RNAi-mediated gene silencing in non-human primates

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RNAi-mediated gene silencing in non-human primates
Engineering Village 2
2006 Elsevier Inc.
Accession number: 063110042585

Title: RNAi-mediated gene silencing in non-human primates

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

Author affiliation: Alnylam Pharmaceuticals Inc., Cambridge, MA 02142, United States

Serial title: Nature

Abbreviated serial title: Nature

Volume: v 441

Issue: n 7089

Issue date: May 4 2006

Publication year: 2006

Pages: p 111-114

Language: English

ISSN: 0028-0836

CODEN: NATUAS

Document type: Journal article (JA)

Publisher: Nature Publishing Group, Basingstoke, Hampshire, RG21 6XS, United Kingdom

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. ? 2006 Nature Publishing Group.

Number of references: 19

Ei main heading: Genetic engineering

Ei controlled terms: RNA - Diseases - Medicine - Proteins - Nucleic acids - Lipids - Drug dosage - Biological organs - Cholesterol

Uncontrolled terms: Stable nucleic acid lipid particles (SNALP) - Lipoproteins - RNA interferences (RNAi) - Gene silencing

Ei classification codes: 461.8.1 Genetic Engineering - 461.2 Biological Materials - 461.6 Medicine - 804.1 Organic Compounds - 801.2 Biochemistry

Treatment: Theoretical (THR); Experimental (EXP)

DOI: 10.1038/nature04688

Database: Compendex

Compilation and indexing terms, ? 2006 Elsevier Inc. All rights reserved
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