Gene Therapy for the Many Forms of Deafness

The World Health Organization estimates that 466 million people, including 34 million children, have a disabling hearing loss of >40dB. At present, treatments for hearing loss consist of hearing aids and cochlear implants, but these technologies are not optimal. Among elderly persons, compliance with hearing aids is extremely poor, with uncontrolled hearing loss leading to significantly increased risk of dementia, among other challenges. In response to these needs, a major goal of hearing research is to develop molecular methods for prevention and treatment of hearing loss, for example by modification or replacement of DNA sequences by gene therapy. While over 120 genes are known to be associated with non-syndromic hearing loss, the most frequently affected genes leading to hearing loss are GJB2, TMC1, MYO15A, MYO7A, SLC26A4 and MYO6, with rarer ones such as SYNE4 and CLIC5. Recent studies show that adeno-associated virus (AAV) gene therapy can be used to rescue hearing function in mice. We are using Syne4, Myo6 and Clic5 mutant mice as models for human deafness, which present hearing loss and vestibular dysfunction. Using a posterior semicircular canal injection of an adeno-associated virus (AAV) vector containing the coding sequences of the target gene, we have been able to rescue hearing in the Syne4 model (Taiber et al. 2021 EMBO Molecular Medicine). Our results demonstrate the relevance of using AAV for therapy in deafness, with implications for human hearing loss (Research funded by US-Israel Binational Science Foundation-BSF and the Israel Precision Medicine Partnership-ISF).