RNAi mediated silencing of TNF a converting enzyme to down regulate soluble TNF a production for treatment of acute and chronic colitis.
Elevated level of tumor necrosis factor a (TNF a) one of the inflammatory cytokines, is considered to be a potential target for the inflammatory bowel disease (IBD) therapy. Recently, TNF a converting enzyme (TACE) a sheddase playing an important role in cleaving and releasing bioactive soluble TNF a, has been challenged with inhibitors to treat inflammatory diseases. Here, we report a novel anti TNF a strategy using a short hairpin RNA silencing TACE (shTACE) to prevent and treat colitis. The shTACE formed stable complexes with nona arginine based bio cleavable disulfide bond linked poly (arginine) (PAs s) for enhanced gene delivery. Systemically administered shTACE/PAs s peptoplexes efficiently decreased TNF a levels, increased survival and alleviated pathophysiological parameters representing colitis severity. Our results demonstrate effectiveness and safety of shTACE/PAs s peptoplexes with the capacity of overcoming acute and chronic ulcerative colitis through modulation of excessive inflammatory responses in the colon, providing a strong potential as a therapeutic agent for a broad variety of inflammatory diseases.
Journal of controlled release official journal of the Controlled Release Society