GCase activity as compared to GCase activity in an individual who does not have a GBA1-related disorder. 475. The method of any one of embodiments 455-474, wherein the subject has one or more mutations in the GBA1 gene. 476. The method of any one of embodiments 465-474, wherein administration of the AAV particle results in amelioration of at least one symptom of the GBA1-related disorder in the subject. 477. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in a method of delivering a payload to a cell or tissue. 478. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in a method of treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, a neuromuscular disorder, or a neuro-oncological disorder. 479. The pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381, for use in the manufacture of a medicament.480. Use of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381 in the manufacture of a medicament. 481. Use of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381 in the manufacture of a medicament for treating a genetic disorder, a neurological disorder, a neurodegenerative disorder, a muscular disorder, a neuromuscular disorder, or a neuro- oncological disorder. 482. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the viral genome encodes a GBA1 protein comprising the amino acid sequence of SEQ ID NO: 1775 or an amino acid sequence at least 90% identical thereto. 483. The AAV particle of embodiment 482, wherein the viral genome encodes a wildtype GBA1 protein. 484. The AAV particle of embodiment 482 or embodiment 483, wherein the viral genome encodes a human GBA1 protein, a dog GBA1 protein, or an equine GBA1 protein. 485. The AAV particle of any one of embodiments 482-484, wherein the viral genome encodes a wildtype human GBA1 protein. 486. The AAV particle of any one of embodiments 482-485, wherein the viral genome does not encode a hemagglutinin (HA) tag. 487. The AAV particle of any one of embodiments 482-486, wherein the GBA1-encoding sequence comprises SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 488. The AAV particle of any one of embodiments 482-487, where the viral genome further comprises a signal sequence comprising the nucleotide sequence of SEQ ID NO: 2005 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 489. The AAV particle of any one of embodiments 482-488, wherein the viral genome comprises the nucleotide sequence of 2001 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.490. The AAV particle of any one of embodiments 482-489, wherein the viral genome encodes a GBA1 protein comprising the amino acid sequence of SEQ ID NO: 1774 or an amino acid sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 491. The AAV particle of any one of embodiments 482-490, wherein the viral genome comprises a promoter operably linked to the GBA1-encoding sequence. 492. The AAV particle of embodiment 491, wherein the promoter comprises an EF-1a promoter, a CBA promoter, a chicken ȕ-actin (CBA) promoter, a CAG promoter, a CAG derivative promoter, a CMV immediate-early enhancer and / or promoter, a CMV promoter, a ȕ glucuronidase (GUSB) promoter, a ubiquitin C (UBC) promoter, a neuron-specific enolase (NSE) promoter, a platelet-derived growth factor (PDGF) promoter, a platelet-derived growth factor B-chain (PDGF-ȕ) promoter, an intercellular adhesion molecule 2 (ICAM-2) promoter, a synapsin (Syn) promoter, a methyl-CpG binding protein 2 (MeCP2) promoter, a Ca2+ / calmodulin-dependent protein kinase II (CaMKII) promoter, a metabotropic glutamate receptor 2 (mGluR2) promoter, a neurofilament light (NFL) or heavy (NFH) promoter, a ȕ-globin minigene nȕ2 promoter, a preproenkephalin (PPE) promoter, an enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, a glial fibrillary acidic protein (GFAP) promoter, a myelin basic protein (MBP) promoter, a cardiovascular promoter (e.g., ĮMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512), or a fragment, e.g., a truncation, or a functional variant thereof. 493. The AAV particle of embodiment 491 or embodiment 492, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 494. The AAV particle of any one of embodiments 482-493, wherein the viral genome further comprises an enhancer. 495. The AAV particle of embodiment 494, wherein the enhancer comprises a CMV immediate-early (CMVie) enhancer. 496. The AAV particle of embodiment 495, wherein the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 497. The AAV particle of any one of embodiments 482-496, wherein the viral genome further comprises an intron.498. The AAV particle of embodiment 497, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 499. The AAV particle of any one of embodiments 482-498, wherein the viral genome further comprises a polyadenylation (polyA) region. 500. The AAV particle of embodiment 499, wherein the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 501. The AAV particle of any one of embodiments 482-500, wherein the viral genome further comprises an inverted terminal repeat (ITR). 502. The AAV particle of embodiment 501, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830. 503. The AAV particle of embodiment 502, 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 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto, and the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical). 504. The AAV particle of any one of embodiments 482-503, wherein the viral genome further comprises one or more miR183 binding sites. 505. The AAV particle of any one of embodiments 482-504, wherein the viral genome comprises at least four miR183 binding sites. 506. The AAV particle of embodiment 505, wherein each of the at least four miR183 binding sites is separated by a spacer.507. The AAV particle of any one of embodiments 504-506, wherein each of the miR183 binding sites comprises the nucleotide sequence of SEQ ID NO: 1847 or a nucleotide sequence that has up to three modifications relative to SEQ ID NO: 1847. 508. The AAV particle of any one of embodiments 482-503, wherein the viral genome further comprises a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 509. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter; (iii) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (iv) a 3’ ITR. 510. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (v) a 3’ ITR. 511. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) an intron; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and(vi) a 3’ ITR. 512. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vi) a 3’ ITR. 513. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vii) a 3’ ITR.514. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5' inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto. 515. The AAV particle of embodiment 514, wherein: (i) the 5' ITR comprises the nucleotide sequence of SEQ ID NO: 1829; (ii) the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831; (iii) the CBA promoter comprises the nucleotide sequence of SEQ ID NO: 1834; (iv) the intron comprises the nucleotide sequence of SEQ ID NO: 1842; (v) the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846; and (viii) the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830. 516. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 517. The AAV particle of embodiment 516, wherein the viral genome comprises or consists of the nucleotide sequence of SEQ ID NO: 2006.518. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter; (iii) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) at least one miR183 binding site; and (v) a 3’ ITR. 519. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter; (iii) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) at least one miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (v) a 3’ ITR. 520. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) at least one miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vi) a 3’ ITR. 521. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer;(iii) a promoter; (iv) an intron; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) at least one miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vii) a 3’ ITR. 522. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) at least one miR183 binding site; and (vii) a 3’ ITR. 523. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto;(v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vii) a 3’ ITR. 524. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) at least one miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 1847; (vii) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto. 525. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto;(iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a GBA1-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vii) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., 95%, 96%, 97%, 98%, or 99% identical) thereto. 526. The AAV particle of embodiment 525, wherein: (i) the 5’ inverted terminal repeat (ITR) comprises the nucleotide sequence of SEQ ID NO: 1829; (ii) the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831; (iii) the CBA promoter comprises the nucleotide sequence of SEQ ID NO: 1834; (iv) the intron comprises the nucleotide sequence of SEQ ID NO: 1842; (v) the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001; (vi) the miR183 binding site series comprises the nucleotide sequence of SEQ ID NO: 1849; (vii) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846; and (viii) the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830. 527. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto. 528. The AAV particle of embodiment 527, wherein the viral genome consists of the nucleotide sequence of SEQ ID NO: 2007. 529. The AAV particle of any one of embodiments 482-528, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) present at positions 577-584 numbered according to SEQ ID NO: 982.530. The AAV particle of any one of embodiments 482-529, wherein the AAV capsid variant comprises a VP1 protein comprising an amino acid sequence at least 95% identical to SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at positions 577-584 numbered according to SEQ ID NO: 982. 531. The AAV particle of embodiment 530, wherein the AAV capsid variant further comprises (i) a VP2 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 738, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (ii) a VP3 protein comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 739, wherein the VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). 532. The AAV particle of any one of embodiments 482-531, wherein the AAV capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 982, wherein the VP1 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) a VP2 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 738, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to SEQ ID NO: 739, wherein the VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). 533. The AAV particle of any one of embodiments 482-532, wherein the AAV variant capsid comprises: (i) a VP1 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 982; (ii) a VP2 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 738; and / or (iii) a VP3 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 739. 534. A cell comprising the AAV particle of any one of embodiments 482-533, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell. In some embodiments, the cell is an isolated cell. 535. A method of making the AAV particle of any one of embodiments 482-533, the method comprising: (i) providing a cell comprising a viral genome comprising a GBA1-encoding sequence and a nucleic acid encoding an AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant;thereby making the AAV particle. 536. The method of embodiment 535, wherein the viral genome comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982. 537. The method of embodiment 535 or embodiment 536, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the cell. 538. The method of any one of embodiments 535-537, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell. 539. The method of any one of embodiments 535-538, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell. 540. A pharmaceutical composition comprising the AAV particle of any one of embodiments 482-533, and a pharmaceutically acceptable excipient. 541. A method of delivering a GBA1 protein to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533, thereby delivering the GBA1 protein. 542. The method of embodiment 541, wherein the subject has, has been diagnosed with having, or is at risk of having a GBA1-related disorder. 543. A method of treating a GBA1-related disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533, thereby treating the GBA1-related disorder. 544. The method of embodiment 543, wherein the subject has, has been diagnosed with having, or is at risk of having a GBA1-related disorder. 545. The method of any one of embodiments 542-544, wherein the GBA1-related disorder is a GBA1- related neurodegenerative or neuromuscular disorder.546. The method of any one of embodiments 542-545, wherein the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease 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), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome. 547. The method of any one of embodiments 542-546, wherein the GBA1-related disorder is PD. 548. The method of any one of embodiments 542-546, wherein the GBA-1 related disorder is LBD. 549. The method of any one of embodiments 542-546, wherein the GBA1-related disorder is GD. 550. A method of treating Parkinson’s Disease (PD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533, thereby treating the PD. 551. The method of embodiment 550, wherein the subject has, has been diagnosed with having, or is at risk of having PD. 552. A method of treating Lewy Body Dementia (LBD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533, thereby treating the LBD. 553. The method of embodiment 551, wherein the subject has, has been diagnosed with having, or is at risk of having LBD. 554. A method of treating Gaucher Disease (GD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533, thereby treating the GD. 555. The method of embodiment 554, wherein the subject has, has been diagnosed with having, or is at risk of having GD (e.g., GD1 or GD3). 556. The method of any one of embodiments 541-555, wherein the subject has one or more mutations in the GBA1 gene.557. The method of any one of embodiments 541-556, wherein, prior to the administration, the subject has lower GCase activity as compared to GCase activity in an individual who does not have a GBA1- related disorder, optionally wherein the level of GCase activity is measured by a 4-MUG assay or a SensoLyte Blue Glucocerebrosidase assay. 558. The method of any one of embodiments 541-557, wherein the administration results in prevention of progression of the disorder in the subject. 559. The method of any one of embodiments 541-558, wherein the administration results in amelioration of at least one symptom of the disorder in the subject. 560. The method of embodiment 559, wherein the amelioration of at least one symptom is as indicated by one or more biomarkers. 561. The method of embodiment 560, wherein the one or more biomarkers comprises a GCase activity, a level of glucocerebroside and other glycolipids, (e.g., within immune cells such as macrophages), a level of synuclein aggregates (e.g., Lewy bodies), or a combination thereof. 562. The method of any one of embodiments 559-561, wherein the at least one symptom comprises developmental delay, progressive encephalopathy, progressive dementia, ataxia, myoclonus, oculomotor dysfunction, bulbar palsy, generalized weakness, trembling of a limb, depression, visual hallucinations, cognitive decline, or a combination thereof. 563. The method of any one of embodiments 541-562, wherein the subject is a human subject. 564. The method of any one of embodiments 541-563, wherein the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the CNS. 565. The method of embodiment 564, wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum. 566. The method of any one of embodiments 541-565, wherein the AAV particle or the pharmaceutical composition is delivered to a peripheral cell or tissue.567. The method of embodiment 566, wherein the peripheral cell or tissue is a cell or tissue of the liver, heart, skeletal muscle, sympathetic ganglia, and / or plasma. 568. The method of any one of embodiments 541-567, further comprising evaluating, e.g., measuring, the level of GBA1 expression (e.g., GBA1 gene expression, GBA1 mRNA expression, and / or GBA1 protein expression) in the subject, e.g., in a cell, tissue, or fluid of the subject. 569. The method of embodiment 568, wherein the level of GBA1 protein expression is measured by an ELISA, a Western blot, or an immunohistochemistry assay. 570. The method of embodiment 568 or embodiment 569, wherein evaluating the subject’s level of GBA1 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of GBA1 expression prior to administration is compared to the subject’s level of GBA1 expression subsequent to administration. 571. The method of any one of embodiments 541-570, comprising evaluating the level of GBA1 expression in a cell or tissue of the central nervous system. 572. The method of any one of embodiments 541-571, wherein the subject’s level of GBA1 protein expression subsequent to administration is increased relative to the subject’s level of GBA1 protein expression prior to administration. 573. The method of any one of embodiments 541-572, further comprising evaluating, e.g., measuring, the level of GCase activity in the subject. 574. The method of any one of embodiments 541-573, wherein the administration results in an increase in: (i) GCase activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum), and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or relative to GCase activity in a cell, tissue, or fluid of an individual with a GBA1-related disorder, who has not been administered the pharmaceutical composition or AAV particle; (ii) the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje celllayer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or (iii) GBA1 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantial nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or relative to GBA1 mRNA expression in a cell or tissue of an individual with a GBA1- related disorder who has not been administered the pharmaceutical composition or AAV particle. 575. The method of any one of embodiments 541-574, further comprising administering to the subject at least one additional therapeutic agent and / or therapy. 576. The method of embodiment 575, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy for treating the GBA1-related disorder. 577. The method of embodiment 576, wherein the at least one additional therapeutic agent and / or therapy comprises enzyme replacement therapy (ERT) (e.g., imiglucerase, velaglucerase alfa, or taliglucerase alfa); substrate reduction therapy (SRT) (e.g., eliglustat or miglustat), levodopa, carbidopa, Safinamide, a dopamine agonist (e.g., pramipexole, rotigotine, or ropinirole), a dopamine antagonist (e.g., quetiapine, clozapine), an anticholinergic (e.g., benztropine or trihexyphenidyl), a cholinesterase inhibitor (e.g., rivastigmine, donepezil, or galantamine), an N-methyl-d-aspartate (NMDA) receptor antagonist (e.g., memantine), or a combination thereof. 578. The method of embodiment 576 or embodiment 577, wherein the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease 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), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome. 579. The method of any one of embodiments 576-578, wherein the GBA1-related disorder is PD, LBD, or GD. 580. The method of embodiment 575, wherein the at least one additional therapeutic agent and / or therapy comprises an immunosuppressant.581. The method of embodiment 580, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine. 582. The method of any one of embodiments 541-581, further comprising administering a blood transfusion to the subject. 583. The pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533 for use in a method of treating a disorder according to any one of embodiments 541-582. 584. The pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533, for use in the treatment of a GBA1-related disorder in a subject. 585. The pharmaceutical composition or AAV particle for use of embodiment 584, wherein the GBA1- related disorder is Parkinson’s Disease (PD), Parkinson’s Disease 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), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome. 586. The pharmaceutical composition or AAV particle for use of embodiment 584 or embodiment 585, wherein the GBA1-related disorder is PD. 587. The pharmaceutical composition or AAV particle for use of any one of embodiments 584-586, wherein the subject has, has been diagnosed with having, or is at risk of having PD. 588. The pharmaceutical composition or AAV particle for use of embodiment 584 or embodiment 585, wherein the GBA1-related disorder is LBD. 589. The pharmaceutical composition or AAV particle for use of any one of embodiments 584, 585, and 588, wherein the subject has, has been diagnosed with having, or is at risk of having LBD. 590. The pharmaceutical composition or AAV particle for use of embodiment 584 or embodiment 585, wherein the GBA1-related disorder is GD.591. The pharmaceutical composition or AAV particle for use of any one of embodiments 584, 585, and 590, wherein the subject has, has been diagnosed with having, or is at risk of having GD. 592. Use of the pharmaceutical composition of embodiment 540 or the AAV particle of any one of embodiments 482-533 in the manufacture of a medicament for the treatment of a GBA1-related disorder in a subject; optionally wherein the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease 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), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome. 593. The use of embodiment 592, wherein the GBA1-related disorder is PD. 594. The use of embodiment 592 or embodiment 593, wherein the subject has, has been diagnosed with having, or is at risk of having PD. 595. The use of embodiment 592, wherein the GBA1-related disorder is GD. 596. The use of embodiment 592 or embodiment 595, wherein the subject has, has been diagnosed with having, or is at risk of having GD. 597. The use of embodiment 592, wherein the GBA1-related disorder is LBD. 598. The use of embodiment 592 or embodiment 597, wherein the subject has, has been diagnosed with having, or is at risk of having LBD.

