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【新闻编译】Nature:用siRNAs降低胆固醇
如何将治疗性siRNAs输送到体内的合适部位，以达到最佳的治疗效果，并减少其不良效果一直是RNAi应用中的关键问题。
通过对siRNAs进行化学的改造，将胆固醇分子与siRNAs分子相联接。静脉注射以后可以保证这些复合物分子与造脂细胞表面的胆固醇受体相结合，最终封闭鼠内源性载脂蛋白B (apo 基因的表达。
结果发现应用该修饰之后的siRNAs之后，肝脏、小肠内的 apoB信使RNA 得以封闭，血浆apoB的水平下降，总胆固醇水平降低。此外，此siRNAs还可以封闭转基因鼠模型的人apoB基因
该结果被证明是通过RNAi 介导的mRNA降解而实现的。研究者检查了一些其他的与靶基因无关的一些基因，发现 apoB mRNA的降解只发生在预期的位置，没有发现有明显的不良反应。
ABSTRACT
RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called 'non-druggable' targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apo after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model. In our in vivo study, the mechanism of action for the siRNAs was proven to occur through RNAi-mediated mRNA degradation, and we determined that cleavage of the apoB mRNA occurred specifically at the predicted site. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.
full text
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v432/n7014/full/nature03121_fs.html [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-08-29 05:14
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