WO2025259575A9 - Méthodes et compositions pour le traitement de la dystrophie musculaire de duchenne - Google Patents

Méthodes et compositions pour le traitement de la dystrophie musculaire de duchenne

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Publication number
WO2025259575A9
WO2025259575A9 PCT/US2025/032826 US2025032826W WO2025259575A9 WO 2025259575 A9 WO2025259575 A9 WO 2025259575A9 US 2025032826 W US2025032826 W US 2025032826W WO 2025259575 A9 WO2025259575 A9 WO 2025259575A9
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domain
sequence
slr
dystrophin
utrophin
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WO2025259575A1 (fr
Inventor
Philippe Moullier
Juan Manuel Iglesias GONZALEZ
Antonia EVRIPIOTI
Amy Margaret FRASER
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AskBio Inc
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AskBio Inc
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Publication of WO2025259575A9 publication Critical patent/WO2025259575A9/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4707—Muscular dystrophy
    • C07K14/4708—Duchenne dystrophy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the technology described herein relates to methods and compositions for the treatment of Duchenne muscular dystrophy.
  • DMD Duchenne muscular dystrophy
  • the mutation(s) in the dystrophin gene result in lowered amounts of dystrophin protein.
  • Dystrophin is necessary for muscle cell structure and function. In patients with DMD. the muscle tissue degrades and is replaced by connective tissue and fat over time.
  • DMD is one of the most common and severe of congenital myopathies.
  • Current treatments such as glucocorticoid therapies may slow the progression of DMD, but do not address the underlying lack of dystrophin or muscle in jury and degradation.
  • utrophin protein is also expressed in muscles.
  • the relatedness of utrophin and dystrophin led to an early hypothesis that utrophin itself, or reduced-sized versions of utrophin, could be used to treat DMD. This approach has not provided the therapeutic effects necessary' to provide clinical treatment of DMD.
  • the invenotrs have found that combining portion of dystrophin and portions of utrophin to provide a novel chimeric protein provides significantly unproved therapeutic effects. Accordingly, the use of the chimeric proteins described herein (and nucleic acids and vectors, including AAV vectors encoding these proteins) are contemplated for use in the treatment of DMD.
  • a polypeptide comprising: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; c) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 24 domain; j) a dystrophin hinge 4 domain; and k) a dystrophin cysteine rich (CR) domain.
  • the polypeptide further comprises a utrophin spectrin-like repeat (SLR) 3 domain.
  • SLR utrophin spectrin-like repeat
  • a polypeptide comprising: a utrophin NT domain; a utrophin hinge 1 domain; a utrophin spectrin-like repeat (SLR) 1 domain; a utrophin spectrin-like repeat (SLR) 2 domain; a utrophin hinge 2 domain; a dystrophin SLR 20 domain; a dystrophin SLR 21 domain; a dystrophin SLR 22 domain; a dystrophin SLR 24 domain; a dystrophin hinge 4 domain; and a dystrophin cysteine rich (CR) domain, a utrophin spectrin-like repeat (SLR) 3 domain.
  • SLR utrophin spectrin-like repeat
  • the polypeptide further comprises a dystrophin SLR 23 domain. In some embodiments of any of the aspects, the polypeptide further comprises a utrophin spectrin-like repeat (SLR) 3 domain and a dystrophin SLR 23 domain. In some embodiments of any of the aspects, the polypeptide further comprises a dystroglycan binding domain.
  • SLR utrophin spectrin-like repeat
  • the polypeptide further comprises a domain selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 15 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • the polypeptide further comprises a domain selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dystrophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR
  • the polypeptide comprises, from N-tenninus to C -terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 24 domain; j) a dystrophin hinge 4 domain; k) a dystrophin cysteine rich (CR) domain; and l) a dystroglycan binding domain.
  • the polypeptide comprises, comprises, from N-terminus to C-terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin spectrin-like repeat (SLR) 3 domain;
  • a utrophin hinge 2 domain 1) a utrophin hinge 2 domain; g) a dystrophin SLR 20 domain; h) a dystrophin SLR 21 domain; i) a dystrophin SLR 22 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; l) a dystrophin cysteine rich (CR) domain; and m) a dystroglycan binding domain.
  • the polypeptide comprises, comprises, from N-terminus to C-tenninus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spcctrin-likc repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 23 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; l) a dystrophin cysteine rich (CR) domain; and m) a dystrogly can binding domain.
  • the utrophin NT domain comprises the sequence of SEQ ID NO: 4 or 51 ; b) the utrophin hinge 1 domain comprises the sequence of SEQ ID NO: 5; c) the utrophin SLR 1 domain comprises the sequence of SEQ ID NO: 6; d) the utrophin SLR 2 domain comprises the sequence of SEQ ID NO: 7; e) the utrophin SLR 3 domain comprises the sequence of SEQ ID NO: 16;
  • the utrophin hinge 2 domain comprises the sequence of SEQ ID NO: 8; g) the dystrophin SLR 20 domain comprises the sequence of SEQ ID NO: 9 or 500; h) the dystrophin SLR 21 domain comprises the sequence of SEQ ID NO: 10 or 501; i) the dystrophin SLR 22 domain comprises the sequence of SEQ ID NO: 11 or 502; j) the dystrophin SLR 23 domain comprises the sequence of SEQ ID NO: 12; k) the dystrophin SLR 24 domain comprises the sequence of SEQ ID NO: 13 or 503; l) the dystrophin hinge 4 domain comprises the sequence of SEQ ID NO: 14 or 504; m) the dystrophin CR domain comprises the sequence of SEQ ID NO: 15 or 505; n) the dystroglycan binding domain comprises the sequence of SEQ ID NO: 17 or 506 and/or o) sequences having at least 85%, at least 90%, at least 95% or greater sequence identity to any of the foregoing sequences.
  • the polypeptide comprises the sequence of one of SEQ ID NOs: 1-3. In some embodiments of any of the aspects, the polypeptide comprises the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide comprises the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide comprises the sequence of SEQ ID NO: 3.
  • the polypeptide does not comprise any of: a) a dystrophin SLR4 - SLR19 domain; b) a utrophin SLR4-SLR19 domain; c) a dystrophin hinge 3 domain; and d) a utrophin hinge 3 domain.
  • the polypeptide does not comprise any of: a) a dystrophin NT domain; b) a dystrophin hinge 1 domain; c) a dystrophin spectrin-like repeat (SLR) 1 domain; and d) a dystrophin spectrin-like repeat (SLR) 2 domain.
  • the polypeptide does not comprise any of: a) a dystrophin NT domain; b) a dystrophin hinge 1 domain; c) a dystrophin spectrin-like repeat (SLR) 1 domain; d) a dystrophin spectrin-like repeat (SLR) 2 domain; and e) a dystrophin hinge 3 domain.
  • the polypeptide does not comprise any of: a) a dystrophin NT domain; b) a dystrophin hinge 1 domain; c) a dystrophin spectrin-like repeat (SLR) 1 domain; d) a dystrophin spectrin-like repeat (SLR) 2 domain; and e) a dystrophin hinge 2 domain.
  • the polypeptide does not comprise any of: a) a dystrophin NT domain; and b) a dystrophin hinge 1 domain.
  • the polypeptide does not comprise any of: a) a utrophin SLR 18 domain; b) a utrophin SLR 19 domain; c) a utrophin SLR 20 domain; d) a utrophin SLR 21 domain; e) a utrophin SLR 22 domain; f) a utrophin hinge 4 domain; and g) a utrophin CR domain.
  • a polypeptide comprising a utrophin N-tenninal portion and a dystrophin C-terminal portion. In one aspect of any of the embodiments, described herein is a polypeptide comprising a dystrophin N-terminal portion and a utrophin C-tenninal portion. In one aspect of any of the embodiments, described herein is a polypeptide, e.g., a microutrophin polypeptide, comprising a utrophin NT domain, a utrophin SLR domain 1.
  • the polypeptide further comprises utrophin hinge domain 1, utrophin hinge domain 2, and utrophin hinge domain 4. In some embodiments of any of the aspects, the polypeptide further comprises utrophin SLR domain 22 and utrophin CR domain.
  • the codon optimized nucleic acid sequence is at least 85% identical to the sequence selected from the group consisting of SEQ ID NOs: 100-111.
  • described herein is a nucleic acid encoding a polypeptide described herein.
