Correction of Hearing and Vestibular Defects in a Mouse Model for Deafness

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DESCRIPTION (provided by applicant): The long-term goal of this work is to develop a curative treatment for congenital deafness, vestibular dysfunction and retinitis pigmentosa in Usher syndrome, the leading genetic cause of combined deafness and blindness. This treatment approach could ultimately be developed as a therapeutic for hearing, balance and vision loss in general. In this project, we investigate the use of antisense oligonucleotides (ASOs) for the treatment of Usher syndrome in mice. We designed an ASO to correct an RNA splicing defect caused by a mutation in the USH1C gene that causes Usher syndrome in mice and humans. Preliminary results show that an USH1C-targeted ASO rescues hearing and vestibular function in mice. The aims of this project are to further develop this ASO-targeting approach by 1) Developing an ASO-based treatment regimen for the prevention/ treatment of deafness and blindness in mice; 2) Assessing the cellular effects of USH1C-targeted ASOs and establishing measurable outcomes of treatment efficacy; and 3) Delivering ASOs locally to the mouse cochlea to improve targeting efficacy. The overall goal of these aims is to translate this ASO-targeting approach into a treatment regimen that will lay a foundation for future clinical trials. One far-reaching contribution of this study is the demonstration that ASOs can effectively and potently target the cochlea to rescue hearing, a finding that advocates ASOs as a promising tool for treating diseases of the ear.