Therapeutic approaches to treat vision loss in Usher syndrome - Project Summary Usher syndrome (Usher) is the leading inherited cause of combined deafness and blindness in the world, affecting 1 in 20,000 individuals worldwide. The Acadians of Louisiana and Canada have a mutation (216G>A) in their USH1C gene that is responsible for a severe form of Usher (Usher Type 1C; USH1C). Patients with USH1C have profound deafness at birth, balance difficulties, and progressively lose their vision beginning at age 10. The 216A mutation causes aberrant splicing of the USH1C gene, producing a truncated, dysfunctional harmonin protein leading to degeneration of photoreceptors and cochlear hair cells. In the eye, harmonin is expressed in both photoreceptors and Müller glial cells and is required in Müller glial cells for proper development and function of photoreceptors. However, the mechanism underlying the retinal pathogenesis of USH1C is not known, creating a translational barrier of which cell type to target for a gene replacement strategy. Our laboratory created a knock-in mouse model containing the human 216A mutation responsible for Acadian USH1C. These mice exhibit impairment in hearing, balance, and vision similar to USH1C patients. Previously, treatment with an antisense oligonucleotide therapy to correct aberrant splicing or gene replacement therapy using a synthetic AAV vector did not improve visual function in the USH1C mouse model most likely due to insufficient transgene expression in target cells of the retina because the treatment effect was mostly limited to site of injection. To improve treatment efficacy, we will test a novel AAV vector capable of spreading more widely through the retina to maximize photoreceptor transduction. In parallel, we will test a novel AAV vector designed to efficiently transduce Müller glial cells to better understand optimal cellular targets for gene replacement therapy. These AAV vectors will be used to deliver gene replacement targeting the 216A mutation in USH1C mice to increase full-length Ush1c transcripts and functional harmonin levels for sustained improvement in vision (Aim 1). While treatments to restore vision in USH1C are currently underway, clinical parameters to determine treatment efficacy are not known in USH1C patients. Studies in this proposal will characterize the natural progression of functional vision (ability to use vision to carry out tasks of daily living) in pediatric, young adult, and adult USH1C patients at different stages of vision loss (Aim 2). Functional vision will be assessed by a virtual reality orientation and mobility test to evaluate visual behavior in a real-world simulated environment. In addition to preparing me to become a clinician-scientist, this project will determine whether gene replacement therapy targeting the 216A mutation is effective in restoring vision in USH1C mice, and help establish a clinical outcome measure to assess therapeutic efficacy in USH1C patients. Our proximity to the Acadian population in Louisiana provides a unique opportunity to learn from and engage with USH1C patients whom we aim to benefit from our studies. Successful translation of these proof-of-concept studies will lay the foundation for the development of therapeutic strategies against vision loss in USH1C, and help guide a future clinical trial.
