Programmed Probiotics for Localized Delivery of a Model Biologic to Treat Crohn’s Disease

Authors: 
McKay, R., University of Maryland
Hauk, P., University of Maryland
Bentley, W. E., University of Maryland, College Park
Ghodasra, M., University of Maryland
Utilizing nonpathogenic bacteria as a delivery vehicle for therapeutics, often referred to as “smart probiotics”, is a concept increasingly investigated in recent years and has even been explored in clinical trials. Notably, the range of applications is largely limited to ailments of the gastrointestinal tract, but can serve as a promising avenue for targeted therapies. For chronic ailments such as Crohn’s Disease (CD), systemic therapies often produce unwanted side effects, and due to poor targeting do not always sufficiently ameliorate symptoms. Bacteria engineered to secrete therapeutics at the site of inflammation in the intestinal tract may serve a more effective approach: a targeted delivery of a medicinal payload could improve treatment efficacy as well as prevent deleterious side effects that arise from systemic treatments. We have developed nonpathogenic E. coli that overproduce and secrete a model biologic suggested to treat Crohn’s Disease symptoms, granulocyte macrophage-colony stimulating factor (GM-CSF). Further, the designed cells only produce GM-CSF in the presence of an endogenous biomarker for CD, nitric oxide. We have also demonstrated the ability of engineered bacteria to selectively target molecules through the phenomenon pseudotaxis by manipulating the motility circuit within the cells. As an alternative to repeated intravenous injections for treatment, through pseudotactic targeting and selective secretion of GM-CSF to localize therapeutic delivery, we believe these genetically engineered “smart probiotics” can better alleviate discomfort in patients with CD.