NITROXIDE THERAPY FOR INFLAMMATORY BOWEL DISEASE

DESCRIPTION (Adapted from the application): Free radicals play important roles in inflammatory bowel disease (IBD), and the reduction or elimination of the adverse effects of these oxidants could provide novel therapies. Antioxidants have been reported to reduce tissue injury in colitis models, but more potent, stable and bioavailable antioxidant compounds are required. This project will test a new class ofantioxidants based on polynitroxylation technology, or linkage of nitroxides (stable N-oxyl radicals) to biological macromolecules. In a preliminary study, polynitroxyl-starch (PNS) acted synergistically with the free (unbound) nitroxide compound Tempol to reduce oxidants (especially superoxide) and attenuate inflammation in TNBS-induced murine colitis. We hypothesize that TNBS colitis involves significant superoxide-mediated injury, and that PNS and Tempol can attenuate this injury. Specific aims are: (1) Produce PNS and characterize its antioxidant activity. (2) Pharmacokinetically define optimal dose and route of administration. (3) Define efficacy in TNBS-induced mouse colitis. If this is successful, Phase II will define mechanisms of action in animal models of IBD (including the IL-10-/- knockout mouse which spontaneously develops colitis) and other studies required for progression to clinical testing in IBD. PROPOSED COMMERCIAL APPLICATION: Inflammatory bowel disease is a significant health problem. If successful this research will lead to the development of a novel therapeutic agent(s) for the treatment of IBD. This would represent a significant commercial opportunity and provide substantial benefit to patients.