SBIR Phase I: Epigenome Editing by Induced Proximity Using Oligonulcleotide-conjugates

The broader impact of this Small Business Innovation Research (SBIR) Phase I project is to develop an entirely new class of gene therapies that can be delivered more safely, cost-effectively, and at scale for a wide range of serious genetic disorders. By harnessing existing mechanisms for turning genes on or off, this approach aims to resolve persistent shortcomings in current gene therapy methods, including delivery challenges, high manufacturing costs, and safety risks.

Initial applications focus on neurodegenerative conditions such as Huntington’s disease and ALS (Amyotrophic Lateral Sclerosis), but the same platform could be adapted to address other inherited and acquired diseases. In addition to reducing disease burden, this project has the potential to lower healthcare expenditures by offering a safer and more flexible alternative to traditional gene therapies.

Broader availability of effective genetic treatments would stimulate growth in the biotechnology sector, accelerate clinical development timelines, and ultimately expand global access to lifesaving and curative therapeutics.

The proposed project leverages short oligonucleotides conjugated with small molecules to induce proximity of endogenous epigenetic machinery to disease-relevant genes in a precise and reversible manner. By eliminating the need for foreign enzymes or viral vectors, this approach aims to reduce immunogenicity, enhance delivery, and simplify manufacturing of gene therapies.

The research plan includes systematic optimization of these oligonucleotide conjugates, advanced cell-based assays, and genome-wide analyses to confirm targeted gene modulation with minimal off-target effects. Focused initially on severe neurological disorders such as Huntington’s disease and ALS, the resulting platform is designed to accommodate other conditions driven by dysregulated gene activity.

Proof-of-concept studies will evaluate the therapeutic potential and specificity of these epigenetic interventions establishing a foundation for further preclinical development. By integrating knowledge of oligonucleotide chemistry, epigenetics, and advanced bioinformatics, the proposed project seeks to overcome barriers in current gene therapy strategies, ultimately delivering a versatile new method with broad relevance to genetic medicine. The anticipated outcome is an efficient, scalable, and clinically translatable platform.

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.