Retrievable bead system for in vivo characterization of engineered microbial protein secretion

Microorganisms are critical to the health and disease of Inflammatory Bowel Disease patients. As such, manipulating them has great therapeutic potential. Indeed, there is now evidence that the engineered microorganisms can treat intestinal inflammation through the delivery of therapeutic proteins. However, this new class of therapies based on living cells have so far been optimized outside of the body in conditions that do not recapitulate the complex disease environment. Therefore, early examples of engineered microbial therapeutics have failed to fully recapitulate therapeutic function in animals and are unlikely to work well in humans. To fill this gap, we propose to develop a new toolbox of genetic components that functions optimally at the site of disease. This system is based on a living host with an established safety profile in humans. During the proposed work we will develop a genetic validation system that works directly in animal models of intestinal inflammation. If successful, this system can lead to orally-administered microbial therapeutics for Inflammatory Bowel Disease. Compared to the current state-of-the-art treatment with anti-tumor necrosis factor, microbial therapies are expected to be orally bioavailable and avoid systemic adverse effects by being localized to the site of disease in the gut.