I-Corps: Tackling Microbiome-Associated Diseases with Precision Editing

The broader impact/commercial potential of this I-Corps project is addressing an unmet need for effective prophylactics to reduce the risk of diseases associated with the microbiome. Growing evidence has associated specific bacteria in the microbiome with both acute conditions and chronic illnesses, but current technologies to mitigate specific microbial threats in the microbiome are extremely limited and underdeveloped. The total addressable market in the US for screening and therapeutics for microbiome-associated diseases exceeds 18 billion USD and the space for targeted prophylactics has remained virtually empty. This approach is both low-cost and scalable and presents an example of the utility of targeted interventions in the microbiome to give agency to patients and physicians for better management of the risk of diseases associated with the microbiome. This I-Corps project is based on the development of a novel approach for massively parallel engineering of bacteriophages to target specific bacteria in complex microbial communities. This pipeline determines which mutations drive activity and specificity in phages and uses a new high throughput method to incorporate curated mutations in complex phage cocktails with thousands of user-designed variants to precisely eliminate targeted bacteria. Compared to traditional approaches for developing phage cocktails, this approach represents increased throughput by nearly four orders of magnitude. This approach has been leveraged to create phage cocktails that eliminate bacteria in the gut microbiome strongly associated with the development of different diseases. Targeting and removing these bacteria presents an elegant solution to manage risk and move the gut microbiome towards a healthy state. 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.