[0081] The details of various aspects or embodiments of the present disclosure are set forth below. Other features, objects, and advantages of the disclosure will be apparent from the description and the claims. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art in the field of this disclosure. In the case of conflict, the present description will control. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] FIGs.1A-1D show immunohistochemistry images from various CNS and peripheral tissues isolated from NHPs (cynomolgus macaques) at 28 days post intravenous administration of AAV particlescomprising the TTN-002 capsid variant (top panels) or AAV9 control capsid (bottom panels) and a self- complementary genome encoding a cynomolgus frataxin protein fused to an HA tag driven by a chicken beta actin (CBA) heterologous promoter. FIG.1A shows, from left to right, the cerebellum (Purkinje cell layer), spinal cord (cervical), cortex (temporal), and the brainstem. FIG.1B shows, from left to right, the globus pallidus, the hippocampus, the thalamus, the putamen, and the dentate. FIG.1C shows, from left to right, the whole brain (level H), the whole brain (level K), and the cerebellum. FIG.1D shows, from left to right, the spinal cord (thoracic), the DRG (thoracic), the liver, and the heart.

[0083] FIG.2 depicts the biodistribution (VG / cell) in the cortex, striatum, and brainstem of wild- type mice at 28 days post-IV injection of VOY101.GBA_VG17 (SEQ ID NO: 1812), VOY101.GBA_VG35 (SEQ ID NO: 2006) or VOY101.GBA_VG36 (SEQ ID NO: 2007).

[0084] FIG.3 depicts the GCase activity in the cortex, striatum, and brainstem of wild-type mice at 28 days post-IV injection of VOY101.GBA_VG17 (SEQ ID NO: 1812), VOY101.GBA_VG35 (SEQ ID NO: 2006) or VOY101.GBA_VG36 (SEQ ID NO: 2007).

[0085] FIG.4 depicts the biodistribution, mRNA expression, and Gcase activities in the brainstem and DRGs of wild-type mice at 28 days post-IV injection of VOY101.GBA_VG17 (SEQ ID NO: 1812), VOY101.GBA_VG35 (SEQ ID NO: 2006) or VOY101.GBA_VG36 (SEQ ID NO: 2007).

[0086] FIG.5 depicts the substrate quantification of glucosylceramide and glucosylsphingosine by LC-MS / MS in the brainstem, striatum, and DRGs of wild-type mice at 28 days post-IV injection of VOY101.GBA_VG17 (SEQ ID NO: 1812), VOY101.GBA_VG35 (SEQ ID NO: 2006) or VOY101.GBA_VG36 (SEQ ID NO: 2007).

[0087] FIG.6 depicts biodistribution (VG / cell) in the cortex and GCase activities in the cortex, striatum, and brainstem of wild-type mice at 28 days post-IV injection of VOY101.GBA_VG17 (SEQ ID NO: 1812) or VOY101.GBA_VG17-HA.

