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

Abstract

The disclosure relates to compositions and methods for altering, e.g., enhancing, the level of frataxin protein via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful in the treatment of subjects who have, have been diagnosed with having, or are at risk of having a disorder associated with frataxin (FXN) deficiency, e.g., Friedreich's Ataxia.

Description

Attorney Docket No.14640.0092-00304 COMPOSITIONS AND METHODS FOR THE TREATMENT OF DISORDERS RELATED TO FRATAXIN DEFICIENCY RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to US Provisional Application Serial No. 63 / 519,952, filed August 16, 2023. SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing file, entitled 14640_0092-00304_SL.xml, was created on June 21, 2024, and is 1,753,602 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety. FIELD

[0003] Described herein are compositions and methods relating to adeno-associated virus (AAV) viral particles for the delivery of polynucleotides, e.g., polynucleotides encoding a frataxin (FXN) protein for use in the treatment of Friedreich’s Ataxia (FA). In some embodiments, compositions described herein may be used to treat a subject in need thereof, such as a human subject diagnosed with FA, or as a research tool in the study of diseases or conditions in cells or animal models of FA. BACKGROUND

[0004] Friedreich’s Ataxia (FA) is an autosomal recessive inherited disease that causes progressive damage to the nervous system. See Parkinson et al., Journal of Neurochemistry, 2013, 126 (Suppl.1), 103-117, the contents of which are herein incorporated by reference in their entirety. FA typically results from the degeneration of nervous tissue in the spinal cord due to reduced expression of the mitochondrial protein frataxin (FXN; also known as, e.g., CyaY, FA, FARR, FRDA, and X25) in sensory neurons that direct muscle movement of the arms and legs. See Koeppen, Arnulf; J Neurol Sci., 2011, April 15; 303(1-2): 1–12. Onset usually occurs at puberty or by age 25. See Campuzano, et al., Science, 271.5254 (Mar 8, 1996): 1423. Initial symptoms of FA include poor coordination such as gait disturbance, poor balance, leg weakness, decreased walking, impaired coordination, dysarthria, nystagmus, impaired sensation, kyphoscoliosis, and foot deformities. See Parkinson et al., Journal of Neurochemistry, 2013, 126 (Suppl.1), 103-117. FA is also associated with scoliosis, heart disease, and diabetes. The disease generally progresses until a wheelchair is required for mobility. Incidence of FA among Caucasian populations is between about 1 in 20,000 and about 1 in 50,000, with a deduced carrier frequency of about 1 in 120 in European populations. See Nageshwaran and Festenstein, Frontiers in Neurology, Vol. 6, Art.262 (2015); Campuzano, et al., Science, 271.5254 (Mar 8, 1996): 1423, the contents of each of which are herein incorporated by reference in their entirety. The expansion of an intronic GAA triplet repeat in the FXN gene is the genetic cause of reduced expression of FXN resulting in FA. See ParkinsonAttorney Docket No.14640.0092-00304 et al., Journal of Neurochemistry, 2013, 126 (Suppl.1), 103-117. Over time, the deficiency causes the aforementioned symptoms, as well as frequent fatigue due to effects on cellular metabolism. Currently, omaveloxolone (Skyclarys®) is the only FDA approved treatment for FA. Omaveloxolone is a semisynthetic oleanane triterpenoid that activates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties. See Reisman et al. (2019) Drug Des Devel Ther.13:1259-1270. While gene therapy constructs for delivering a frataxin protein have been described in the arm, there remains a need to develop improved constructs for better targeting of the appropriate tissues in the body.

[0005] 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.

[0006] There remains a need for effective methods of treatment using AAV capsids that are capable of delivering FXN to a target cell or tissue, e.g., a CNS cell or tissue. SUMMARY

[0007] The present disclosure addresses these challenges by providing AAV-based compositions, AAV-based compositions for use in methods for treating Friedreich’s Ataxia (FA) in subjects, and methods for treating FA in subjects. Disclosed herein are compositions and methods directed to AAV- based gene delivery of FXN (e.g., human FXN) to ameliorate loss-of-function and to improve FXN expression (e.g., in the brain, e.g., in neurons). In some embodiments, the compositions and methods can be used to slow, halt, or reverse symptoms of FA.

[0008] In some aspects, the present disclosure provides an AAV particle comprising an AAV capsid and a nucleotide sequence encoding a FXN protein, also referred to herein as a FXN-encoding sequence or as a FXN protein-encoding sequence. In some embodiments, the nucleotide sequence encoding a FXN protein is comprised in a viral genome. In some embodiments, the FXN protein is a human FXN protein. In some embodiments, the FXN protein is a wildtype human FXN protein. In some embodiments, the AAV particle comprises a viral genome encoding the FXN protein (e.g., a human FXN protein) and the AAV capsid is an AAV capsid variant. In some embodiments, the viral genome comprises a truncated chicken ȕ-actin (CBA) promoter operably linked to the FXN-encoding sequence, and the AAV capsid variant is an AAV5 capsid variant.

[0009] 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 other words, the peptide has replaced the amino acid corresponding to position 577 of 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. 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 aAttorney Docket No.14640.0092-00304 peptide comprising one, two, or three—but no more than three—substitutions relative to the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). In some embodiments, the peptide comprising the amino acid sequence of SEQ ID NO: 943 has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138 (in other words, the peptide comprising the amino acid sequence comprising no more than three substitutions relative to SEQ ID NO: 943 has replaced the amino acid corresponding to position 577 of 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. In some embodiments, the peptide comprising the amino acid sequence of SEQ ID NO: 943 has replaced a threonine at amino acid position 577 as numbered according to SEQ ID NO: 138 (in other words, the peptide comprising the amino acid sequence of SEQ ID NO: 943 has replaced the amino acid corresponding to position 577 of 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.

[0010] 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 frataxin (FXN)-encoding sequence and the AAV capsid variant comprises an amino acid sequence having the formula [N2]-[N3], wherein: (i) [N2] comprises X1, X2, X3, X4, and X5, wherein X1 is Y, N, or C; X2 is P, K, T, or Q; X3is A or P; X4is E, S, or A; and 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.

[0011] In some embodiments, [N2]-[N3] is present in loop VIII, wherein loop VIII is present at amino acids comprising those corresponding to positions 571-599 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, [N2]-[N3] is present immediately subsequent to an amino acid corresponding to position 576 of the amino acid sequence of SEQ ID NO: 982.

[0012] 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.

[0013] 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).

[0014] In some embodiments, the AAV capsid variant further comprises [N1] comprising XD, XE, and XF, wherein: XDof [N1] is Q, T, S, A, I, L, or H; XEof [N1] is S, G, A, or R; and 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).Attorney Docket No.14640.0092-00304

[0015] In some embodiments, the AAV capsid variant further comprises [N0] comprising XA, XB, and XC, wherein: XAof [N0] is T, I, or N; XBof [N0] is N; and 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).

[0016] In some embodiments, the AAV capsid variant further comprises [N4] comprising XGand XH, wherein: XGof [N4] is T, P, or N; and (b) 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).

[0017] 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.

[0018] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a frataxin (FXN)-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, at least 5, at least 6, at least 7, or all 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 at amino acids corresponding to positions 577-583 of the amino acid sequence of SEQ ID NO: 982. In some embodiments, the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943) present at amino acids corresponding to positions 577-584 of the amino acid sequence of SEQ ID NO: 982.Attorney Docket No.14640.0092-00304

[0019] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising: (i) a viral genome comprising a frataxin (FXN)-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).

[0020] 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 frataxin (FXN)-encoding sequence and the AAV capsid variant comprises (i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (iii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

[0021] 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.

[0022] In some embodiments, the FXN-encoding sequence encodes a FXN protein that is not a cynomolgus monkey FXN protein. In some embodiments, the FXN-encoding sequence encodes a human FXN protein. In some embodiments, the human FXN protein comprises the amino acid sequence of SEQ ID NO: 1825, or an amino acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the human FXN protein is a wildtype human FXN protein. In some embodiments, the FXN-encoding sequence comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 1825. In some embodiments, the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0023] In some embodiments, the viral genome further comprises a promoter operably linked to the FXN-encoding sequence. In some embodiments, the promoter comprises a human elongation factor 1Į- subunit (EF1Į) promoter, a cytomegalovirus (CMV) immediate-early enhancer and / or promoter, a chicken ȕ-actin (CBA) promoter, a CAG promoter, a ȕ glucuronidase (GUSB) promoter, a ubiquitin CAttorney Docket No.14640.0092-00304 (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, a 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 chain (NFL) promoter, a neurofilament heavy chain (NFH) promoter, a ȕ-globin minigene nȕ2 promoter, a preproenkephalin (PPE) promoter, a 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 functional fragment or truncation of any of the foregoing. In some embodiments, the promoter is a CMV promoter or CBA promoter, or a functional fragment or truncation of a CMV promoter or CBA promoter.

[0024] In some embodiments, the promoter is a truncated CBA promoter. In some embodiments, the truncated CBA promoter is 50-400 nucleotides in length, e.g., 100-332 nucleotides in length. In some embodiments, the promoter comprises the nucleotide sequence of any one of SEQ ID NOs: 1738, 1740, and 1742 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0025] In some embodiments, the promoter is a truncated CMV promoter. In some embodiments, the truncated CMV promoter is 50-300 nucleotides in length. In some embodiments, the promoter comprises the nucleotide sequence of SEQ ID NO: 1750 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0026] In some embodiments, the viral genome further comprises a microRNA (miR) binding site that modulates expression of the encoded FXN protein in a cell or tissue of the liver. In some embodiments, the viral genome comprises 3 copies of the miR binding site. In some embodiments, the 3 copies of the miR binding site are identical. In some embodiments, the 3 copies of the miR binding site are continuous.

[0027] In some embodiments, the miR binding site is a miR122 binding site. In some embodiments, the miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1827 or a sequence having one, two, three, or at most four substitutions relative to the nucleotide sequence of SEQ ID NO: 1827. In some embodiments, the viral genome comprises 3 copies of a miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 1826 or a sequence having one, two, three, four, five, six, seven, eight, nine, or at most ten substitutions relative to the nucleotide sequence of SEQ ID NO: 1826.

[0028] In some embodiments, the viral genome further comprises at least one inverted terminal repeat (ITR) region. In some embodiments, the at least one ITR region comprises an AAV2 ITR. In some embodiments, the viral genome comprises a 5’ ITR region and a 3’ ITR region. In some embodiments,Attorney Docket No.14640.0092-00304 the 5’ ITR region and 3’ ITR region are each an AAV2 ITR. In some embodiments, the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0029] In some embodiments, the viral genome further comprises an intron / exon region comprising an intron region and / or an exon region. In some embodiments, the intron / exon region comprises: an immediate-early 1 (ie1) intron region and / or a human beta-globin (hBglobin) intron 2 region; and / or an ie1 exon region and / or an hBglobin exon region.

[0030] In some embodiments, the intron region comprises: the nucleotide sequence of SEQ ID NO: 1819 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or the nucleotide sequence of SEQ ID NO: 1820 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. In some embodiments, the exon region comprises: the nucleotide sequence of SEQ ID NO: 1817 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or the nucleotide sequence of SEQ ID NO: 1821 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0031] In some embodiments, the viral genome further comprises a polyadenylation (polyA) region. In some embodiments, the polyA region comprises a human growth hormone (hGH) polyA region. In some embodiments, the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0032] In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0033] In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%,Attorney Docket No.14640.0092-00304 at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0034] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; and (iv) a 3’ ITR region.

[0035] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (iv) at least one miR122 binding site; and (v) a 3’ ITR region.

[0036] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) an intron / exon region; (iv) the FXN-encoding sequence, wherein the FXN- encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (v) at least one miR122 binding site; and (vi) a 3’ ITR region.

[0037] In some embodiments, the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) an intron / exon region; (iv) the FXN-encoding sequence, wherein the FXN- encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (v) at least one miR122 binding site; (vi) a polyadenylation (polyA) region; and (vii) a 3’ ITR region.

[0038] In some embodiments, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) an intron and / or exon region; (iv) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (v) at least one miR122 binding site; (vi) a polyadenylation (polyA) region; (vii) a filler sequence; and (viii) a 3’ ITR region.Attorney Docket No.14640.0092-00304

[0039] In some embodiments, (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1742 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. In some embodiments, the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1841 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

[0040] In some embodiments, (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1750 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at leastAttorney Docket No.14640.0092-00304 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. In some embodiments, the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1840 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

[0041] In some embodiments, (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1738 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. In some embodiments, the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO:Attorney Docket No.14640.0092-00304 1838 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

[0042] In some embodiments, (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1740 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. In some embodiments, the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1839 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

[0043] In some embodiments, the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%,Attorney Docket No.14640.0092-00304 at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0044] In some embodiments, (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1742; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824;(v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828; and (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812. In some embodiments, the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1841, wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region. In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797. In some embodiments, the viral genome consists of the nucleotide sequence of SEQ ID NO: 1797.

[0045] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome comprising a frataxin (FXN)-encoding sequence, wherein the AAV capsid variant comprises: (i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 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 95% identity (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 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 95% identity (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and wherein the viral genome comprises: (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at leastAttorney Docket No.14640.0092-00304 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

[0046] In some aspects, the present disclosure provides an adeno-associated virus (AAV) particle comprising a viral genome comprising the nucleotide sequence of SEQ ID NO: 1824 and an AAV capsid variant comprising 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. In some embodiments, the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797.