  • the nucleic acid comprises the sequence of one of SEQ ID NOs: 85-87, or a sequence having at least 85%. at least 90%, at least 95% or greater sequence identity to any of the foregoing sequences.
  • one or more of the regions or domains is encoded by a codon-optimized sequence of one of SEQ ID NOs: 100-111, or a sequence having at least 80%. at least 85%, at least 90%. at least 95%, or greater sequence identity to any of the foregoing sequences.
  • the utrophin NT region, the utrophin SLR domain 1, the utrophin SLR domain 2, and/or the utrophin SLR domain 3 are encoded by a codon-optimized sequence of one of SEQ ID NOs: 400-474, or a sequence having at least 80%, at least 85%. at least 90%, at least 95%, or greater sequence identity to any of the foregoing sequences.
  • the utrophin SLR domain 3 are encoded by a codon-optimized sequence of one of SEQ ID NOs: 400-432 and 434-474, or a sequence having at least 80%. at least 85%, at least 90%, at least 95%, or greater sequence identity to any of the foregoing sequences.
  • the utrophin NT region and the utrophin hinge 2 domain are encoded by a codon-optimized sequence of one of SEQ ID NOs: 400- 412 and 463-474, or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or greater sequence identity to any of the foregoing sequences.
  • the nucleic acid and/or sequence encoding a polypeptide is operably connected to a promoter.
  • the promoter is a muscle-specific promoter.
  • the musclespecific promoter is selected from the group consisting of: SP0524; SPc5-12; SP0525; SP0526; SP0527; SP0528; SCP1; and CRE0053.
  • the musclespecific promoter is a SP0524 promoter or a SPc5-12 promoter.
  • the muscle -specific promoter is a SP0524 promoter or a SP0527 promoter.
  • the muscle-specific promoter is a SP0524 promoter. In some embodiments of any of the aspects, the muscle-specific promoter comprises the sequence of one of SEQ ID NOs: 18, 19, 20. 24, 25, 26, 27, 28. 29, or 83. In some embodiments of any of the aspects. the musclc-spccific promoter comprises the sequence of one of SEQ ID NOs: 18, 20, 24, 25, 26, 27, 28, or 29.
  • the nucleic acid and/or sequence encoding a polypeptide is flanked by AAV inverted terminal repeats (ITRs).
  • the nucleic acid further comprises one or more additional regulatory elements and/or a polyA sequence.
  • the muscle-specific promoter is a SP0524 promoter and the polyA sequence is the sequence of SEQ ID NO: 52.
  • the one or more additional regulatory elements is selected from die group consisting of an enhancer, a 5’ untranslated region (5’UTR), an intron, a reverse RNA pol II terminator sequence, and combinations thereof.
  • the intron is an I VS intron.
  • the I VS intron comprises a nucleic acid sequence of SEQ ID NO: 22, a nucleic acid having at least 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98%, or 99% sequence identity thereto.
  • a vector comprising a nucleic acid sequence described herein.
  • a vector comprising, from 5’ to 3’: a) a first inverted terminal repeat (ITR); b) a promoter; c) the nucleic acid sequence as described herein (e.g., encoding a polypeptide as described herein), operably linked to the promoter; d) a poly-A sequence 3’ of the nucleic acid sequence as described herein (e.g., encoding a polypeptide as described herein); and e) a second ITR.
  • ITR inverted terminal repeat
  • the vector is an AAV vector, an adenoviral vector, a retroviral vector, or a lentiviral vector. In some embodiments of any of the aspects, the vector is an AAV vector.
  • a recombinant adeno- associated virus (rAAV) vector comprising in its genome a nucleic acid sequence as described herein (e.g., encoding a polypeptide as described herein).
  • a recombinant adeno-associated virus (rAAV) vector comprising in its genome: a) 5‘ and 3’ AAV inverted terminal repeats (ITR) sequences; and b) located between the 5’ and 3’ ITRs, a nucleic acid sequence as described herein (e.g., encoding a polypeptide as described herein).
  • the AAV genome further comprises at least one of: a) a 5’ ITR; b) an intron; c) a poly A sequence; and d) a 3’ ITR.
  • the AAV genome comprises, in the 5’ to 3’ direction: a) a 5’ ITR; b) a muscle-specific promoter; c) an intron; d) a nucleic acid sequence as described herein (e.g.. encoding a polypeptide as described herein); e) a poly A sequence;
  • the intron is selected from the group consisting of an IVS sequence, a MVM sequence, a HBB2 sequence, an CMVIE intron sequence, a UBC intron sequence, and a SV40 sequence.
  • at least one of the 5’ ITR or 3’ITR comprises an insertion, deletion or substitution.
  • one or more CpG islands in the ITR are removed.
  • the poly A sequence is a full length SV40 polyA sequence or HGF poly A sequence. In some embodiments of any of the aspects, poly A sequence is selected from SEQ ID NO: 23 or 52. or a nucleic acid sequence at least 80% sequence identity thereto.
  • the rAAV vector is a chimeric AAV vector, haploid AAV vector, a hybrid AAV vector or polyploid AAV vector. In some embodiments of any of the aspects, the rAAV vector is a rational haploid capsid, a mosaic AAV capsid, a chemically modified AAV capsid, or a AAV capsid from any AAV seroty pes.
  • the rAAV capsid is a capsid from an AAV serotype selected from the group consisting of: AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAVrh74, AAVrhlO, pol, AAV9-PHP.B, AAV9-ePHP.B, AAV LK03, AAV Anc80L65, AAVDJ, AAVlA6ii, AAVlP5ii, AAV4Alii, AAV7P4i, AAV9AH, AAV9A2i, AAV9A6i, AAV9Pli, AAV9P2i, AAV9P5i, AAVrhlOAli, AAVrhlOA2i.
  • the rAAV capsid is a capsid from an AAV serotype selected from the group consisting of: AAV9, AAV8. AAVrh74, and AAVMyo.
  • a phannaceutical composition comprising the vector or rAAV vector as described herein, in a pharmaceutically acceptable carrier. 2.
  • a method of treating Duchenne Muscular Dystrophy (DMD) in a subject in need thereof comprising administering a nucleic acid as described herein, or a vector as described herien, or a composition as described herein to the subject.
  • DMD Duchenne Muscular Dystrophy
  • described herein is a nucleic acid as described herein, or a vector as described herien, or a composition as described herein, for use in a method of treating DMD.
  • the administering is systemic administration. In some embodiments of any of the aspects, the systemic administration is intravenous administration. In some embodiments of any of the aspects, the administering is local administration. In some embodiments of any of the aspects, the local administration is by injection into a muscle. In some embodiments of any of the aspects, the rAAV vector is administered at a dosage range of between 1.0E9 vg/kg to 5.0E14vg/kg.
  • Fig. 1 A depicts a schematic of utrophin and dystrophin, reference sequences, and exemplary chimeric sequences described herein.
  • Fig. IB depicts a key for Fig. 1A.
  • Fig. 2 depicts a schematic of the plasmid design for chimeric constructs described herein.
  • the sequences are human, are not codon-optimized, and the cassette design does not comprise added restriction sites.
  • Fig. 3 depicts a table of construct identities.
  • Figs. 4A-4C depict normalized fatigue and twitch/tetanus responses after prior art DNA2 administration.
  • Figs. 5A-5C depict normalized fatigue and twitch/tetanus responses after SI- trophin_07_AE (DNA3) administration.
  • Figs. 6A-6C depict normalized fatigue and twitch/tetanus responses after SI-trophin_09 (DNA4) administration.
  • Figs. 7A-7C depict normalized fatigue and twitch/tetanus responses after SI- trophin_09_AE (DNA5) administration.
  • Figs. 8A-8C depict normalized fatigue and twitch/tetanus responses after prior art DNA6 administration.
  • Fig. 9 depicts a schematic of u Utrophin construct domains.
  • the jiUtrophin schematic depicts the domains included in all of the codon-optimized sequences of Example 2.
  • Fig. 10 depicts a table of the constructs utilized in Example 2.
  • Fig 11 depicts a diagram of the experimental design for Example 2.
  • Figs. 12A-12C depicts the expression in the diaphragm.
  • Figs. 13A-13C depicts the expression in the heart.
  • Figs. 14A-14C depicts the expression in the heart.
  • Figs. 15A-15C depicts the expression in the heart.
  • Fig. 16 depicts graphs of Twitch and Tetanic force.