[0088] FIG.7A depicts immunohistochemical analysis of HA expression in the cortex, striatum, and brainstem of wild-type mice at 28 days post-IV injection of VOY101.GBA_VG17 (SEQ ID NO: 1812) or VOY101.GBA_VG17-HA. FIG.7B depicts immunohistochemical analysis of HA expression in the cerebellum, thalamus, and hippocampus of wild-type mice at 28 days post-IV injection of VOY101.GBA_VG17 (SEQ ID NO: 1812) or VOY101.GBA_VG17-HA. DETAILED DESCRIPTION Overview

[0089] Described herein, inter alia, are compositions comprising an AAV capsid variant for delivery of a sequence encoding GBA1 protein, e.g., a wildtype GBA1 protein, e.g., a wildtype human GBA1 protein. In some embodiments, the present disclosure provides a method for delivering the AAV capsid variant comprising the sequence encoding the GBA1 protein to a cell or tissue in a subject. In some embodiments, the present disclosure provides a method for delivering the AAV capsid variant, thereby providing a GBA1 protein, e.g., wildtype GBA1 protein, e.g., a wildtype human GBA1 protein, to a cellor tissue in a subject. The AAV capsid variants described herein have enhanced CNS tropism compared to other cells or tissues in the body, e.g., liver and / or the DRG.

[0090] AAVs have proven to be useful as a biological tool due to their relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. Engineered adeno-associated virus (AAV) capsids with improved brain tropism represent an attractive solution to the limitations of CNS delivery. AAV-derived vectors are promising tools for clinical gene transfer because of their non-pathogenic nature, their low immunogenic profile, low rate of integration into the host genome, and long-term transgene expression in non-dividing cells. However, the transduction efficiency of naturally occurring AAVs in certain organs is too low for clinical applications, and capsid neutralization by pre-existing neutralizing antibodies may prevent treatment of a large proportion of patients. For these reasons, considerable efforts have been devoted to obtaining capsid variants with enhanced properties. Of many approaches tested so far, significant advances have resulted from directed evolution of AAV capsids using in vitro or in vivo selection of capsid variants created by capsid sequence randomization using either error-prone PCR, shuffling of various parent serotypes, or insertion of fully randomized short peptides at defined positions.

[0091] The genome of the virus may be modified to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload. The genome of the virus may encode a GBA1 protein, and the viral particle comprising said genome may be delivered to a target cell, tissue, or organism. In some embodiments, the genome encodes a human GBA1 protein, e.g., a wildtype human GBA1 protein. In some embodiments, the target cell is a CNS cell. In some embodiments, the target tissue is a CNS tissue. In some embodiments, the target CNS tissue is brain tissue.

[0092] In some embodiments, the genome encodes a wildtype GBA1 protein. In some embodiments, the genome comprises a codon-optimized, CpG-reduced (e.g., CpG-depleted) nucleotide sequence encoding a wildtype GBA1 protein, e.g., as compared to a wildtype GBA1 encoding sequence (e.g., comprising the nucleotide sequence of SEQ ID NO: 1776 or 1777). In some embodiments, the target cell is a CNS cell. In some embodiments, the target tissue is a CNS tissue. The target CNS tissue may be brain tissue. In some embodiments, the CNS tissue comprises spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and cerebellum, or a combination thereof.

[0093] Gene therapy presents an alternative approach for treating a GBA1-related disorder, e.g., Parkinson’s Disease (PD) or Gaucher Disease (GD). AAVs are commonly used in gene therapy approaches as a result of a number of advantageous features. Without wishing to be bound by theory, it is believed in some embodiments, an AAV particle described herein can be used to administer and / ordeliver a gene encoding GBA1 (e.g., a human GBA1 protein) preferentially to the CNS (e.g., the brain or the spinal cord).

[0094] Provided herein are compositions and methods which may provide for improved features compared to prior AAV-mediated enzyme replacement approaches, including (i) increased biodistribution throughout the CNS (e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum), (ii) elevated GBA1 expression in multiple brain regions (e.g., cortex, thalamus, and brain stem); and (iii) preferential biodistribution in the CNS over the liver and / or DRG, of the subject. In some embodiments, an AAV viral genome comprising a codon-optimized, CpG-reduced (e.g., CpG-depleted) nucleotide sequence encoding a GBA1 protein (e.g., SEQ ID NO: 2001 or SEQ ID NO: 2002) results in high biodistribution in the CNS; increased GCase activity in the CNS, peripheral tissues, and / or fluid; and successful transgene transcription and expression.

[0095] Also provided herein are AAV capsid variants (e.g., AAV5 capsid variants) with improved properties compared to wildtype AAV5 and / or wildtype AAV9, such as (i) increased penetrance through the blood brain barrier following intravenous administration, (ii) wider distribution throughout the multiple brain regions, e.g., visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum, (iii) elevated GBA1 expression in multiple brain regions, (iv) wider distribution in one or more peripheral tissues, e.g., the heart, muscle, and / or liver, and / or (v) elevated GBA1 expression in one or more peripheral tissues. In some embodiments, the AAV capsids described herein enhance the delivery of GBA1 to multiple regions of the brain including, for example, the visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum. In some embodiments, the AAV capsids described herein enhance the delivery of GBA1 to the spinal cord. In some embodiments, the AAV capsid variants with enhanced brain tropism described herein are capable of significantly increasing GBA1 mRNA expression in the brain.

[0096] Thus, the compositions and methods described herein can be used in the treatment of GBA1- related disorders. In some embodiments, GBA1-related disorders are disorders associated with a lack of GBA1 protein expression and / or GCase activity and include neuronopathic (affects the CNS) and non- neuronopathic (affects non-CNS) Gaucher disease (e.g., Type 1 GD (GD1), Type 2 GD (GD2), or Type 3 GD (GD3)), PD associated with at least one mutation in a GBA gene, Parkinson’s disease dementia (PDD), Dementia with Lewy Bodies (DLB), and Lewy Body Dementia (LBD). In some embodiments, the disclosure provides an AAV particle comprising one of the AAV capsid variants disclosed herein and an AAV viral genome comprising a codon-optimized, CpG-reduced (e.g., CpG-depleted) nucleotide sequence encoding a GBA1 protein (e.g., comprising the nucleotide sequence of SEQ ID NO: 2001 orSEQ ID NO: 2002 or a nucleotide sequence that is at least 90% identical to SEQ ID NO: 2001 or SEQ ID NO: 2002). In some embodiments, the codon-optimized, CpG-reduced e.g., CpG-depleted) nucleotide sequence has reduced immunogenicity compared to a codon-optimized sequence comprising one or more or all CpG motifs. In some embodiments, the codon-optimized, CpG-reduced e.g., CpG-depleted) nucleotide sequence is suitable for use in treating disorders associated with a lack of a GBA1 protein expression and / or GCase activity, such as neuronopathic (affects the CNS) and non-neuronopathic (affects non-CNS), Gaucher disease (e.g., GD1, GD2, or GD3), PD associated with at least one mutation in a GBA gene, Parkinson’s disease dementia (PDD), Dementia with Lewy Bodies (DLB), and Lewy Body Dementia (LBD). I. Compositions Adeno-associated viral (AAV) vectors

[0097] AAVs have a genome of about 5,000 nucleotides in length and contains two open reading frames encoding the proteins responsible for replication (Rep) and the structural protein of the capsid (Cap). The open reading frames are flanked by two Inverted Terminal Repeat (ITR) sequences, which serve as the origin of replication of the viral genome. The wild-type AAV viral genome comprises nucleotide sequences for two open reading frames, one for the four non-structural Rep proteins (Rep78, Rep68, Rep52, Rep40, encoded by Rep genes) and one for the three capsid, or structural, proteins (VP1, VP2, VP3, encoded by capsid genes or Cap genes). The Rep proteins are important for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid. Alternative splicing and alternate initiation codons and promoters result in the generation of four different Rep proteins from a single open reading frame and the generation of three capsid proteins from a single open reading frame. Though it varies by AAV serotype, as a non-limiting example, for AAV5 (SEQ ID NO: 138 and 137) VP1 refers to amino acids 1-724, VP2 refers to amino acids 137-724, and VP3 refers to amino acids 193-724. In some embodiments, e.g., for the amino acid sequence of SEQ ID NO: 982, VP1 comprises amino acids 1-731, VP2 comprises amino acids 137-731, and VP3 comprises amino acids 193-731. In other words, VP1 is the full-length capsid protein sequence, while VP2 and VP3 are shorter components of the whole. As a result, changes in the sequence in the VP3 region, are also changes to VP1 and VP2, however, the percent difference as compared to the parent sequence will be greatest for VP3 since it is the shortest sequence of the three. Though described here in relation to the amino acid sequence, the nucleic acid sequence encoding these proteins can be similarly described. Together, the three capsid proteins assemble to create the AAV capsid protein. While not wishing to be bound by theory, the AAV capsid protein typically comprises a molar ratio of 1:1:10 of VP1:VP2:VP3.

[0098] The AAV particle typically requires a co-helper (e.g., adenovirus) to undergo productive infection in cells. In the absence of such helper functions, the AAV virions essentially enter host cells but do not integrate into the cells’ genome.

[0099] AAV particles have been investigated for delivery of gene therapeutics because of several unique features. Non-limiting examples of the features include (i) the ability to infect both dividing andnon-dividing cells; (ii) a broad host range for infectivity, including human cells; (iii) wild-type AAV has not been associated with any disease and has not been shown to replicate in infected cells; (iv) the lack of cell-mediated immune response against the vector, and (v) the non-integrative nature in a host chromosome thereby reducing potential for long-term genetic alterations. Moreover, infection with AAV particles has minimal influence on changing the pattern of cellular gene expression (Stilwell and Samulski et al., Biotechniques, 2003, 34, 148, the contents of which are herein incorporated by reference in their entirety).

