Summary The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1.4 million people in the United States. The etiology of IBD is unclear, yet aberrant innate and adaptive immune responses directed towards the commensal microbiota are believed to underlie disease pathogenesis. Numerous pro-inflammatory factors contribute to disease severity and targeting some of these factors has proven effective in the treatment of IBD patients. TNFα in particular plays a crucial role as a pro- inflammatory mediator in the pathogenesis of IBD and the anti-TNFα monoclonal antibody, infliximab, is now successfully used in the clinic to treat human IBD. However, anti-TNFα therapy is only effective in a subset of IBD patients and concerns remain regarding adverse effects, such as cancer and opportunistic infections. The observed adverse effects are mainly due to the lack of targeted treatment and the “over dosage” that is usually inherent to systemic drug administration. More recently, a monoclonal antibody targeting IL-12 and IL-23, ustekinumab, was shown to be effective in IBD patients, especially those in which anti-TNFα therapy had previously failed. Thus, treatment of human IBD may be optimized by novel delivery regimens that allow for targeted, low-dose inhibition of both TNF-α and IL-12/23. We have demonstrated that oral administration of nanoparticles loaded with TNFα siRNA and encapsulated in an alginate-chitosan hydrogel can be efficiently targeted to the colon without toxicity and reduce intestinal inflammation in a mouse model. Our exciting preliminary data demonstrate that specific targeting of nanoparticles containing siRNA to intestinal antigen presenting cells may enhance the beneficial effects of this novel therapeutic approach. In the course of these studies, we also discovered that inhibition of pro-inflammatory cytokines can have the unexpected side effect of inhibiting critical wound-healing factors, such as IL-22. These finding have led us to propose that nanoparticle-mediated manipulation of TNFα, IL-12/23 and IL-22 limits intestinal inflammation and promotes wound healing during IBD. These novel strategies aimed at locally inhibiting key pro-inflammatory cytokines while simultaneously promoting wound healing may contribute to the development of improved therapies for the treatment of human IBD.

Project Narrative The present Multi-PI application will focus on defining specific factors and cells that may be targeted to treat IBD. We propose here an innovative central hypothesis that nanoparticle-mediated manipulation of TNFα, IL- 12/23 and IL-22 limits established intestinal inflammation and promotes wound healing during IBD. We will explore this hypothesis with state-of-the-art approaches employing siRNA nanoparticles that target key cytokines—in particular TNFα and/or IL-12/23—which are involved in the pathogenesis of IBD. Using complementary models of acute and chronic intestinal inflammation, we will further define which specific intestinal antigen-presenting cells should be targeted by nanoparticles and the beneficial effect of co-delivering IL-22 in order to promote wound healing. These studies will help to define novel biological functions of nanoparticle-mediated siRNA delivery during intestinal inflammation and have the potential to contribute meaningful new findings for the treatment of human IBD.