Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs
Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs
复制标题
DOI：
10.1038/nature03121
复制
发表时间：
2004-11-11
期刊：
影响因子：
64.8
通讯作者：
Vornlocher, HP
中科院分区：
文献类型：
--
作者：
Soutschek, J;Akinc, A;Vornlocher, HP
RNA干扰（RNAi）作为沉默致病基因的治疗方法具有相当大的前景，特别是那些编码所谓的“非药物化”靶点的基因，这些靶点不适合常规治疗，如小分子、蛋白质或单克隆抗体。通过RNAi技术实现体内基因沉默的主要障碍是递送。在这里，我们表明，化学修饰的短干扰RNA（siRNA）可以沉默内源性基因编码载脂蛋白B（apo B）静脉注射后，在小鼠。施用化学修饰的siRNA导致肝脏和空肠中apoB信使RNA沉默，降低血浆apoB蛋白水平，并降低总胆固醇。我们还表明，这些siRNA可以沉默人载脂蛋白B在转基因小鼠模型。在我们的体内研究中，证明siRNAs的作用机制是通过RNA干扰介导的mRNA降解发生的，并且我们确定apoB mRNA的切割特异性地发生在预测的位点。这些发现证明了siRNA用于治疗疾病的治疗潜力。
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.