Abstract
Patients with mutations in the
TMPRSS3
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
TMPRSS3
mutation. The
Tmprss3
A306T/A306T
homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human
TMPRSS3
gene, AAV2-h
TMPRSS3
injection in the adult knock-in mouse inner ears results in
TMPRSS3
expression in the hair cells and the spiral ganglion neurons. A single AAV2-h
TMPRSS3
injection in aged
Tmprss3
A306T/A306T
mice leads to sustained rescue of the auditory function, to a level similar to the wildtype mice. AAV2-h
TMPRSS3
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
TMPRSS3
gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.