Nature 441, 111-114 (4 May 2006) | doi:10.1038/nature04688; Received 12 January 2006; Accepted 6 March 2006; Published online 26 March 2006

RNAi-mediated gene silencing in non-human primates

Tracy S. Zimmermann1, Amy C. H. Lee2, Akin Akinc1, Birgit Bramlage3, David Bumcrot1, Matthew N. Fedoruk2, Jens Harborth1, James A. Heyes2, Lloyd B. Jeffs2, Matthias John3, Adam D. Judge2, Kieu Lam2, Kevin McClintock2, Lubomir V. Nechev1, Lorne R. Palmer2, Timothy Racie1, Ingo Röhl3, Stephan Seiffert3, Sumi Shanmugam1, Vandana Sood2, Jürgen Soutschek3, Ivanka Toudjarska1, Amanda J. Wheat2, Ed Yaworski2, William Zedalis1, Victor Koteliansky1, Muthiah Manoharan1, Hans-Peter Vornlocher3 & Ian MacLachlan2

  1. Alnylam Pharmaceuticals Inc., 300 Third Street, Cambridge, Massachusetts 02142, USA
  2. Protiva Biotherapeutics Inc., 100-3480 Gilmore Way, Burnaby, British Columbia V5G 4YI, Canada
  3. Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany

Correspondence to: Tracy S. Zimmermann1Ian MacLachlan2 Correspondence and requests for materials should be addressed to T.S.Z. (Email: tzimmermann@alnylam.com) or I.M. (Email: ian@protivabio.com).

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines1, 2. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs)3, 4, 5, there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA6, 7, 8, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg-1. A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.


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