Soutschek Jürgen, Akinc Akin, Bramlage Birgit, Charisse Klaus, Constien Rainer, Donoghue Mary, Elbashir Sayda, Geick Anke, Hadwiger Philipp, Harborth Jens, John Matthias, Kesavan Venkitasamy, Lavine Gary, Pandey Rajendra K, Racie Timothy, Rajeev Kallanthottathil G, Röhl Ingo, Toudjarska Ivanka, Wang Gang, Wuschko Silvio, Bumcrot David, Koteliansky Victor, Limmer Stefan, Manoharan Muthiah, Vornlocher Hans-Peter
Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany.
Nature. 2004 Nov 11;432(7014):173-8. doi: 10.1038/nature03121.
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 (apoB) 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.
RNA干扰（RNAi）作为一种沉默致病基因的治疗方法具有巨大潜力，尤其是那些编码所谓“不可成药”靶点的基因，这些靶点无法通过小分子、蛋白质或单克隆抗体等传统疗法进行治疗。通过RNAi技术在体内实现基因沉默的主要障碍是递送问题。在此，我们表明化学修饰的小干扰RNA（siRNA）在小鼠静脉注射后能够沉默编码载脂蛋白B（apoB）的内源性基因。给予化学修饰的siRNA导致肝脏和空肠中apoB信使RNA沉默，血浆中apoB蛋白水平降低，总胆固醇减少。我们还表明，这些siRNA可以在转基因小鼠模型中沉默人apoB。在我们的体内研究中，已证明siRNA的作用机制是通过RNAi介导的mRNA降解发生的，并且我们确定apoB mRNA的切割特异性发生在预测位点。这些发现证明了siRNA在疾病治疗中的潜在治疗价值。
