Provided herein are gene therapy vectors containing a polynucleotide encoding a cardiac-specific promoter operably linked to a polynucleotide encoding Troponin I3, and methods of using such vectors for preventing, mitigating, ameliorating, reducing, inhibiting, eliminating and/or reversing one or more symptoms of cardiomyopathy.

Described herein are recombinant AAV vectors comprising a polynucleotide sequence comprising β-sarcoglycan and methods of using the recombinant vectors to reduce or prevent fibrosis in a mammalian subject suffering from a muscular dystrophy. Also described herein are combination therapies comprising administering AAV vector(s) expressing β-sarcoglycan and miR-29c to a mammalian subject suffering from a muscular dystrophy.

Synthetic nucleic acids encoding mini and microdystrophin genes comprising the membrane binding motifs or domains of the R10-R11-R12 region are provided. Also provided are vectors, host cells, and related methods of using the same to treat a subject suffering from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) or X-linked dilated cardiomyopathy (XLDC), or for ameliorating one or more adverse effects of DMD, BMD, or XLDC. Also provided are a fusion protein comprising a nNOS binding domain of dystrophin R16-R17 that is operably linked to a syntrophin PDZ domain and synthetic nucleic acids comprising the same that can be used to treat subjects with diseases characterized by loss of sarcolemmal neuronal nitric oxide synthase (nNOS) activity.

Aspects of the disclosure relate to compositions and methods useful for delivering minigenes to a subject. Accordingly, the disclosure is based, in part, on isolated nucleic acids and gene therapy vectors, such as viral (e.g., rAAV) vectors, comprising one or more gene fragments encoding a therapeutic gene product, such as a protein or peptide (e.g. a minigene). In some embodiments, the disclosure relates to gene therapy vectors encoding a USH1B protein (e.g. the gene product of USH1B, also referred to as MY07A) or a portion thereof. In some embodiments, compositions described by the disclosure are useful for treating diseases associated with mutations in the USH1B (MY07A) gene, for example Usher Syndrome.

Truncated junctophilin-2 related proteins, transcriptional repressor domains, vectors encoding the proteins or domains, and methods of using the proteins and domains, are provided.

The present disclosure provides methods and compositions useful for the treatment or prevention of heart disease. In particular, the present disclosure provides a vector comprising a modified troponin T promoter operatively linked to a therapeutic gene product for the treatment or prevention of heart disease, e.g., cardiomyopathy. The gene product may be MYBPC3. The disclosure also provides recombinant adeno-associated virus (rAAV) virions, rAAV viral genomes, and expression cassettes and pharmaceutical compositions thereof. The disclosure further provides methods for treating a disease or disorder, such as heart disease.

Provided herein are materials and methods for efficiently delivering nucleic acids to cochlear and vestibular cells, and methods of treating sensory transduction disorders associated with a genetic defect. Some embodiments are directed to a synthetic inner ear hair cell targeting adeno-associated virus (AAV) vector, a cell comprising the synthetic inner ear hair cell targeting AAV vector, and method of treating Usher Syndrome in a subject using the synthetic inner ear hair cell targeting AAV vector.

Provided herein are synthetic RNA molecules for reconstitution of RNA molecules, including compositions and methods of using these molecules. For example, such molecules can be used to deliver a protein coding sequence over two or more viral vectors (such as AAVs), resulting in reconstitution of the full-length protein in a cell. Such methods can be used to deliver a therapeutic protein, for example to treat a genetic disease or cancer.

Disclosed are materials and methods for treating diseases of the mammalian eye, and in particular, Usher syndrome 1B (USH1B). The invention provides AAV-based, dual-vector systems that facilitate the expression of full-length proteins whose coding sequences exceed that of the polynucleotide packaging capacity of an individual AAV vector. In one embodiment, vector systems are provided that include i) a first AAV vector polynucleotide that includes an inverted terminal repeat at each end of the polynucleotide and a suitable promoter followed by a partial coding sequence that encodes an N-terminal portion of a full-length polypeptide; and ii) a second AAV vector polynucleotide that includes an inverted terminal repeat at each end of the polynucleotide and a partial coding sequence that encodes a C-terminal portion of a full-length polypeptide, optionally followed by a polyadenylation (pA) signal sequence. In another embodiment, the vector system includes i) a first AAV vector polynucleotide comprising an inverted terminal repeat at each end, a suitable promoter followed by a partial coding sequence that encodes an N-terminal portion of a full-length polypeptide followed by a splice donor site and intron and ii) a second AAV vector polynucleotide comprising an inverted terminal repeat at each end, followed by an intron and a splice-acceptor site for the intron, followed by a partial coding sequence that encodes a C-terminal portion of a full-length polypeptide, optionally followed by a polyadenylation (pA) signal sequence. The coding sequence or the intron sequence in the first and second AAV vectors preferably includes a sequence region that overlaps.

The invention, in some aspects, relates to polypeptide molecules and their encoding nucleic acid molecules and use of such molecules to target opsins to the soma of cells in which they are expressed. Compositions of the invention may be delivered to cells and subjects and used in methods to modulate electrical activity of cells in which they are expressed, and for treatment of diseases and conditions in subjects.