[0047] In some embodiments, the viral genome is single-stranded.

[0048] In some aspects, the present disclosure provides a cell comprising an AAV particle disclosed herein. In some embodiments, the cell is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.

[0049] In some aspects, the present disclosure provides a method of making and AAV particle disclosed herein, wherein the method comprises: (i) providing a cell comprising the viral genome comprising a FXN-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. In some embodiments, the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943). In someAttorney Docket No.14640.0092-00304 embodiments, the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and 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.

[0050] In some embodiments of the method of making an AAV particle, the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797 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.

[0051] In some embodiments of the 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.

[0052] In some aspects, the present disclosure provides a pharmaceutical composition comprising an AAV particle disclosed herein and a pharmaceutically acceptable excipient.

[0053] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a frataxin (FXN) protein to a cell, comprising administering an effective amount of a pharmaceutical composition or AAV particle described 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 disorder associated with FXN deficiency. In some embodiments, the disorder is Friedreich’s Ataxia (FA).

[0054] In some aspects, the present disclosure provides a method of delivering an AAV particle encoding a frataxin (FXN) protein to a subject, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle described herein. In some embodiments, the subject has, has been diagnosed with having, or is at risk of having a disorder associated with FXN deficiency. In some embodiments, the disorder is Friedreich’s Ataxia (FA).

[0055] In some aspects, the present disclosure provides a method of treating a subject having or diagnosed with having a disorder associated with frataxin (FXN) deficiency, comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle described herein. InAttorney Docket No.14640.0092-00304 some embodiments, the subject has, has been diagnosed with having, or is at risk of having Friedreich’s Ataxia (FA).

[0056] In some aspects, the present disclosure provides a method of treating a subject having or diagnosed with having a disorder, wherein the disorder is Friedreich’s Ataxia (FA), comprising administering to the subject an effective amount of a pharmaceutical composition or AAV particle described herein.

[0057] In some embodiments of a method of treating, 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 some embodiments, the at least one symptom comprises impaired sensory functions, impaired motor function (e.g., ataxia and / or involuntary movements), fatigue, chronic pain, seizures, impaired speech, sleep disturbances, metabolic disorders (e.g., diabetes), and / or increased spasticity. In some embodiments, the treating stabilizes, slows the progression of, or improves the subject’s disorder as determined by the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and / or the International Cooperative Ataxia Rating Scale (ICARS). In some embodiments, the treatment slows the subject’s progression of the disorder as measured by mFARS, SARA, and / or ICARS relative to an individual with the disorder who has not been administered the pharmaceutical composition or the AAV particle.

[0058] In some embodiments of a method of delivering or treating, the subject is a human. 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, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum, or a combination thereof.

[0059] In some embodiments of a method of delivering or treating, the AAV particle or the pharmaceutical composition is delivered to the subject via intravenous administration.

[0060] In some embodiments of a method of delivering or treating, the method further comprises evaluating, e.g., measuring, the level of FXN expression, e.g., FXN gene expression, FXN mRNA expression, and / or FXN protein expression, in the subject, e.g., in a cell, tissue, or fluid of the subject. In some embodiments, the level of FXN protein expression is measured by an enzyme-linked immunosorbent assay (ELISA), a Western blot, an immunohistochemistry assay, or a frataxin biofluid assay. In some embodiments, evaluating the subject’s level of FXN expression is performed before and / or after administration of the pharmaceutical composition or AAV particle. In some embodiments, the subject’s level of FXN expression before administration is compared to the subject’s level of FXN expression after administration.

[0061] In some embodiments, the method of delivering or treating further comprises evaluating the level of FXN expression in a cell or tissue of the CNS. In some embodiments, the cell or tissue of the CNS is a cell or tissue of the spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen,Attorney Docket No.14640.0092-00304 caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum.

[0062] In some embodiments, the method of delivering or treating further comprises evaluating the level of FXN expression in a peripheral cell or tissue. In some embodiments, the peripheral cell or tissue is a cell or tissue of the heart and / or muscle.

[0063] In some embodiments, the subject’s level of FXN protein expression after administration is increased relative to the subject’s level of FXN protein expression before administration.

[0064] In some embodiments, the method of delivering or treating further comprises evaluating, e.g., measuring, the level of FXN protein activity in the subject.

[0065] In some embodiments of a method of delivering or treating, administering the pharmaceutical composition or AAV particle to the subject results in an increase in: (i) the level of FXN protein or FXN gene expression in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, 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; (ii) the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, 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) the level of FXN activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or relative to FXN activity in a cell, tissue, or fluid of an individual with a disorder associated with FXN deficiency who has not been administered the pharmaceutical composition or AAV particle.

[0066] In some embodiments of a method of delivering or treating, the method 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 a disorder associated with FXN deficiency (e.g., Friedreich’s Ataxia). In some embodiments, the at least one additional therapeutic agent and / or therapy comprises omaveloxolone or idebenone.

[0067] In some embodiments of a method of delivering or treating, the method further comprises administering an immunosuppressant to the subject. In some embodiments, the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

[0068] 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.Attorney Docket No.14640.0092-00304

[0069] In some aspects, the present disclosure provides a pharmaceutical composition or AAV particle disclosed herein for use in the treatment of a disorder associated with FXN deficiency in a subject. In some embodiments, the disorder is Friedreich’s Ataxia (FA). In some embodiments, the subject has, has been diagnosed with having, or is at risk of having FA.

