Resolution of liver cirrhosis using vitamin A–coupled liposomes to deliver siRNA against a collagen-specific chaperone

肝硬化 小干扰RNA 化学 纤维化 肝星状细胞 癌症研究 维生素 生物化学 生物 药理学 脂质体 医学 内科学 核糖核酸 基因
作者
Yasushi Sato,Kazuyuki Murase,Junji Kato,Masayoshi Kobune,Tsutomu Sato,Yutaka Kawano,Rishu Takimoto,Kouichi Takada,Koji Miyanishi,Takuya Matsunaga,Tetsuji Takayama,Yoshiro Niitsu
出处
期刊:Nature Biotechnology [Springer Nature]
卷期号:26 (4): 431-442 被引量:555
标识
DOI:10.1038/nbt1396
摘要

There are currently no approved antifibrotic therapies for liver cirrhosis. We used vitamin A‐coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to hepatic stellate cells. Our approach exploits the key roles of these cells in both fibrogenesis as well as uptake and storage of vitamin A. Five treatments with the siRNA-bearing vitamin A‐coupled liposomes almost completely resolved liver fibrosis and prolonged survival in rats with otherwise lethal dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent manner. Rescue was not related to off-target effects or associated with recruitment of innate immunity. Receptor-specific siRNA delivery was similarly effective in suppressing collagen secretion and treating fibrosis induced by CCl4 or bile duct ligation. The efficacy of the approach using both acute and chronic models of liver fibrosis suggests its therapeutic potential for reversing human liver cirrhosis. Liver cirrhosis, or fibrosis, the ultimate pathological feature of all forms of chronic hepatic damage, is responsible for much morbidity and mortality worldwide. The principal cell type responsible for liver fibrosis is the hepatic stellate (HS) cell, a resident perisinusoidal cell that takes up vitamin A from circulation and stores it. When stimulated by reactive oxygen intermediates or cytokines, HS cells become activated and are transformed to proliferative, fibrogenic and contractile myofibroblasts 1 , which synthesize and secrete procollagen, which accumulates as insoluble collagen after its terminal domains are cleaved by procollagen peptides, causing fibrosis. The collagen-specific chaperone, heat shock protein 47 (HSP47), facilitates collagen secretion by ensuring proper triple-helix formation of procollagen in the endoplasmic reticulum and has also been implicated in translational regulation of procollagen synthesis 2,3 .
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