Gene Therapy for Usher Syndrome (USH1C)

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DESCRIPTION (provided by applicant): The broad, long-term goal of the proposed research is to develop gene therapy approaches that can be used successfully in vivo to slow or prevent deafness and blindness in Usher syndrome. This study is made possible only by combining the unique skills, diverse scientific interests, knowledge, and resources of the two key investigators. They have selected the most severe form of Usher syndrome, type 1 (USH1), for study as this causes congenital profound deafness, constant vestibular dysfunction, and prepubertal onset retinitis pigmentosa (leading to blindness) (Nicoll et al. 1988, Aust NZJ Ophthalmol 16:205-8; Armitage et al. 1995, Arch Dis Child 73:53-6; Admiral et al. 2000, Int J Pediatr Otorhinolaryngol 55:133-142). USH1C, an autosomal recessive form of the disease, will be the focus of the studies since: 1) this accounts for a significant percentage of USH1 disease (33-44%); 2) the USH1C gene, which encodes harmonin (also known as PDZ domain-containing protein; PDZ73 (OMIM, 2005)) can, when mutated, result in other (non-syndromic) inherited forms of congenital deafness; 3) recent data indicate that the first PDZ domain (PDZ1) of harmonin is critical to the interaction of proteins underlying five forms of USH1s; and 4) animal models with Ush1c (harmonin) mutations and congenital deafness are available. Methods the investigators have developed to deliver genes to the cochlea are used to optimize gene transfer to the affected cells and test therapeutic effects of delivery of the wild-type harmonin gene. Safety and toxicity of single treatment cochlear gene therapy will be evaluated with respect to effects on target sensorineural cells, exposure to cells outside of the target organ, and systemic effects. The data resulting from this study will provide the platform for a human clinical trial for gene therapy for congenital hearing loss, which will be a motivating factor for improving neonatal hearing (and retinal) screening programs, and should provide the groundwork for development of other novel gene-based treatments for congenital sensorineural disease.