Transmembrane Channel-Like (Tmc) Gene Therapy Restores Auditory Function in Deaf Mice

Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mouse models of genetic deafness. We focused on DFNB7/11 and DFNA36, which are autosomal recessive and dominant deafnesses, respectively, caused by mutations in Transmembrane channel-like 1 (TMC1). Thirty-nine recessive mutations and five dominant mutations have been identified in human TMC1. Mice that carry targeted deletion of Tmc1, or a dominant point mutation, known as Beethoven, are good models for human DFNB7/11 and DFNA36. We screened several adeno-associated viral (AAV) serotypes and promoters and identified AAV2/1 and the chicken beta-actin promoter as an efficient combination for driving expression of exogenous Tmc1 in inner hair cells in vivo. We find that exogenous Tmc1 or its closely related ortholog, Tmc2, are capable of restoring sensory transduction, auditory brainstem responses and acoustic startle reflexes in otherwise deaf mice, suggesting that gene augmentation with Tmc1 or Tmc2 is well-suited for further development as a strategy for restoration of auditory function in deaf patients who carry TMC1 mutations.