Exon 13-skipped USH2A protein retains functional integrity in mice, suggesting an exo-skipping therapeutic approach to treat USH2A-associated disease

Mutations in the gene are the most common cause of non-syndromic inherited retinal degeneration and Usher syndrome, which is characterized by congenital deafness and progressive vision loss. Development of a vector mediated therapy for -associated disease has been challenging due to its large size of coding sequence (~15.6kb). Therefore, there is an unmet need to develop alternative therapeutic strategies. The USH2A protein (Usherin) contains many repetitive domains, and it has been hypothesized that some domains may be dispensable with regard to protein function. Here, we show that skipping of exon 13 of the human gene or the equivalent exon 12 of the mouse gene results in an in-frame transcript that produces functional Usherin protein. This nearly full length Usherin rescues the ciliogenesis in null cells as well as the cochlear and retinal phenotypes in null mice. Together, our results support the development of exon-skipping strategies to treat both visual and hearing loss in patients with -associated disease due to mutations in exon 13.