Development of targeted gene therapy platform for Neurofibromatosis Type I

Herein we propose to develop a gene therapy system that will address three current challenges. 1) We will compare cell specific promoters and novel adeno-associated virus (AAV) capsids to deliver NF1 to Schwann cells in a mouse model of NF1.  2) We will investigate a novel RNA editing approach to replace mutation-carrying exons with artificial exons that encode the normal NF1 sequence. 3) We will validate and scale up therapeutic testing of optimized AAV gene therapy in a pig model of NF1 that reproduces many of the disease features found in patients. We are utilizing disease-specific, targeted approaches in two NF1 animal models to produce strong preclinical data to rapidly, yet safely, advance a therapy to the clinic for NF1.