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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We are grateful to P. Sharp, J. Maraganore and N. Mahanthappa for their assistance and support in this study. We would also like to thank W. J. Schneider, J. Frohlich, M. Hayden and J. E. Vance for discussions. We acknowledge the technical assistance of C. Woppmann and A. Wetzel, and thank V. Kesavan and G. Wang for preparation of the cholesterol-conjugated siRNA used in this study. Finally, we thank S. Young for providing anti-ApoB antibodies. This work was supported by grants from the National Science and Engineering Research Council of Canada (to A.J.W. and M.N.F.). Author Contributions This work represents the outcome of a collaboration between scientists at Alnylam Pharmaceuticals and Protiva Biotherapeutics Inc.