[0100] Typically, AAV particles for GBA1 delivery may be recombinant viral vectors which are replication defective as they lack sequences encoding functional Rep and Cap proteins within the viral genome. In some cases, the replication defective AAV particles may lack most or all coding sequences and essentially only contain one or two AAV ITR sequences and a nucleic acid sequence encoding a GBA1 protein (e.g., a human GBA1 protein).

[0101] In some embodiments, the AAV particles of the present disclosure may be introduced into mammalian cells.

[0102] AAV particles may be modified to enhance the efficiency of delivery. Such modified AAV particles of the present disclosure can be packaged efficiently and can be used to successfully infect the target cells at high frequency and with minimal toxicity.

[0103] In other embodiments, AAV particles of the present disclosure may be used to deliver GBA1 to the CNS (see, e.g., U.S. Pat. No.6,180,613; the contents of which are herein incorporated by reference in their entirety) or to specific tissues of the CNS.

[0104] It is understood that the compositions described herein may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0105] In some embodiments, AAV capsid variants disclosed herein comprise one or more modifications (e.g., one or more substitutions) in the loop VIII region of AAV5. In some embodiments, the AAV5 loop VIII region comprises amino acid positions 571-579, e.g., position 577, numbered relative to SEQ ID NO: 138. In some embodiments, the AAV5 loop VIII region (e.g., positions 571-579, e.g., position 577) protrudes above the 3-fold axis of symmetry, e.g., is a surface-exposed location in the AAV5 capsid, e.g., as described in Govindasamy et al. “Structural Insights into Adeno-Associated Virus Serotype 5,” Journal of Virology, 2013, 87(20):11187-11199 (the contents of which are hereby incorporated by reference in their entirety). In some embodiments, the term "loop" (e.g., as used in loop VIII) is used interchangeably herein with the term "variable region" (e.g., variable region VIII), or "VR" (e.g., VR-VIII). In some embodiments, loop VIII (e.g., VR-VIII) comprises positions 571-599 (e.g., amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)), numbered according to SEQ ID NO: 982. In some embodiments, loop VIII or variable region VIII (VR-VIII) is as described in Govindasamy et al. (supra) (the contents of which are hereby incorporated by reference in their entirety).

[0106] The AAV particles and payloads of the disclosure may be delivered to one or more target cells, tissues, organs, or organisms. In some embodiments, the AAV particles of the disclosuredemonstrate enhanced tropism for a target cell type, tissue, or organ. As a non-limiting example, the AAV particle may have enhanced tropism for cells and tissues of the central or peripheral nervous systems (CNS and PNS, respectively). In some embodiments, an AAV particle of the disclosure may, in addition, or alternatively, have decreased tropism for a cell-type, tissue or organ.

[0107] In some embodiments, AAV are used as a biological tool due to a relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. The genome of the virus may be manipulated to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload.

[0108] In some embodiments, the AAV is a recombinant AAV. In some embodiments, the wild-type AAV vector genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length. In some embodiments, inverted terminal repeats (ITRs) cap the viral genome at both the 5’ and the 3’ end, providing origins of replication for the viral genome. In some embodiments, an AAV viral genome comprises two ITR sequences. In some embodiments, the ITRs have a characteristic T-shaped hairpin structure defined by a self-complementary region (145nt in wild-type AAV) at the 5’ and 3’ ends of the ssDNA which form an energetically stable double stranded region. In some embodiments, the double stranded hairpin structures comprise multiple functions including, but not limited to, acting as an origin for DNA replication by functioning as primers for the endogenous DNA polymerase complex of the host viral replication cell.

[0109] AAV vectors of the present disclosure may be produced recombinantly and may be based on adeno-associated virus (AAV) reference sequences. In some embodiments, the present disclosure provides for an AAV particle comprising a single-stranded viral genome (ssAAV). In addition to single stranded AAV viral genomes (e.g., ssAAVs), the present disclosure also provides for an AAV particle comprising a self-complementary viral genome (scAAV).

[0110] In some embodiments, a self-complementary viral genome (scAAV) may contain one or more DNA strands which anneal together to form double stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the transduced cell. In some embodiments, the AAV particle of the present disclosure is an scAAV.

[0111] Methods for producing and / or modifying AAV particles are disclosed in the art such as pseudotyped AAV vectors (PCT Patent Publication Nos. WO200028004; WO200123001; WO2004112727; WO2005005610; and WO2005072364, the content of each of which is incorporated herein by reference in its entirety).

[0112] As described herein, the AAV particles of the disclosure comprising an AAV capsid variant, and a viral genome, have enhanced tropism for a cell-type or a tissue, e.g., a CNS cell-type, region, or tissue.Capsid Peptides

[0113] Disclosed herein are AAV particles comprising an AAV capsid variant comprising a peptide (e.g., inserted into a wildtype AAV capsid and / or in substitution of an amino acid or peptide in a wildtype AAV capsid) for enhanced or improved transduction of a target tissue (e.g., cells of the CNS or PNS). In some embodiments, the nucleic acid encoding the peptide is an isolatednucleic acid.

[0114] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of the CNS. The cell of the CNS may be, but is not limited to, neurons (e.g., excitatory, inhibitory, motor, sensory, autonomic, sympathetic, parasympathetic, Purkinje, Betz, etc.), glial cells (e.g., microglia, astrocytes, oligodendrocytes) and / or supporting cells of the brain such as immune cells (e.g., T cells). The tissue of the CNS may be, but is not limited to, the cortex (e.g., frontal, parietal, occipital, temporal), thalamus, hypothalamus, striatum, putamen, caudate nucleus, hippocampus, entorhinal cortex, basal ganglia, or deep cerebellar nuclei. In some embodiments, the tissue of the CNS is a visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, cerebellum, cervical spinal cord, thoracic spinal cord, or lumbar spinal cord.

[0115] In some embodiments, the peptide may modulate distribution of an AAV particle to a cell, region, or tissue of the CNS. In some embodiments, the peptide may decrease distribution of an AAV particle to the DRG.

[0116] In some embodiments, the peptide may increase distribution of an AAV particle to the CNS (e.g., the cortex) after intravenous administration. In some embodiments, the peptide may increase distribution of an AAV particle to the CNS (e.g., the cortex) following focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0117] In some embodiments, the peptide may modulate distribution of an AAV particle to the PNS (e.g., DRG) after intravenous administration. In some embodiments, the peptide may increase distribution of an AAV particle to non-DRG cells of the PNS following focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration. In some embodiments, the peptide may decrease distribution of an AAV particle to the DRG following focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.

[0118] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of a heart, e.g., a heart atrium or a heart ventricle. In some embodiments, the peptide may increase distribution of an AAV particle to a heart cell, region, or tissue after intravenous administration.

[0119] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of a muscle. In some embodiments, the muscle is a heart muscle (e.g., a heart atrium or aheart ventricle) or a quadriceps. In some embodiments, the peptide may increase distribution of an AAV particle to a muscle cell, region, or tissue after intravenous administration.

[0120] In some embodiments, a peptide may comprise a sequence as set forth in Table 1 (e.g., comprising the amino acid sequence of any of SEQ ID NOs: 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590-1593, 1598-1624, or 2064-2079). In some embodiments, a peptide may comprise a sequence as set forth in Table 2A or 2B. In some embodiments, the peptide may comprise a sequence set forth in Table 14 or 20-25. Table 1. Exemplary Peptide SequencesTable 2A. Exemplary Peptide SequencesTable 2B. Exemplary Peptide Sequences

[0121] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5and [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, position X1of [N2] is Y, N, C, or T. In some embodiments, position X2of [N2] is P, E, K, T, or Q. In some embodiments, position X3of [N2] is A or P. In some embodiments, position X4of [N2] is E, S, D, or A. In some embodiments, position X5 of [N2] is V, L, or E. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X5. In some embodiments, the amino acid sequence of [N3] comprises VQK. In some embodiments, the amino acid sequence of [N3] consists of VQK.

