Gene Therapy for Hearing Loss and Vestibular Dysfunction

The auditory and vestibular systems, respectively, define the ability to hear sounds and to maintain balance. Both systems depend on many synchronized processes, including coding genes and regulatory elements. More than 150 genes have been identified that play a role in the normal function of the human auditory system, and a significant effort has been made to understand the mechanisms of hearing loss, as it affects approximately 6-8% of the world’s population. Although more than half of cases are due to genetic variants, most treatments today include amplifying hearing aids and cochlear implants. Therefore, other therapeutic strategies, such as biological treatment, are essential for curing genetic hearing loss, and the potential for rescue needs to be examined. Our gene therapy research focuses on the genes Syne4 (encoding Nesprin-4), Clic5 (encoding Chloride intracellular channel 5), and Myo6 (encoding myosin VI), affecting the morphology of hair cells in the inner ear. Pathogenic variants in each of these genes in the human form are associated with autosomal dominant or recessive deafness and in some cases, vestibular areflexia in humans. For Syne4, we succeeded in rescuing deafness in the knockout mice, as well as preserving the morphological structure of the hair cells (Taiber et al. EMBO Molecular Medicine, 2020). We are working towards restoring both auditory and vestibular functions in the Clic5 and Myo6 mouse models, using the adeno-associated virus (AAV) gene replacement therapy method. Most recently, gene therapy for otoferlin (OTOF) was successful in human clinical trials. The research on mouse models will contribute to advancing translational research to treat hearing and balance disorders in humans in the future.