The DOI matches its Crossref record; 20 of the 20 references it cites were found in a registry or an index.
RNAi-mediated gene silencing in non-human primates
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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“This study demonstrates the potential of systemic lipid-lowering by liposome-encapsulated siRNA.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [76]
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“Therefore, siRNA therapy can be applied for treating GARDs by targeted silencing of the disease-causing genes.[50, 52]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [52]
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Metadata
- 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
- Venue
- Nature
- Published
- 2006-03-26
- Volume
- 441
- Issue
- 7089
- Pages
- 111-114
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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