[0122] In some embodiments, a peptide described herein comprises an amino acid sequence having the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5and [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, [N3] comprises the amino acid sequence of VQK, EQK, or VKK. In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, [N3] consists of the amino acid sequence VQK. In some embodiments, position X1of [N2] is Y, N, or C. In some embodiments, position X1of [N2] is Y or N. In some embodiments, position X2of [N2] is P, K, T, or Q. In some embodiments, position X2of [N2] is P, T, or Q. In some embodiments, position X3of [N2] is A or P. In some embodiments, position X3of [N2] is A. In some embodiments, position X4of [N2] is E, S, or A. In some embodiments, position X5of [N2] is V, L, or E. In some embodiments, position X5of [N2] is V or L. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X5. In some embodiments, [N2] comprises YPA, YPP, NKA, YTA, YQA, YTP, NPA, CPA, THA, PAE, PPS, KAE, TAE, QAE, TPS, PAA, HAS, AEV, PSL, AEE, or AAV. In some embodiments, [N2] comprises YPAE (SEQ ID NO: 21), YPPS (SEQ ID NO: 22), NKAE (SEQ ID NO: 23), YTAE (SEQ ID NO: 24), YQAE (SEQ ID NO: 25), YTPS (SEQ ID NO: 26), YPAA (SEQ ID NO: 27), NPAE (SEQ ID NO: 28), CPAE (SEQ ID NO: 29), THAS (SEQ ID NO: 30), PAEV (SEQ ID NO: 17), PPSL (SEQ ID NO: 31), KAEV (SEQ ID NO: 32), TAEV (SEQ ID NO: 16), PAEE (SEQ ID NO: 18), QAEV (SEQ ID NO: 15), TPSL (SEQ ID NO: 33), PAAV (SEQ ID NO: 34), or QAEE (SEQ ID NO: 35). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11). In some embodiments, [N2] comprises the amino acid sequence of YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises the amino acidsequence of AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46). In some embodiments, [N2]-[N3] comprises the amino acid sequence PAEVVQK (SEQ ID NO: 20), PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48), TAEVVQK (SEQ ID NO: 49), PAEVEQK (SEQ ID NO: 50), PAEEVQK (SEQ ID NO: 51), QAEVVQK (SEQ ID NO: 52), TPSLVQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61), or QAEEVQK (SEQ ID NO: 62). In some embodiments, [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943), YPPSLVQK (SEQ ID NO: 946), NKAEVVQK (SEQ ID NO: 947), YTAEVVQK (SEQ ID NO: 948), YPAEVEQK (SEQ ID NO: 949), YPAEEVQK (SEQ ID NO: 950), YQAEVVQK (SEQ ID NO: 951), YTPSLVQK (SEQ ID NO: 952), YPPSLEQK (SEQ ID NO: 953), YPPSLVKK (SEQ ID NO: 954), YPAEVVKK (SEQ ID NO: 955), YPAEVVHK (SEQ ID NO: 956), YPAAVVQK (SEQ ID NO: 957), NPAEVVQK (SEQ ID NO: 958), YPAEVVQQ (SEQ ID NO: 959), CPAEVVQK (SEQ ID NO: 960), YTAEVVKK (SEQ ID NO: 961), YPAEVLQK (SEQ ID NO: 962), or YQAEEVQK (SEQ ID NO: 963); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943). In some embodiments, [N2]-[N3] comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0123] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [N2]-[N3], further comprises [N1], which comprises positions XD, XE, and XF. In some embodiments, position XDof [N1] is Q, T, S, A, I, L, or H. In some embodiments, position XEof [N1] is S, G, A, or R. In some embodiments, position XFof [N1] is S, K, L, R, A, or T. In some embodiments, [N1] comprises SK, SL, SS, SR, GA, GS, AS, ST, RS, QS, TS, AG, IG, QA, LG, HS, LS, or QR. In some embodiments, [N1] is or comprises QSS, QSK, TSL, SSS, QSR, AGA, IGS, QAS, ASS, LGS, QST, HSS, LSS, or QRS. In some embodiments, the amino acid sequence of [N1] is QSS. In some embodiments, [N1]-[N2] comprises SSYPA (SEQ ID NO: 63), SKYPA (SEQ ID NO: 64), SLYPA (SEQ ID NO: 65), SRYPA (SEQ ID NO: 66), SSYPP (SEQ ID NO: 67), GAYPA (SEQ ID NO: 68), GSYPA (SEQ ID NO: 69), ASYPA (SEQ ID NO: 70), STNKA (SEQ ID NO: 71), SSYTA (SEQ ID NO: 72), SSYQA (SEQ ID NO: 73), SSYTP (SEQ ID NO: 74), SSNPA (SEQ ID NO: 75), SLCPA (SEQ ID NO: 76), RSYTA (SEQ ID NO: 77), or SSTHA (SEQ ID NO: 78). In some embodiments, [N1]-[N2] comprises SSYPAE (SEQ ID NO: 79), SKYPAE (SEQ ID NO: 80), SLYPAE (SEQ ID NO: 81),SRYPAE (SEQ ID NO: 82), SSYPPS (SEQ ID NO: 83), GAYPAE (SEQ ID NO: 84), GSYPAE (SEQ ID NO: 85), ASYPAE (SEQ ID NO: 86), STNKAE (SEQ ID NO: 87), SSYTAE (SEQ ID NO: 88), SSYQAE (SEQ ID NO: 89), SSYTPS (SEQ ID NO: 90), SSYPAA (SEQ ID NO: 91), SSNPAE (SEQ ID NO: 92), SLCPAE (SEQ ID NO: 93), RSYTAE (SEQ ID NO: 94), SSTHAS (SEQ ID NO: 95). In some embodiments, [N1]-[N2] is or comprises QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), HSSYPAAV (SEQ ID NO: 115), QSSNPAEV (SEQ ID NO: 116), QSSYTAEV (SEQ ID NO: 117), TSLCPAEV (SEQ ID NO: 118), QRSYTAEV (SEQ ID NO: 119), or QSSYQAEE (SEQ ID NO: 120); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [N1]-[N2] is QSSYPAEV (SEQ ID NO: 96). In some embodiments, [N1]-[N2]-[N3] comprises SSYPAEVVQ (SEQ ID NO: 121), SKYPAEVVQ (SEQ ID NO: 122), SLYPAEVVQ (SEQ ID NO: 123), SRYPAEVVQ (SEQ ID NO: 124), SSYPPSLVQ (SEQ ID NO: 125), GAYPAEVVQ (SEQ ID NO: 126), GSYPAEVVQ (SEQ ID NO: 127), ASYPAEVVQ (SEQ ID NO: 128), STNKAEVVQ (SEQ ID NO: 129), SSYTAEVVQ (SEQ ID NO: 130), SKYPAEVEQ (SEQ ID NO: 131), SLYPAEEVQ (SEQ ID NO: 132), SSYQAEVVQ (SEQ ID NO: 133), SSYTPSLVQ (SEQ ID NO: 134), SRYPAEEVQ (SEQ ID NO: 135), SSYPPSLEQ (SEQ ID NO: 136), SSYPPSLVK (SEQ ID NO: 140), SSYPAEVVK (SEQ ID NO: 141), SKYPAEVVH (SEQ ID NO: 142), SSYPAAVVQ (SEQ ID NO: 143), SSNPAEVVQ (SEQ ID NO: 144), SLCPAEVVQ (SEQ ID NO: 145), RSYTAEVVQ (SEQ ID NO: 146), SSYTAEVVK (SEQ ID NO: 147), SSYPAEVLQ (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149). In some embodiments, [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ IDNO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, the amino acid sequence of [N1]-[N2]-[N3] is QSSYPAEVVQK (SEQ ID NO: 150).

[0124] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N0], wherein [N0] comprises positions XA, XB, and XC. In some embodiments, position XAof [N0] is T, I, or N. In some embodiments, positions XBof [N0] is N. In some embodiments, position XCof [N0] is N, T, S, or K. In some embodiments, [N0] comprises TN, IN, NN, NT, NS, or NK. In some embodiments, [N0] is or comprises TNN, TNT, INN, TNS, NNN, or TNK. In some embodiments, the amino acid sequence of [N0] is TNN. In some embodiments, [N0]-[N1] is or comprises TNNQSS (SEQ ID NO: 183), TNNQSK (SEQ ID NO: 184), TNNTSL (SEQ ID NO: 185), TNNSSS (SEQ ID NO: 186), TNNQSR (SEQ ID NO: 187), TNNAGA (SEQ ID NO: 188), TNNIGS (SEQ ID NO: 189), TNNQAS (SEQ ID NO: 190), TNTASS (SEQ ID NO: 191), TNNLGS (SEQ ID NO: 192), TNNQST (SEQ ID NO: 193), TNNHSS (SEQ ID NO: 194), TNNQSK (SEQ ID NO: 184), TNNLSS (SEQ ID NO: 195), INNQSS (SEQ ID NO: 196), TNSQSS (SEQ ID NO: 197), NNNQSR (SEQ ID NO: 198), TNSTSL (SEQ ID NO: 199), TNNQRS (SEQ ID NO: 200), or TNKQAS (SEQ ID NO: 201); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1] is TNNQSS (SEQ ID NO: 183). In some embodiments, [N0]-[N1]-[N2]-[N3] is or comprises TNNQSSYPAEVVQK (SEQ ID NO: 500), TNNQSKYPAEVVQK (SEQ ID NO: 503), TNNTSLYPAEVVQK (SEQ ID NO: 506), TNNSSSYPAEVVQK (SEQ ID NO: 508), TNNQSRYPAEVVQK (SEQ ID NO: 510), TNNQSSYPPSLVQK (SEQ ID NO: 512), TNNAGAYPAEVVQK (SEQ ID NO: 513), TNNIGSYPAEVVQK (SEQ ID NO: 514), TNNQASYPAEVVQK (SEQ ID NO: 517), TNTASSYPAEVVQK (SEQ ID NO: 520), TNNLGSYPAEVVQK (SEQ ID NO: 523), TNNQSTNKAEVVQK (SEQ ID NO: 524), TNNHSSYPAEVVQK (SEQ ID NO: 525),TNNSSSYTAEVVQK (SEQ ID NO: 526), TNNQSKYPAEVEQK (SEQ ID NO: 529), TNNTSLYPAEEVQK (SEQ ID NO: 530), TNTASSYQAEVVQK (SEQ ID NO: 531), TNNQSSYTPSLVQK (SEQ ID NO: 533), TNNQSRYPAEEVQK (SEQ ID NO: 534), TNNQSSYPPSLEQK (SEQ ID NO: 535), TNNQSSYPPSLVKK (SEQ ID NO: 536), TNNLSSYQAEVVQK (SEQ ID NO: 539), TNNSSSYPAEVVKK (SEQ ID NO: 540), TNNQSKYPAEVVHK (SEQ ID NO: 542), INNQSSYPAEVVQK (SEQ ID NO: 543), TNNHSSYPAAVVQK (SEQ ID NO: 545), TNSQSSNPAEVVQK (SEQ ID NO: 548), TNNSSSYPAEVVQQ (SEQ ID NO: 551), NNNQSRYPAEVVQK (SEQ ID NO: 552), TNNQSSYTAEVVQK (SEQ ID NO: 553), TNNTSLCPAEVVQK (SEQ ID NO: 554), TNSTSLYPAEVVQK (SEQ ID NO: 556), TNNQRSYTAEVVQK (SEQ ID NO: 557), TNNQSSYTAEVVKK (SEQ ID NO: 558), TNNHSSYPAEVLQK (SEQ ID NO: 560), TNNQSSYQAEEVQK (SEQ ID NO: 562) or TNKQASYPAEVVQK (SEQ ID NO: 563); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3] is TNNQSSYPAEVVQK (SEQ ID NO: 500).

