Rescue of Auditory Function by a Single Administration of AAV- Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8.

Patients with mutations in the gene suffer from recessive deafness DFNB8/DFNB10 for whom cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knock-in mouse model with a frequent human DFNB8 mutation. The homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human gene, AAV2-h injection in the adult knock-in mouse inner ears results in expression in the hair cells and the spiral ganglion neurons. A single AAV2-h injection in aged mice leads to sustained rescue of the auditory function, to a level similar to the wildtype mice. AAV2-h delivery rescues the hair cells and the spiral ganglions. This is the first study to demonstrate successful gene therapy in an aged mouse model of human genetic deafness. This study lays the foundation to develop AAV2-h gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.