[0070] 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 disorder associated with FXN deficiency in a subject. In some embodiments, the disorder is Friedreich’s Ataxia (FA). In some embodiments, the subject has, has been diagnosed with having, or is at risk of having FA. Enumerated Embodiments 1. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises an amino sequence comprising the following formula: [N2]-[N3], wherein: (i) [N2] comprises X1, X2, X3, X4, and X5, wherein: (a) X1is Y, N, C, or T; (b) X2is P, E, K, T, or Q; (c) X3is A or P; (d) X4is E, S, D, or A; and (e) X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK. 2. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises an amino sequence comprising the following formula: [N2]-[N3], wherein: (i) [N2] comprises X1, X2, X3, X4, and X5, wherein: (a) X1 is Y, N, or C; (b) X2is P, K, T, or Q; (c) X3is A or P; (d) X4is E, S, or A; and (e) X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence of VQK, EQK, VKK, VHK, VQQ, or LQK.Attorney Docket No.14640.0092-00304 3. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [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 NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11); (iv) an [N3] comprising VQK, EQK, VKK, VHK, VQQ, or LQK; and (v) an [N4] comprising TA, PA, or NA. 4. The AAV particle of embodiment 1 or 2, wherein: (a) X1 is Y or N; (b) X2 is P, T or Q; (c) X3is A; (d) X4is E or S; and / or (e) 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 IDAttorney Docket No.14640.0092-00304 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;Attorney Docket No.14640.0092-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 relative to any one 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 relative to any one 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 atAttorney Docket No.14640.0092-00304 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), 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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 XD, XE, and XF, wherein: (a) XDis Q, T, S, A, I, L, or H; (b) XEis S, G, A, or R; andAttorney Docket No.14640.0092-00304 (c) 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 relative to any one 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 relative to any one 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).Attorney Docket No.14640.0092-00304 25. The AAV particle of embodiment 3 or any one of embodiments 20-24, wherein [N1]-[N2] is or comprises: (i) QSSYPAEV (SEQ ID NO: 96), QSKYPAEV (SEQ ID NO: 97), TSLYPAEV (SEQ ID NO: 98), SSSYPAEV (SEQ ID NO: 99), QSRYPAEV (SEQ ID NO: 100), QSSYPPSL (SEQ ID NO: 101), AGAYPAEV (SEQ ID NO: 102), IGSYPAEV (SEQ ID NO: 103), QASYPAEV (SEQ ID NO: 104), ASSYPAEV (SEQ ID NO: 105), LGSYPAEV (SEQ ID NO: 106), QSTNKAEV (SEQ ID NO: 107), HSSYPAEV (SEQ ID NO: 108), SSSYTAEV (SEQ ID NO: 109), TSLYPAEE (SEQ ID NO: 110), ASSYQAEV (SEQ ID NO: 111), QSSYTPSL (SEQ ID NO: 112), QSRYPAEE (SEQ ID NO: 113), LSSYQAEV (SEQ ID NO: 114), HSSYPAAV (SEQ ID NO: 115), QSSNPAEV (SEQ ID NO: 116), QSSYTAEV (SEQ ID NO: 117), TSLCPAEV (SEQ ID NO: 118), QRSYTAEV (SEQ ID NO: 119), or QSSYQAEE (SEQ ID NO: 120); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, or 7 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 relative to any one 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).Attorney Docket No.14640.0092-00304 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 (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 XA, XB, and XC, wherein: (a) XAis T, I, or N; (b) XBis N; (c) 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.Attorney Docket No.14640.0092-00304 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 relative to any one 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);Attorney Docket No.14640.0092-00304 (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 XGand XH, wherein: (a) XG is T, P, or N; and (b) XHis A; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a) or (b). 36. The AAV particle of embodiment 35, wherein [N4] is or comprises TA, PA, or NA. 37. The AAV particle of any one of embodiments 3, 35, and 36, wherein [N3]-[N4] is or comprises: (i) VQKTA (SEQ ID NO: 564), EQKTA (SEQ ID NO: 565), VKKTA (SEQ ID NO: 566),(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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).Attorney Docket No.14640.0092-00304 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 relative to any one 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:Attorney Docket No.14640.0092-00304 1327), TNNQSSYPPSLEQKTA (SEQ ID NO: 1590), TNNQSSYPPSLVKKTA (SEQ ID NO: 1591), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024). 41. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises an amino sequence comprising the following formula: [B]-[C] (SEQ ID NO: 2113), wherein (i) [B] comprises X1, X2, and X3, wherein: (a) X1is Q, T, S, A, I, L, or H; (b) X2is S, G, or A; and (c) X3 is S, K, L, R, or A; and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 42. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [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 optionally wherein [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) X1 is Q, T, S, A, or H; (b) X2 is S or G; and (c) 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.Attorney Docket No.14640.0092-00304 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 relative to any one 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 relative to any one 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.Attorney Docket No.14640.0092-00304 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, 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, 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, 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, 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, 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, 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 XA, XB, and XC, wherein: (a) XA is T, I, or N; (b) XBis N; and (c) 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). 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;Attorney Docket No.14640.0092-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 relative to any one 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), 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), 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:Attorney Docket No.14640.0092-00304 (i) a T at position 578 and / or an A at position 579, 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, 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 numbered according to SEQ ID NO: 982; or (iii) an N at position 578 and / or an A at position 579, 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 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 X4 and X5, wherein: (a) X4 is T or N; and (b) 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 relative to any one 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),Attorney Docket No.14640.0092-00304 (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids relative to any one of the amino acid sequences in (i). 65. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNQSSYPAEVVQKTA (SEQ ID NO: 1533). 66. The AAV particle of embodiment 42 or any one of embodiments 61-64, wherein [A]-[B]-[C]-[D] is or comprises TNNAGAYPAEVVQKTA (SEQ ID NO: 1021), TNNTSLYPAEVVQKTA (SEQ ID NO: 1232), TNNQSKYPAEVVQKTA (SEQ ID NO: 1538), TNNQSRYPAEVVQKTA (SEQ ID NO: 1327), or INNQSSYPAEVVQKTA (SEQ ID NO: 1024). 67. An AAV particle comprising a viral genome comprising a frataxin (FXN)-encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises an amino sequence comprising the formula [N2]-[N3], wherein: (i) [N2] comprises X1, X2, X3, X4, and X5, wherein: (a) X1 is Y or T; (b) X2 is Q, T, P, or E; (c) X3 is A; (d) X4 is E or D; and (e) X5 is V or E; and (ii) [N3] comprises the amino acid sequence of VQK or VQN. 68. An AAV particle comprising a viral genome encoding a frataxin (FXN)-encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [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.Attorney Docket No.14640.0092-00304 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 comprises73. 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 relative to any one 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;Attorney Docket No.14640.0092-00304 (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 relative to any one 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 the amino acid corresponding to position 577, of 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), 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, 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, 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, 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, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982; orAttorney Docket No.14640.0092-00304 (v) a Q at position 574, a T at position 575, and / or an S at position 576, 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 XD, XE, and XF, wherein: (a) XD is Q or S; (b) XEis S, L, A, or T; and (c) 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 relative to any one 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 relative to any of the amino acid sequences in (i); orAttorney Docket No.14640.0092-00304 (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 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 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 XA, XB, and XC, wherein: (a) XAis T; (b) XBis N; andAttorney Docket No.14640.0092-00304 (c) 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 relative to any one 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 relative to any one 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).Attorney Docket No.14640.0092-00304 94. The AAV particle of embodiment 1 or any one of embodiments 67-93, which further comprises [N4], wherein [N4] comprises XGand XH, wherein: (a) XG is T, P, or N; and (b) XHis 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). 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, or 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 relative to any one 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 relative to any one 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).Attorney Docket No.14640.0092-00304 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 a viral genome comprising a frataxin (FXN)-encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises the formula [K1]-[K2], wherein: (i) [K1] comprises LSY or LYY; and (ii) [K2] comprises X1, X2, X3, and X4, wherein: (a) X1is Q, T, or P; (b) X2is A; (c) X3 is E or D; and (d) X4 is V or E. 100. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [K0], which comprises TNNS (SEQ ID NO: 14); (ii) an [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).Attorney Docket No.14640.0092-00304 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:(ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 relative to any one 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), 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, 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 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).Attorney Docket No.14640.0092-00304 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 relative to any one 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 relative to any one 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 relative to any one 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 relative to any one of the amino acid sequences in (i); orAttorney Docket No.14640.0092-00304 (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 relative to any one 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 XA, XB, and XC, wherein: (a) XAis V; (b) XBis Q; and (c) XC is 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 relative to any one 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).Attorney Docket No.14640.0092-00304 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 relative to any one 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 relative to any one 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 XDand XE, wherein: (a) XDis T, P, or N; and (b) 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);Attorney Docket No.14640.0092-00304 (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, or 4 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one of the amino acid sequences in (i); or (iv) an amino acid sequence comprising one, two, or three but no more than four different amino acids relative to any one of the amino acid sequences in (i). 124. The AAV particle of any one of embodiments 100 or any one of embodiments 121-123, wherein [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 relative to any one 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 adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises [B]-[C] (SEQ ID NO: 2114), wherein: (i) [B] comprises X1, X2, and X3, wherein: (a) X1is Q or S; (b) X2is S, L, or A; and (c) X3 is S, Y, or T; and (ii) [C] comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943). 126. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant), wherein the AAV capsid variant comprises one, two, three, four, or all of: (i) an [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] comprisingAttorney Docket No.14640.0092-00304 optionally wherein [C] replaces position 577 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 relative to any one 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 relative to any one 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), numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0092-00304 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, 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, 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, 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, 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 XA, XB, and XC, wherein: (a) XAis T; (b) XBis N; and (c) XCis N, T, S, or K; and optionally wherein the AAV capsid variant comprises an amino acid modification, e.g., a conservative substitution, of any of the aforesaid amino acids in (a)-(c). 135. The AAV particle of embodiment 126 or 134, wherein [A]: (i) comprises TN, NS, NT, NK, or NN; (ii) is or comprises TNN, TNS, TNT, or TNK. 136. The AAV particle of any one of embodiments 126, 134, and 135, wherein [A]-[B] is or comprises: (i) TNNQSS (SEQ ID NO: 183), TNSSLY (SEQ ID NO: 648), TNTSAT (SEQ ID NO: 649), TNSSLS (SEQ ID NO: 647), or TNKSAT (SEQ ID NO: 651); (ii) an amino acid sequence comprising any portion of an amino acid sequence in (i), e.g., any 2, 3, 4, or 5 amino acids, e.g., consecutive amino acids, thereof; (iii) an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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:Attorney Docket No.14640.0092-00304 (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 relative to any one 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, 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, 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, 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, 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 X4and X5, wherein: (a) X4is T, N, or P; and (b) X5is 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.Attorney Docket No.14640.0092-00304 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 relative to any one 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 relative to any one 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 is present at amino acids corresponding to positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)) numbered according to the amino acid sequence of 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 is present at amino acids corresponding positions 571-592 (e.g., amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ IDAttorney Docket No.14640.0092-00304 NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)) numbered according to the amino acid sequence of 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., the positions of amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., the positions of amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)) numbered according to the amino acid sequence of 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, 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), 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), 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 the amino acid sequence of SEQ ID NO: 982. 153. The AAV particle of any one of embodiments 1-152, wherein the AAV capsid variant comprises an amino acid other than T at position 577, 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 AAV capsid variant comprises a Y at position 577, 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, numbered according to the amino acid sequence of SEQ ID NO: 138 or 982.Attorney Docket No.14640.0092-00304 156. The AAV particle of any one of embodiments 1-40, 59, 60, 67-98, 139, 140, and 146-155, wherein X1of [N2] corresponds to position 577 (e.g., Y577), X2of [N2] corresponds to position 578 (e.g., P588), X3of [N2] corresponds to position 579 (e.g., A579), X4of [N2] corresponds to position 580 (e.g., E580), and X5of [N2] corresponds to position 581 (e.g., V581) of the amino acid sequence 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, 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 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), 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 the amino acid sequence 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, 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), 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), 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.Attorney Docket No.14640.0092-00304 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, 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), 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), 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), 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, 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), 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]-Attorney Docket No.14640.0092-00304 [N2]-[N3]-[N4] replaces positions 574-579 (e.g., Q574, S575, S576, T577, T578, and A579), 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, 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), 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), 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, 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), 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), 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 the amino acid sequence of SEQ ID NO: 982.Attorney Docket No.14640.0092-00304 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, 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), 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), 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 the amino acid sequence 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 the amino acid sequence of 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 the amino acid sequence of 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 the amino acid sequence of 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 the amino acid sequence of SEQ ID NO: 982; (ii) XD of [N1] is present at position 574, XE of [N1] is present at position 575, and XF of [N1] is present at position 576, numbered according to the amino acid sequence of SEQ ID NO: 982;Attorney Docket No.14640.0092-00304 (iii) X1 of [N2] is present at position 577, X2 of [N2] is present at position 578, X3 of [N2] is present at position 579, X4 of [N2] is present at position 580, and X5 of [N2] is present at position 581, numbered according to the amino acid sequence of SEQ ID NO: 982; (iv) [N3] is present at positions 582-584, numbered according to the amino acid sequence of 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 the amino acid sequence of 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 the amino acid sequence of SEQ ID NO: 982; (ii) [N1] is present at positions 574-576, numbered according to the amino acid sequence of SEQ ID NO: 982; (iii) [N2] is present at positions 577-581, numbered according to the amino acid sequence of SEQ ID NO: 982; (iv) [N3] is present at positions 582-584, numbered according to the amino acid sequence of SEQ ID NO: 982; (v) [N4] is present at positions 585-586, numbered according to the amino acid sequence of SEQ ID NO: 982; (vi) [N2]-[N3] is present at positions 577-584, numbered according to the amino acid sequence of SEQ ID NO: 982; and / or (vii) [N0]-[N1]-[N2]-[N3]-[N4] is present at positions 571-586, numbered according to the amino acid sequence of 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 AAV 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 AAV capsid variant comprises, from N-terminus to C-terminus, [N1]-[N2]-[N3].Attorney Docket No.14640.0092-00304 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., the positions of amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., the positions of amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)), numbered according to the amino acid sequence of 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., the positions of amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., the positions of amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)), numbered according to the amino acid sequence of 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., the positions of amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., the positions of amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)), numbered according to the amino acid sequence of 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, numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0092-00304 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), 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), 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, 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), 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), 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 the amino acid sequence 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, 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), 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, andAttorney Docket No.14640.0092-00304 wherein [B]-[C] replaces positions 574-577 (e.g., Q574, S575, S576, and T577), 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 the amino acid sequence 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, 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), 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), 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 the amino acid sequence 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, 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), 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), numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0092-00304 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 the amino acid sequence 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, 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), 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), 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, 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), 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), 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 the amino acid sequence 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 the amino acid sequence of SEQ ID NO: 982.Attorney Docket No.14640.0092-00304 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 the amino acid sequence of SEQ ID NO: 138; or positions 585 and 586, numbered according to the amino acid sequence of 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 the amino acid sequence of 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, 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), 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), 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 the amino acid sequence of SEQ ID NO: 982. 234. