Development of a Gene Therapy for Treatment of the Visual Impairment in Usher Syndrome 1B

Shannon Boye, PhD: Usher Syndrome Type 1B (USH1B) is an autosomal recessive disease characterized by congenital profound sensorineural hearing loss, vestibular defects and early onset visual impairment, and caused by mutations in the gene encoding Myosin 7A (MYO7A). We are developing a novel gene therapy to treat the retinitis pigmentosa associated with USH1B, which relies on two proprietary AAV technologies. The first technology is an AAV capsid (AAV.SPR) that has the unique ability to laterally spread beyond the site of subretinal injection to distal areas including the fovea. This allows foveal gene expression, without the need for surgical detachment of this sensitive retinal area. One of the challenges of USH1B gene therapy development is the large size of MYO7A gene. Conventional AAVs cannot accommodate large genes, so the second technology utilized is dual AAV technology. Two AAVs are used to encode the front and back portions of the gene, and following co-delivery to cells and recombination, the full length MYO7A protein is generated. Studies in non-human primates demonstrated that physiological levels of full length MYO7A can be achieved and the protein is localized to the photoreceptors at the site of injection, as well as in the fovea. These results demonstrate that these optimized dual AAV.SPR-MYO7A vectors mediate physiologically relevant levels of MYO7A in the retina and show promise for the treatment of the retinitis pigmentosa associated with USH1B.