Vestibular dysfunction and the development of therapies for Usher syndrome

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Project Summary Collectively, rare diseases affect ~350 million people in the world, and most of them lack specific treatments resulting in a tremendous unmet medical need. Understanding the underlying genetic and molecular mechanisms and developing therapies for rare diseases are essential for our efforts to address this urgent need. The present application focuses on understanding and treating Usher syndrome (Usher), a rare disease characterized by multisensory loss (hearing, vision, and balance) that creates a major communication and mobility burden affecting all aspects of life. Currently, there are no treatments to prevent or slow the progression of Usher. To fill these important gaps, we propose three aims in this collaborative project to determine the progression of vestibular dysfunction over time in the knock-in mouse model for the most common type 1 Usher mutation in the Acadian populations of Louisiana and Canada (USH1C c.216G>A) (Aim 1) and in a cohort of pediatric, young adult, and adult USH1C patients (Aim 3), and to test the therapeutic efficacies of antisense and gene replacement therapies when delivered at different stages of disease progression in the USH1C mice (Aim 2). These aims are driven by the central hypothesis that USH1C-related vestibular dysfunction progresses over time and is end-organ specific, which is supported by our strong preliminary studies that show age-dependent declines of the vestibulo-ocular reflexes, and progressive saccular hair cell degeneration in USH1C mice. In Aim 1, we will employ a combination of molecular, structural, single vestibular afferent neurophysiology, and behavioral biomarkers to define the progression of vestibular dysfunction in USH1C mice over a 1-year time course. In Aim 2, we will continue studies to restoring vestibular function in neonatal USH1C mice using the antisense and gene replacement therapies and further test their effectiveness when delivered at various stages of disease progression. In parallel, in Aim 3, we will define the natural history of vestibular dysfunction in a cohort of 50 USH1C patients by testing their vestibular function at baseline and 6 months later. These results will fill the important gaps in understanding and treating Usher disease and allow us to define the clinical outcome measures for future clinical trials. Results from this collaborative project will identify lead clinical drug candidates, an optimal treatment regimen for restoring vestibular function in USH1C mice, and define measurable clinical outcomes to guide a first-in-human study of a treatment for vestibular dysfunction in USH1C.