RNAi-mediated gene silencing in non-human primates View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-05

AUTHORS

Tracy S. Zimmermann, Amy C. H. Lee, Akin Akinc, Birgit Bramlage, David Bumcrot, Matthew N. Fedoruk, Jens Harborth, James A. Heyes, Lloyd B. Jeffs, Matthias John, Adam D. Judge, Kieu Lam, Kevin McClintock, Lubomir V. Nechev, Lorne R. Palmer, Timothy Racie, Ingo Röhl, Stephan Seiffert, Sumi Shanmugam, Vandana Sood, Jürgen Soutschek, Ivanka Toudjarska, Amanda J. Wheat, Ed Yaworski, William Zedalis, Victor Koteliansky, Muthiah Manoharan, Hans-Peter Vornlocher, Ian MacLachlan

ABSTRACT

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 medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, 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. More... »

PAGES

111

Journal

TITLE

Nature

ISSUE

7089

VOLUME

441

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature04688

    DOI

    http://dx.doi.org/10.1038/nature04688

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1026190446

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/16565705


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