Preclinical validation of small molecule immunomodulators for the treatment of Crohn's disease

Project Summary Crohn’s disease is a debilitating and chronic inflammatory disorder of the gastrointestinal tract characterized by aberrant healing and intestinal stricturing. In the US, rt500,000 patients suffer from Crohn’s disease and over 30,000 patients are newly diagnosed each year. No curative treatments exist. Instead, current treatments focus on managing symptoms and reducing the occurrence of new episodes. New treatments are urgently needed.We hypothesize that targeted modulation of the intestinal mucosal barrier and local immune signaling in the bowel can reverse disease progression. A promising way to modulate immunity and mucosal healing is utilizing molecules that are released by commensal bacteria in the gastrointestinal tract as the immune system has evolved specific ways to interact with these molecules. However, besides some preliminary data showing that such molecules protect against acute bowel inflammation in mice, the utility of these immunomodulatory molecules for treating bowel inflammation remains unclear. We have developed a new molecule inspired by these bacterial molecules that shows improved protection against bowel inflammation upon intraperitoneal injection in an acute mouse model of bowel inflammation. However, it is unclear whether our molecule can be administered orally instead of by injection. Thus, in the first part of this project, we will evaluate the therapeutic effect of our molecule upon oral administration in mice experiencing acute bowel inflammation.Next, as acute models of bowel inflammation only mimic certain aspects of disease and fail to capture the multi-faceted, chronic, progressive inflammation observed in Crohn’s disease, we will further validate whether our molecule provides a promising therapeutic strategy for Crohn’s disease by examining our molecule for its therapeutic effect in a genetic mouse model of spontaneously developing, chronic bowel inflammation. This mouse model relies on an engineered genetic defect in the Mdr1a gene. MDR1A plays a role in the regulation of innate and adaptive immunity in the intestinal mucosa. Upon genetic inactivation of Mdr1a, mice develop chronic bowel inflammation at 8-14 weeks of age that more closely resembles what occurs in Crohn’s disease patients than chemically induced acute models. Thus, positive results in this Mdr1a-/- mouse model will provide further validation for the utility of our class of molecules for treating Crohn’s disease.At the completion of these studies, we expect to have determined whether our molecule can be used orally and whether it can protect mice from chronic bowel inflammation that more closely resembles Crohn’s disease. The results from these studies are critical to define the next steps in the drug development process of our molecule, which is aimed at developing an easy-to-use, gut directed therapeutic for Crohn’s disease. This is important because current treatment options for Crohn’s disease show limited efficacy and often require (self)-injection. Crohn’s patients look forward to new and practical, non-immunosuppressive drugs.