  • Fig. 17 depicts a graph of the different fatigue blocks used in Example 1.
  • Fig. 18 depicts an exemplary waveform for day 20 fatigue. Multiple tetanic stimulation, with 0.5 second rest period were used. The parameters are designed to fatigue the DMD control to at least 70% of initial force.
  • Figs. 19A-19B depict graphs of day 20 normalized fatigue (Fig. 19A) and normalized force at contraction #50 (Fig. 19B) for prior art DNA2.
  • Figs. 20A-20B depict graphs of day 20 normalized fatigue (Fig. 20 A) and normalized force at contraction #50 (Fig. 20B) for SI-trophin_07_AE (DNA3).
  • Figs. 21A-21B depict graphs of day 20 normalized fatigue (Fig. 21A) and normalized force at contraction #50 (Fig. 21B) for SI-trophin_09 (DNA4).
  • Figs. 22A-22B depict graphs of day 20 normalized fatigue (Fig. 22A) and normalized force at contraction #50 (Fig. 22B) for SI-trophin_09_AE (DNA5).
  • Figs. 23A-23B depict graphs of day 20 normalized fatigue (Fig. 23A) and normalized force at contraction #50 (Fig. 23B) for prior art DNA6.
  • aspects of the invention described herein arise from the identification of novel chimeric polypeptides that provide therapeutic effects in subjects with Duchenne muscular dystrophy (DMD).
  • Nucleic acids encoding these polypeptides can be used to produce vectors for gene therapy (e.g., AAV based gene therapy) to treat DMD.
  • Recombinant vectors (e.g., AAV) vectors and expression cassettes can be used to deliver the novel chimeric polypeptides, e.g., in expressible nucleic acid form, to the subject.
  • recombinant AAV (rAAV) vector and constructs described herein for delivering the novel chimeric polypeptides to a subject comprise improvements such as, e.g.. incorporation of an intron upstream of the nucleic acid expressing the polypeptide and the promoter, and use of specific terminator sequences 3’ of nucleic acid encoding the polypeptide, such as, e.g., specific poly A sequences and/or terminator sequences.
  • viral vectors e.g., using rAAV vectors as a non-limiting example, that comprise a nucleotide sequence containing inverted tenninal repeats (ITRs), a promoter (e.g., muscle specific promoter), a heterologous gene, a poly -A tail and potentially other regulator elements (e.g.. an intron) for use to treat DMD, where the heterologous gene is a nucleic acid encoding a polypeptide described herein.
  • the vector e.g., rAAV. can be administered to a patient in a therapeutically effective dose that is delivered to the appropriate tissue and/ or organ (e.g., msucle tissue) for expression of the heterologous gene and treatment of the disease, c.g., DMD.
  • One aspect of the invention relates to a polypeptide comprising: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 24 domain; j) a dystrophin hinge 4 domain; and k) a dystrophin cysteine rich (CR) domain.
  • the polypeptide further comprises a utrophin spectrin-like repeat (SLR) 3 domain.
  • SLR utrophin spectrin-like repeat
  • a polypeptide comprising: a utrophin NT domain; a utrophin hinge 1 domain; a utrophin spectrin-like repeat (SLR) 1 domain; a utrophin spectrin-like repeat (SLR) 2 domain; a utrophin hinge 2 domain; a dystrophin SLR 20 domain; a dystrophin SLR 21 domain; a dystrophin SLR 22 domain; a dystrophin SLR 24 domain; a dystrophin hinge 4 domain; a dystrophin cysteine rich (CR) domain; and a utrophin spectrin-like repeat (SLR) 3 domain.
  • the polypeptide further comprises a dystrophin SLR 23 domain. In some embodiments of any of the aspects, the polypeptide further comprises a utrophin spectrin-like repeat (SLR) 3 domain and a dystrophin SLR 23 domain.
  • SLR utrophin spectrin-like repeat
  • the polypeptide further comprises a domain selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 15 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • the polypeptide further comprises at least one further domain selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 1 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • a utrophin SLR 4 domain a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a
  • the polypeptide further comprises at least two further domains selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 15 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • the polypeptide further comprises at least three further domains selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 15 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • the polypeptide further comprises at least four further domains selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 15 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • the poly peptide further comprises at least five further domains selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 15 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • the polypeptide further comprises at least six further domains selected from the group consisting of: a utrophin SLR 4 domain, a utrophin SLR 5 domain, a utrophin SLR 6 domain, a utrophin SLR 7 domain, a utrophin SLR 8 domain, a utrophin SLR 9 domain, a utrophin SLR 10 domain, a utrophin SLR 11 domain, a utrophin SLR 12 domain, a utrophin SLR 13 domain, a utrophin SLR 14 domain, a utrophin SLR 15 domain, a utrophin SLR 16 domain, a utrophin SLR 17 domain, and a utrophin hinge 3 domain.
  • the polypeptide further comprises a domain selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dystrophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR
  • the polypeptide further comprises at least one further domain selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dystrophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin
  • the polypeptide further comprises at least two further domains selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dystrophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystroph
  • the polypeptide further comprises at least three further domains selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dy strophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dy strophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dy strophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dy strophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9
  • the polypeptide further comprises at least four further domains selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dystrophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystroph
  • the polypeptide further comprises at least five further domains selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dystrophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain
  • a dystrophin SLR 6 domain a dystrophin SLR 7 domain
  • a dystrophin SLR 8 domain a dystrophin SLR 9 domain
  • a dystrophin SLR 10 domain a dystroph
  • the polypeptide further comprises at least six further domains selected from the group consisting of: a dystrophin SLR 4 domain, a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystrophin SLR 11 domain, a dystrophin SLR 12 domain, a dystrophin SLR 13 domain, a dystrophin SLR 14 domain, a dystrophin SLR 15 domain, a dystrophin SLR 16 domain, a dystrophin SLR 17 domain, dystrophin SLR 18 domain, and a dystrophin SLR 19 domain.
  • a dystrophin SLR 4 domain a dystrophin SLR 5 domain, a dystrophin SLR 6 domain, a dystrophin SLR 7 domain, a dystrophin SLR 8 domain, a dystrophin SLR 9 domain, a dystrophin SLR 10 domain, a dystroph
  • the polypeptide comprises, from N-terminus to C-terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 24 domain; j) a dystrophin hinge 4 domain; and k) a dystrophin cysteine rich (CR) domain.
  • the polypeptide comprises, from N-terminus to C- tenninus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin spectrin-like repeat (SLR) 3 domain; l a utrophin hinge 2 domain; g) a dystrophin SLR 20 domain; h) a dystrophin SLR 21 domain; i) a dystrophin SLR 22 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; and l) a dystrophin cysteine rich (CR) domain.
  • the polypeptide comprises, from N-terminus to C- terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 23 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; and l) a dystrophin cysteine rich (CR) domain.
  • the polypeptide further comprises a dystroglycan binding domain.
  • the polypeptide comprises, from N-terminus to C-terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dy strophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 24 domain; j) a dystrophin hinge 4 domain; k) a dystrophin cysteine rich (CR) domain; and l) a dystroglycan binding domain.
  • the polypeptide comprises, from N-terminus to C- terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spcctrin-likc repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin spectrin-like repeat (SLR) 3 domain; f a utrophin hinge 2 domain; g) a dystrophin SLR 20 domain; h) a dystrophin SLR 21 domain; i) a dystrophin SLR 22 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; l) a dystrophin cysteine rich (CR) domain; and m) a dystroglycan binding domain.
  • the polypeptide comprises, from N-terminus to C- terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 23 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; l) a dy strophin cysteine rich (CR) domain; and m) a dy stroglycan binding domain.
  • the polypeptide consists of, from N-terminus to C-terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 24 domain; j) a dystrophin hinge 4 domain; k) a dystrophin cysteine rich (CR) domain; and l) a dystroglycan binding domain.
  • the polypeptide consists of, from N-terminus to C- terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin spectrin-like repeat (SLR) 3 domain; f) a utrophin hinge 2 domain; g) a dystrophin SLR 20 domain; h) a dystrophin SLR 21 domain; i) a dystrophin SLR 22 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; l) a dystrophin cysteine rich (CR) domain; and m) a dystroglycan binding domain.
