RNAi-mediated silencing of TNF-alpha converting enzyme to down-regulate soluble TNF-alpha production for treatment of acute and chronic colitis

Abstract

Elevated level of tumor necrosis factor-alpha (TNF-alpha), one of the inflammatory cytokines, is considered to be a potential target for the inflammatory bowel disease (IBD) therapy. Recently, TNF-alpha converting enzyme (TACE), a sheddase playing an important role in cleaving and releasing bioactive soluble TNF-alpha, has been challenged with inhibitors to treat inflammatory diseases. Here, we report a novel anti-TNF-alpha 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-alpha 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. (C) 2016 Elsevier B.V. All rights reserved.