[0125] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3], further comprises [N4], which comprises positions XGand XH. In some embodiments, position XGof [N4] is T, P, or N. In some embodiments, position XGof [N4] is T. In some embodiments, position XHof [N4] is A. In some embodiments, [N4] is or comprises TA, PA, or NA. In some embodiments, [N4] is TA. In some embodiments, [N3]-[N4] is or comprises VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566), VQKPA (SEQ ID NO: 567), VHKTA (SEQ ID NO: 568), VQQTA (SEQ ID NO: 569), VQKNA (SEQ ID NO: 570), or LQKTA (SEQ ID NO: 571); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N3]-[N4] is VQKTA (SEQ ID NO: 564). In some embodiments, [N0]-[N1]-[N2]-[N3]-[N4] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNSSSYPAEVVQKTA (SEQ ID NO: 1539), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), TNNQSSYPPSLVQKTA (SEQ ID NO: 1300), TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNIGSYPAEVVQKTA (SEQ ID NO: 1112),TNNQASYPAEVVQKTA (SEQ ID NO: 1194), TNTASSYPAEVVQKTA (SEQ ID NO: 1575), TNNLGSYPAEVVQKTA (SEQ ID NO: 1027), TNNQSTNKAEVVQKTA (SEQ ID NO: 1578), TNNHSSYPAEVVQKTA (SEQ ID NO: 1310), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNSSSYTAEVVQKTA (SEQ ID NO: 1214), TNNQSKYPAEVEQKTA (SEQ ID NO: 1254), TNNTSLYPAEEVQKTA (SEQ ID NO: 1583), TNTASSYQAEVVQKTA (SEQ ID NO: 1584), TNNQSSYTPSLVQKTA (SEQ ID NO: 1585), TNNQSRYPAEEVQKTA (SEQ ID NO: 1342), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), TNNLSSYQAEVVQKTA (SEQ ID NO: 1592), TNNQSSYPPSLVQKPA (SEQ ID NO: 1593), TNNSSSYPAEVVKKTA (SEQ ID NO: 1331), TNNQSKYPAEVVHKTA (SEQ ID NO: 1453), TNNSSSYPAEVVQKPA (SEQ ID NO: 1142), INNQSSYPAEVVQKTA (SEQ ID NO: 1024), TNNHSSYPAAVVQKTA (SEQ ID NO: 1598), TNSQSSNPAEVVQKTA (SEQ ID NO: 1599), TNNSSSYPAEVVQQTA (SEQ ID NO: 1419), NNNQSRYPAEVVQKTA (SEQ ID NO: 1601), TNNQSSYTAEVVQKNA (SEQ ID NO: 1602), TNNTSLCPAEVVQKTA (SEQ ID NO: 1603), TNSTSLYPAEVVQKTA (SEQ ID NO: 1605), TNNQRSYTAEVVQKTA (SEQ ID NO: 1604), TNNQSSYTAEVVKKTA (SEQ ID NO: 1606), TNNHSSYPAEVLQKTA (SEQ ID NO: 1607), TNNQSSYQAEEVQKTA (SEQ ID NO: 1608), or TNKQASYPAEVVQKTA (SEQ ID NO: 1587); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N0]-[N1]-[N2]-[N3]- [N4] is TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

[0126] In some embodiments, a peptide described herein comprises the formula [N2]-[N3], wherein [N2] comprises positions X1, X2, X3, X4, and X5and [N3] comprises the amino acid sequence of VQK or VQN. In some embodiments, [N3] comprises the amino acid sequence VQK. In some embodiments, position X1of [N2] is Y or T. In some embodiments, position X2of [N2] is Q, T, P, or E. In some embodiments, position X3of [N2] is A. In some embodiments, position X4of [N2] is E or D. In some embodiments, position X4of [N2] is E or D. In some embodiments, position X5of [N2] is V or E. In some embodiments, [N2] comprises Y at position X1. In some embodiments, [N2] comprises P at position X2. In some embodiments, [N2] comprises A at position X3. In some embodiments, [N2] comprises E at position X4. In some embodiments, [N2] comprises V at position X5.In some embodiments, [N2] comprises YP, YQ, YT, TE, QA, TA, PA, EA, EV, EE, DV, AE, or AD. In some embodiments, [N2] comprises YPA, YQA, YTA, TEA, QAE, TAE, PAE, EAE, PAD, AEV, AEE, or ADV. In some embodiments, [N2] comprises YPAE (SEQ ID NO: 21), YQAE (SEQ ID NO: 25), YTAE (SEQ ID NO: 24), TEAE (SEQ ID NO: 587), YPAD (SEQ ID NO: 588), QAEV (SEQ ID NO: 15), TAEV (SEQ ID NO: 16), PAEV (SEQ ID NO: 17), PAEE (SEQ ID NO: 18), EAEV (SEQ ID NO: 590),or PADV (SEQ ID NO: 19). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YQAEV (SEQ ID NO: 6), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), TEAEV (SEQ ID NO: 12), or YPADV (SEQ ID NO: 13). In some embodiments, [N2] is YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises AEVVQK (SEQ ID NO: 36), AEEVQK (SEQ ID NO: 39), AEVVQN (SEQ ID NO: 591), or ADVVQK (SEQ ID NO: 593). In some embodiments, [N2]-[N3] comprises PAEVVQN (SEQ ID NO: 594), QAEVVQK (SEQ ID NO: 52), TAEVVQK (SEQ ID NO: 49), PAEVVQK (SEQ ID NO: 20), PAEEVQK (SEQ ID NO: 51), EAEVVQK (SEQ ID NO: 595), or PADVVQK (SEQ ID NO: 596). In some embodiments, [N2]-[N3] is or comprises YPAEVVQK (SEQ ID NO: 943), YQAEVVQK (SEQ ID NO: 951), YTAEVVQK (SEQ ID NO: 948), YPAEEVQK (SEQ ID NO: 950), YPAEVVQN (SEQ ID NO: 964), TEAEVVQK (SEQ ID NO: 965), or YPADVVQK (SEQ ID NO: 966); an amino acid sequence comprising any portion of any of the aforesaid amino acid sequences (e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to any of the aforesaid amino acid sequences; or an amino acid sequence comprising one, two, or three but no more than four different amino acids, relative to any one of the aforesaid amino acid sequences. In some embodiments, [N2]-[N3] is YPAEVVQK (SEQ ID NO: 943).

[0127] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [N2]-[N3], further comprises [N1], which comprises positions XD, XE, and XF. In some embodiments, position XD of [N1] is Q or S. In some embodiments, position XE of [N1] is S, L, A, or T. In some embodiments, position XFof [N1] is S, Y, or T. In some embodiments, [N1] comprises QS, SL, SA, QT, LS, LY, AT, TS, or SS. In some embodiments, [N1] is or comprises QSS, SLS, SLY, SAT, or QTS. In some embodiments, [N1] is QSS. In some embodiments, [N1]-[N2] comprises SSYPA (SEQ ID NO: 63), LSYQA (SEQ ID NO: 597), LSYTA (SEQ ID NO: 598), LYYPA (SEQ ID NO: 600), ATYPA (SEQ ID NO: 601), LSYPA (SEQ ID NO: 603), or TST...

Claims

CLAIMS What is claimed is:

1. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence and the AAV capsid variant comprises an amino acid sequence having the formula [N2]-[N3], wherein: (i) [N2] comprises positions X1, X2, X3, X4, and X5, wherein: (a) position X1is Y, N, or C; (b) position X2is P, K, T, or Q; (c) position X3is A or P; (d) position X4is E, S, or A; and (e) position X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence VQK, EQK, VKK, VHK, VQQ, or LQK; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% identical thereto.

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

982.

3. The AAV particle of claim 1 or claim 2, wherein [N2]-[N3] is present immediately subsequent to an amino acid position 576 as numbered according to SEQ ID NO:

982.

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

138.

5. The AAV particle of any one of claims 1-4, wherein [N2] comprises the amino acid sequence YP, YPA, YPAE (SEQ ID NO: 21), or YPAEV (SEQ ID NO: 1).

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

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

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

9. The AAV particle of any one of claims 1-8, wherein the AAV capsid variant further comprises [N1] comprising positions XD, XE, and XF, wherein: (a) position XD of [N1] is Q, T, S, A, I, L, or H; (b) position XEof [N1] is S, G, A, or R; and (c) position XFof [N1] is S, K, L, R, A, or T; wherein [N1] immediately precedes [N2]-[N3].

10. The AAV particle of claim 9, wherein [N1] comprises the amino acid sequence QS, SS, or QSS.

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

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

13. The AAV particle of any one of claims 9-12, wherein the AAV capsid variant further comprises [N0] comprising positions XA, XB, and XC, wherein: (a) position XAof [N0] is T, I, or N; (b) position XBof [N0] is N; and (c) position XC of [N0] is N, T, S, or K; wherein [N0] immediately precedes [N1].

14. The AAV particle of claim 13, wherein [N0] comprises the amino acid sequence TN, NN, or TNN.

15. The AAV particle of claim 13 or claim 14, wherein [N0]-[N1] comprises the amino acid sequence TNNQSS (SEQ ID NO: 183).

16. The AAV particle of any one of claims 13-15, wherein [N0]-[N1]-[N2]-[N3] comprises the amino acid sequence TNNQSSYPAEVVQK (SEQ ID NO: 500).

17. The AAV particle of any one of claims 13-16, wherein the AAV capsid variant further comprises [N4] comprising positions XGand XH, wherein: (a) position XGof [N4] is T, P, or N; and (b) position XH of [N4] is A; wherein [N4] is present immediately subsequent to [N3].

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

19. The AAV particle of claim 17 or claim 18, wherein [N0]-[N1]-[N2]-[N3]-[N4] comprises the amino acid sequence TNNQSSYPAEVVQKTA (SEQ ID NO: 1533).