  • SLR utrophin spectrin-like repeat
  • SLR utrophin spectrin-like repeat
  • the polypeptide consists of. from N-terminus to C- terminus: a) a utrophin NT domain; b) a utrophin hinge 1 domain; c) a utrophin spectrin-like repeat (SLR) 1 domain; d) a utrophin spectrin-like repeat (SLR) 2 domain; e) a utrophin hinge 2 domain; f) a dystrophin SLR 20 domain; g) a dystrophin SLR 21 domain; h) a dystrophin SLR 22 domain; i) a dystrophin SLR 23 domain; j) a dystrophin SLR 24 domain; k) a dystrophin hinge 4 domain; l) a dystrophin cysteine rich (CR) domain; and m) a dystroglycan binding domain.
  • utrophin and dystrophin are known in the art, including the structures and sequences of the domains of utrophin and dystrophin described herein.
  • the structures of utrophin and dystrophin arc described in Blake ct al. Brain Pathology 6:37- 47 (1996) and Muthu et al. PLoS One 7(7):e40066 (2012); each of which is incorporated by reference herein in its entirety .
  • a utrophin NT domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 51.
  • a utrophin NT domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 51.
  • a utrophin NT domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain comprises the sequence of SEQ ID NO: 51. In some embodiments of any of the aspects, a utrophin NT domain consists of the sequence of SEQ ID NO: 51.
  • a utrophin NT domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 4.
  • a utrophin NT domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 4.
  • a utrophin NT domain consists of a sequence which has at least 90% sequence identity to tire sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 4.
  • a utrophin NT domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain comprises the sequence of SEQ ID NO: 4. In some embodiments of any of the aspects, a utrophin NT domain consists of the sequence of SEQ ID NO: 4.
  • a utrophin hinge 1 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 5.
  • a utrophin hinge 1 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 5.
  • a utrophin hinge 1 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain comprises the sequence of SEQ ID NO: 5. In some embodiments of any of the aspects, a utrophin hinge 1 domain consists of the sequence of SEQ ID NO: 5.
  • Utrophin hinge 1 domain (SEQ ID NO: 5) TLPRKYKKECEEEAINIQSTAPEEEHESPRAETPST
  • a utrophin SLR 1 domain comprises a sequence which has at least 80% sequence identity' to the sequence of SEQ ID NO: 6.
  • a utrophin SLR 1 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 6.
  • a utrophin SLR 1 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 6.
  • a utrophin SLR 1 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utrophin SLR 1 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utrophin SLR 1 domain consists of a sequence which has at least 90% sequence identity' to the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utrophin SLR 1 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 6.
  • a utrophin SLR 1 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utrophin SLR 1 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utrophin SLR 1 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utrophin SLR 1 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 6.
  • a utrophin SLR 1 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utropliin SLR 1 domain comprises the sequence of SEQ ID NO: 6. In some embodiments of any of the aspects, a utrophin SLR 1 domain consists of the sequence of SEQ ID NO: 6.
  • a utrophin SLR 2 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain consists of a sequence which has at least 80% sequence identity 7 to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 7.
  • a utrophin SLR 2 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain consists of a sequence which has at least 90% sequence identity 7 to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 7.
  • a utrophin SLR 2 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain comprises the sequence of SEQ ID NO: 7. In some embodiments of any of the aspects, a utrophin SLR 2 domain consists of the sequence of SEQ ID NO: 7.
  • a utrophin hinge 2 domain comprises a sequence which has at least 80% sequence identity' to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utropliin hinge 2 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 8.
  • a utrophin hinge 2 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 8.
  • a utrophin hinge 2 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain comprises the sequence of SEQ ID NO: 8. In some embodiments of any of the aspects, a utrophin hinge 2 domain consists of the sequence of SEQ ID NO: 8.
  • a dystrophin SLR 20 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 80% sequence identity' to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 9.
  • a dystrophin SLR 20 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 9.
  • a dystrophin SLR 20 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 9.
  • a dystrophin SLR 20 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises the sequence of SEQ ID NO: 9. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of the sequence of SEQ ID NO: 9.
  • a dystrophin SLR 20 domain comprises a sequence which has at least 80% sequence identity’ to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 85% sequence identity’ to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 500.
  • a dystrophin SLR 20 domain comprises a sequence which has at least 90% sequence identity' to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 95% sequence identity’ to the sequence of SEQ ID NO: 500.
  • a dystrophin SLR 20 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain comprises the sequence of SEQ ID NO: 500. In some embodiments of any of the aspects, a dystrophin SLR 20 domain consists of the sequence of SEQ ID NO: 500.
  • a dystrophin SLR 21 domain comprises a sequence which has at least 80% sequence identity to tire sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 10.
  • a dystrophin SLR 21 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 10.
  • a dystrophin SLR 21 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain comprises the sequence of SEQ ID NO: 10. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of the sequence of SEQ ID NO: 10.
  • a dystrophin SLR 21 domain comprises a sequence which has at least 80% sequence identity to tire sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 501.
  • a dystrophin SLR 21 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 501.
  • a dystrophin SLR 21 domain comprises a sequence which has at least 98% sequence identity’ to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 501.
  • a dystrophin SLR 21 domain comprises the sequence of SEQ ID NO: 501. In some embodiments of any of the aspects, a dystrophin SLR 21 domain consists of the sequence of SEQ ID NO: 501.
  • a dystrophin SLR 22 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 85% sequence identity' to the sequence of SEQ ID NO: 11.
  • a dystrophin SLR 22 domain comprises a sequence which has at least 90% sequence identity' to the sequence of SEQ ID NO: 11 . In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises a sequence which has at least 95% sequence identity' to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 11.
  • a dystrophin SLR 22 domain comprises a sequence which has at least 98% sequence identity to tire sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises the sequence of SEQ ID NO: 11. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of the sequence of SEQ ID NO: 11.
  • a dystrophin SLR 22 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 502.
  • a dystrophin SLR 22 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any?
  • a dystrophin SLR 22 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain comprises the sequence of SEQ ID NO: 502. In some embodiments of any of the aspects, a dystrophin SLR 22 domain consists of the sequence of SEQ ID NO: 502.
  • a dystrophin SLR 23 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 12.
  • a dystrophin SLR 23 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 12.
  • a dystrophin SLR 23 domain comprises a sequence which has at least 98% sequence identity’ to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain consists of a sequence which has at least 99% sequence identity' to the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain comprises the sequence of SEQ ID NO: 12. In some embodiments of any of the aspects, a dystrophin SLR 23 domain consists of the sequence of SEQ ID NO: 12.
  • a dystrophin SLR 24 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 80% sequence identity to die sequence of SEQ ID NO: 13.
  • a dystrophin SLR 24 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 13.
  • a dystrophin SLR 24 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 95% sequence identity’ to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain comprises a sequence which has at least 98% sequence identity' to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 13.
  • a dystrophin SLR 24 domain comprises a sequence which has at least 99% sequence identity’ to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 99% sequence identity' to the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain comprises the sequence of SEQ ID NO: 13. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of the sequence of SEQ ID NO: 13.
  • Dystrophin SLR 24 domain (SEQ ID NO: 13) rlqelqeatd eldlklrqae vikgswqpvg dllidslqdh lekvkalrge iaplkenvsh vndlarqlt Igiqlspynl stledlntrw kllqvavedr vrqlhe
  • a dystrophin SLR 24 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 503.
  • a dystrophin SLR 24 domain comprises a sequence which has at least 90% sequence identity' to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 503.
  • a dystrophin SLR 24 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain comprises the sequence of SEQ ID NO: 503. In some embodiments of any of the aspects, a dystrophin SLR 24 domain consists of the sequence of SEQ ID NO: 503.
  • a dystrophin hinge 4 domain comprises a sequence which has at least 80% sequence identity' to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 14.
  • a dystrophin hinge 4 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 14.
  • a dystrophin hinge 4 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises the sequence of SEQ ID NO: 14. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of the sequence of SEQ ID NO: 14.
  • a dystrophin hinge 4 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any?
  • a dystrophin hinge 4 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 504.
  • a dystrophin hinge 4 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dy strophin hinge 4 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain comprises the sequence of SEQ ID NO: 504. In some embodiments of any of the aspects, a dystrophin hinge 4 domain consists of the sequence of SEQ ID NO: 504.
  • Dystrophin hinge 4 domain (SEQ ID NO: 504) AHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLA DLNNVRFSAYRTAMKL
  • a dystrophin CR domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 505.
