Modulating XIAP for the Treatment of Inflammatory Bowel Disease

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PROPOSAL SUMMARY Inflammatory bowel disease (IBD) is a highly prevalent intestinal disorder for which there is currently no cure. The current treatment is comprised of anti-TNF therapy which alleviates the symptoms but does not target the cause of the disease. Mutations in the X-linked Inhibitor of apoptosis protein (XIAP) have been identified in IBD patients, suggesting that reduced XIAP activity causes IBD. One of the characteristic manifestations in IBD is excessive death and damage to the intestinal epithelium, which contributes to intestinal inflammation because of the compromised intestinal epithelial barrier against luminal microbiota. We propose to target the root cause of IBD by directly restoring XIAP activity to homeostatic levels in patients with IBD. XIAP is the most potent inhibitor of caspases and apoptosis. Reduced XIAP is associated with increased activation of the inflammasome pathway of innate immune host defense and the upregulation of inflammatory tumor necrosis factor (TNF) and interleukin (IL)-1b cytokines, resulting in hyperinflammation, which is also a characteristic of IBD. We predict that regaining the normal activity of XIAP in IBD would control the excessive cell death of intestinal epithelial cells and restore the healthy function and homeostatic turnover of the intestinal epithelium. The studies we propose here will exploit the pro-apoptotic protein ARTS, which negatively regulates XIAP and promotes its degradation by the Ubiquitin-Proteasome System. We hypothesize that ARTS serves as an important therapeutic target for IBD by boosting the reduced activity of XIAP back to normal. Working with murine and human colonic organoids, we will test the idea that reduced activity of XIAP in cells harboring IBD-associated mutations can be overcome by inhibition of ARTS. Since expression of ARTS is induced in response to stress and DNA-damage, this may also account for reduced XIAP activity in IBD patients without XIAP mutations. Thus, strategies to raise XIAP activity may have broad impact beyond cases in which XIAP mutations are implicated in IBD. Utilizing a complementary approach, we will modulate the activities of ARTS and XIAP using a proprietary panel of small-molecule “ARTS-antagonists” and “XIAP-agonists” which we have identified. We seek to provide proof-of-concept that our “ARTS-antagonists” and “XIAP-agonists” will be able to restore to normal the XIAP function in cells with IBD-associated XIAP mutations as a novel treatment strategy for IBD. We will also test these small molecules in an animal model of IBD. We have two specific aims: (1) Determine the role of ARTS in regulating XIAP-induced apoptosis and inflammation in IBD, and (2) Identify the most potent ARTS-antagonist and XIAP-agonist small molecules that restore XIAP expression and function in IBD models. Our proposal provides a radical new approach for regulating XIAP by its natural antagonist ARTS, whose therapeutic exploitation has not yet been investigated. Our long-term goal is the clinical development of compounds that reverse damage to the intestinal epithelium and promote mucosal healing for an effective and long-lasting treatment of IBD.