20. The AAV particle of any one of claims 16-18, wherein [N0]-[N1]-[N2]-[N3]-[N4] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO:

982.

21. The AAV particle of claim 20, wherein: (i) [N0] is present at amino acids corresponding to positions 571-573 of the amino acid sequence of SEQ ID NO: 982; (ii) [N1] is present at amino acids corresponding to positions 574-576 of the amino acid sequence of SEQ ID NO: 982; (iii) [N2] is present at amino acids corresponding to positions 577- 581 of the amino acid sequence of SEQ ID NO: 982; (iv) [N3] is present at amino acids corresponding to positions 582-584 of the amino acid sequence of SEQ ID NO: 982; and (v) [N4] is present at amino acids corresponding to positions 585-586 of the amino acid sequence of SEQ ID NO:

982.

22. An adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises at least 4, 5, 6, 7, or 8 consecutive amino acids from the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

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

982.

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

982.

25. An adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence; and (ii) an AAV capsid variant comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO:

982.

26. The AAV particle of claim 25, wherein the AAV capsid variant further comprises (i) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (ii) an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

27. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the viral genome comprises a ȕ-glucocerebrosidase 1 (GBA1)-encoding sequence and wherein the AAV capsid variant comprises (i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

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

739.

29. The AAV particle of any one of claims 1-28, wherein the viral genome encodes a GBA1 protein comprising the amino acid sequence of SEQ ID NO: 1775 or an amino acid sequence at least 90% identical thereto.

30. The AAV particle of any one of claims 1-29, wherein the viral genome encodes a wildtype GBA1 protein.

31. The AAV particle of any one of claims 1-30, wherein the viral genome encodes a human GBA1 protein, a dog GBA1 protein, or an equine GBA1 protein.

32. The AAV particle of any one of claims 1-31, wherein the viral genome encodes a wildtype human GBA1 protein.

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

34. The AAV particle of any one of claims 1-33, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2002 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

35. The AAV particle of any one of claims 1-34, where the viral genome further comprises a signal sequence comprising the nucleotide sequence of SEQ ID NO: 2005 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

36. The AAV particle of any one of claims 1-35, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2001 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

37. The AAV particle of any one of claims 1-36, wherein the viral genome encodes a GBA1 protein comprising the amino acid sequence of SEQ ID NO: 1774 or an amino acid sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

38. The AAV particle of any one of claims 1-37, wherein the viral genome comprises a promoter operably linked to the GBA1-encoding sequence.

39. The AAV particle of claim 38, wherein the promoter comprises a human elongation factor 1 alpha (EF-1a) promoter, a chicken ȕ-actin (CBA) promoter, a CAG promoter, a CAG derivative promoter, a CMV immediate-early enhancer and / or promoter, a CMV promoter, a ȕ glucuronidase (GUSB) promoter, a ubiquitin C (UBC) promoter, a neuron-specific enolase (NSE) promoter, a platelet-derived growth factor (PDGF) promoter, a platelet-derived growth factor B-chain (PDGF-ȕ) promoter, an intercellular adhesion molecule 2 (ICAM-2) promoter, a synapsin (Syn) promoter, a methyl-CpG binding protein 2 (MeCP2) promoter, a Ca2+ / calmodulin-dependent protein kinase II (CaMKII) promoter, a metabotropic glutamate receptor 2 (mGluR2) promoter, a neurofilament light (NFL) promoter, a heavy (NFH) promoter, a ȕ-globin minigene nȕ2 promoter, a preproenkephalin (PPE) promoter, an enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoter, a glial fibrillary acidic protein (GFAP) promoter, a myelin basic protein (MBP) promoter, a cardiovascular promoter (e.g., ĮMHC, cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512), or a fragment, e.g., a truncation, or a functional variant thereof.

40. The AAV particle of claim 38 or claim 39, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

41. The AAV particle of any one of claims 1-40, wherein the viral genome further comprises an enhancer.

42. The AAV particle of claim 41, wherein the enhancer comprises a CMV immediate-early (CMVie) enhancer; optionally wherein the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

43. The AAV particle of any one of claims 1-42, wherein the viral genome further comprises an intron; optionally wherein the intron comprises the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

44. The AAV particle of any one of claims 1-43, wherein the viral genome further comprises a polyadenylation (polyA) region;optionally wherein the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

45. The AAV particle of any one of claims 1-44, wherein the viral genome further comprises an inverted terminal repeat (ITR); optionally wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to the nucleotide sequence of SEQ ID NO: 1829 or SEQ ID NO: 1830.

46. The AAV particle of claim 45, 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 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto, and the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

47. The AAV particle of any one of claims 1-46, wherein the viral genome further comprises one or more miR183 binding sites.

48. The AAV particle of any one of claims 1-47, wherein the viral genome comprises at least four miR183 binding sites.

49. The AAV particle of claim 48, wherein each of the at least four miR183 binding sites is separated by a spacer.

50. The AAV particle of any one of claims 46-49, wherein each of the miR183 binding sites comprises the nucleotide sequence of SEQ ID NO: 1847 or a nucleotide sequence that has up to three modifications relative to SEQ ID NO: 1847.

51. The AAV particle of any one of claims 1-46, wherein the viral genome further comprises a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

52. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR);(ii) a promoter; (iii) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (iv) a 3’ ITR.

53. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (v) a 3’ ITR.

54. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) an intron; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vi) a 3’ ITR.

55. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto;(v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vi) a 3’ ITR.

56. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vii) a 3’ ITR.

57. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5' inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto;(v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto.

58. The AAV particle of claim 57, wherein: (i) the 5' ITR comprises the nucleotide sequence of SEQ ID NO: 1829; (ii) the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831; (iii) the CBA promoter comprises the nucleotide sequence of SEQ ID NO: 1834; (iv) the intron comprises the nucleotide sequence of SEQ ID NO: 1842; (v) the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846; and (viii) the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830.

59. The AAV particle of any one of claims 1-57, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

60. The AAV particle of claim 59, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006.

61. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter; (iii) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) at least one miR183 binding site; and (v) a 3’ ITR.

62. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a promoter;(iii) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (v) a 3’ ITR.

63. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vi) a 3’ ITR.

64. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) an enhancer; (iii) a promoter; (iv) an intron; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vii) a 3’ ITR.

65. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto;(iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising at least one miR183 binding site and at least one spacer sequence; and (vii) a 3’ ITR.

66. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR); (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and (vii) a 3’ ITR.

67. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto;(iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) at least one miR183 binding site comprising the nucleotide sequence of SEQ ID NO: 1847; (vii) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and (viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto.

68. The AAV particle of any one of claims 1-28, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) comprising the nucleotide sequence of SEQ ID NO: 1829 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (ii) a CMV immediate-early (CMVie) enhancer comprising the nucleotide sequence of SEQ ID NO: 1831 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iii) a chicken beta actin (CBA) promoter comprising the nucleotide sequence of SEQ ID NO: 1834 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (iv) an intron comprising the nucleotide sequence of SEQ ID NO: 1842 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; (v) the GBA1-encoding sequence, wherein the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001 or SEQ ID NO: 2002, or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vi) a miR183 binding site series comprising the nucleotide sequence of SEQ ID NO: 1849 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; (vii) a polyadenylation (polyA) region comprising the nucleotide sequence of SEQ ID NO: 1846 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto; and(viii) a 3’ ITR comprising the nucleotide sequence of SEQ ID NO: 1830 or a nucleotide sequence at least 95% identical (e.g., at least 95%, 96%, 97%, 98%, or 99% identical) thereto.

69. The AAV particle of claim 68, wherein: (i) the 5’ ITR comprises the nucleotide sequence of SEQ ID NO: 1829; (ii) the CMVie enhancer comprises the nucleotide sequence of SEQ ID NO: 1831; (iii) the CBA promoter comprises the nucleotide sequence of SEQ ID NO: 1834; (iv) the intron comprises the nucleotide sequence of SEQ ID NO: 1842; (v) the GBA1-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 2001; (vi) the miR183 binding site series comprises the nucleotide sequence of SEQ ID NO: 1849; (vii) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1846; and (viii) the 3’ ITR comprises the nucleotide sequence of SEQ ID NO: 1830.

70. The AAV particle of any one of claims 1-68, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto.

71. The AAV particle of claim 70, wherein the viral genome consists of the nucleotide sequence of SEQ ID NO: 2007.

72. A cell comprising the AAV particle of any one of claims 1-71, optionally wherein the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

73. A method of making the AAV particle of any one of claims 1-71, the method comprising: (i) providing a cell comprising the viral genome comprising a GBA1-encoding sequence and a nucleic acid encoding the AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle.

74. The method of claim 73, wherein the viral genome comprises: (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and wherein the AAV capsid variant comprises(i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); or (iii) the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence having at least 90% identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

75. The method of claim 73, wherein the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 2006 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; or (b) the nucleotide sequence of SEQ ID NO: 2007 or a nucleotide sequence at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) thereto; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO:

739.

76. The method of claim 73, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 2006 or SEQ ID NO: 2007 and the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982, the amino acid sequence of SEQ ID NO: 738, and / or the amino acid sequence of SEQ ID NO:

739.

77. The method of any one of claims 73-76, further comprising, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell.

78. The method of any one of claims 73-77, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell.

79. The method of any one of claims 73-78, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

80. A pharmaceutical composition comprising the AAV particle of any one of claims 1-71 and a pharmaceutically acceptable excipient.

81. A method of delivering an AAV particle encoding a GBA1 protein to a cell, comprising administering an effective amount of the pharmaceutical composition of claim 78 or the AAV particle of any one of claims 1-71.

82. The method of claim 81, wherein the cell is in a subject, optionally wherein subject has, has been diagnosed with having, or is at risk of having a GBA1-related disorder.