  • a dystrophin CR domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 505.
  • a dystrophin CR domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 505.
  • a dystrophin CR domain comprises the sequence of SEQ ID NO: 505. In some embodiments of any of the aspects, a dy strophin CR domain consists of the sequence of SEQ ID NO: 505.
  • a dystrophin CR domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 85% sequence identity to tire sequence of SEQ ID NO: 15.
  • a dystrophin CR domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 15.
  • a dystrophin CR domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain comprises the sequence of SEQ ID NO: 15. In some embodiments of any of the aspects, a dystrophin CR domain consists of the sequence of SEQ ID NO: 15.
  • Dystrophin CR domain (SEQ ID NO: 15) nvrfs ayrtamklrr Iqkalcldll slsaacdald qhnlkqndqp mdilqiincl ttiydrleqe hnnlvnvplc vdmclnwlln vydtgrtgri rvlsfktgii slckahledk yrylfkqvas stgfcdqrrl glllhdsiqi prqlgevasf ggsniepsvr scfqfannkp eieaalfldw mrlepqsmvw Ipvlhr
  • a utrophin SLR 3 domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 16.
  • a utrophin SLR 3 domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain consists of a sequence which has at least 95% sequence identity to tire sequence of SEQ ID NO: 16.
  • a utrophin SLR 3 domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain consists of a sequence which has at least 99% sequence identity’ to the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain comprises the sequence of SEQ ID NO: 16. In some embodiments of any of the aspects, a utrophin SLR 3 domain consists of the sequence of SEQ ID NO: 16.
  • a dystroglycan binding domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 17.
  • a dystroglycan binding domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystrogly can binding domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dy stroglycan binding domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 17.
  • a dystroglycan binding domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain comprises the sequence of SEQ ID NO: 17. In some embodiments of any of the aspects, a dystroglycan binding domain consists of the sequence of SEQ ID NO: 17.
  • Dystroglycan binding domain (SEQ ID NO: 17) rvaaa etakhqakcn ickecpiigf ryrslkhfhy dicqscffsg rvakghkmhy pmveyctptt sgedvrdfak vlknkfrtkr y fakhprmgy Ipvqtvlegd nmet
  • a dystroglycan binding domain comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 506.
  • a dystroglycan binding domain comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 506.
  • a dystroglycan binding domain comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 506.
  • a dystroglycan binding domain comprises the sequence of SEQ ID NO: 506. In some embodiments of any of the aspects, a dystroglycan binding domain consists of the sequence of SEQ ID NO: 506. [00111] Dystroglycan binding domain (SEQ ID NO: 506) TTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLK QNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKT GIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRS CFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYR SLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKV
  • the polypeptide has the polypeptide sequence set forth in one of SEQ ID NOs: 1-3. or a polypeptide having at least 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%. or 98%, or 99% sequence identity thereto.
  • the polypeptide comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 1.
  • the polypeptide consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the poly peptide comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 1.
  • the polypeptide comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide comprises the sequence of SEQ ID NO: 1. In some embodiments of any of the aspects, the polypeptide consists of the sequence of SEQ ID NO: 1. In some embodiments, the polypeptide has the polypeptide sequence set forth in SEQ ID NO: 1, or a polypeptide having at least 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, or 98%, or 99% sequence identity thereto.
  • the polypeptide comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 85% sequence identity to tire sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 2.
  • the polypeptide consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 98% sequence identity’ to the sequence of SEQ ID NO: 2.
  • the polypeptide comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide comprises the sequence of SEQ ID NO: 2. In some embodiments of any of the aspects, the polypeptide consists of the sequence of SEQ ID NO: 2. In some embodiments, the polypeptide has the polypeptide sequence set forth in SEQ ID NO: 2, or a polypeptide having at least 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%. or 98%, or 99% sequence identity thereto.
  • the poly peptide comprises a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 80% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 85% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 3.
  • the polypeptide consists of a sequence which has at least 90% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 95% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide comprises a sequence which has at least 98% sequence identity to die sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 98% sequence identity to the sequence of SEQ ID NO: 3.
  • the polypeptide comprises a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide consists of a sequence which has at least 99% sequence identity to the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide comprises the sequence of SEQ ID NO: 3. In some embodiments of any of the aspects, the polypeptide consists of the sequence of SEQ ID NO: 3. In some embodiments, the polypeptide has the polypeptide sequence set forth in SEQ ID NO: 3, or a polypeptide having at least 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, or 98%, or 99% sequence identity thereto.
  • SI-trophin_07_AE_protein SEQ ID NO: 1
  • SI-trophin_09 protein (SEQ ID NO: 2) 1 makygeheas pdngqnefsd iiksrsdehn dvqkktftkw inarfsksgk ppindmftdl 61 kdgrklldll egltgtslpk ergstrvhal nnvnrvlqvl hqnnvelvni ggtdivdgnh 121 kltlgllwsi ilhwqvkdvm kdvmsdlqqt nsekillswv rqttrpysqv n x lnftts ⁇ t 181 dglafiiavlh rhkpdlfswd kvvkmspier lehafskaqt ylgieklldp edvavqlpdk 241 k
  • SI-trophin_09_AE protein (SEQ ID NO: 3)
  • SI-trophin_07_AE_nucleic acid sequence SEQ ID NO: 85
  • SI-trophin_09 nucleic acid sequence SEQ ID NO: 86
  • SI-trophin_09_AE nucleic acid sequence SEQ ID NO: 87
  • the polypeptide is engineered. In some embodiments of any of the aspects, the poly peptide is chimeric. In some embodiments of any of the aspects, the polypeptide is not a naturally -occuring polypeptide.
  • the polypeptide has less than 95% sequence identity to wild-type dystrophin (e.g., SEQ ID NO: 30). In some embodiments of any of the aspects, the polypeptide has less than 90% sequence identity to wild-type dystrophin (e.g., SEQ ID NO: 30). In some embodiments of any of the aspects, the polypeptide has less than 80% sequence identity to wild-type dystrophin (e.g., SEQ ID NO: 30). In some embodiments of any of the aspects, the polypeptide has less than 70% sequence identity to wild-type dystrophin (e.g.. SEQ ID NO: 30). In some embodiments of any of the aspects, the polypeptide has less than 60% sequence identity’ to wildtype dystrophin (e.g., SEQ ID NO: 30).
  • the polypeptide has less than 95% sequence identity to dystrophin isoform Dp427m (e.g., SEQ ID NO: 668). In some embodiments of any of the aspects, the polypeptide has less than 90% sequence identity to dystrophin isoform Dp427m (e.g., SEQ ID NO: 668). In some embodiments of any of the aspects, the polypeptide has less than 80% sequence identity to dystrophin isoform Dp427m (e.g.. SEQ ID NO: 668). In some embodiments of any of the aspects, the polypeptide has less than 70% sequence identity to dystrophin isoform Dp427m (e.g.. SEQ ID NO: 668). In some embodiments of any of the aspects, the polypeptide has less than 60% sequence identity to dystrophin isofonn Dp427m (e.g.. SEQ ID NO: 668).
  • the polypeptide has less than 95% sequence identity to wild-type utrophin (e.g., SEQ ID NO: 31). In some embodiments of any of the aspects, the polypeptide has less than 90% sequence identity to wild-type utrophin (e.g.. SEQ ID NO: 31). In some embodiments of any of the aspects, the polypeptide has less than 80% sequence identity to wildtype utrophin (e.g., SEQ ID NO: 31). In some embodiments of any of the aspects, the polypeptide has less than 70% sequence identity to wild-ty pe utrophin (e.g., SEQ ID NO: 31). In some embodiments of any of the aspects, the polypeptide has less than 60% sequence identity to wild-type utrophin (e.g.,
  • the polypeptide does not comprise any of dystrophin SLR4-SLR19 domains. In some embodiments of any of the aspects, the polypeptide does not comprise any of utrophin SLR4-SLR19 domains. In some embodiments of any of the aspects, the polypeptide does not comprise a dystrophin hinge 3 domain. In some embodiments of any of the aspects, the polypeptide does not comprise a utrophin hinge 3 domain.
  • the polypeptide does not comprise any of: dystrophin SLR4-SLR19 domains; utrophin SLR4-SLR19 domains; a dystrophin hinge 3 domain; and a utrophin hinge 3 domain.
