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RNAi-mediated gene silencing in non-human primates

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 tar... Full description

Journal Title: Nature May 4, 2006, Vol.441(7089), p.111
Main Author: Zimmermann, Tracy S.
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0028-0836
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recordid: gale_ofa185452236
title: RNAi-mediated gene silencing in non-human primates
format: Article
creator:
  • 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
subjects:
  • Genes
  • Ribonucleic Acids
  • Primates
  • Silence
  • Monkeys
  • Reduction
  • Harnesses
  • Surgical Implants
  • General and Nonclassified (MD)
  • General and Nonclassified (EC)
  • General and Nonclassified (Ed)
  • General and Nonclassified (Ep)
  • Surveying, Theory, and Analysis (CE)
  • Design Principles, Theory, and Analysis (Mt)
  • Computing Milieux (General) (Ci)
  • Electronics and Communications Milieux (General) (Ea)
  • Solid State Milieux (General) (So)
  • Article
ispartof: Nature, May 4, 2006, Vol.441(7089), p.111
description: 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.[PUBLICATION ]
language: English
source:
identifier: ISSN: 0028-0836
fulltext: fulltext
issn:
  • 0028-0836
  • 00280836
url: Link


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titleRNAi-mediated gene silencing in non-human primates
creatorZimmermann, 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
ispartofNature, May 4, 2006, Vol.441(7089), p.111
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descriptionThe 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.[PUBLICATION ]
subjectGenes ; Ribonucleic Acids ; Primates ; Silence ; Monkeys ; Reduction ; Harnesses ; Surgical Implants ; General and Nonclassified (MD) ; General and Nonclassified (EC) ; General and Nonclassified (Ed) ; General and Nonclassified (Ep) ; Surveying, Theory, and Analysis (CE) ; Design Principles, Theory, and Analysis (Mt) ; Computing Milieux (General) (Ci) ; Electronics and Communications Milieux (General) (Ea) ; Solid State Milieux (General) (So) ; Article;
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