title: RNAi-mediated silencing of TNF-α converting enzyme to down-regulate soluble TNF-α production for treatment of acute and chronic colitis.
abstract: Elevated level of tumor necrosis factor-α (TNF-α), one of the inflammatory cytokines, is considered to be a potential target for the inflammatory bowel disease (IBD) therapy. Recently, TNF-α converting enzyme (TACE), a sheddase playing an important role in cleaving and releasing bioactive soluble TNF-α, has been challenged with inhibitors to treat inflammatory diseases. Here, we report a novel anti-TNF-α 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-α 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.
authors: Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea.
authors: Yoonsung
authors: Y
authors: Song
authors: Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea.
authors: Ye-Ram
authors: YR
authors: Kim
authors: Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea.
authors: So Mi
authors: SM
authors: Kim
authors: Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea.
authors: Qurrat
authors: Q
authors: Ul Ain
authors: Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors: Kiseok
authors: K
authors: Jang
authors: Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea. Electronic address: chulsuyang@hanyang.ac.kr.
authors: Chul-Su
authors: CS
authors: Yang
authors: Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea. Electronic address: yongheekim@hanyang.ac.kr.
authors: Yong-Hee
authors: YH
authors: Kim
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D015536:Down-Regulation / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D051379:Mice; D000067996:RAW 264.7 Cells; D034622:RNA Interference / Q000502:physiology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000072198:ADAM17 Protein
keywords: Inflammatory bowel disease; RNA interference; TNF-α converting enzyme; Tumor necrosis factor-α