Prion diseases are neurodegenerative diseases caused by the generation of a misfolded form of the prion protein (PrP). Genetic mutations within the PrP gene act to destabilize PrP, causing it to misfold into an abnormal shape. This misfolded PrP accumulates and causes neuronal toxicity. While everyone carries two copies of every gene, only one copy of the PrP gene is mutated in genetic prion diseases. In this study, we will attempt to alleviate the development of prion disease using a transgenic mouse model of genetic prion disease developed in our lab. We will specifically inhibit the mutated gene to significantly reduce the levels of only the mutated PrP, leaving non-mutated PrP unaffected. This targeted gene-therapy will be tested in cultured cells, then neuronal cultures from our transgenic mice, and then in live mice. These studies will be used as the foundation for strategies to treat genetic diseases in humans.
James Mastrianni, M.D., Ph.D.