Nature:否定RNA療法還為時過早

    Nature雜誌去年發表的一篇論文似乎斷定由RNA幹涉調控的沉寂作用來進行基因治療的前景不妙。該論文表明，大劑量的短髮夾RNA會阻斷小鼠的微RNA通道，造成致命後果。現在，一項新的研究表明，否定RNA療法還為時過早。一種不同類型的抑制性RNA——小幹涉RNA（siRNAs）——可以給實驗鼠施用，而不產生毒性。肝臟微RNA的活性仍然不受siRNAs影響，儘管小鼠和倉鼠肝臟細胞中的目標基因80%被沉寂。

原始出處:

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

1. Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany
2. Alnylam Pharmaceuticals Inc., 300 Third Street, Cambridge, Massachusetts 02142, USA
3. Department of Chemistry, and,
4. Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetss 02139, USA
5. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA
6. 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: [e-mail]).

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.

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