  • the polypeptide does not comprise any of: a dystrophin NT domain, a dystrophin hinge 1 domain, a dystrophin SLR1 domain, and a dystrophin SLR2 domain.
  • the polypeptide docs not comprise any of: a dystrophin NT domain, a dystrophin hinge 1 domain, a dystrophin SLR1 domain, a dystrophin SLR2 domain; and a dystrophin hinge 2 domain.
  • the polypeptide does not comprise any of: a dystrophin NT domain, a dystrophin hinge 1 domain, a dystrophin SLR1 domain, a dystrophin SLR2 domain; and a dystrophin hinge 3 domain.
  • the polypeptide does not comprise any of: a dystrophin NT domain and a dystrophin hinge 1 domain.
  • the polypeptide does not comprise any of: a utrophin SLR18 domain; a utrophin SLR19 domain; a utrophin SLR20 domain; a utrophin SLR21 domain; a utrophin SLR22 domain; a utrophin hinge 4 domain; and a utrophin CR domain.
  • the polypeptide does not comprise a polypeptide encoded by any of: SEQ ID NO: 600-603. In some embodiments of any of the aspects, the nuclec acid does not comprise any of: SEQ ID NO: 600-603. [00136] In some embodiments of any of the aspects, the polypeptide docs not comprise a polypeptide encoded by SEQ ID NO: 600. In some embodiments of any of the aspects, the nuclec acid does not comprise SEQ ID NO: 600. In some embodiments of any of the aspects, the polypeptide does not comprise a polypeptide encoded by SEQ ID NO: 601. In some embodiments of any of the aspects, the nuclec acid does not comprise SEQ ID NO: 601.
  • the polypeptide does not comprise a polypeptide encoded by SEQ ID NO: 602. In some embodiments of any of the aspects, the nuclec acid does not comprise SEQ ID NO: 602. In some embodiments of any of the aspects, the polypeptide does not comprise a polypeptide encoded by SEQ ID NO: 603. In some embodiments of any of the aspects, the nuclec acid does not comprise SEQ ID NO: 603.
  • polypeptide does not comprise the sequence of any of SEQ ID NO: 604-607.
  • the polypeptide does not comprise the sequence of SEQ ID NO: 604. In some embodiments of any of the aspects, the polypeptide does not comprise the sequence of SEQ ID NO: 605. In some embodiments of any of tire aspects, the polypeptide does not comprise the sequence of SEQ ID NO: 606. In some embodiments of any of the aspects, the polypeptide does not comprise the sequence of SEQ ID NO: 607.
  • a polypeptide comprising a utrophin N-terminal portion and a dystrophin C-terminal portion. In one aspect of any of the embodiments, described herein is a polypeptide comprising a dystrophin N-tcrminal portion and a utrophin C-terminal portion.
  • a microutrophin polypeptide comprising a utrophin NT domain, a utrophin SLR domain 1, a utrophin SLR domain 2, and a utrophin SLR domain 3, wherein the microutrophin polypeptide is encoded by a codon optimized nucleic acid sequence.
  • a microutrophin polypeptide consisting of a utrophin NT domain, a utrophin SLR domain 1, a utrophin SLR domain 2, and a utrophin SLR domain 3. wherein the microutrophin polypeptide is encoded by a codon optimized nucleic acid sequence.
  • a microutrophin polypeptide comprising a utrophin NT domain, a utrophin SLR domain 1, a utrophin SLR domain 2, and a utrophin SLR domain 3, wherein each of the utrophin NT domain, utrophin SLR domain 1, utrophin SLR domain 2, and utrophin SLR domain 3 are encoded by a codon optimized nucleic acid sequence.
  • a microutrophin polypeptide consisting of a utrophin NT domain, a utrophin SLR domain 1, a utrophin SLR domain 2.
  • utrophin SLR domain 3 a utrophin SLR domain 3, wherein each of the utrophin NT domain, utrophin SLR domain 1.
  • utrophin SLR domain 2, and utrophin SLR domain 3 are encoded by a codon optimized nucleic acid sequence.
  • the microutrophin polypeptide further comprises a utrophin hinge domain 1, utrophin hinge domain 2. and utrophin hinge domain 4. In some embodiments of any of the aspects, the microutrophin polypeptide further comprises a utrophin hinge domain 1. In some embodiments of any of the aspects, the microutrophin polypeptide further comprises a utrophin hinge domain 2. In some embodiments of any of the aspects, the microutrophin polypeptide further comprises a utrophin hinge domain 4.
  • the microutrophin poly peptide further comprises a utrophin SLR22 domain and a utrophin CR domain. In some embodiments of any of the aspects, the microutrophin polypeptide further comprises a utrophin SLR22 domain. In some embodiments of any of the aspects, the microutrophin polypeptide further comprises a utrophin CR domain.
  • the microutrophin polypeptide further comprises a utrophin hinge domain 1.
  • utrophin hinge domain 2 utrophin hinge domain 4, a utrophin SLR22 domain, and a utrophin CR domain.
  • one or more of utrophin hinge domain 1, the utrophin hinge domain 2, the utrophin hinge domain 4, the utrophin SLR22 domain, and the utrophin CR domain are encoded by a codon optimized nucleic acid sequence.
  • each of utrophin hinge domain 1, the utrophin hinge domain 2, the utrophin hinge domain 4, the utrophin SLR22 domain, and the utrophin CR domain arc encoded by a codon optimized nucleic acid sequence.
  • the microutrophin polypeptide is encoded by a codon-optimized sequence selected from one of SEQ ID NOs: 100-111 or 400-474. In some embodiments of any of the aspects, the microutrophin polypeptide is encoded by a codon-optimized sequence selected from one of SEQ ID NOs: 100-111, 400-432, and 434-474.
  • Described herein are codon-optimised versions of chimeric utrophin polypeptides.
  • a nucleic acid molecule comprising a sequence with at least 70% sequence identity to one of SEQ ID NOs: 100-111.
  • a nucleic acid molecule comprising a sequence with at least 75% sequence identity to one of SEQ ID NOs: 100-111.
  • a nucleic acid molecule comprising a sequence with at least 80% sequence identity to one of SEQ ID NOs : 100- 111.
  • nucleic acid molecule comprising a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100- 111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-111.
  • nucleic acid molecule comprising a sequence with at least 99% sequence identity to one of SEQ ID NOs : 100- 111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to one of SEQ ID NOs: 100-111.
  • nucleic acid molecule comprising a sequence with at least 70% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 75% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence identical to one of SEQ ID NOs: 100-111 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100-111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-111.
  • nucleic acid molecule consisting of a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100-111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100- 111. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to one of SEQ ID NOs: 100-111.
  • nucleic acid molecule comprising a sequence with at least 70% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 75% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-109.
  • nucleic acid molecule comprising a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to one of SEQ ID NOs: 100-109.
  • nucleic acid molecule comprising a sequence with at least 70% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 75% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g.. encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g.. encoding a chimeric trophin poly peptide.
  • nucleic acid molecule comprising a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule comprising a sequence identical to one of SEQ ID NOs: 100-109 or a functional equivalent thereof, e.g., encoding a chimeric trophin polypeptide.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-109.
  • nucleic acid molecule consisting of a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100- 109. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to one of SEQ ID NOs: 100-109.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100-103.
  • nucleic acid molecule comprising a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to one of SEQ ID NOs: 100-103.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100-103.
  • nucleic acid molecule consisting of a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100- 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to one of SEQ ID NOs: 100-103.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 90% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of tire embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to one of SEQ ID NOs: 101-103.
  • nucleic acid molecule comprising a sequence with at least 98% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to one of SEQ ID NOs: 101-103.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to one of SEQ ID NOs: 101-103.
  • nucleic acid molecule consisting of a sequence with at least 95% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 98% sequence identity to one of SEQ ID NOs: 101-103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to one of SEQ ID NOs: 101- 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to one of SEQ ID NOs: 101-103.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100, 102, or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100, 102, or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100. 102, or 103.
  • nucleic acid molecule comprising a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100, 102, or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100, 102. or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100. 102, or 103.
  • nucleic acid molecule comprising a sequence identical to one of SEQ ID NOs: 100, 102. or 103. [00167] In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 80% sequence identity to one of SEQ ID NOs: 100, 102, or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to one of SEQ ID NOs: 100, 102, or 103.
