SBIR Phase II:Development of a safe gene editing system via CRISPR-Cas and Cas inhibitor co-delivery

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project will be the development of a curative therapy for spinal muscular atrophy using a novel and proprietary precision gene editing technology. The proposed technology will increase the safety and efficacy of gene editing by optimizing the precision of editing to correct the disease. This technology can be used to improve and even cure patients of genetic disease.This Small Business Innovation Research (SBIR) Phase II project will develop and validate a curative therapy for spinal muscular atrophy (SMA) using a novel and proprietary CRISPR-Cas precision gene editing system. Manipulation of the human genome using CRISPR-Cas gene editors has been validated in early clinical trials to correct genetic diseases. However, application of this technology has been limited by the high degree of unintended 'off-target' editing events. This problem is particularly acute for in vivo therapies where the editing system will be delivered systemically or directly to the target organs, eliminating the ability to screen cells for unwanted editing outcomes. High precision gene editing technology must be developed to ensure the safety and efficacy of in vivo gene editing therapies. This project will develop an engineered anti-CRISPR (ErAcr) protein to eliminate unintended off-target editing. The ErAcr protein will be paired with a novel CRISPR-Cas nuclease and developed into a therapy for SMA greater thanThe therapy will be packaged into an adeno-associated viral vector and tested for editing and SMA disease correction in patient-derived cells and in an SMA mouse model. Effective editing will lead to disease correction in both patient cells and mice with no observable off-target editing events.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.