SBIR-STTR Award

The broader impact of this Small Business Innovation Research (SBIR) Phase I project is to enable safe and effective human gene editing, providing therapies targeting myriad human genetic diseases. CRISPR (clustered, regularly interspaced, short palindromic repeats) and CRISPR-associated (Cas) genes compose adaptive microbial `immune systems' found in diverse bacterial species, serving as a defense mechanism against viral infection. The simplicity, programmability, and versatility of CRISPR-Cas systems have enabled genetic modification of many organisms and offer immense therapeutic potential for treating human diseases. However, CRISPR-based gene editing can also cause off-target edits, resulting in the introduction of mutations, insertions, deletions, or DNA restructuring at unintended off-target editing. This effect can cause significant problems. The proposed technology will develop tools to safely translate CRISPR-based gene editing to in vivo human therapeutics. This Small Business Innovation Research (SBIR) Phase I project is to advance a technology based on virus-encoded CRISPR-Cas inhibitor off-switches, enabling control of off-target gene editing. These anti-CRISPR proteins are a novel class of robust protein inhibitors that can be genetically encoded for co-delivery with the CRISPR editing machinery. This proposal will focus on understanding CRISPR editing kinetics to pinpoint the ideal ?editing window? providing the highest therapeutic benefit while minimizing off-target risk. Second, the project will design a system for simultaneous delivery of the CRISPR editing machinery along with the anti-CRISPR inhibitor to leverage this new ?editing window?. Genetic regulatory elements will be used to tune the expression of the various components of the system and provide the framework for a therapeutic delivery system. This work will enable safe and effective gene editing in a therapeutically relevant context, providing a toolkit for translation.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.

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> The 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.