STTR Phase I: Harnessing the power of introns for safe and effective therapeutics and genomic screening

The broader impact/commercial potential of this Small Business Technology Transfer (STTR) Phase I project will be the development of a safe and effective treatment for a devastating form of pediatric epilepsy called Dravet syndrome. Dravet syndrome is an inherited disease that is caused by mutations in an ion channel called SCN1A. Gene therapy is an approach that involves replacement of mutated DNA sequences but broad use of these approaches have been limited by safety issues. Indeed, replacement of SCN1A with a gene therapy approach has been held back by the risk of safety issues associated with activity of the gene therapy outside of specific tissues in the brain. This project proposes a unique RNA editing approach to replace defective sequences in SCN1A, treating Dravet syndrome only in specific tissue and cell types within the brain. The resulting approach could form the first safe and effective gene therapy for this devastating disease. This Phase I SBIR will be instrumental towards developing a treatment for nearly 30,000 patients in the US with this condition and would constitute a multibillion-dollar market. This Small Business Technology Transfer (STTR) Phase I project focuses on the development of an RNA editing approach that replaces defective sequences within mutated RNAs as a means to address inherited human disease. We will focus on Dravet syndrome, a dominantly inherited disease that causes recurrent and devastating seizures in children. Dravet syndrome is caused by mutations in SCN1A which is an ion channel that is primarily expressed in inhibitory neurons. By targeting defective RNAs with a system that is active only in inhibitory neurons, we will devise an approach that avoids the risk of toxicities associated with aberrant ion channel expression. Indeed, this disease has resisted gene replacement approaches due to this risk of off-target activities. Our system also avoids the use of immunogenic proteins and functions via repurposing of cellular machinery. The result is an inherently non-immunogenic systems which will avoid the varied safety risks associated with use of non-human transcription factor or gene editing systems such as CRISPR. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.