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-233, wherein: (i) XAof [A] is present at position 571, XBof [A] is present at position 572, and XCof [A] is present at position 573, numbered according to the amino acid sequence of SEQ ID NO: 982; (ii) X1 of [B] is present at position 574, X2 of [B] is present at position 575, and X3 of [B] is present at position 576, numbered according to the amino acid sequence of SEQ ID NO: 982; (iii) [C] is present at positions 577-584, numbered according to the amino acid sequence of 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 the amino acid sequence of SEQ ID NO: 982. 235. The AAV particle of any one of embodiments 42, 52-66, 126, 134-145, and 198-234, wherein:Attorney Docket No.14640.0092-00304 (i) [A] is present at positions 571-573, numbered according to the amino acid sequence of SEQ ID NO: 982; (ii) [B] is present at positions 574-576, numbered according to the amino acid sequence of SEQ ID NO: 982; (iii) [C] is present at positions 577-584, numbered according to the amino acid sequence of SEQ ID NO: 982; (iv) [D] is present at positions 585-586, numbered according to the amino acid sequence of SEQ ID NO: 982; and / or (v) [A]-[B]-[C]-[D] is present at positions 571-586, numbered according to the amino acid sequence of 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., the positions of amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., the positions of amino acidsAttorney Docket No.14640.0092-00304 TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)), numbered according to the amino acid sequence of 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., the positions of amino acids TNNQSSTTAPATGTYNLQEIVP (SEQ ID NO: 736)) numbered according to the amino acid sequence of SEQ ID NO: 138, or positions 571-599 (e.g., the positions of amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)) numbered according to the amino acid sequence of 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, 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), 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), 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, 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), 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), 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, numbered according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0092-00304 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), 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), 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, 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), 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), 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, 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), 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), 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].Attorney Docket No.14640.0092-00304 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 adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) any one of the amino acid sequences provided in Table 1, 2A, 2B, 14, or 23-28; (b) an amino acid sequence comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 consecutive amino acids from any one of the amino acid sequences provided in Tables 1, 2A, 2B, 14, or 23-28; (c) an amino acid sequence comprising one, two, or three but no more than four different amino acids relative to any one of the amino acid sequences provided in Table 1, 2A, 2B, 14, or 23-28; or (d) an amino sequence comprising one, two, or three but no more than four modifications relative to any one of the amino acid sequences provided in Table 1, 2A, 2B, 14, or 23-28. 268. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 943, 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590, 1591-1593, 1598-1608, and 1610-1624;Attorney Docket No.14640.0092-00304 (b) an amino acid sequence comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 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 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 adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080; (b) an amino acid sequence comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 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 relative to the amino acid sequence of SEQ ID NOs: 943 or any one of SEQ ID NOs: 2064-2080. 270. An adeno-associated virus (AAV) particle comprising a viral genome comprising a frataxin (FXN)- encoding sequence (e.g., encoding a human FXN protein) and an AAV capsid variant (e.g., an AAV5 capsid variant) comprising: (a) the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1232, 1300, 1327, 1533, 1538, 1585, 1590, and 1591; (b) an amino acid sequence comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 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; orAttorney Docket No.14640.0092-00304 (d) an amino sequence comprising one, two, or three but no more than four modifications 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, at least 4, at least 5, at least 6, or at least 7 consecutive amino acids from SEQ ID NO: 943 or of any one of SEQ ID NOs: 946-966. 272. The AAV particle of embodiment 271, wherein the at least 3 consecutive amino acids comprise YPA. 273. The AAV particle of embodiment 271, wherein the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21). 274. The AAV particle of embodiment 271, wherein the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1). 275. The AAV particle of embodiment 271, wherein the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725). 276. The AAV particle of embodiment 271, wherein the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726). 277. The AAV particle of embodiment 271, wherein the amino acid sequence comprises YPAEVVQK (SEQ ID NO: 943). 278. The AAV particle of any one of embodiments 267, 268, and 270, wherein the AAV capsid variant comprises: (i) YTP; (ii) YTPS (SEQ ID NO: 26); (iii) YTPSL (SEQ ID NO: 7); (iv) YTPSLV (SEQ ID NO: 727); (v) 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 at least 3 consecutive amino acids comprise YPP;Attorney Docket No.14640.0092-00304 (ii) the at least 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the at least 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the at least 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the at least 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 at least 3 consecutive amino acids comprise YPP; (ii) the at least 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the at least 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the at least 6 consecutive amino acids comprise YPPSLE (SEQ ID NO: 733); (v) the at least 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 at least 3 consecutive amino acids comprise YPP; (ii) the at least 4 consecutive amino acids comprise YPPS (SEQ ID NO: 22); (iii) the at least 5 consecutive amino acids comprise YPPSL (SEQ ID NO: 2); (iv) the at least 6 consecutive amino acids comprise YPPSLV (SEQ ID NO: 729); (v) the at least 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 one 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 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 one of SEQ ID NOs: 946, 952, 953, and 954.Attorney Docket No.14640.0092-00304 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 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 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 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, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or ten modifications, but no more than ten modifications, , relative to the nucleotide sequence of SEQ ID NO: 944; or (ii) a nucleotide sequence comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or ten different nucleotides, 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, at least two, at least three, at least four, at least five, at least six, or at least seven modifications, but no more than ten modifications, relative to the nucleotide sequence of SEQ ID NO: 944; or (ii) a nucleotide sequence comprising at least one, at least two, at least three, at least four, at least five, at least six, or at least 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 AAV 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, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 consecutive amino acids from any one of SEQ ID NOs: 2024-2063;Attorney Docket No.14640.0092-00304 (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 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 AAV capsid variant comprises: (a) the amino acid sequence of any one of SEQ ID NOs: 1632-1733, 1735-1737, 1739, 1741, 1744-1749, 1751-1796, 1798-1800, 1802-1807, 1810, 1813-1815, 1818, 1822, 1823, 1829-1837, 1842- 2023, and 2087-2112; (b) an amino acid sequence comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 consecutive amino acids from any one of SEQ ID NOs: 1632-1733, 1735-1737, 1739, 1741, 1744-1749, 1751-1796, 1798- 1800, 1802-1807, 1810, 1813-1815, 1818, 1822, 1823, 1829-1837, 1842-2023, and 2087-2112; (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: 1632-1733, 1735-1737, 1739,Attorney Docket No.14640.0092-00304 1741, 1744-1749, 1751-1796, 1798-1800, 1802-1807, 1810, 1813-1815, 1818, 1822, 1823, 1829-1837, 1842-2023, and 2087-2112; or (d) an amino sequence comprising one, two, or three but no more than four modifications relative to the amino acid sequence of any one of SEQ ID NOs: 1632-1733, 1735-1737, 1739, 1741, 1744-1749, 1751-1796, 1798-1800, 1802-1807, 1810, 1813-1815, 1818, 1822, 1823, 1829-1837, 1842-2023, and 2087-2112. 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: 1632-1733, 1735-1737, 1739, 1741, 1744-1749, 1751-1796, 1798-1800, 1802-1807, 1810, 1813-1815, 1818, 1822, 1823, 1829-1837, 1842-2023, and 2087-2112, 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 / orAttorney Docket No.14640.0092-00304 (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, 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), 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, 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, 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, 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 the amino acid sequence of 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, 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 according to the amino acid sequence of SEQ ID NO: 138.Attorney Docket No.14640.0092-00304 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 according to the amino acid sequence of 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 according to the amino acid sequence of 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), 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 according to the amino acid sequence of 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 according to the amino acid sequence of 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 according to the amino acid sequence of 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 according to the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 982.Attorney Docket No.14640.0092-00304 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 according to the amino acid sequence of SEQ ID NO: 138 or 982; or (ii) T at position 574 and L at position 576, numbered according to the amino acid sequence of 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 according to the amino acid sequence of SEQ ID NO: 138 or 982; or (ii) R at position 576, numbered according to the amino acid sequence of 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 according to the amino acid sequence of 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 the amino acid sequence of 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 according to the amino acid sequence of 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 the amino acid sequence of 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 according to the amino acid sequence of 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 the amino acid sequence of 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:Attorney Docket No.14640.0092-00304 (i) R at position 576 and Y at position 577, numbered according to the amino acid sequence of 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 the amino acid sequence of 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 according to the amino acid sequence of 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 the amino acid sequence of 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 the amino acid sequence of 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 the amino acid sequence of 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 the amino acid sequence of 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 the amino acid sequence of 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 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, at least two, or at least three modifications,Attorney Docket No.14640.0092-00304 but not more than 30, not more than 20, or not more than 10 modifications, 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, at least two, or at least three, but no more than 30, no more than 20, or no more than 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 138. 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 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to SEQ ID NO: 138. [Embodiments 325-327 are intentionally absent.] 328. The AAV particle of any one of the embodiments provided herein, wherein the AAV 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 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto. 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 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto. 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 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to 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 80%, at least 85%, at least 90%, at least 95%, at least 96%, atAttorney Docket No.14640.0092-00304 least 97%, at least 98%, or at least 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, at least 4, at least 5, or at least 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%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 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, at least 4, at least 5, or at least 6 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), wherein: (i) the at least 3 consecutive amino acids comprise YPA; (ii) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21); (iii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1); (iv) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725); or (v) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726); wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982; (b) a VP2 protein comprising the amino acid sequence of positions 137- 731 of SEQ ID NO: 982; (c) a VP3 protein comprising the amino acid sequence of positions 193-731 of SEQ ID NO: 982; or (d) an amino acid sequence with at least 90% (e.g., at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to any one 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;Attorney Docket No.14640.0092-00304 (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 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to any one 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%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 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 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 982. 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 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto. 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 AAV 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 AAV 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, at least two, or at least three modifications, but not more than 30, not more than 20, or not more than 10 modifications, relative to the amino acid sequence of SEQ ID NO: 982.Attorney Docket No.14640.0092-00304 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 AAV capsid variant comprises an amino acid sequence comprising at least one, at least two, or at least three, but not more than 30, not more than 20, or not more than 10 different amino acids, relative to the amino acid sequence of SEQ ID NO: 982. 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 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity thereto. 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 an AAV particle comprising an AAV capsid comprising the amino acid sequence of SEQ ID NO: 138. 351. The AAV particle of any one of embodiments 1-66, 139, 140, 146-241, 267, 268, 270-289, and 294- 344, which has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of an AAV particle comprising an AAV capsid 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 an AAV particle comprising an AAV capsid 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, at least 2.2, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 3.0, at least 3.2, at least 3.5, at least 3.7, atAttorney Docket No.14640.0092-00304 least 4.0, at least 4.2, at least 4.5, at least 4.7, at least 4.9, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, or at least 35-fold greater as compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 15, at least 17, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, or at least 65-fold in the brain compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 10, at least 12, at least 15, at least 17, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 61, at least 62, at least 63, at least 64, or at least 65-fold in the brain compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 at least three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), e.g., as compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 15, at least 17, at least 20, at least 25, at least 30, at least 35, at least 40, or at least 45-fold in the brain of at least two to at least three species, e.g., a non-human primate and rodent (e.g., rat and / or mouse), compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 at least 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 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, atAttorney Docket No.14640.0092-00304 least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, or at least 225-fold, in the brain compared to an AAV particle comprising an AAV capsid comprising the amino acid 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, at least 25, at least 30, or at least 35-fold, as compared to an AAV particle comprising an AAV capsid comprising the amino acid 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, at least 2.2, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 3.0, at least 3.2, at least 3.5, at least 3.7, at least 4.0, at least 4.2, at least 4.5, at least 4.7, at least 4.9, or at least 5-fold as compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 3, at least 3.5, at least 4, at least 4.5, at least 5, at least 5.5, at least 6, or at least 6.5-fold in a spinal cord region compared to an AAV particle comprising an AAV capsid comprising the amino acid 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.Attorney Docket No.14640.0092-00304 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 an AAV particle comprising an AAV capsid 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 an AAV particle comprising an AAV capsid 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, at least 2, or at least 2.5-fold, as compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 an AAV particle comprising an AAV capsid 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 4, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50-fold in the heart compared to an AAV particle comprising an AAV capsid comprising the amino acid sequence of SEQ ID NO: 982, e.g., when measured by an assay as described in Example 4.Attorney Docket No.14640.0092-00304 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 an AAV particle comprising an AAV capsid 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 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, or at least 35-fold in the muscle compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 an AAV particle comprising an AAV capsid 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 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 110, at least 115, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 185, or at least 190-fold in the liver compared to an AAV particle comprising an AAV capsid comprising the amino acid 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 protein, Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 protein 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 protein, Rep52 protein, and / or a Rep40 protein (e.g., a Rep78 protein 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.Attorney Docket No.14640.0092-00304 [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 cell comprising a viral genome comprising a frataxin (FXN)-encoding sequence and a nucleic acid encoding an AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle. 451. The method of embodiment 450, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the host cell. 452. The method of embodiment 450 or 451, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell. 453. The method of embodiment 452, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule. 454. A pharmaceutical composition comprising the AAV particle of any one of embodiments 1-381, and a pharmaceutically acceptable excipient. 455. A method of delivering a frataxin protein to a subject, comprising administering an effective amount of the pharmaceutical composition of embodiment 454 or the AAV particle of any one of embodiments 1-381.Attorney Docket No.14640.0092-00304 456. The method of embodiment 455, wherein the frataxin protein is delivered to a cell or tissue of the CNS (e.g., a cell or tissue of a brain or spinal cord region). 457. The method of embodiment 456, 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. [Embodiment 458 is intentionally absent.] 459. The method of embodiment 455 or 456, wherein the cell or tissue of the CNS comprises a neuron, a sensory neuron, a motor neuron, an astrocyte, a glial cell, or an 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 a disorder associated with FXN deficiency. 464. The method of embodiment 460 or 461, wherein the subject has, has been diagnosed with having, or is at risk of having Friedreich's Ataxia. 465. A method of treating a disorder associated with FXN deficiency 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 disorder associated with FXN deficiency. 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.Attorney Docket No.14640.0092-00304 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 Friedreich's Ataxia (FA). 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. [Embodiments 474-475 are intentionally absent.] 476. The method of any one of embodiments 465-474, wherein administration of the AAV particle results in an increased presence, level, and / or activity of a frataxin gene, mRNA, protein, or a combination thereof. 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, or a neuromuscular disorder.Attorney Docket No.14640.0092-00304 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, or a neuromuscular disorder. 482. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the encoded frataxin (FXN) protein comprises an amino acid sequence of SEQ ID NO: 1825, or an amino acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the amino acid sequence of SEQ ID NO: 1825, wherein, optionally, the encoded FXN protein is a human FXN protein. 483. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the FXN-encoding sequence comprises a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to the nucleotide sequence of SEQ ID NO: 1824. 484. The AAV particle, pharmaceutical composition, cell, method, or use of any one of the embodiments provided herein, wherein the frataxin-encoding sequence comprises a nucleotide sequence that is at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to the nucleotide sequence of SEQ ID NO: 1824. 485. The AAV particle of embodiment 483 or embodiment 484, wherein the frataxin-encoding sequence comprises a nucleotide sequence at least 95% identical to the nucleotide sequence of SEQ ID NO: 1824. 