Development of Mutation Suppression Therapy in a Swine Model of NF1

One in five neurofibromatosis type 1 (NF1) patients have nonsense mutations in the NF1 gene that causes its protein production machinery to stop early, resulting in a shortened and usually non-functional product. Drugs called a “nonsense mutation suppressor” restore full-length production of protein in genes that have these mutations. These drugs are being developed for diseases like Cystic Fibrosis and Duchenne Muscular Dystrophy, and many clinical trials are underway for these patients.

Unfortunately, the immense impact these drugs could have on NF1 patients with these mutations has yet to be explored. The goal of this project is to investigate the potential of nonsense mutation suppression therapies in NF1 patients. Our group has developed a minipig model of NF1 that shows many of the clinical signs seen in human patients of NF1, including café au lait spots, dermal neurofibromas, and optic pathway glioma. Here, we aim to develop a new swine model of NF1 with a slightly different mutation that will be suitable for testing these nonsense mutation suppression therapies. We will establish the preclinical utility of these drugs with the goal of initiating a clinical trial in NF1 patients with a drug that is safe, tolerable, and effective in restoring NF1 gene function. We expect that the NF1 pig model developed in this proposal will develop tumors similar to those found in human patients and can be used to evaluate the ability of these novel therapies to eradicate the underlying genetic abnormality and cure existing manifestations of the condition in people living with NF1.