Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone
Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone
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DOI：
10.1038/nbt1396
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发表时间：
2008-04-01
影响因子：
46.9
通讯作者：
Niitsu, Yoshiro
中科院分区：
文献类型：
--
作者：
Sato, Yasushi;Murase, Kazuyuki;Niitsu, Yoshiro
目前没有批准的肝硬化抗纤维化疗法。我们使用维生素A偶联脂质体提供小干扰RNA（siRNA）对gp 46，大鼠同源的人热休克蛋白47，肝星状细胞。我们的方法利用了这些细胞在纤维形成以及维生素A的摄取和储存中的关键作用。用siRNA-维生素A-偶联脂质体进行的5次治疗几乎完全解决了肝纤维化，并以剂量和持续时间依赖性方式延长了具有其他致死性二甲基亚硝胺诱导的肝硬化的大鼠的生存期。拯救与脱靶效应无关，也与先天免疫的募集无关。受体特异性siRNA递送在抑制胶原蛋白分泌和治疗由CCl 4或胆管结扎诱导的纤维化中同样有效。使用急性和慢性肝纤维化模型的方法的功效表明其逆转人类肝硬化的治疗潜力。
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.