486. The AAV particle of any one of embodiments 483-485, wherein the frataxin-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824.Attorney Docket No.14640.0092-00304 487. The AAV particle of any one of embodiments 483-486, wherein the frataxin-encoding sequence consists of the nucleotide sequence of SEQ ID NO: 1824. 488. The AAV particle of any one of embodiments 482-487, wherein the AAV capsid variant comprises at least 4, at least 5, at least 6, at least 7, or 8 consecutive amino acids from the amino acid sequence of YPAEVVQK (SEQ ID NO: 943), and wherein the AAV capsid variant comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 739. 489. The AAV particle of embodiment 488, wherein: (i) the at least 4 consecutive amino acids comprise YPAE (SEQ ID NO: 21), optionally wherein YPAE (SEQ ID NO: 21) is present at positions 577-580 numbered according to the amino acid sequence of SEQ ID NO: 982; (ii) the at least 5 consecutive amino acids comprise YPAEV (SEQ ID NO: 1), optionally wherein YPAEV (SEQ ID NO: 1) is present at positions 577-581 numbered according to the amino acid sequence of SEQ ID NO: 982; (iii) the at least 6 consecutive amino acids comprise YPAEVV (SEQ ID NO: 725), optionally wherein YPAEVV (SEQ ID NO: 725) is present at positions 577-582 numbered according to the amino acid sequence of SEQ ID NO: 982; or (iv) the at least 7 consecutive amino acids comprise YPAEVVQ (SEQ ID NO: 726), optionally wherein YPAEVVQ (SEQ ID NO: 726) is present at positions 577-583 numbered according to the amino acid sequence of SEQ ID NO: 982. 490. The AAV particle of embodiment 488 or 489, wherein the AAV capsid variant comprises the amino acid sequence of YPAEVVQK (SEQ ID NO: 943) present at positions 577-584 numbered according to SEQ ID NO: 982. 491. The AAV particle of any one of embodiments 488-490, wherein the AAV capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 982; or (ii) a VP2 protein comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 738. 492. The AAV particle of any one of embodiments 488-491, wherein the AAV capsid variant comprises: (i) a VP1 protein comprising an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982; (ii) a VP2 protein comprising an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738; orAttorney Docket No.14640.0092-00304 (iii) a VP3 protein comprising an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 739. 493. The AAV particle of any one of embodiments 488-492, wherein the AAV capsid variant comprises (i) a VP1 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 982; (ii) a VP2 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 738; or (iii) a VP3 protein comprising or consisting of the amino acid sequence of SEQ ID NO: 739; or wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 984 or a sequence at least 90% identical thereto. 494. The AAV particle of any one of the embodiments provided herein, wherein the viral genome further comprises a promoter operably linked to the FXN-encoding sequence. 495. The AAV particle of embodiment 494, wherein the promoter comprises a human elongation factor 1Į-subunit (EF1Į) promoter, a cytomegalovirus (CMV) immediate-early enhancer and / or promoter, a chicken ȕ-actin (CBA) promoter, a CAG 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, a 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 chain (NFL) or neurofilament heavy chain (NFH) promoter, a ȕ-globin minigene nȕ2 promoter, a preproenkephalin (PPE) promoter, a 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 functional fragment or truncation of any of the foregoing. 496. The AAV particle of embodiment 495, wherein the promoter comprises a CMV promoter. 497. The AAV particle of embodiment 495, wherein the promoter comprises a CBA promoter. 498. The AAV particle of embodiment 497, wherein the promoter is or comprises a truncated CBA promoter. 499. The AAV particle of embodiment 498, wherein the truncated CBA promoter is 50-400 nucleotides in length (e.g., 100-332 nucleotides in length).Attorney Docket No.14640.0092-00304 500. The AAV particle of embodiment 499, wherein the truncated CBA promoter comprises or consists of the nucleotide sequence of any one of SEQ ID NOs: 1738, 1740, or 1742 or a nucleotide sequence that is at least 95% identical to any one of SEQ ID NOs: 1738, 1740, or 1742. 501. The AAV particle of embodiment 496, wherein the promoter comprises a truncated CMV promoter. 502. The AAV particle of embodiment 501, wherein the truncated CMV promoter is 109 nucleotides in length. 503. The AAV particle of embodiment 502, wherein the truncated CMV promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 1750 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1750. 504. The AAV particle of any one of embodiments 494-593, wherein the viral genome further comprises a microRNA (miR) binding site, e.g., a miR binding site that modulates, e.g., reduces, expression of the FXN protein encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed. 505. The AAV particle of embodiment 504, wherein the miR binding site is fully or partially complementary to a miRNA expressed in a cell or tissue of the liver. 506. The AAV particle of embodiment 504 or embodiment 505, wherein the viral genome comprises at least 1, 2, 3, 4, or 5 copies of the miR binding site. 507. The AAV particle of embodiment 506, wherein the viral genome comprises at least 3 copies of the miR binding site, optionally wherein the viral genome has 3 copies of the miR binding site. 508. The AAV particle of embodiment 507, wherein the 3 copies of the miR binding site are identical, optionally wherein the 3 copies of the miR binding site are continuous. 509. The AAV particle of any one of embodiments 504-508, wherein the miR binding site is or comprises a miR122 binding site. 510. The AAV particle of any one of embodiments 504-509, wherein the viral genome encodes at least 1- 5 copies, e.g., 3 copies, of the miR122 binding site.Attorney Docket No.14640.0092-00304 511. The AAV particle of embodiment 510, wherein the viral genome encodes 3 copies of the miR122 binding site, optionally wherein the 3 copies of the miR122 binding site are identical, further optionally wherein the 3 copies of the miR122 binding site are continuous. 512. The AAV particle of embodiment 510 or embodiment 511, wherein each copy of the miR122 binding site comprises or consists of the nucleotide sequence of SEQ ID NO: 1827. 513. The AAV particle of any one of embodiments 504-512, wherein the viral genome comprises a miR122 binding site series comprising the nucleotide sequence of SEQ ID NO: 1826 or a sequence having one, two, three, four, five, six, seven, eight, nine, or at most ten substitutions relative to the nucleotide sequence of SEQ ID NO: 1826. 514. The AAV particle of any one of embodiments 494-513, wherein the viral genome further comprises at least one inverted terminal repeat (ITR) region, optionally wherein the at least one ITR region is an AAV2 ITR. 515. The AAV particle of embodiment 514, wherein the viral genome comprises a 5’ ITR region and a 3’ ITR region, optionally wherein the 5’ ITR region and the 3’ ITR region is each an AAV2 ITR. 516. The AAV particle of embodiment 515, wherein: the 5’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or the 3’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. 517. The AAV particle of any one of embodiments 494-517, wherein the viral genome further comprises an intron region. 518. The AAV particle of embodiment 517, wherein the intron region comprises an immediate-early 1 (ie1) intron region and / or a hemoglobin-beta (HB) intron region. 519. The AAV particle of any one of embodiments 494-518, wherein the viral genome further comprises an exon region. 520. The AAV particle of embodiment 519, whereinAttorney Docket No.14640.0092-00304 (a) the exon region comprises an ie1 exon region and / or an HB exon region, and / or (b) the intron region comprises: an ie1 intron 1 comprising or consisting of the nucleotide sequence of SEQ ID NO: 1819 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or a hBglobin intron 2 comprising the nucleotide sequence of SEQ ID NO: 1820 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. 521. The AAV particle of any one of embodiments 494-510, wherein the viral genome further comprises a polyadenylation (polyA) region. 522. The AAV particle of embodiment 521, wherein the polyA region comprises a human growth hormone (hGH) polyA region, optionally wherein the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. 523. The AAV particle of any one of embodiments 494-522, wherein the encoded FXN protein is a wildtype frataxin protein, optionally wherein the encoded FXN protein is not a cynomolgus monkey FXN protein, further optionally wherein the encoded FXN protein is a human frataxin protein. 524. The AAV particle of embodiment 523, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1797. 525. The AAV particle of embodiment 523, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1801. 526. The AAV particle of embodiment 523, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1808.Attorney Docket No.14640.0092-00304 527. The AAV particle of any one of embodiment 523, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1809. 528. The AAV particle of any one of embodiments 494-527, wherein the viral genome is single-stranded. 529. The AAV particle of any one of embodiments 494-527, wherein the viral genome is self- complementary. 530. The AAV particle of any one of the embodiments provided herein, wherein the viral genome comprises: (i) a promoter; and (ii) a FXN-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824. 531. The AAV particle of embodiment 530, wherein the viral genome further comprises a 5’ inverted terminal repeat (ITR) region and / or a 3’ ITR region. 532. The AAV particle of embodiment 530 or embodiment 531, wherein the viral genome comprises, e.g., in 5’ to 3’ order: (i) a 5’ ITR region; (ii) a promoter; (iii) a FXN-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (iv) at least one miR122 binding site; and (v) a 3’ ITR region. 533. The AAV particle of embodiment 532, wherein the viral genome comprises, e.g., in 5’ to 3’ order: (i) a 5’ ITR region; (ii) a promoter; (iii) an intron and / or exon region;Attorney Docket No.14640.0092-00304 (iv) a FXN-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (v) at least one miR122 binding site; and (vi) a 3’ ITR region. 534. The AAV particle of embodiment 533, wherein the viral genome comprises, e.g., in 5’ to 3’ order: (i) a 5’ ITR region; (ii) a promoter; (iii) an intron and / or exon region; (iv) a FXN-encoding sequence comprising the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (v) at least one miR122 binding site; (vi) a polyadenylation (polyA) region; and (vi) a 3’ ITR region, optionally wherein the viral genome further comprises a filler sequence. 535. The AAV particle of embodiment 534, wherein: (i) the 5’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 1742 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding region comprises the nucleotide sequence of SEQ ID NO: 1824 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises a miR122 binding site series comprising the nucleotide sequence of SEQ ID NO: 1826 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto;Attorney Docket No.14640.0092-00304 (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; optionally wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1841 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, further optionally wherein the filler region is positioned 3’ to the polyA region and 5’ to the 3’ ITR region. 536. The AAV particle of embodiment 535, wherein the promoter consists of the nucleotide sequence of SEQ ID NO: 1742 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. 537. The AAV particle of embodiment 534, wherein: (i) the 5’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 1750 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding region comprises the nucleotide sequence of SEQ ID NO: 1824 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises a miR122 binding site series comprising the nucleotide sequence of SEQ ID NO: 1826 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto;Attorney Docket No.14640.0092-00304 (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; optionally wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1840 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, further optionally wherein the filler region is positioned 3’ to the polyA region and 5’ to the 3’ ITR region. 538. The AAV particle of embodiment 537, wherein the promoter consists of the nucleotide sequence of SEQ ID NO: 1750 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. 539. The AAV particle of embodiment 534, wherein: (i) the 5’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 1738 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding region comprises the nucleotide sequence of SEQ ID NO: 1824 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises a miR122 binding site series comprising the nucleotide sequence of SEQ ID NO: 1826 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto;Attorney Docket No.14640.0092-00304 (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; optionally wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1838 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, further optionally wherein the filler region is positioned 3’ to the polyA region and 5’ to the 3’ ITR region. 540. The AAV particle of embodiment 539, wherein the promoter consists of the nucleotide sequence of SEQ ID NO: 1738 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. 541. The AAV particle of embodiment 534, wherein: (i) the 5’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 1740 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding region comprises the nucleotide sequence of SEQ ID NO: 1824 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises a miR122 binding site series comprising the nucleotide sequence of SEQ ID NO: 1826 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto;Attorney Docket No.14640.0092-00304 (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a sequence that is at least 90% identical (e.g at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3’ ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; optionally wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1839 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, further optionally wherein the filler region is positioned 3’ to the polyA region and 5’ to the 3’ ITR region. 542. The AAV particle of embodiment 541, wherein the promoter consists of the nucleotide sequence of SEQ ID NO: 1740 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. [Embodiments 543-696 are intentionally absent.] 697. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome, wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, wherein the VP1 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (b) a VP2 protein comprising the amino acid sequence of SEQ ID NO: 738 or an amino acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, wherein the VP2 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / or (c) a VP3 protein comprising the amino acid sequence of SEQ ID NO: 739 or an amino acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, wherein the VP3 protein comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and wherein the viral genome comprises: (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at leastAttorney Docket No.14640.0092-00304 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1797; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1801; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1808; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to the nucleotide sequence of SEQ ID NO: 1809. 698. The AAV particle of embodiment 697, wherein: (a) the VP1 protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 982; (b) a VP2 protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 738; and / or (c) a VP3 protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 739. 699. The AAV particle of embodiment 698, wherein: (a) the VP1 protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 982; (b) a VP2 protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 738; and / or (c) a VP3 protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 739. 700. The AAV particle of any one of embodiments 697-699, wherein: (a) the VP1 protein comprises the amino acid sequence of SEQ ID NO: 982; (b) the VP2 protein comprises the amino acid sequence of SEQ ID NO: 738; and / or (c) the VP3 protein comprises the amino acid sequence of SEQ ID NO: 739.Attorney Docket No.14640.0092-00304 701. The AAV particle of embodiment 701, wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 984 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto. 702. The AAV particle of embodiment 701, wherein the AAV capsid variant is encoded by the nucleotide sequence of SEQ ID NO: 984. 703. The AAV particle of any one of embodiments 482-702, further comprising a nucleic acid encoding a Rep protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein. 704. A vector encoding the AAV particle of any one of embodiments 660-703. 705. A cell comprising the AAV particle of any one of embodiments 660-703 or the vector of embodiment 704. 706. The cell of embodiment 705, which is a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell. 707. A method of making an AAV particle of any one of embodiments 482-706, wherein the method comprises: (i) providing a cell comprising a viral genome comprising a frataxin (FXN)-encoding sequence and a nucleic acid encoding an AAV capsid variant; and (ii) incubating the cell under conditions suitable to encapsulate the viral genome in the AAV capsid variant; thereby making the AAV particle. 708. The method of embodiment 707, wherein: the viral genome comprises a nucleotide sequence of any one of SEQ ID NOs: 1797, 1801, 1808, and 1809, or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to any one of SEQ ID NOs: 1797, 1801, 1808, and 1809; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 982. 709. The method of embodiment 708, further comprising, prior to step (i), introducing a nucleic acid comprising the viral genome into the cell.Attorney Docket No.14640.0092-00304 710. The method of embodiment 708 or embodiment 709, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell. 711. The method of any one of embodiments 707-710, wherein the cell comprises a mammalian cell, an insect cell, or a bacterial cell. 712. The method of embodiment 711, wherein the cell is an HEK293 cell or an Sf9 cell. 713. A pharmaceutical composition comprising the AAV particle of any one of embodiments 485-703 and a pharmaceutically acceptable excipient. 714. A method of delivering a FXN protein to a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 482-704, thereby delivering the FXN protein. 715. The method of embodiment 714, wherein the subject has, has been diagnosed with having, or is at risk of having a disorder associated with FXN deficiency, optionally wherein the disorder is Friedreich’s Ataxia (FA). 716. A method of treating a disorder associated with frataxin (FXN) deficiency in a subject, comprising administering an effective amount of the pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 485-703, thereby treating the disorder, optionally wherein the subject has, has been diagnosed with having, or is at risk of having a disorder associated with FXN deficiency, further optionally wherein the disorder is FA. 717. The method of any one of embodiments 714-716, wherein the subject has a reduced level of FXN protein or gene expression as compared to a healthy individual. 718. The method of embodiment 716 or embodiment 717, wherein the treatment results in a 0.5-3x increase in the subject’s FXN protein level as compared to baseline. 719. The method of any one of embodiments 716-718, wherein the treatment results in amelioration of at least one symptom of FA. 720. The method of embodiment 719, wherein the at least one symptom of FA includes impaired sensory functions, impaired motor function, e.g., ataxia and / or involuntary movements, fatigue, chronic pain,Attorney Docket No.14640.0092-00304 seizures, impaired speech, sleep disturbances, metabolic disorders, e.g., diabetes, and increased spasticity. 721. The method of any one of embodiments 716-718, wherein the treatment stabilizes, slows the progression of, or improves the subject’s FA as determined by the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and / or the International Cooperative Ataxia Rating Scale (ICARS). 722. The method of any one of embodiments 716-718, wherein the treatment slows the subject’s progression of FA as measured by mFARS, SARA, or ICARS relative to an individual with the disorder associated with FXN deficiency (e.g., FA) who has not been administered the pharmaceutical composition or the AAV particle. 723. The method of any one of embodiments 714-722, wherein the subject is a human. 724. The method of any one of embodiments 714-723, wherein the AAV particle is administered to the subject intravenously, intracerebrally (IC), via intrathalamic (ITH) administration, intramuscularly, intrathecally, intracerebroventricularly, via intraparenchymal administration, via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration, or via intra-cisterna magna injection (ICM). 725. The method of any one of embodiments 714-724, wherein the AAV particle is delivered to a cell, tissue, or region of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum, or a combination thereof. 726. The method of any one of embodiments 714-725, further comprising evaluating (e.g., measuring the level of FXN gene, FXN mRNA, and / or FXN protein expression) in the subject (e.g., in a cell, tissue, or fluid of the subject), optionally wherein the level of FXN protein is measured by an assay described herein. 727. The method of embodiment 726, wherein the level of FXN protein expression is measured by an enzyme-linked immunosorbent assay (ELISA), a Western blot, an immunohistochemistry assay, or a frataxin biofluid assay. 728. The method of embodiment 726 or embodiment 727, wherein the cell or tissue is a cell or tissue of the central nervous system (e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen,Attorney Docket No.14640.0092-00304 caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) or a peripheral cell or tissue (e.g., the liver, heart, and / or muscle). 729. The method of any one of embodiments 716-728, wherein the treatment results in an increase in: (i) the level of FXN protein or FXN gene expression in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, 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, optionally wherein the level of FXN protein or gene expression is increased by 0.5-3x as compared to baseline; and / or (ii) the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, 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. 730. The method of any one of embodiments 714-729, further comprising administering to the subject at least one additional therapeutic agent and / or therapy. 731. The method of embodiment 730, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy for treating the disorder associated with FXN deficiency (e.g., Friedreich’s ataxia), optionally wherein the at least one additional therapeutic agent and / or therapy comprises omaveloxolone or idebenone. 732. The method of embodiment 730, wherein the at least one additional therapeutic agent and / or therapy comprises an immunosuppressant, optionally wherein the immunosuppressant is a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine. 733. The pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 485-703 for use in the treatment of a disorder associated with FXN deficiency in a subject, optionally wherein the disorder is Friedreich’s Ataxia (FA). 734. Use of an effective amount of the pharmaceutical composition of embodiment 713 or the AAV particle of any one of embodiments 485-703 in the manufacture of a medicament for the treatment of a disorder associated with FXN deficiency in a subject, optionally wherein the disorder Friedreich’s Ataxia (FA).Attorney Docket No.14640.0092-00304 735. The pharmaceutical composition or use of embodiment 733 or embodiment 734, wherein the subject has, has been diagnosed with having, or is at risk of having FA.