  • nucleic acid molecule consisting of a sequence with at least 90% sequence identity to one of SEQ ID NOs: 100, 102, or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 95% sequence identity to one of SEQ ID NOs: 100, 102, or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 98% sequence identity to one of SEQ ID NOs: 100, 102. or 103.
  • nucleic acid molecule consisting of a sequence with at least 99% sequence identity to one of SEQ ID NOs: 100, 102. or 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to one of SEQ ID NOs: 100, 102. or 103. [00168] In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 80% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to SEQ ID NO: 100.
  • nucleic acid molecule comprising a sequence with at least 90% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 98% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to SEQ ID NO: 100.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 95% sequence identity to SEQ ID NO: 100.
  • nucleic acid molecule consisting of a sequence with at least 98% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to SEQ ID NO: 100. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to SEQ ID NO: 100.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 90% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to SEQ ID NO: 101.
  • nucleic acid molecule comprising a sequence with at least 98% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to SEQ ID NO: 101.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 95% sequence identity to SEQ ID NO: 101.
  • nucleic acid molecule consisting of a sequence with at least 98% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to SEQ ID NO: 101. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to SEQ ID NO: 101.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 90% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to SEQ ID NO: 102.
  • nucleic acid molecule comprising a sequence with at least 98% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to SEQ ID NO: 102.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 95% sequence identity to SEQ ID NO: 102.
  • nucleic acid molecule consisting of a sequence with at least 98% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to SEQ ID NO: 102. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to SEQ ID NO: 102.
  • nucleic acid molecule comprising a sequence with at least 80% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 85% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 90% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 95% sequence identity to SEQ ID NO: 103.
  • nucleic acid molecule comprising a sequence with at least 98% sequence identity' to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence with at least 99% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule comprising a sequence identical to SEQ ID NO: 103.
  • nucleic acid molecule consisting of a sequence with at least 80% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 85% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 90% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 95% sequence identity to SEQ ID NO: 103.
  • nucleic acid molecule consisting of a sequence with at least 98% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence with at least 99% sequence identity to SEQ ID NO: 103. In one aspect of any of the embodiments, described herein is a nucleic acid molecule consisting of a sequence identical to SEQ ID NO: 103.
  • polypeptide comprising a sequence with at least 80% sequence identity to a polypeptide encoded by one of SEQ ID NOs: 100- 111. In one aspect of any of the embodiments, described herein is a polypeptide comprising a sequence with at least 85% sequence identity to a polypeptide encoded by one of SEQ ID NOs: 100- 111. In one aspect of any of the embodiments, described herein is a polypeptide comprising a sequence with at least 90% sequence identity to a polypeptide encoded by one of SEQ ID NOs: 100- 111.
  • polypeptide comprising a sequence with at least 95% sequence identity to a polypeptide encoded by one of SEQ ID NOs: 100- 111. In one aspect of any of the embodiments, described herein is a polypeptide comprising a sequence with at least 98% sequence identity to a polypeptide encoded by one of SEQ ID NOs: 100- 111. In one aspect of any of the embodiments, described herein is a polypeptide comprising a sequence with at least 99% sequence identity to a polypeptide encoded by one of SEQ ID NOs: 100- 111. In one aspect of any of the embodiments, described herein is a polypeptide comprising a sequence identical to a polypeptide encoded by one of SEQ ID NOs: 100-111.
  • a nucleic acid molecule described herein does not comprise the sequence of SEQ ID NO: 112. In some embodiments of any of the aspects, a nucleic acid molecule described herein does not comprise the sequence of SEQ ID NO: 113. In some embodiments of any of the aspects, a nucleic acid molecule described herein does not comprise the sequence of SEQ ID NO: 112 or the sequence of SEQ ID NO: 113.
  • G3 SEQ ID NO : 100
  • G4 SEQ ID NO : 101
  • G5 SEQ ID NO : 102
  • G8 SEQ ID NO : 105
  • G9 SEQ ID NO : 106
  • G12 SEQ ID NO : 109
  • G13 SEQ ID NO : 110
  • G1 SEQ ID NO : 111
  • nucleic acid encoding a polypeptide described herein.
  • the nucleic acid comprises a sequence with at least 70% sequence identity to one of SEQ ID NOs: 85-87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 75% sequence identity to one of SEQ ID NOs: 85-87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 80% sequence identity to one of SEQ ID NOs: 85-87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 85% sequence identity to one of SEQ ID NOs: 85-87.
  • the nucleic acid comprises a sequence with at least 90% sequence identity to one of SEQ ID NOs: 85-87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 95% sequence identity to one of SEQ ID NOs: 85-87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 98% sequence identity to one of SEQ ID NOs: 85-87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 99% sequence identity to one of SEQ ID NOs: 85-87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence identical to one of SEQ ID NOs: 85-87.
  • the nucleic acid comprises a sequence with at least 70% sequence identity to SEQ ID NO: 85. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 75% sequence identity to SEQ ID NO: 85. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 80% sequence identity to SEQ ID NO: 85. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 85% sequence identity to SEQ ID NO: 85. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 90% sequence identity to SEQ ID NO: 85.
  • the nucleic acid comprises a sequence with at least 95% sequence identity to SEQ ID NO: 85. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 98% sequence identity to SEQ ID NO: 85. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 99% sequence identity to SEQ ID NO: 85. In some embodiments of any of the aspects, the nucleic acid comprises a sequence identical to SEQ ID NO: 85.
  • the nucleic acid comprises a sequence with at least 70% sequence identity to SEQ ID NO: 86. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 75% sequence identity to SEQ ID NO: 86. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 80% sequence identity to SEQ ID NO: 86. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 85% sequence identity to SEQ ID NO: 86. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 90% sequence identity to SEQ ID NO: 86.
  • the nucleic acid comprises a sequence w ith at least 95% sequence identity to SEQ ID NO: 86. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 98% sequence identity to SEQ ID NO: 86. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 99% sequence identity' to SEQ ID NO: 86. In some embodiments of any of the aspects, the nucleic acid comprises a sequence identical to SEQ ID NO: 86.
  • the nucleic acid comprises a sequence with at least 70% sequence identity to SEQ ID NO: 87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 75% sequence identity to SEQ ID NO: 87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 80% sequence identity to SEQ ID NO: 87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 85% sequence identity to SEQ ID NO: 87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 90% sequence identity to SEQ ID NO: 87.
  • the nucleic acid comprises a sequence with at least 95% sequence identity to SEQ ID NO: 87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 98% sequence identity' to SEQ ID NO: 87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence with at least 99% sequence identity to SEQ ID NO: 87. In some embodiments of any of the aspects, the nucleic acid comprises a sequence identical to SEQ ID NO: 87.
  • the nucleic acid comprises a sequence which is codon-optimized for expression in human cells.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises a codon-optimized sequence selected from one of SEQ ID NOs: 400- 412, or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to one of the foregoing sequences.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 400, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 400. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 400.
  • SEQ ID NO: 400 Codon-optimized sequence encoding utrophin NT domain
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 401, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 401.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 401.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 402, or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 402.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 402.
  • SEQ ID NO: 402 Codon-optimized sequence encoding utrophin NT domain
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 403, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity’ to SEQ ID NO: 403.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 403.
  • SEQ ID NO: 403 Codon-optimized sequence encoding utrophin NT
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 404, or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 404. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 404.
  • SEQ ID NO: 404 Codon-optimized sequence encoding utrophin NT
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 405, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 405. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 405.
  • SEQ ID NO: 405 Codon-optimized sequence encoding utrophin NT
  • SEQ ID NO: 406 Codon-optimized sequence encoding utrophin NT
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 407, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 407.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 407.
  • SEQ ID NO: 407 Codon-optimized sequence encoding utrophin NT
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 408, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 408. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 408.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 409, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 409.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 409.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 410, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 410.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 410.
  • SEQ ID NO: 410 Codon-optimized sequence encoding utrophin NT ATGGCTAAGTATGGGGAACATGAGGCCAGTCCAGACAATGGGCAGAATGAATTCTCTGATATCATTAA GTCCAGATCTGATGAACACAATGATGTGCAGAAGAAAACCTTTACCAAATGGATAAATGCTAGATTTT CAAAGAGTGGGAAACCACCCATCAATGACATGTTCACTGACCTCAAAGATGGGAGAAAGCTACTAGAT CTTCTAGAAGGCCTCACTGGAACATCACTGCCCAAGGAAAGGGGTTCCACAAGGGTACATGCCTTAAA TAATGTCAACAGAGTGCTGCAGGTTTTACATCAGAACAATGTGGAACTGGTGAATATAGGTGGCACTG ACATTGTGGATGGCAATCACAAACTGACTTTGGGGTTACTTTGGTCTATCATTTTGCACTGGCAGGTG AAAGATGTCATGAAGGATGTGATGTCAGACCTGCAGCAGACAAACTCAGAAAAGATCCTGCT
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 411. or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 411.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 411.
