Lay Summary

Proposal No. IBD-0194R
Principal Investigator:  Bharat Ramratnam, M.D.
Applicant Organization:  Rhode Island Hospital (Providence, U.S.A.)
Project Title:  Transient gene therapy for inflammatory bowel disease
Period of Award:  March 15, 2007  – March 14, 2009

Therapies of IBD were developed based upon suppressing the inflammatory response or altering the luminal contents of the gut with antibiotics or probiotics. Recent advances in unraveling the cells and molecules that promote inflammation in IBD have led to the development of more specific therapies targeting the pathways inappropriately activated in IBD.  Data from animal and human studies have demonstrated that certain genes responsible for increasing inflammation are activated excessively in colonic tissue from patients with IBD. Two examples include the genes for tumor necrosis factor alpha (TNF-α) and nuclear factor κ-B (NFκ-B). One important new advance in IBD therapy in the last few years has been the use of drugs that target TNF-α.  Blocking TNF-α with therapies that can be delivered directly to the gut would have definite advantages over the current strategy of intravenous administration, with potentially far less risk of side-effects. Recent results from animal studies of colitis have also identified NFα-B as another important potential molecular target in IBD.  Decreasing NFκ-B by antisense oligonucleotide technology considerably reduced colonic inflammation and was more effective than glucocorticoids.

We will test a new strategy for decreasing the expression of pro-inflammatory proteins in IBD. Our strategy uses the novel technique of “RNA interference” to specifically deliver short interfering RNA (siRNA) to the colon. We have developed methods using animal models to deliver siRNA to the colons of mice as an enema formulation. The siRNA molecules penetrate the mucosa extremely well, and by designing siRNA molecules that can specifically decrease levels of TNF-α we have demonstrated in pilot studies that this can lead to an improvement of chemical-induced colitis in mice. We will extend these studies to evaluate whether siRNA against NFκ-B can also be used to improve colitis in mice through decreasing the levels of TNF-α and to determine the optimal methods of delivering this new therapy. Ultimately our goal is to apply the knowledge gained from these animal studies to develop locally-delivered siRNA therapy for patients with IBD.