[0071] 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

[0072] FIGs.1A-1D show immunohistochemistry images from various CNS and peripheral tissues isolated from NHPs (cynomolgus macaques) at 28 days post intravenous administration of AAV particles comprising the TTN-002 capsid variant (top panels) or AAV9 control capsid (bottom panels) and a self- complementary genome encoding a cynomolgus monkey 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.

[0073] FIGs.2A-2D depict frataxin expression and the number of viral genomes per cell in the heart (FIG.2A); cerebellum (FIG.2B); lumbar and DRG (FIG.2C); and liver (FIG.2D).

[0074] FIG.3 shows an exemplary ITR-to-ITR construct encoding FXN.

[0075] FIG.4A shows biodistribution of AAV particles in the cerebellum of wildtype (“WT”) or frataxin-deficient (“FXN-deficient”) mice. The AAV particles comprise a TTN-002 capsid encapsulating a viral genome comprising SEQ ID NO: 1797 (“TTN-002_FXN”).

[0076] FIG.4B shows expression of human frataxin (“hFXN”) in the cerebellum of wildtype (“WT”) or frataxin-deficient (“FXN-deficient”) mice after administration of AAV particles comprising a TTN-002 capsid encapsulating a viral genome comprising SEQ ID NO: 1797 (“TTN-002_FXN”). DETAILED DESCRIPTION Overview

[0077] Described herein, inter alia, are compositions comprising an AAV capsid variant comprising a sequence encoding a FXN protein, e.g., a human FXN protein. In some embodiments, the present disclosure provides a method for delivering the AAV capsid variant comprising the sequence encoding the FXN 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 FXN protein, e.g., a human FXNAttorney Docket No.14640.0092-00304 protein, to a cell or tissue in a subject. The AAV capsid variants described herein have enhanced CNS tropism compared to other cells or tissues in the body, e.g., liver and / or the DRG.

[0078] AAV 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 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.

[0079] 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 FXN. The genome of the virus may encode a FXN 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 FXN protein, e.g., a wildtype human FXN protein. In some embodiments, the target cell is a CNS cell. In some embodiments, the target tissue is a CNS tissue. The target CNS tissue may be brain tissue.

[0080] Without being bound by theory, it is believed, in some embodiments, that expression vectors, e.g., an adeno-associated viral vector (AAVs) or AAV particle, e.g., an AAV particle described herein, can be used to administer and / or deliver a gene encoding FXN (e.g., human FXN) preferentially to the CNS (e.g., the brain or the spinal cord).

[0081] Provided herein are compositions and methods which may provide for improved features compared to prior AAV-mediated enzyme replacement approaches, including (i) increased biodistribution of the AAV particle throughout the CNS (e.g., the cortex, striatum, thalamus, cerebellum, brainstem, and / or spinal cord) of the subject, (ii) elevated FXN expression, e.g., FXN mRNA or protein expression, in multiple brain regions (e.g., cortex, thalamus, and brain stem) of the subject; and (iii) reduced biodistribution of the AAV particle in the liver and / or DRG of the subject.

[0082] Also provided herein are AAV capsid variants (e.g., AAV5 capsid variants) with improved properties compared to wildtype AAV5 and / or wildtype AAV9, such as (i) increased penetrance through the blood brain barrier following intravenous administration, (ii) wider distribution throughout the multiple brain regions, e.g., temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate,Attorney Docket No.14640.0092-00304 thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, cerebellum, (iii) elevated FXN expression in multiple brain regions, (iv) wider distribution in one or more peripheral tissues, e.g., the heart and / or muscle, and / or (v) elevated FXN expression in one or more peripheral tissues. In some embodiments, the AAV capsids described herein enhance the delivery of FXN to multiple regions of the brain including, for example, the temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum. In some embodiments, the AAV capsids described herein enhance the delivery of FXN to the forebrain. In some embodiments, the AAV capsids described herein enhance the delivery of FXN to the frontal cortex. In some embodiments, the AAV capsids described herein enhance the delivery of FXN to the spinal cord. In some embodiments, the AAV capsids described herein enhance the delivery of FXN to the cerebellum. In some embodiments, the AAV capsids described herein enhance the delivery of FXN to the dentate nucleus.

[0083] As demonstrated in the Examples, the AAV capsid variants with enhanced brain tropism described herein are capable of significantly increasing FXN mRNA expression in the brain.

[0084] Thus, the compositions and methods described herein can be used in the treatment of Friedreich’s Ataxia (FA). In some embodiments, the disclosure provides an AAV particle comprising one of the AAV capsid variants disclosed herein and an AAV viral genome comprising a nucleotide sequence comprising a truncated promoter region and a sequence encoding a FXN protein (e.g., comprising the nucleotide sequence of any one of SEQ ID NOs: 1797, 1801, 1808, 1809) for use in treating FA. I. Compositions Adeno-associated viral (AAV) particles

[0085] AAVs have a genome of about 5,000 nucleotides in length and contain 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) 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 toAttorney Docket No.14640.0092-00304 VP1 and VP2, however, the percent difference as compared to the parent sequence will be greatest for VP3 since it is the shortest sequence of the three. Though described here in relation to the amino acid sequence, the nucleic acid sequence encoding these proteins can be similarly described. Together, the three capsid proteins assemble to create the AAV capsid. Without being bound by theory, the AAV capsid typically comprises a molar ratio of 1:1:10 of VP1:VP2:VP3.

[0086] The AAV vector 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.

[0087] AAV vectors have been investigated for delivery of gene therapeutics because of several unique features. Non-limiting examples of the features include (i) the ability to infect both dividing and non-dividing cells; (ii) a broad host range for infectivity, including human cells; (iii) wild-type AAV has not been associated with any disease and has not been shown to replicate in infected cells; (iv) the lack of cell-mediated immune response against the vector, and (v) the non-integrative nature in a host chromosome thereby reducing potential for long-term genetic alterations. Moreover, infection with AAV vectors 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).

[0088] Typically, AAV vectors for FXN protein 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 defective AAV vectors may lack most or all coding sequences and essentially only contain one or two AAV ITR sequences and a sequence encoding a FXN protein.

[0089] In some embodiments, the AAV particles of the present disclosure may be introduced into mammalian cells.

[0090] AAV vectors may be modified to enhance the efficiency of delivery. Such modified AAV vectors 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.

[0091] In other embodiments, AAV particles of the present disclosure may be used to deliver FXN protein to the central nervous system (see, e.g., U.S. Pat. No.6,180,613; the contents of which are herein incorporated by reference in their entirety) or to specific tissues of the CNS.

[0092] 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.

[0093] In some embodiments, AAV capsid variants disclosed herein comprise one or more modifications (e.g., one or more insertions and / or 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 according to SEQ ID NO: 138. In some embodiments, the AAV5 loop VIII region is present (is located) at amino acids corresponding to positions 571-579 of the amino acid sequence of SEQ ID NO: 138. In some embodiments, the AAV5 loop VIII region (e.g., positions 571-579, e.g.,Attorney Docket No.14640.0092-00304 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, the AAV5 loop VIII is present (is located) at amino acids corresponding to positions 571-599 (e.g., amino acids TNNQSSYPAEVVQKTAPATGTYNLQEIVP (SEQ ID NO: 756)) of the amino acid sequence of 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).

[0094] The AAV particles and payloads of the disclosure may be delivered to one or more target cells, tissues, organs, or organisms. In some embodiments, the AAV particles of the disclosure demonstrate enhanced tropism for a target cell type, tissue, or organ. As a non-limiting example, the AAV particle may have enhanced tropism for cells and tissues of the central or peripheral nervous systems (CNS and PNS, respectively). In some embodiments, an AAV particle of the disclosure may, in addition, or alternatively, have decreased tropism for a cell-type, tissue or organ.

[0095] 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.

[0096] In some embodiments, the AAV is a recombinant AAV. In some embodiments, the wild-type AAV viral genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length. In some embodiments, 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.

[0097] AAV particles described herein may be produced recombinantly and may be based on AAV reference sequences. In addition to single stranded AAV viral genomes (e.g., ssAAVs), the present disclosure also provides for self-complementary AAV (scAAV) viral genomes. scAAV viral genomesAttorney Docket No.14640.0092-00304 contain 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 is an scAAV. In some embodiments, the AAV particle is an ssAAV.

[0098] 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).

[0099] 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

[0100] 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 isolated nucleic acid. In some embodiments, the nucleic acid encoding the peptide is a recombinant nucleic acid.

[0101] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of the CNS. The cell of the CNS may be, but is not limited to, neurons (e.g., excitatory, inhibitory, motor, sensory, autonomic, sympathetic, parasympathetic, Purkinje, Betz, etc.), glial cells (e.g., microglia, astrocytes, oligodendrocytes) and / or supporting cells of the brain such as immune cells (e.g., T cells). The tissue of the CNS may be, but is not limited to, the cortex (e.g., frontal, parietal, occipital, temporal), thalamus, hypothalamus, striatum, putamen, caudate nucleus, hippocampus, entorhinal cortex, basal ganglia, or deep cerebellar nuclei. In some embodiments, the tissue of the CNS is a temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, cerebellum, cervical spinal cord, thoracic spinal cord, or lumbar spinal cord.

[0102] 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.

[0103] 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.

[0104] 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.,Attorney Docket No.14640.0092-00304 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.

[0105] 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.

[0106] In some embodiments, the peptide may increase distribution of an AAV particle to a cell, region, or tissue of a muscle. In some embodiments, the muscle is a heart muscle (e.g., a heart atrium or a heart ventricle) or a quadriceps. In some embodiments, the peptide may increase distribution of an AAV particle to a muscle cell, region, or tissue after intravenous administration.

