John Matthias, Constien Rainer, Akinc Akin, Goldberg Michael, Moon Young-Ah, Spranger Martina, Hadwiger Philipp, Soutschek Jürgen, Vornlocher Hans-Peter, Manoharan Muthiah, Stoffel Markus, Langer Robert, Anderson Daniel G, Horton Jay D, Koteliansky Victor, Bumcrot David
Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany.
Nature. 2007 Oct 11;449(7163):745-7. doi: 10.1038/nature06179. Epub 2007 Sep 26.
Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates. Whether or not in vivo gene silencing by synthetic siRNA can disrupt the endogenous microRNA (miRNA) pathway remains to be addressed. Here we show that effective target-gene silencing in the mouse and hamster liver can be achieved by systemic administration of synthetic siRNA without any demonstrable effect on miRNA levels or activity. Indeed, siRNA targeting two hepatocyte-specific genes (apolipoprotein B and factor VII) that achieved efficient (approximately 80%) silencing of messenger RNA transcripts and a third irrelevant siRNA control were administered to mice without significant changes in the levels of three hepatocyte-expressed miRNAs (miR-122, miR-16 and let-7a) or an effect on miRNA activity. Moreover, multiple administrations of an siRNA targeting the hepatocyte-expressed gene Scap in hamsters achieved long-term mRNA silencing without significant changes in miR-122 levels. This study advances the use of siRNAs as safe and effective tools to silence gene transcripts in animal studies, and supports the continued advancement of RNA interference therapeutics using synthetic siRNA.
合成小干扰RNA（siRNA）的全身给药可有效沉默啮齿动物和灵长类动物肝细胞中的基因表达。合成siRNA在体内进行基因沉默是否会破坏内源性微小RNA（miRNA）途径仍有待研究。在此我们表明，通过合成siRNA的全身给药可在小鼠和仓鼠肝脏中实现有效的靶基因沉默，而对miRNA水平或活性无任何明显影响。实际上，将靶向两个肝细胞特异性基因（载脂蛋白B和因子VII）的siRNA（其实现了信使RNA转录本的高效（约80%）沉默）以及第三个无关的siRNA对照给予小鼠后，三种肝细胞表达的miRNA（miR-122、miR-16和let-7a）的水平未发生显著变化，且对miRNA活性也无影响。此外，在仓鼠中多次给予靶向肝细胞表达基因Scap的siRNA可实现长期的mRNA沉默，而miR-122水平无显著变化。本研究推动了siRNA在动物研究中作为安全有效的工具用于沉默基因转录本，并支持使用合成siRNA的RNA干扰疗法的持续发展。
