Abstract: The disclosure features compositions and methods for the treatment of inner ear dysfunction, such as hearing loss or vestibular dysfunction, that reduce inflammatory or cell-mediated immune toxicity in the inner ear, thereby improving transduction and therapeutic efficacy. The disclosure provides a variety of compositions that include a nucleic acid vector that contains a polynucleotide encoding a therapeutic agent operably linked to a ubiquitous promoter and inhibitor of inflammatory or immune cell signaling. The disclosed compositions and methods can be used to increase expression of the therapeutic agent in a subject, such as a human subject suffering from an inner ear dysfunction, while minimizing undesirable immune activation resulting from off-target expression of the target protein in immune cells of the inner ear.

Abstract: The disclosure provides nucleic acidvectors containing a high expression promoter, such as a high expression, supporting cell-specific promoter, operably linked to a polynucleotide encoding Atoh1. Such vectors and compositions containing the same can be used to induce robust regeneration of mature hair cells (e.g., cochlear and/or vestibular hair cell regeneration). Accordingly, the nucleic acid vectors and compositions described herein can be used to treat subjects having or at risk of developing hearing loss or vestibular dysfunction.

Abstract: The disclosure provides polynucleotides containing inner hair cell-specific promoters, as well as vectors containing the same, that can be used to promote expression of a transgene specifically in inner hair cells. The polynucleotides described herein may be operably linked to a transgene, such as a transgene encoding a therapeutic protein, so as to promote inner hair cell-specific expression of the transgene. The polynucleotides described herein may be operably linked to a therapeutic transgene and used for the treatment of subjects having or at risk of developing hearing loss.

Abstract: The disclosure provides polynucleotides containing SLC6A14 promoters, as well as vectors containing the same, that can be used to promote expression of a transgene in vestibular supporting cells. The polynucleotides described herein may be operably linked to a transgene, such as a transgene encoding a therapeutic protein, so as to promote vestibular supporting cell expression of the transgene. The polynucleotides described herein may be operably linked to a therapeutic transgene and used for the treatment of subjects having or at risk of developing vestibular dysfunction.

Abstract: The invention provides AAV1 vectors that can be used to transduce multiple inner ear cell types and their use for treatment of hearing loss, deafness, tinnitus, and vestibular dysfunction.