[0107] In some embodiments a peptide may comprise a sequence as set forth in Table 1 (e.g., comprising the amino acid sequence of any one of SEQ ID NOs: 1021, 1024, 1027, 1112, 1142, 1214, 1232, 1254, 1300, 1310, 1327, 1331, 1342, 1419, 1453, 1533, 1538, 1539, 1575, 1578, 1583-1587, 1590- 1593, 1598-1624, or 2064-2079). In some embodiments a peptide may comprise a sequence as set forth in Table 2A or 2B. In some embodiments, the peptide may comprise a sequence set forth in Tables 14 or 23-28. Table 1. Exemplary Peptide SequencesAttorney Docket No.14640.0092-00304 Table 2A. Exemplary Peptide SequencesTable 2B. Exemplary Peptide Sequences

[0108] In some embodiments, a peptide comprises an amino acid sequence having the formula [N2]- [N3], wherein [N2] comprises X1, X2, X3, X4, and X5and [N3] comprises the amino acid sequence of VQK, VQN, EQK, VKK, VHK, VQQ, or LQK. In some embodiments, X1of [N2] is Y, N, C, or T. In some embodiments, X2of [N2] is P, E, K, T, or Q. In some embodiments, X3of [N2] is A or P. In some embodiments, X4of [N2] is E, S, D, or A. In some embodiments, X5of [N2] is V, L, or E. In some embodiments, X1 of [N2] is Y. In some embodiments, X2 of [N2] is P. In some embodiments, X3 of [N2] is A. In some embodiments, X4of [N2] is E. In some embodiments, X5of [N2] is V. In some embodiments, the amino acid sequence of [N3] comprises VQK. In some embodiments, the amino acid sequence of [N3] consists of VQK. In some embodiments, [N2]-[N3] replaces an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

[0109] In some embodiments, a peptide comprises an amino acid sequence having the formula [N2]- [N3], wherein [N2] comprises 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, X1of [N2] is Y, N, or C. In some embodiments, X1of [N2] is Y or N. In some embodiments, X2of [N2] is P, K, T, or Q. In some embodiments, X2of [N2] is P, T, or Q. In some embodiments, X3of [N2] is A or P. In some embodiments, X3of [N2] is A. In some embodiments, X4of [N2] is E, S, or A. In some embodiments, X5of [N2] is V, L, or E. In some embodiments, X5of [N2] is V or L. In some embodiments, X1of [N2] is Y. In some embodiments, X2of [N2] is P. In some embodiments, X3of [N2] is A. In some embodiments, X4of [N2] is E. In some embodiments, X5of [N2] is V. 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), YQAEAttorney Docket No.14640.0092-00304 (SEQ ID NO: 25), YTPS (SEQ ID NO: 26), YPAA (SEQ ID NO: 27), NPAE (SEQ ID NO: 28), CPAE (SEQ ID NO: 29), THAS (SEQ ID NO: 30), PAEV (SEQ ID NO: 17), PPSL (SEQ ID NO: 31), KAEV (SEQ ID NO: 32), TAEV (SEQ ID NO: 16), PAEE (SEQ ID NO: 18), QAEV (SEQ ID NO: 15), TPSL (SEQ ID NO: 33), PAAV (SEQ ID NO: 34), or QAEE (SEQ ID NO: 35). In some embodiments, [N2] is or comprises YPAEV (SEQ ID NO: 1), YPPSL (SEQ ID NO: 2), NKAEV (SEQ ID NO: 3), YTAEV (SEQ ID NO: 4), YPAEE (SEQ ID NO: 5), YQAEV (SEQ ID NO: 6), YTPSL (SEQ ID NO: 7), YPAAV (SEQ ID NO: 8), NPAEV (SEQ ID NO: 9), CPAEV (SEQ ID NO: 10), or YQAEE (SEQ ID NO: 11). In some embodiments, [N2] comprises the amino acid sequence of YPAEV (SEQ ID NO: 1). In some embodiments, the amino acid sequence of [N2] consists of YPAEV (SEQ ID NO: 1). In some embodiments, [N2]-[N3] comprises the amino acid sequence of AEVVQK (SEQ ID NO: 36), PSLVQK (SEQ ID NO: 37), AEVEQK (SEQ ID NO: 38), AEEVQK (SEQ ID NO: 39), PSLEQK (SEQ ID NO: 40), PSLVKK (SEQ ID NO: 41), AEVVKK (SEQ ID NO: 42), AEVVHK (SEQ ID NO: 43), AAVVQK (SEQ ID NO: 44), AEVVQQ (SEQ ID NO: 45), or AEVLQK (SEQ ID NO: 46). In some embodiments, [N2]-[N3] comprises the amino acid sequence PAEVVQK (SEQ ID NO: 20), PPSLVQK (SEQ ID NO: 47), KAEVVQK (SEQ ID NO: 48), TAEVVQK (SEQ ID NO: 49), PAEVEQK (SEQ ID NO: 50), PAEEVQK (SEQ ID NO: 51), QAEVVQK (SEQ ID NO: 52), TPSLVQK (SEQ ID NO: 53), PPSLEQK (SEQ ID NO: 54), PPSLVKK (SEQ ID NO: 55), PAEVVKK (SEQ ID NO: 56), PAEVVHK (SEQ ID NO: 57), PAAVVQK (SEQ ID NO: 58), PAEVVQQ (SEQ ID NO: 59), TAEVVKK (SEQ ID NO: 60), PAEVLQK (SEQ ID NO: 61), or QAEEVQK (SEQ ID NO: 62). In some embodiments, [N2]-[N3] is or comprises 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 one 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 relative to any one 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). In some embodiments, [N2]-[N3] (e.g., comprising the amino acid sequence of SEQ ID NO: 943) replaces an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

[0110] In some embodiments, the peptide comprising the amino acid sequence comprising the formula of [N2]-[N3] further comprises [N1], which comprises XD, XE, and XF. In some embodiments, XDof [N1] is Q, T, S, A, I, L, or H. In some embodiments, XEof [N1] is S, G, A, or R. In someAttorney Docket No.14640.0092-00304 embodiments, 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 one 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 relative to any one 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), SSYPAEVLQAttorney Docket No.14640.0092-00304 (SEQ ID NO: 148), or SSYQAEEVQ (SEQ ID NO: 149). In some embodiments, [N1]-[N2]-[N3] is or comprises QSSYPAEVVQK (SEQ ID NO: 150), QSKYPAEVVQK (SEQ ID NO: 151), TSLYPAEVVQK (SEQ ID NO: 152), SSSYPAEVVQK (SEQ ID NO: 153), QSRYPAEVVQK (SEQ ID NO: 154), QSSYPPSLVQK (SEQ ID NO: 155), AGAYPAEVVQK (SEQ ID NO: 156), IGSYPAEVVQK (SEQ ID NO: 157), QASYPAEVVQK (SEQ ID NO: 158), ASSYPAEVVQK (SEQ ID NO: 159), LGSYPAEVVQK (SEQ ID NO: 160), QSTNKAEVVQK (SEQ ID NO: 161), HSSYPAEVVQK (SEQ ID NO: 162), SSSYTAEVVQK (SEQ ID NO: 163), QSKYPAEVEQK (SEQ ID NO: 164), TSLYPAEEVQK (SEQ ID NO: 165), ASSYQAEVVQK (SEQ ID NO: 166), QSSYTPSLVQK (SEQ ID NO: 167), QSRYPAEEVQK (SEQ ID NO: 168), QSSYPPSLEQK (SEQ ID NO: 169), QSSYPPSLVKK (SEQ ID NO: 170), LSSYQAEVVQK (SEQ ID NO: 171), SSSYPAEVVKK (SEQ ID NO: 172), QSKYPAEVVHK (SEQ ID NO: 173), HSSYPAAVVQK (SEQ ID NO: 174), QSSNPAEVVQK (SEQ ID NO: 175), SSSYPAEVVQQ (SEQ ID NO: 176), QSSYTAEVVQK (SEQ ID NO: 177), TSLCPAEVVQK (SEQ ID NO: 178), QRSYTAEVVQK (SEQ ID NO: 179), QSSYTAEVVKK (SEQ ID NO: 180), HSSYPAEVLQK (SEQ ID NO: 181), or QSSYQAEEVQK (SEQ ID NO: 182); an amino acid sequence comprising any portion of any one 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 relative to any one 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). In some embodiments, [N2]-[N3] is present immediately subsequent to [N1] and replaces an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

[0111] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3] further comprises [N0], wherein [N0] comprises XA, XB, and XC. In some embodiments, XAof [N0] is T, I, or N. In some embodiments, XBof [N0] is N. In some embodiments, 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 one 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 relative to any one of the aforesaid amino acid sequences; orAttorney Docket No.14640.0092-00304 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 one 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 relative to any one 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). In some embodiments, [N2]-[N3] is present immediately subsequent to [N0]-[N1] and replaces an amino acid corresponding to T577 of the amino acid sequence of SEQ ID NO: 138.

[0112] In some embodiments, the peptide comprising the amino acid sequence comprising the formula [N2]-[N3] further comprises [N4], which comprises XGand XH. In some embodiments, XGof [N4] is T, P, or N. In some embodiments, XGof [N4] is T. In some embodiments, 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 one of the aforesaid amino acid sequences (e.g., any 2, 3, or 4 aminoAttorney Docket No.14640.0092-00304 acids, e.g., consecutive amino acids) thereof; an amino acid sequence comprising one, two, or three but no more than four modifications relative to any one 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 one 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 relative to any one of the aforesaid amino acid sequences; or an amino acid sequence comprising one, tw...

Claims

Attorney Docket No.14640.0092-00304 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 frataxin (FXN)-encoding sequence and the AAV capsid variant comprises an amino acid sequence having the formula [N2]-[N3], wherein: (i) [N2] comprises X1, X2, X3, X4, and X5, wherein: (a) X1 is Y, N, or C; (b) X2is P, K, T, or Q; (c) X3is A or P; (d) X4is E, S, or A; and (e) X5is V, L, or E; and (ii) [N3] comprises the amino acid sequence VQK, EQK, VKK, VHK, VQQ, or LQK; and wherein the AAV capsid variant comprises the amino acid sequence of SEQ ID NO: 739, or an amino acid sequence at least 95% identical thereto.

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

982.

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

982.

4. The AAV particle of any one of claims 1-3, wherein the AAV capsid variant is an AAV5 capsid variant comprising [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).Attorney Docket No.14640.0092-00304 9. The AAV particle of any one of claims 1-8, wherein the AAV capsid variant further comprises [N1] comprising XD, XE, and XF, wherein: (a) XDof [N1] is Q, T, S, A, I, L, or H; (b) XEof [N1] is S, G, A, or R; and (c) XF of [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 XA, XB, and XC, wherein: (a) XAof [N0] is T, I, or N; (b) XB of [N0] is N; and (c) XCof [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 XGand XH, wherein: (a) XG of [N4] is T, P, or N; and (b) XHof [N4] is A; wherein [N4] is present immediately subsequent to [N3].Attorney Docket No.14640.0092-00304 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 frataxin (FXN)-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, at least 5, at least 6, at least 7, or all 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;Attorney Docket No.14640.0092-00304 (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 frataxin (FXN)-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 frataxin (FXN)-encoding sequence and the AAV capsid variant comprises (i) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 982, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); (ii) an amino acid sequence having at least 99% identity to the amino acid sequence of SEQ ID NO: 738, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and / orAttorney Docket No.14640.0092-00304 (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 FXN-encoding sequence encodes a FXN protein that is not a cynomolgus monkey FXN protein.

30. The AAV particle of any one of claims 1-29, wherein the FXN-encoding sequence encodes a human FXN protein.

31. The AAV particle of claim 30, wherein the human FXN protein comprises the amino acid sequence of SEQ ID NO: 1825, or an amino acid sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, optionally wherein the human FXN protein is a wildtype human FXN protein.

32. The AAV particle of any one of claims 1-31, wherein the FXN-encoding sequence comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 1825.

33. The AAV particle of any one of claims 1-32, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

34. The AAV particle of any one of claims 1-33, wherein the viral genome further comprises a promoter operably linked to the FXN-encoding sequence.

35. The AAV particle of claim 34, wherein the promoter comprises a human elongation factor 1Į-subunit (EF1Į) promoter, a cytomegalovirus (CMV) immediate-early enhancer and / or promoter, a chicken ȕ- actin (CBA) promoter, a CAG 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, a intercellular adhesion molecule 2 (ICAM-Attorney Docket No.14640.0092-00304 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 chain (NFL) promoter, a neurofilament heavy chain (NFH) promoter, a ȕ-globin minigene nȕ2 promoter, a preproenkephalin (PPE) promoter, a 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 functional fragment or truncation of any of the foregoing.

36. The AAV particle of claim 32 or claim 33, wherein the promoter is a CMV promoter or CBA promoter, or a functional fragment or truncation of a CMV promoter or CBA promoter.

37. The AAV particle of claim 36, wherein the promoter is a truncated CBA promoter.

38. The AAV particle of claim 37, wherein the truncated CBA promoter is 50-400 nucleotides in length, e.g., 100-332 nucleotides in length.

39. The AAV particle of any one of claims 36-38, wherein the promoter comprises the nucleotide sequence of any one of SEQ ID NOs: 1738, 1740, and 1742 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

40. The AAV particle of claim 36, wherein the promoter is a truncated CMV promoter.

41. The AAV particle of claim 40, wherein the truncated CMV promoter is 50-300 nucleotides in length.

42. The AAV particle of claim 40 or claim 41, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 1750 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

43. The AAV particle of any one of claims 1-42, wherein the viral genome further comprises a microRNA (miR) binding site that modulates expression of the encoded FXN protein in a cell or tissue of the liver.

44. The AAV particle of claim 43, wherein the viral genome comprises 3 copies of the miR binding site.Attorney Docket No.14640.0092-00304 45. The AAV particle of claim 44, wherein the 3 copies of the miR binding site are identical.

46. The AAV particle of claim 44 or claim 45, wherein the 3 copies of the miR binding site are continuous.

47. The AAV particle of any one of claims 43-46, wherein the miR binding site is a miR122 binding site, optionally wherein: the miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1827 or a sequence having one, two, three, or at most four substitutions relative to the nucleotide sequence of SEQ ID NO: 1827; or the viral genome comprises 3 copies of a miR122 binding site comprising the nucleotide sequence of SEQ ID NO: 1826 or a sequence having one, two, three, four, five, six, seven, eight, nine, or at most ten substitutions relative to the nucleotide sequence of SEQ ID NO: 1826.

48. The AAV particle of any one of claims 1-47, wherein the viral genome further comprises at least one inverted terminal repeat (ITR) region.

