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: dbumcrot@alnylam.com).

Abstract

Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates^{1, 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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