83. A method of treating a subject having or diagnosed with having a GBA1-related disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71.

84. The method of claim 83, wherein the subject has, has been diagnosed with having, or is at risk of having a GBA1-related disorder.

85. The method of any one of claims 82-84, wherein the GBA1-related disorder is a GBA1-related neurodegenerative or neuromuscular disorder.

86. The method of any one of claims 82-85, wherein the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome.

87. The method of any one of claims 82-86, wherein the GBA1-related disorder is PD.

88. The method of any one of claims 82-86, wherein the GBA1-related disorder is LBD.

89. The method of any one of claims 82-86, wherein the GBA1-related disorder is DLB.

90. The method of any one of claims 82-86, wherein the GBA1-related disorder is GD (e.g., GD type 1, GD type 2, or GD type 3).

91. A method of treating Parkinson’s Disease (PD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71.

92. The method of claim 91, wherein the subject has, has been diagnosed with having, or is at risk of having PD.

93. A method of treating Lewy Body Dementia (LBD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71.

94. The method of claim 93, wherein the subject has, has been diagnosed with having, or is at risk of having LBD.

95. A method of treating Dementia with Lewy Bodies (DLB) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71.

96. The method of claim 95, wherein the subject has, has been diagnosed with having, or is at risk of having DLB.

97. A method of treating Gaucher Disease (GD) in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71.

98. The method of claim 97, wherein the subject has, has been diagnosed with having, or is at risk of having GD (e.g., GD type 1, GD type 2, or GD type 3).

99. The method of claim 98, wherein the GD is GD type 1.

100. The method of claim 98, wherein the GD is GD type 2.

101. The method of claim 98, wherein the GD is GD type 3.

102. The method of any one of claims 83-101, wherein the subject has one or more mutations in the GBA1 gene.

103. The method of any one of claims 83-102, wherein, prior to the administration, the subject has lower GCase activity as compared to GCase activity in an individual who does not have a GBA1-related disorder, optionally wherein the level of GCase activity is measured by a 4-MUG assay or a SensoLyte Blue Glucocerebrosidase assay.

104. The method of any one of claims 83-103, wherein the treating results in prevention of progression of the disorder in the subject.

105. The method of any one of claims 83-104, wherein the treating results in amelioration of at least one symptom of the disorder in the subject, e.g., as indicated by one or more biomarkers.

106. The method of claim 105, wherein the one or more biomarkers comprises a GCase activity, a level of glucocerebroside and other glycolipids, (e.g., within immune cells such as macrophages), a level of synuclein aggregates (e.g., Lewy bodies), or a combination thereof.

107. The method of claim 105, wherein the at least one symptom comprises developmental delay, progressive encephalopathy, progressive dementia, ataxia, myoclonus, oculomotor dysfunction, bulbar palsy, generalized weakness, trembling of a limb, depression, visual hallucinations, cognitive decline, or a combination thereof.

108. The method of any one of claims 82-107, wherein the subject is a human.

109. The method of any one of claims 82-108, wherein the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the central nervous system (CNS) in the subject.

110. The method of claim 109, wherein the cell or tissue of the CNS is a cell or tissue of the spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum.

111. The method of any one of claims 82-110, wherein the AAV particle or the pharmaceutical composition is delivered to a peripheral cell or tissue in the subject.

112. The method of claim 111, wherein the peripheral cell or tissue is a cell or tissue of the liver, heart, skeletal muscle, sympathetic ganglia, and / or plasma.

113. The method of any one of claims 82-112, wherein the AAV particle or pharmaceutical composition is delivered to the subject via intravenous administration.

114. The method of any one of claims 82-113, further comprising evaluating, e.g., measuring, the level of GBA1 expression (e.g., GBA1 gene expression, GBA1 mRNA expression, and / or GBA1 protein expression) in the subject, e.g., in a cell, tissue, or fluid of the subject.

115. The method of claim 114, wherein the level of GBA1 protein expression is measured by an ELISA, a Western blot, or an immunohistochemistry assay.

116. The method of claim 114 or claim 115, wherein evaluating the subject’s level of GBA1 expression is performed prior to and / or subsequent to administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of GBA1 expression prior to administration is compared to the subject’s level of GBA1 expression subsequent to administration.

117. The method of any one of claims 114-116, comprising evaluating the level of GBA1 expression in a cell or tissue of the central nervous system.

118. The method of any one of claims 114-117, wherein the subject’s level of GBA1 protein expression subsequent to administration is increased relative to the subject’s level of GBA1 protein expression prior to administration.

119. The method of any one of claims 82-118, further comprising evaluating, e.g., measuring, the level of GCase activity in the subject.

120. The method of any one of claims 82-119, wherein administering the pharmaceutical composition or AAV particle to the subject results in an increase in: (i) GCase activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum), and / or fluid (e.g., CSF and / or serum) of the subject relative to baseline and / or relative to GCase activity in a cell, tissue, or fluid of an individual with a GBA1-related disorder who has not been administered the pharmaceutical composition or AAV particle; (ii) the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantia nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to the number and / or level of VG per cell in a peripheral tissue of the subject; and / or(iii) GBA1 mRNA expression in a cell or tissue (e.g., a cell or tissue of the CNS, e.g., spinal cord, visual cortex, frontal cortex, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, substantial nigra, hippocampus, hilus of the dentate gyrus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or relative to GBA1 mRNA expression in a cell or tissue of an individual with a GBA1- related disorder who has not been administered the pharmaceutical composition or AAV particle.

121. The method of any one of claims 82-120, further comprising administering to the subject at least one additional therapeutic agent and / or therapy.

122. The method of claim 121, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating the GBA1-related disorder.

123. The method of claim 122, wherein the at least one additional therapeutic agent and / or therapy suitable for treating the GBA1-related disorder comprises enzyme replacement therapy (ERT) (e.g., imiglucerase, velaglucerase alfa, or taliglucerase alfa); substrate reduction therapy (SRT) (e.g., eliglustat or miglustat), levodopa, carbidopa, Safinamide, a dopamine agonist (e.g., pramipexole, rotigotine, or ropinirole), a dopamine antagonist (e.g., quetiapine, clozapine), an anticholinergic (e.g., benztropine or trihexyphenidyl), a cholinesterase inhibitor (e.g., rivastigmine, donepezil, or galantamine), an N-methyl- d-aspartate (NMDA) receptor antagonist (e.g., memantine), or a combination thereof.

124. The method of claim 122 or claim 123, wherein the at least one additional therapeutic agent and / or therapy is suitable for treating Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome.

125. The method of claim 124, wherein the GBA1-related disorder is PD, LBD, or GD, wherein, optionally, the GD is GD type 1, GD type 2, or GD type 3.

126. The method of any one of claims 82-125, further comprising administering an immunosuppressant to the subject.

127. The method of claim 126, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

128. The method of any one of claims 82-127, further comprising administering a blood transfusion to the subject.

129. The pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71 for use in a method of treating a disorder according to any one of claims 81-128.

130. The pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71, for use in the treatment of a GBA1-related disorder in a subject.

131. The pharmaceutical composition or AAV particle for use of claim 130, wherein the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome.

132. The pharmaceutical composition or AAV particle for use of claim 130 or claim 131, wherein the GBA1-related disorder is PD.

133. The pharmaceutical composition or AAV particle for use of any one of claims 129-132, wherein the subject has, has been diagnosed with having, or is at risk of having PD.

134. The pharmaceutical composition or AAV particle for use of claim 130 or claim 131, wherein the GBA1-related disorder is LBD.

135. The pharmaceutical composition or AAV particle for use of any one of claims 129-131 and 134, wherein the subject has, has been diagnosed with having, or is at risk of having LBD.

136. The pharmaceutical composition or AAV particle for use of claim 130 or claim 131, wherein the GBA1-related disorder is DLB.

137. The pharmaceutical composition or AAV particle for use of any one of claims 129-131 and 136, wherein the subject has, has been diagnosed with having, or is at risk of having DLB.

138. The pharmaceutical composition or AAV particle for use of claim 130 or claim 131, wherein the GBA1-related disorder is GD (e.g., GD type 1, GD type 2, or GD type 3).

139. The pharmaceutical composition or AAV particle for use of any one of claims 129-131 and 138, wherein the subject has, has been diagnosed with having, or is at risk of having GD (e.g., GD type 1, GD type 2, or GD type 3).

140. Use of the pharmaceutical composition of claim 80 or the AAV particle of any one of claims 1-71 in the manufacture of a medicament for the treatment of a GBA1-related disorder in a subject.

141. The use of claim 140, wherein the GBA1-related disorder is Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD), Gaucher Disease (GD) (e.g., GD type 1, GD type 2, or GD type 3), Dementia with Lewy Bodies (DLB), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Pure Autonomic Failure, Neurodegeneration with brain iron accumulation type 1 (NBIA 1), or Hallervorden-Spatz Syndrome.

142. The use of claim 140 or claim 141, wherein the GBA1-related disorder is PD.

143. The use of claim 140 or claim 142, wherein the subject has, has been diagnosed with having, or is at risk of having PD.

144. The use of claim 140, wherein the GBA1-related disorder is GD.

145. The use of claim 140 or claim 144, wherein the subject has, has been diagnosed with having, or is at risk of having GD.

146. The use of claim 144 or claim 145, wherein the GD is GD type 1.

147. The use of claim 144 or claim 145, wherein the GD is GD type 2.

148. The use of claim 144 or claim 145, wherein the GD is GD type 3.

149. The use of claim 140, wherein the GBA1-related disorder is LBD.

150. The use of claim 140 or claim 149, wherein the subject has, has been diagnosed with having, or is at risk of having LBD.

151. The use of claim 140, wherein the GBA1-related disorder is DLB.

152. The use of claim 140 or claim 151, wherein the subject has, has been diagnosed with having, or is at risk of having DLB.

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