49. The AAV particle of claim 48, wherein the at least one ITR region comprises an AAV2 ITR.

50. The AAV particle of claim 48 or claim 49, wherein the viral genome comprises a 5’ ITR region and a 3’ ITR region.

51. The AAV particle of claim 50, wherein the 5’ ITR region and 3’ ITR region are each an AAV2 ITR.

52. The AAV particle of claim 51, wherein the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

53. The AAV particle of any one of claims 1-52, wherein the viral genome further comprises an intron / exon region comprising an intron region and / or an exon region.

54. The AAV particle of claim 53, wherein the intron / exon region comprises: an immediate-early 1 (ie1) intron region and / or a human beta-globin (hBglobin) intron 2 region; and / orAttorney Docket No.14640.0092-00304 an ie1 exon region and / or an hBglobin exon region.

55. The AAV particle of claim 53 or claim 54, wherein the intron region comprises: the nucleotide sequence of SEQ ID NO: 1819 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or the nucleotide sequence of SEQ ID NO: 1820 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

56. The AAV particle of claim 55, wherein the exon region comprises: the nucleotide sequence of SEQ ID NO: 1817 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or the nucleotide sequence of SEQ ID NO: 1821 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

57. The AAV particle of any one of claims 1-56, wherein the viral genome further comprises a polyadenylation (polyA) region.

58. The AAV particle of claim 57, wherein the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

59. The AAV particle of any one of claims 1-30, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

60. The AAV particle of any one of claims 1-30, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.Attorney Docket No.14640.0092-00304 61. The AAV particle of any one of claims 1-30, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

62. The AAV particle of any one of claims 1-30, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

63. The AAV particle of any one of claims 1-30, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; and (iv) a 3’ ITR region.

64. The AAV particle of any one of claims 1-30, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (iv) at least one miR122 binding site; and (v) a 3’ ITR region.

65. The AAV particle of any one of claims 1-30, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) an intron / exon region; (iv) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824;Attorney Docket No.14640.0092-00304 (v) at least one miR122 binding site; and (vi) a 3’ ITR region.

66. The AAV particle of any one of claims 1-30, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) an intron / exon region; (iv) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (v) at least one miR122 binding site; (vi) a polyadenylation (polyA) region; and (vii) a 3’ ITR region.

67. The AAV particle of any one of claims 1-30, wherein the viral genome comprises: (i) a 5’ inverted terminal repeat (ITR) region; (ii) a promoter; (iii) an intron and / or exon region; (iv) the FXN-encoding sequence, wherein the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) to SEQ ID NO: 1824; (v) at least one miR122 binding site; (vi) a polyadenylation (polyA) region; (vii) a filler sequence; and (viii) a 3’ ITR region.

68. The AAV particle of claim 66 or claim 67, wherein: (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1742 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at leastAttorney Docket No.14640.0092-00304 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

69. The AAV particle of claim 68, wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1841 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

70. The AAV particle of claim 66 or claim 67, wherein: (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1750 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at leastAttorney Docket No.14640.0092-00304 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

71. The AAV particle of claim 70, wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1840 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

72. The AAV particle of claim 66 or claim 67, wherein: (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1738 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, atAttorney Docket No.14640.0092-00304 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / or (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

73. The AAV particle of claim 72, wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1838 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

74. The AAV particle of claim 66 or claim 67, wherein: (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1740 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and / orAttorney Docket No.14640.0092-00304 (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

75. The AAV particle of claim 74, wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1839 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto, optionally wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.

76. The AAV particle of claim 66 or claim 67, wherein the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

77. The AAV particle of any one of claims 66-68, wherein: (i) the 5' ITR region comprises the nucleotide sequence of SEQ ID NO: 1811; (ii) the promoter comprises the nucleotide sequence of SEQ ID NO: 1742; (iii) the intron / exon region comprises the nucleotide sequence of SEQ ID NO: 1816; (iv) the FXN-encoding sequence comprises the nucleotide sequence of SEQ ID NO: 1824; (v) the at least one miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1826; (vi) the polyA region comprises the nucleotide sequence of SEQ ID NO: 1828; and (vii) the 3' ITR region comprises the nucleotide sequence of SEQ ID NO: 1812.

78. The AAV particle of claim 77, wherein the viral genome further comprises a filler sequence comprising the nucleotide sequence of SEQ ID NO: 1841, wherein the filler sequence is positioned 3’ to the polyA region and 5’ to the 3’ ITR region.Attorney Docket No.14640.0092-00304 79. The AAV particle of any one of claims 66-68 or any one of claims 76-78, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797.

80. The AAV particle of any one of claims 66-68 or any one of claims 76-79, wherein the viral genome consists of the nucleotide sequence of SEQ ID NO: 1797.

81. An adeno-associated virus (AAV) particle comprising an AAV capsid variant and a viral genome comprising a frataxin (FXN)-encoding sequence, wherein the AAV capsid variant comprises: (i) the amino acid sequence of SEQ ID NO: 982 or an amino acid sequence having at least 95% identity (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 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 95% identity (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 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 95% identity (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943); and wherein the viral genome comprises: (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence that is at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto.

82. An adeno-associated virus (AAV) particle comprising a viral genome comprising the nucleotide sequence of SEQ ID NO: 1824 and an AAV capsid variant comprising 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.Attorney Docket No.14640.0092-00304 83. The AAV particle of claim 82, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797.

84. The AAV particle of any one of claims 1-83, wherein the viral genome is single-stranded.

85. A cell comprising the AAV particle of any one of claims 1-84, 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.

86. A method of making the AAV particle of any one of claims 1-84, wherein the method comprises: (i) providing a cell comprising the viral genome comprising a FXN-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.

87. The method of claim 86, wherein the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at leastAttorney Docket No.14640.0092-00304 96%, at least 97%, at least 98%, or at least 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity) thereto, wherein the AAV capsid variant comprises the amino acid sequence YPAEVVQK (SEQ ID NO: 943).

88. The method of claim 86, wherein the viral genome comprises (a) the nucleotide sequence of SEQ ID NO: 1797 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (b) the nucleotide sequence of SEQ ID NO: 1801 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; (c) the nucleotide sequence of SEQ ID NO: 1808 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; or (d) the nucleotide sequence of SEQ ID NO: 1809 or a nucleotide sequence at least 90% identical (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical) thereto; and 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.

89. The method of claim 86, wherein the viral genome comprises the nucleotide sequence of SEQ ID NO: 1797 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.

90. The method of any one of claims 86-89, further comprising, prior to step (i), introducing a nucleic acid molecule comprising the viral genome into the cell.

91. The method of any one of claims 86-90, further comprising, prior to step (i), introducing the nucleic acid encoding the AAV capsid variant into the cell.

92. The method of any one of claims 86-91, wherein the cell comprises a mammalian cell (e.g., an HEK293 cell), an insect cell (e.g., an Sf9 cell), or a bacterial cell.Attorney Docket No.14640.0092-00304 93. A pharmaceutical composition comprising the AAV particle of any one of claims 1-84 and a pharmaceutically acceptable excipient.

94. A method of delivering an AAV particle encoding a frataxin (FXN) protein to a cell, comprising administering an effective amount of the pharmaceutical composition of claim 93 or the AAV particle of any one of claims 1-84.

95. The method of claim 94, wherein the cell is in a subject.

96. The method of claim 95, wherein the subject has, has been diagnosed with having, or is at risk of having a disorder associated with FXN deficiency, optionally wherein the disorder is Friedreich’s Ataxia (FA).

97. A method of treating a subject having or diagnosed with having a disorder associated with frataxin (FXN) deficiency, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 93 or the AAV particle of any one of claims 1-84.

98. The method of claim 97, wherein the subject has, has been diagnosed with having, or is at risk of having Friedreich’s Ataxia (FA).

99. A method of treating a subject having or diagnosed with having a disorder, wherein the disorder is Friedreich’s Ataxia (FA), comprising administering to the subject an effective amount of the pharmaceutical composition of claim 93 or the AAV particle of any one of claims 1-84.

100. The method of any one of claims 97-99, wherein the treating results in prevention of progression of the disorder in the subject.

101. The method of any one of claims 97-100, wherein the treating results in amelioration of at least one symptom of the disorder.

102. The method of claim 101, wherein the at least one symptom comprises impaired sensory functions, impaired motor function (e.g., ataxia and / or involuntary movements), fatigue, chronic pain, seizures, impaired speech, sleep disturbances, metabolic disorders (e.g., diabetes), and / or increased spasticity.

103. The method of any one of claims 97-102, wherein the treating stabilizes, slows the progression of, or improves the subject’s disorder as determined by the modified Friedreich Ataxia Rating ScaleAttorney Docket No.14640.0092-00304 (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and / or the International Cooperative Ataxia Rating Scale (ICARS).

104. The method of claim 103, wherein the treatment slows the subject’s progression of the disorder as measured by mFARS, SARA, and / or ICARS relative to an individual with the disorder who has not been administered the pharmaceutical composition or the AAV particle.

105. The method of any one of claims 95-104, wherein the subject is a human.

106. The method of any one of claims 95-105, wherein the AAV particle or the pharmaceutical composition is delivered to a cell or tissue of the central nervous system (CNS) in the subject.

107. The method of claim 106, 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, cerebellum, or a combination thereof.

108. The method of any one of claims 95-107, wherein the AAV particle or the pharmaceutical composition is delivered to the subject via intravenous administration.

109. The method of any one of claims 95-108, further comprising evaluating, e.g., measuring, the level of FXN expression, e.g., FXN gene expression, FXN mRNA expression, and / or FXN protein expression, in the subject, e.g., in a cell, tissue, or fluid of the subject.

110. The method of claim 109, wherein the level of FXN protein expression is measured by an enzyme- linked immunosorbent assay (ELISA), a Western blot, an immunohistochemistry assay, or a frataxin biofluid assay.

111. The method of claim 109 or claim 110, wherein evaluating the subject’s level of FXN expression is performed before and / or after administration of the pharmaceutical composition or AAV particle, optionally wherein the subject’s level of FXN expression before administration is compared to the subject’s level of FXN expression after administration.

112. The method of any one of claims 109-111, comprising evaluating the level of FXN expression in a cell or tissue of the CNS.Attorney Docket No.14640.0092-00304 113. The method of claim 112, 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, and / or cerebellum.

114. The method of any one of claims 109-111, comprising evaluating the level of FXN expression in a peripheral cell or tissue.

115. The method of claim 114, wherein the peripheral cell or tissue is a cell or tissue of the heart and / or muscle.

116. The method of any one of claims 109-115, wherein the subject’s level of FXN protein expression after administration is increased relative to the subject’s level of FXN protein expression before administration.

117. The method of any one of claims 95-116, further comprising evaluating, e.g., measuring, the level of FXN protein activity in the subject.

118. The method of any one of claims 95-117, wherein administering the pharmaceutical composition or AAV particle to the subject results in an increase in: (i) the level of FXN protein or FXN gene expression in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, 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; (ii) the number and / or level of viral genomes (VG) per cell in a CNS tissue (e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, 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) the level of FXN activity in a cell, tissue, (e.g., a cell or tissue of the CNS, e.g., spinal cord, temporal cortex, perirhinal cortex, globus pallidus, putamen, caudate, thalamus, hippocampus, geniculate nucleus, Purkinje cell layer, deep cerebellar nuclei, dentate nucleus, brainstem, and / or cerebellum) of the subject relative to baseline and / or relative to FXN activity in a cell, tissue, or fluid of an individual with a disorder associated with FXN deficiency who has not been administered the pharmaceutical composition or AAV particle.

119. The method of any one of claims 95-116, further comprising administering to the subject at least one additional therapeutic agent and / or therapy.Attorney Docket No.14640.0092-00304 120. The method of claim 119, wherein the at least one additional therapeutic agent and / or therapy comprises an agent and / or therapy suitable for treating a disorder associated with FXN deficiency (e.g., Friedreich’s Ataxia).

121. The method of claim 119 or claim 120, wherein the at least one additional therapeutic agent and / or therapy comprises omaveloxolone or idebenone.

122. The method of any one of claims 95-121, further comprising administering an immunosuppressant to the subject.

123. The method of claim 122, wherein the immunosuppressant comprises a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and / or dexamethasone), rapamycin, mycophenolate mofetil, tacrolimus, rituximab, and / or eculizumab hydroxychloroquine.

124. The pharmaceutical composition of claim 93 or the AAV particle of any one of claims 1-84 for use in a method of treating a disorder according to any one of claims 97-123.

125. The pharmaceutical composition of claim 93 or the AAV particle of any one of claims 1-84 for use in the treatment of a disorder associated with FXN deficiency in a subject, optionally wherein the disorder is Friedreich’s Ataxia (FA).

126. The pharmaceutical composition or the AAV particle of claim 125, wherein the subject has, has been diagnosed with having, or is at risk of having FA.

127. Use of the pharmaceutical composition of claim 93 or the AAV particle of any one of claims 1-84 in the manufacture of a medicament for the treatment of a disorder associated with FXN deficiency in a subject, optionally wherein the disorder is Friedreich’s Ataxia (FA).

128. The use of claim 127, wherein the subject has, has been diagnosed with having, or is at risk of having FA.

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