Status: Funded - Open
William Johnston, MD
BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic disorder that causes severe skin abnormalities and high rates of gastrointestinal strictures, respiratory dysfunction, ocular abnormalities, and contractures, leading to significant morbidity and shortened mortality. There is no cure for RDEB, and treatment is currently limited to aggressive wound care, supportive therapy, and injury prevention. GAP: Current research trials such as skin grafting and bone marrow transplantation are limited by significant side effects and waning efficacy over time. HYPOTHESIS: Provide one to two sentences stating the hypothesis of your study. Our objective is to perform in-utero CRISPR based gene editing in a mouse model to address common RDEB disease causing mutations. We hypothesize that doing so will restore collagen VII production and rescue the phenotype. Furthermore, we expect mice injected in utero to demonstrate multi-system editing, whereas mice injected after birth will only display injection site editing. METHODS: We will initially perform gene editing of human fibroblast and mouse N2A cell lines to demonstrate the feasibility of our therapy in vitro. We will then perform in vivo experiments to first prove our ability to target multiple organs including the skin via intra-amniotic injection, and then to perform multi-organ gene editing of healthy and diseased mice. RESULTS: Pending. IMPACT: This research will be significant as it will establish a single-shot treatment that cures skin and systemic manifestations of a severe form of DEB in a mouse model. Furthermore, this research will be significant by providing the foundation for future studies of in utero gene editing in preclinical DEB models with an eye toward clinical in utero gene editing for DEB.