Individuals with FA are at an exceptionally high risk of developing squamous cell carcinomas (SCC) in non-keratinizing squamous epithelia lining the oral cavity, proximal esophagus, and anogenital region. The origins of these FA-associated cancers are not well understood. The goal of this project is to determine the potential of oral mucosal gene therapy to modify the risk for oral mucosal cancer in individuals with FA.

This project is asking a simple question: could oral gene therapy in individuals with FA correct the oral mucosal FA defect, and reduce or suppress the risk of oral cancer? Our rationale is provided by the success of blood stem cell gene correction in suppressing FA-associated bone marrow failure and the emergence of leukemia, and by observing rare spontaneous reversion mutations that allow skin epithelial cells to outcompete and suppress the skin defect in individuals with a rare blistering skin disease. We will test our parallel hypothesis by Fanconi gene-correcting oral mucosal epithelial cells in a state-of-the-art FA mutant mouse model of oral cancer predisposition.