SBIR Phase I: A Novel Precision Microbiome Therapy for Phenylketonuria

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project proposed by the small business will develop the proprietary, precision microbiome-based therapeutic platform for Phenylketonuria (PKU) incorporating engineered native bacteria. PKU is a rare inherited metabolic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase, resulting in toxic accumulation of phenylalanine (Phe) in the body. Current treatment options include lifelong adherence to a strict low-Phe diet and enzyme substitution therapies that are effective only in subsets of patients or associated with serious adverse events, including anaphylaxis. The small business’ proposed microbiome therapeutic platform introduces a novel PKU therapeutic regimen (covering the entire PKU population) that delivers persistent functional activity within the gut. The long-acting treatment will have a significant advantage over current alternatives, which require burdensome daily dosing for life. With a substantial dosing and adherence advantage over daily chronic therapies, the proposed microbiome-based therapeutic platform is positioned to capitalize on a significant PKU commercial opportunity. Once validated for the treatment of PKU, the same approach can be used for different organ systems (e.g., skin, lungs, vagina), expanding the small business’ precision microbiome therapeutic platform to several other microbiome-mediated/modulated chronic diseases. This Small Business Innovation Research (SBIR) Phase I project seeks to develop a novel PKU therapy based on microbiome-based therapeutic platform. Current microbiome-based therapies often fail to target proximal gut where early intervention is critical and rely on non-colonizing strains that require frequent and burdensome re-dosing. These challenges have constrained the therapeutic potential, underscoring the need for a more robust, targeted, and patient-friendly solution The small business applies a native, human-derived E. coli strain as a chassis to introduce phenylalanine metabolizing transgenes that engraft throughout the patient's gut leading to stable and long-term colonization, regulated gene expression as intended without effect on bacterial fitness, and continuous phenylalanine catabolism. The Phase I activities will focus on (i) demonstrating successful engraftment of engineered mouse-native E. coli (expressing phenylalanine metabolizing transgenes) and sustained therapeutic activity in the PKU mouse, (ii) evaluating long-term safety in-vivo, and (iii) isolating and initial genetic tractability testing of porcine-native E. coli strains to prepare for preclinical studies in Yucatan minipig. The successful completion of the Phase I activities will validate the feasibility of using the engineered native E. coli bacterial strain from a human host as a chassis for PKU therapy and a broader range of chronic diseases. 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.