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

A dual vector system comprising:

• a first adeno-associated virus (AAV) vector comprising a Myo15 promoter operably linked to a first coding polynucleotide that encodes an N-terminal portion of an Otoferlin (OTOF) isoform 5 protein, a splice donor signal sequence positioned 3′ of the first coding polynucleotide, and a first recombinogenic region positioned 3′ of the splice donor signal sequence;
• and
• a second AAV vector comprising a second recombinogenic region, a splice acceptor signal sequence positioned 3′ of the second recombinogenic region, a second coding polynucleotide that encodes a C-terminal portion of the OTOF isoform 5 protein positioned 3′ of the splice acceptor signal sequence, and a poly(A) sequence positioned 3′ of the second coding polynucleotide,
• wherein the first coding polynucleotide and the second coding polynucleotide that encode the OTOF isoform 5 protein do not overlap,
• wherein neither the first nor second AAV vector encodes the full-length OTOF isoform 5 protein,
• and wherein the first AAV vector comprises a polynucleotide sequence comprising the sequence of nucleotides 235 to 4004 of SEQ ID NO:
• 66 and the second AAV vector comprises a polynucleotide sequence comprising the sequence of nucleotides 229 to 4438 of SEQ ID NO:
• 67.