Cited by 1,357RNA Interference and Gene DeliveryVirus-based gene therapy researchRNA Research and Splicing

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RNAi-mediated gene silencing in non-human primates

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, Röhl, Ingo, Seiffert, Stephan, Shanmugam, Sumi, Sood, Vandana, Soutschek, Jürgen, Toudjarska, Ivanka, Wheat, Amanda J., Yaworski, Ed, Zedalis, William, Koteliansky, Victor, Manoharan, Muthiah, Vornlocher, Hans-Peter, MacLachlan, Ian·2006·Nature

DOI 10.1038/nature04688

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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.

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“phenotypes, or by gross measures of lymphocyte activation (124,125).”
Background
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Interaction of Cholesterol-Conjugated Ionizable Amino Lipids with Biomembranes: Lipid Polymorphism, Structure–Activity Relationship, and Implications for siRNA Delivery
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Splicing modulation therapy in the treatment of genetic diseases
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Amphoteric liposomes enable systemic antigen‐presenting cell–directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis
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Molecular Imaging Study on In Vivo Distribution and Pharmacokinetics of Modified Small Interfering RNAs (siRNAs)
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Enhanced Extravasation, Stability and in Vivo Cardiac Gene Silencing via in Situ siRNA–Albumin Conjugation
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“siRNAs were classically unsuitable for use in vivo, due to their poor cellular uptake and susceptibility to degradation, but advances such as modified RNA backbones and/or sugar rings, conjugated cholesterol or stabilized nanoparticles have improved outcomes after in vivo administration [74].”
Background
Treatment of erythropoietin deficiency in mice with systemically administered siRNA
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“When injected into both mice [91] and primates [92] ApoB-specific small interfering RNAs cause rapid and lasting RNA interference-mediated attenuation with marked reductions in plasma cholesterol and apoB concentrations.”
Background

Authors: Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., Judge, A. D., Lam, K., McClintock, K., Nechev, L. V., Palmer, L. R., Racie, T., Röhl, I., Seiffert, S., Shanmugam, S., Sood, V., Soutschek, J., Toudjarska, I., Wheat, A. J., Yaworski, E., Zedalis, W., Koteliansky, V., Manoharan, M., Vornlocher, H.-P., & MacLachlan, I.
Affiliations: Alnylam Pharmaceuticals (United States) (US)
Electronic Arts (Canada) (CA)
Corresponding author: Zimmermann, Tracy S.
MacLachlan, Ian
ORCID: Lee, Amy C. H.
Fedoruk, Matthew N.
Harborth, Jens
Heyes, James A.
Lam, Kieu
McClintock, Kevin
Palmer, Lorne R.
Manoharan, Muthiah
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2006-03-26
Volume: 441
Issue: 7089
Pages: 111-114
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature04688
OpenAlex: W2095151181
Cited by: 1,357
References: 20
Citations by year: 2026: 21 · 2025: 22 · 2024: 30 · 2023: 42 · 2022: 40 · 2021: 35 · 2020: 35 · 2019: 46 · 2018: 30 · 2017: 47 · 2016: 54 · 2015: 70 · 2014: 97 · 2013: 113 · 2012: 111
FWCI: 46.06
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Alnylam Pharmaceuticals
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords: RNA interference, gene silencing, siRNA, apolipoprotein B, siRNA therapeutics, systemic siRNA delivery, Macaca fascicularis, non-human primates, hypercholesterolemia, LDL cholesterol, B-cell lymphoma, CARD11
MeSH terms: Animals, Apolipoproteins B, Phenotype, Primates, RNA, Messenger, RNA Interference, RNA, Small Interfering

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RNAi-mediated gene silencing in non-human primates

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