  • the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 412, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 412. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin NT domain comprises the codon-optimized sequence of SEQ ID NO: 412.
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises a codon-optimized sequence selected from one of SEQ ID NOs: 413-424, or a sequence having at least 70%. at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to one of the foregoing sequences.
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 413, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 413. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 413.
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 414, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 414. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 414.
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 415, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 415. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 415.
  • SEQ ID NO: 415 Codon-optimized sequence encoding utrophin hinge 1 domain
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 416, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 416. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 416.
  • SEQ ID NO: 416 Codon-optimized sequence encoding utrophin hinge 1 domain
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 417, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 417. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 417.
  • SEQ ID NO: 417 Codon-optimized sequence encoding utrophin hinge 1 domain
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 418, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 418. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 418.
  • SEQ ID NO: 418 Codon-optimized sequence encoding utrophin hinge 1 domain ACCCTCCCAAGGAAATATAAAAAAGAATGTGAGGAAGAGGCCATTAATATACAGTCCACAGCACCAGA GGAGGAGCATGAGAGTCCCAGGGCTGAAACTCCCAGCACT
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 419, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 419. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 419.
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 420, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 420. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 420.
  • SEQ ID NO: 420 Codon-optimized sequence encoding utrophin hinge 1 domain
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon -optimized sequence of SEQ ID NO: 421, or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 421. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 421.
  • SEQ ID NO: 421 Codon-optimized sequence encoding utrophin hinge 1 domain ACCCTCCCAAGGAAATATAAAAAAGAATGTGAGGAAGAGGCAATTAATATACAGTCTACTGCTCCTGA GGAGGAGCATGAGAGTCCCAGAGCAGAAACTCCCAGCACA
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 422, or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 422. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 422.
  • SEQ ID NO: 422 Codon-optimized sequence encoding utrophin hinge 1 domain ACTCTCCCAAGGAAATATAAAAAAGAATGTGAGGAAGAGGCAATTAATATACAGTCCACAGCCCCTGA GGAGGAGCATGAGAGTCCCAGAGCTGAGACTCCCAGCACA
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon -optimized sequence of SEQ ID NO: 423, or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 423. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 423.
  • SEQ ID NO: 423 Codon-optimized sequence encoding utrophin hinge 1 domain AC AC T C C C T AGGAAAT AT AAAAAAGAAT GT GAAGAAGAGGC AAT TAATATACAGAGTACAGCCC C AGA AGAGGAGCATGAGAGTCCCAGGGCTGAGACTCCCAGCACT
  • the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 424, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 424. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 1 domain comprises the codon-optimized sequence of SEQ ID NO: 424.
  • SEQ ID NO: 424 Codon-optimized sequence encoding utrophin hinge 1 domain
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises a codon-optimized sequence selected from one of SEQ ID NOs: 425-438, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to one of the foregoing sequences.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises a codon-optimized sequence selected from one of SEQ ID NOs: 425-432 and 434- 438, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to one of the foregoing sequences.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 425. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 425. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 425.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 426. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 426.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 426.
  • SEQ ID NO: 426 Codon-optimized sequence encoding utrophin SLR1 domain
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 427, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity’ to SEQ ID NO: 427. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 427.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 428, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 428. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 428.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 430, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity’ to SEQ ID NO: 430.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimizcd sequence of SEQ ID NO: 430.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 431. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 431. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 431.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 432, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 432. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 432.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 434. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 434. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 434.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 435.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 435.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 436. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 436. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 436.
  • SEQ ID NO: 436 Codon-optimized sequence encoding utrophin SLR1 domain
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 437, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 437. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 437.
  • the portion of the nucleic acid encoding the utrophin SLR1 domain comprises the codon-optimized sequence of SEQ ID NO: 438, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 438, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 438, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 438, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 438,
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises a codon-optimized sequence selected from one of SEQ ID NOs: 439-450, or a sequence having at least 70%. at least 75%, at least 80%. at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to one of the foregoing sequences.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 439, or a sequence having at least 70%, at least 75%. at least 80%. at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 439. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 439.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 440, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity’ to SEQ ID NO: 440. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 440.
  • SEQ ID NO: 440 Codon-optimized sequence encoding utrophin SLR2 domain
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 441.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 441.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 442, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 442. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 442.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 443, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 443.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 443.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 444. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 444. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 444.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 445, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 445. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 445.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 446, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 446. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 446.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 447, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 447.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 447. [00293] SEQ ID NO: 447 Codon-optimized sequence encoding utrophin SLR2 domain
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 448, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity’ to SEQ ID NO: 448. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 448.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 449, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 449. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 449.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 450, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 450.
  • the portion of the nucleic acid encoding the utrophin SLR2 domain comprises the codon-optimized sequence of SEQ ID NO: 450.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises a codon-optimized sequence selected from one of SEQ ID NOs: 451-462, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to one of the foregoing sequences.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 451, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 451.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 451.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 452, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 452. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 452.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 453, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 453. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 453.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 454, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 454. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 454.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 455, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 455. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 455.
  • SEQ ID NO: 455 Codon-optimized sequence encoding utrophin SLR3 domain
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 456, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 456. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 456.
  • SEQ ID NO: 456 Codon-optimized sequence encoding utrophin SLR3 domain CAGGAATTATTGGAAGAACAGTGCTTGTTGAAAGCATGGTTAACTGAAAAAGAAGAGGCTTTAAATAA AGTCCAGACAAGCAACTTCAAAGACCAAAAGGAACTAAGTGTCAGTGTTAGGAGGCTGGCTATTTTGA AGGAAGACAT GGAAAT GAAGAGACAAACAT T GGATCAGCT GAGT GAGAT AGGCCAGGATGT GGGACAA TTACTTGATAATTCCAAGGCCTCTAAGAAGATCAACTCAGATTCAGAGGAACTGACTCAAAGGTGGGA TTCCTTGGTTCAGAGACTAGAAGATTCCTCCAACCAGGTGACT
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 457, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 457. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 457.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 458. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 458. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 458.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 459, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 459. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 459.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 460, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 460. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 460.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 461. or a sequence having at least 70%. at least 75%, at least 80%, at least 85%. at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 461.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 461.
  • the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 462, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 462. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin SLR3 domain comprises the codon-optimized sequence of SEQ ID NO: 462.
  • the portion of the nucleic acid encoding the utrophin hinge 2 domain comprises a codon-optimized sequence selected from one of SEQ ID NOs: 463-474, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%
  • the portion of the nucleic acid encoding the utrophin hinge 2 domain comprises the codon-optimized sequence of SEQ ID NO: 463, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%. or at least 99% sequence identity to SEQ ID NO: 463. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 2 domain comprises the codon-optimized sequence of SEQ ID NO: 463.
  • the portion of the nucleic acid encoding the utrophin hinge 2 domain comprises the codon-optimized sequence of SEQ ID NO: 464, or a sequence having at least 70%, at least 75%. at least 80%. at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 464. In some embodiments of any of the aspects, the portion of the nucleic acid encoding the utrophin hinge 2 domain comprises the codon-optimized sequence of SEQ ID NO: 464.
  • the portion of the nucleic acid encoding the utrophin hinge 2 domain comprises the codon -optimized sequence of SEQ ID NO: 465, or a sequence having at least 70%, at least 75%. at least 80%, at least 85%, at least 90%. at least 95%, at least 98%, or at least 99% sequence identity’ to SEQ ID NO: 465.
  • the portion of the nucleic acid encoding the utrophin hinge 2 domain comprises the codon-optimized sequence of SEQ ID NO: 465.

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Abstract

La technologie décrite dans la présente invention concerne des méthodes et des compositions se rapportant à des polypeptides chimériques, par exemple, pour le traitement de la dystrophie musculaire de Duchenne.
PCT/US2025/032826 2024-06-10 2025-06-09 Méthodes et compositions pour le traitement de la dystrophie musculaire de duchenne Pending WO2025259575A1 (fr)

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