Non-viral systemic delivery of Fas siRNA suppresses cyclophosphamide-induced diabetes in NOD mice

JOURNAL OF CONTROLLED RELEASE

卷:143

Article

Jeong, Ji Hoon^1,2  Kim, Sun Hwa³  Lee, Minhyung⁴  Kim, Won Jong⁵  Park, Tae Gwan⁶  Ko, Kyung Soo⁷  Kim, Sung Wan^2,4 

[1] Sungkyunkwan Univ, Coll Pharm, Suwon 440746, South Korea

[2] Univ Utah, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA

[3] Yonsei Univ Hlth Syst, Yonsei Integrat Res Inst Cerebral & Cardiovasc Di, Seoul 120752, South Korea

[4] Hanyang Univ, Coll Engn, Dept Bioengn, Seoul 133791, South Korea

[5] Pohang Univ Sci & Technol, Dept Chem, Pohang 790784, South Korea

[6] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea

[7] Inje Univ, Coll Med, Mitochondrial Res Grp, Dept Internal Med, Seoul, South Korea

关键词: Type-1 diabetes;    siRNA;    Fas;    Gene delivery;    Non-viral vector;   

DOI  :  10.1016/j.jconrel.2009.12.005

来源: Elsevier

【 摘 要 】

A membrane receptor, Fas (CD95), and its ligand FasL have been considered as key players in diabetes pathogenesis. They are known to mediate interactions between beta cells and cytotoxic T cells, which results in apoptotic cell death. We hypothesized that the interruption of Fas-FasL interactions by suppressing Fas expression in beta cells would affect the development of diabetes. The effect of Fas-silencing siRNA (Fas siRNA) on diabetes development was evaluated in a cyclophosphamide (CY)-accelerated diabetes animal model after intravenous administration using a polymeric carrier, polyethylenimine (PEI). The systemic non-viral delivery of Fas siRNA showed significant delay in diabetes incidence up to 40 days, while the control mice treated with naked Fas siRNA, scrambled dsRNA, or PBS were afflicted with diabetes within 20 days. The retardation of diabetes incidence after the treatment of Fas siRNA may be due to the delayed progression of the pancreatic insulitis. In this study, the potential use of a non-viral carrier based siRNA gene therapy for the prevention of type-1 diabetes is demonstrated. (C) 2009 Elsevier B.V. All rights reserved.

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