Jun Yang, PhD

University of Utah - Visionary

Project Title: "Disease Mechanism and Treatment of Retinitis Pigmentosa in Usher Syndrome Type 2."
 
Usher syndrome is the most common condition that impacts both vision and hearing. It affects 10-20 thousand people in the United States. The vision problem in Usher syndrome is manifested as retinitis pigmentosa. Recently, USH2A, VLGR1 and whirlin have been identified as the causative genes for the most predominant form of Usher syndrome, the type 2 form. However, the disease mechanism of retinal degeneration caused by the mutations in these genes remains unknown and there is no cure for this disease. Our laboratory is focused on understanding the mechanistic relationship of the mutations in these genes to the loss of sight. This understanding will move the field toward informed therapeutic strategies for Usher syndrome. Toward this end, we have generated mice with mutations in the whirlin, Ush2a and Vlgr1 genes. The whirlin and Ush2a knockout mice exhibit progressive retinal degeneration and congenital hearing defects, similar to the symptoms found in patients with Usher syndrome. While the Vlgr1 mutant mouse exhibits congenital hearing defects, its retinal phenotype is not known. Therefore, to understand the pathogenesis of retinal degeneration in Usher syndrome type 2, we propose to thoroughly characterize the phenotypes in the retina of our various murine models of Usher syndrome type 2. Additionally, we will examine the therapeutic effects of rAAV2/5-mediated delivery of the whirlin gene, Ush2a minigene, and Vlgr1 minigene in our murine models of Usher syndrome type 2.
 
The significance of this work is four fold. First, it will shed new light on the functions of Usher syndrome type 2 proteins and the disease mechanisms underlying retinitis pigmentosa in Usher syndrome. Second, it will provide valuable information for the final development of gene therapy for patients with Usher syndrome type 2. Third, it may increase our understanding of the complex of Usher syndrome type 2 proteins in other tissues, especially in hair cells. Finally, it may contribute a missing, fundamental element to our knowledge about trafficking in photoreceptors, which is crucial for the survival of photoreceptors.