Nature 432, 173-178 (11 November 2004) | doi:10.1038/nature03121; Received 2 September 2004; Accepted 20 October 2004

Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs

Jürgen Soutschek1, Akin Akinc2, Birgit Bramlage1, Klaus Charisse2, Rainer Constien1, Mary Donoghue2, Sayda Elbashir2, Anke Geick1, Philipp Hadwiger1, Jens Harborth2, Matthias John1, Venkitasamy Kesavan2, Gary Lavine2, Rajendra K. Pandey2, Timothy Racie2, Kallanthottathil G. Rajeev2, Ingo Röhl1, Ivanka Toudjarska2, Gang Wang2, Silvio Wuschko1, David Bumcrot2, Victor Koteliansky2, Stefan Limmer1, Muthiah Manoharan2 & Hans-Peter Vornlocher1

  1. Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany
  2. Alnylam Pharmaceuticals Inc., 300 3rd Street, Cambridge, Massachusetts 02142, USA

Correspondence to: Jürgen Soutschek1 Email:


RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called 'non-druggable' targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model. In our in vivo study, the mechanism of action for the siRNAs was proven to occur through RNAi-mediated mRNA degradation, and we determined that cleavage of the apoB mRNA occurred specifically at the predicted site. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.


These links to content published by NPG are automatically generated.


Research Highlights

Nature Biotechnology News and Views (01 Dec 2004)