Compositions and methods for treating sensorineural hearing loss using otoferlin dual vector systems

A method of treating a subject having sensorineural hearing loss or auditory neuropathy or carrying an OTOF gene mutation, the method comprising administering to the subject a therapeutically effective amount of a composition comprising:

• a first adeno-associated virus (AAV) vector comprising a myosin 15 (Myo15) promoter having at least 95% sequence identity to the sequence of SEQ ID NO:
• 36, wherein the Myo15 promoter is operably linked to a first coding polynucleotide that encodes an N-terminal portion of a human otoferlin (OTOF) protein;
• and
• a second AAV vector comprising a second coding polynucleotide that encodes a C-terminal portion of the human OTOF protein and a polyadenylation sequence positioned at a 3′ end of the second coding polynucleotide,
• wherein neither the first AAV vector nor the second AAV vector encodes a full-length OTOF protein, and, when introduced into a mammalian cell, the first AAV vector and the second AAV vector undergo homologous recombination or concatemerization to form a recombined nucleic acid that encodes the full-length OTOF protein.