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

Jürgen Soutschek (), Akin Akinc, Birgit Bramlage, Klaus Charisse, Rainer Constien, Mary Donoghue, Sayda Elbashir, Anke Geick, Philipp Hadwiger, Jens Harborth, Matthias John, Venkitasamy Kesavan, Gary Lavine, Rajendra K. Pandey, Timothy Racie, Kallanthottathil G. Rajeev, Ingo Röhl, Ivanka Toudjarska, Gang Wang, Silvio Wuschko, David Bumcrot, Victor Koteliansky, Stefan Limmer, Muthiah Manoharan and Hans-Peter Vornlocher
Additional contact information
Jürgen Soutschek: Alnylam Europe AG
Akin Akinc: Alnylam Pharmaceuticals Inc.
Birgit Bramlage: Alnylam Europe AG
Klaus Charisse: Alnylam Pharmaceuticals Inc.
Rainer Constien: Alnylam Europe AG
Mary Donoghue: Alnylam Pharmaceuticals Inc.
Sayda Elbashir: Alnylam Pharmaceuticals Inc.
Anke Geick: Alnylam Europe AG
Philipp Hadwiger: Alnylam Europe AG
Jens Harborth: Alnylam Pharmaceuticals Inc.
Matthias John: Alnylam Europe AG
Venkitasamy Kesavan: Alnylam Pharmaceuticals Inc.
Gary Lavine: Alnylam Pharmaceuticals Inc.
Rajendra K. Pandey: Alnylam Pharmaceuticals Inc.
Timothy Racie: Alnylam Pharmaceuticals Inc.
Kallanthottathil G. Rajeev: Alnylam Pharmaceuticals Inc.
Ingo Röhl: Alnylam Europe AG
Ivanka Toudjarska: Alnylam Pharmaceuticals Inc.
Gang Wang: Alnylam Pharmaceuticals Inc.
Silvio Wuschko: Alnylam Europe AG
David Bumcrot: Alnylam Pharmaceuticals Inc.
Victor Koteliansky: Alnylam Pharmaceuticals Inc.
Stefan Limmer: Alnylam Europe AG
Muthiah Manoharan: Alnylam Pharmaceuticals Inc.
Hans-Peter Vornlocher: Alnylam Europe AG

Nature, 2004, vol. 432, issue 7014, 173-178

Abstract: Abstract 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.

Date: 2004
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Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:432:y:2004:i:7014:d:10.1038_nature03121

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DOI: 10.1038/nature03121

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