Gene Therapy for Treating Human Genetic Deafness Tested in Animal Models

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 DESCRIPTION (provided by applicant): Genetic mutations are responsible for more than half of all congenital permanent hearing loss cases. The prevalence can be as high as 6 per 1,000 among school-age children. Mutations in the gap junction (GJ) proteins (e.g., GJB2) cause some of the most common forms of human congenital non-syndromic deafness. Genetic predisposition is also known to be an essential factor in age-dependent hearing loss (ADHL) and noise-induced hearing loss (NIHL), which affect tens of millions of patients. Today there is no biological treatment to correct the root cellular and genetic causes of inherited sensorineural hearing loss. Multiple research groups in the hearing field have worked for years to introduce gene therapy into clinical applications for the treatment of sensorineural deafness. Recent reports have yielded some promising results; however, the in vivo feasibility and reliability of virally mediated gene therapy in correcting the most common forms of non-syndromic human inherited deafness remain to be demonstrated. To date, gene therapy has not been successful at treating hearing loss in adult-stage mouse models. Moreover, none of the gene therapy studies for treating sensorineural hearing loss have advanced to the stage of systematic in vivo preclinical trials yet. The present project is the first to conduct major experiments required for n vivo preclinical studies of a gene therapy approach for treating the most common forms of non-syndromic deafness, as well as ADHL and NIHL, using mouse models. Studies will test the efficacy of gene therapy at both the postnatal and adult stages. We will study the feasibility and reliability of using a virally mediated gene replacement/augmentation therapy to prevent hearing loss in conditional Gjb2-/-, Gjb6-/-, and C57BL/6J (a popular mouse model for studying ADHL and NIHL) mice. We will also investigate the long-term efficacy and safety of the treatment in these mouse models. Carrying out the specific aims outlined here should fulfill some of the vital and necessary steps required for the translation of gene therapy into clinical applications.