SBIR Phase I: A Novel Gene Therapy Platform to Overcome AAV Cargo Size Limitations

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project lies in transforming the lives of individuals affected by inherited hearing disorders. Hearing loss impacts more than 430 million individuals worldwide and can significantly limit communication, learning, and social connection, while creating a lifetime economic burden that can exceed $500,000 per person. This project advances the development of innovative therapies that are compatible with existing gene delivery technologies, with the potential to benefit thousands of patients across the U.S. If successful, it could enable first-in-class treatments for forms of deafness that currently have no effective options. The proposed commercial model utilizes an outcome-based strategy, amortizing costs over several years based on real-world evidence of patient improvement. This approach reduces risk for insurers while supporting broad patient access, with conservative projections estimating $350 million in revenue from treating 1,000 patients within the first three years following approval. Beyond hearing loss, this platform opens the door to treating other genetic diseases caused by oversized genes, addressing a major unmet need in genomic medicine. By enabling scalable therapies for rare and ultra-rare conditions, this project strengthens U.S. leadership in biotechnology and delivers meaningful, long-term improvements in quality of life. This Small Business Innovation Research (SBIR) Phase I project aims to overcome the size limits of adeno-associated virus (AAV) gene therapy caused by large mutated genes that are currently AAV incompatible. AAVs are widely used in gene therapy due to their safety and clinical success. However, its limited packaging capacity prevents delivery of many genes. This project will develop and validate a scalable platform for designing compact therapeutic gene constructs prioritizing one gene associated with inherited hearing loss. Traditional approaches have been slow and unpredictable, particularly for poorly characterized genes such as the gene of interest. On the contrary, this project will apply an evolution-guided, AI-assisted design approach to generate miniaturized gene constructs that preserve essential biological function while satisfying viral delivery limits. Phase I research will focus on designing and selecting top candidates to evaluate their biological activity in animal models with proof-of-concept evidence of disease-modifying potential. Anticipated outcomes include identification of at least one functional minigene candidate and validation of a repeatable workflow for converting oversized genes into viable therapeutic candidates. Successful completion of Phase I will de-risk further development by establishing feasibility, defining performance benchmarks, and positioning the technology to advance toward future commercialization and platforming. 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.