Gene editing to treat hereditary deafness

Roughly 2/1000 children are born with hearing loss, mostly hereditary. Although >150 genes cause hereditary deafness, by far the most common is GJB2. Among GJB2 mutations, the most common is a missense, p.M34T; about 1,100 children are born per year in the United States with hearing loss caused by this mutation. This could be treated with gene addition, but cochlear cells expressing GJB2 slowly turn over, eventually diluting the AAV episomal DNA. Correction of M34T by gene editing would be permanent, with the corrected gene replicated with each cell division. In this project we will develop cytosine base editing for the M34T mutation. We will first optimize editors in vitro and create AAVs to deliver the best editor. Concurrently, we will characterize a mouse model carrying the GJB2 M34T mutation. Finally, we will deliver the vectors to the mouse inner ear, and test editing both with sequencing of cochlear DNA and functional tests of hearing. Several gene therapy companies would be interested in licensing this technology for GJB2.