Designer Probiotics for the Targeted Delivery of IL-10 and IL-10 Mimetics to the Intestinal Lumen.

New drug delivery platforms are needed for the targeted delivery of high-specificity therapeutics to sites of disease to maximize efficacy and limit off-target effects. This is particularly true in the treatment of inflammatory bowel disease (IBD), as therapeutics that bind to and neutralize pro-inflammatory factors have had profound positive effects on the quality of life of innumerable IBD patients. However, the current systemic route of administration of these therapies carries a risk of life-threatening infections and the increases the risk of some cancers. To circumvent these issues, we have developed designer probiotics equipped with sophisticated nanomachines that enable the deposition of therapeutic payloads directly into the lumen of the intestines, delivering drugs directly to the primary site of disease in patients with IBD. To further improve therapeutic efficacy and limit off-target effects, we have engineered these probiotics to recognize and secrete nanobodies, a new class of therapeutic biomolecules with exquisite neutralizing specificity, thus further limiting off-target effects. Herein, we propose to test the efficacy of these probiotics in multiple mouse preclinical models of IBD as a first step in the development of these probiotics as a new paradigm for the treatment of patients with both Crohn’s disease and ulcerative colitis.