Specific hepatic delivery of procollagen α1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis.
Specific hepatic delivery of procollagen α1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis.
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DOI：
10.1002/hep.27936
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Schuppan D
中科院分区：
文献类型：
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作者：
Jiménez Calvente C;Sehgal A;Popov Y;Kim YO;Zevallos V;Sahin U;Diken M;Schuppan D
纤维化伴随着对慢性肝损伤的伤口愈合反应，其特征在于以I型胶原为主的过度肝胶原积累，其通常进展为肝硬化。在此，我们提供了充足的体内证据，表明在患有进行性和晚期肝纤维化的小鼠中，前胶原α1（I）表达抑制高达90%，隔膜形成减少，胶原沉积减少40-60%，这些小鼠接受了负载有针对前胶原α1（I）基因的小干扰RNA的阳离子脂质纳米粒（LNP-siCol 1a 1）。静脉注射后，高达90%的LNP-siCol 1a 1保留在纤维化小鼠的肝脏中，并在非实质细胞>实质细胞中长时间积累，显著改善纤维化的进展并加速纤维化的消退。本研究中报告的数据广泛表明，LNP-siCol 1a 1特异性降低总肝胶原含量，而没有可检测到的副作用，可能有资格作为纤维化肝病的治疗。
Fibrosis accompanies the wound-healing response to chronic liver injury and is characterized by excessive hepatic collagen accumulation dominated by collagen type I that often progresses to cirrhosis. Here we present ample in-vivo evidence of an up to 90% suppression of procollagen α1(I) expression, a reduction of septa formation and a 40–60% decrease of collagen deposition in mice with progressive and advanced liver fibrosis, that received cationic lipid nanoparticles loaded with small interfering RNA to the procollagen α1(I) gene (LNP-siCol1a1). After intravenous injection up to ninety percent of LNP-siCol1a1 were retained in the liver of fibrotic mice and accumulated in nonparenchymal > parenchymal cells for prolonged periods, significantly ameliorating progression and accelerating regression of fibrosis. The data reported in the present study extensively show that LNP-siCol1a1 specifically reduce total hepatic collagen content without detectable side effects, potentially qualifying as a therapy for fibrotic liver diseases.