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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Jürgen Soutschek & Akin Akinc & Birgit Bramlage & Klaus Charisse & Rainer Constien & Mary Donoghue & Sayda Elbashir & Anke Geick & Philipp Hadwiger & Jens Harborth & Matthias John & Venkitasamy Kesava, 2004. "Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs," Nature, Nature, vol. 432(7014), pages 173-178, November.
    • Handle: RePEc:nat:nature:v:432:y:2004:i:7014:d:10.1038_nature03121
    DOI: 10.1038/nature03121
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    Cited by:

    1. Hasan Vatandaslar & Aitor Garzia & Cindy Meyer & Svenja Godbersen & Laura T. L. Brandt & Esther Griesbach & Jeffrey A. Chao & Thomas Tuschl & Markus Stoffel, 2023. "In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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