Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway

Matthias John, Rainer Constien, Akin Akinc, Michael Goldberg, Young Ah Moon, Martina Spranger, Philipp Hadwiger, Jürgen Soutschek, Hans Peter Vornlocher, Muthiah Manoharan, Markus Stoffel, Robert Langer, Daniel G. Anderson, Jay D. Horton, Victor Koteliansky, David Bumcrot

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


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 (∼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.

Original languageEnglish (US)
Pages (from-to)745-747
Number of pages3
Issue number7163
StatePublished - Oct 11 2007

ASJC Scopus subject areas

  • General


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