Nature杂志去年发表的一篇论文似乎断定由RNA干涉调控的沉寂作用来进行基因治疗的前景不妙。该论文表明，大剂量的短发夹RNA会阻断小鼠的微RNA通道，造成致命后果。现在，一项新的研究表明，否定RNA疗法还为时过早。一种不同类型的抑制性RNA——小干涉RNA（siRNAs）——可以给实验鼠施用，而不产生毒性。肝脏微RNA的活性仍然不受siRNAs影响，尽管小鼠和仓鼠肝脏细胞中的目标基因80%被沉寂。
原始出处:
Nature 449, 745-747 (11 October 2007) | doi:10.1038/nature06179; Received 17 November 2006; Accepted 16 August 2007; Published online 26 September 2007
Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway
Matthias John1, Rainer Constien1, Akin Akinc2, Michael Goldberg3, Young-Ah Moon5, Martina Spranger6, Philipp Hadwiger1, Jürgen Soutschek1, Hans-Peter Vornlocher1, Muthiah Manoharan2, Markus Stoffel6, Robert Langer3,4, Daniel G. Anderson4, Jay D. Horton5, Victor Koteliansky2 & David Bumcrot2
Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany
Alnylam Pharmaceuticals Inc., 300 Third Street, Cambridge, Massachusetts 02142, USA
Department of Chemistry, and,
Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetss 02139, USA
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA
Institute of Molecular Systems Biology, Swiss Federal Institute of Technology ETH Zürich, HPT E73, CH-8093 Zürich, Switzerland
Correspondence to: David Bumcrot2 Correspondence and requests for materials should be addressed to D.B. (Email: dbumcrot@alnylam.com).
Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates1, 2, 3. 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 (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.
