Grant: Project Grant

Inflammatory bowel disease (IBD) describes debilitating ailments of the intestine that affect a large number of Canadians and for which effective treatment alternatives are lacking. Intestinal inflammation can be caused by excessive inflammatory responses to the detection of danger signals. The identification of those pathways is essential to the understanding of the pathogenesis of IBD and to the discovery of novel therapeutic targets and strategies. Our laboratory focusses on extracellular nucleotides, an emerging class of danger signals released by cells in inflammatory conditions to sustain and amplify inflammation. We found that the blockade of their signalling at the surface of the intestine fully prevented colitis in a mouse model. We also found that NTPDase8, an enzyme naturally present at the surface of the intestine, is capable of destroying these nucleotides. Interestingly, the activity of NTPDase8 totally prevented colitis in mouse models. Unfortunately, there is not enough of this enzyme at the surface of the intestine to prevent the bulk of nucleotides released during flares of inflammation. In this proposal, we plan to develop a soluble form of NTPDase8 and demonstrate its potential as a biological therapeutic agent using animal models of IBD. We also propose to define the mechanisms by which this enzyme exerts anti-inflammatory effects in both mouse and human using normal intestinal epithelial cells in culture. Since we found that the same pathway of signaling is also present in the human intestine, we believe that the results obtained so far with NTPDase8 in mice may be applicable to humans. Our preliminary data make us anticipate that this work will lead to a novel biological treatment for IBD patients by targeting a pathway of bowel inflammation that we have identified. In theory, this treatment, envisioned as an oral enteric formulation, would be more economical and acceptable to patients than current injectable immunotherapies.