Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

LNA-mediated microRNA silencing in non-human primates


microRNAs (miRNAs) are small regulatory RNAs that are important in development and disease1,2,3 and therefore represent a potential new class of targets for therapeutic intervention4. Despite recent progress in silencing of miRNAs in rodents5,6, the development of effective and safe approaches for sequence-specific antagonism of miRNAs in vivo remains a significant scientific and therapeutic challenge. Moreover, there are no reports of miRNA antagonism in primates. Here we show that the simple systemic delivery of a unconjugated, PBS-formulated locked-nucleic-acid-modified oligonucleotide (LNA-antimiR) effectively antagonizes the liver-expressed miR-122 in non-human primates. Acute administration by intravenous injections of 3 or 10 mg kg-1 LNA-antimiR to African green monkeys resulted in uptake of the LNA-antimiR in the cytoplasm of primate hepatocytes and formation of stable heteroduplexes between the LNA-antimiR and miR-122. This was accompanied by depletion of mature miR-122 and dose-dependent lowering of plasma cholesterol. Efficient silencing of miR-122 was achieved in primates by three doses of 10 mg kg-1 LNA-antimiR, leading to a long-lasting and reversible decrease in total plasma cholesterol without any evidence for LNA-associated toxicities or histopathological changes in the study animals. Our findings demonstrate the utility of systemically administered LNA-antimiRs in exploring miRNA function in rodents and primates, and support the potential of these compounds as a new class of therapeutics for disease-associated miRNAs.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Silencing of miR-122 function in normal and hypercholesterolaemic mice by LNA-antimiR.
Figure 2: Silencing of miR-122 in non-human primates by LNA-antimiR.
Figure 3: LNA-mediated miR-122 silencing is safe in non-human primates.

Accession codes

Primary accessions


Data deposits

The microarray data have been submitted to the ArrayExpress database under accession number E-MEXP-1406.


  1. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004)

    Article  CAS  ADS  PubMed  Google Scholar 

  2. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

    Article  CAS  PubMed  Google Scholar 

  3. Kloosterman, W. P. & Plasterk, R. H. The diverse functions of microRNAs in animal development and disease. Dev. Cell 11, 441–450 (2006)

    Article  CAS  PubMed  Google Scholar 

  4. Soifer, H. S., Rossi, J. J. & Saetrom, P. MicroRNAs in disease and potential therapeutic applications. Mol. Ther. 12, 2070–2079 (2007)

    Article  CAS  Google Scholar 

  5. Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3, 87–98 (2006)

    Article  CAS  PubMed  Google Scholar 

  6. Krutzfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alvarez-Garcia, I. & Miska, E. A. MicroRNA functions in animal development and human disease. Development 132, 4653–4662 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. Abelson, J. F. et al. Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science 310, 317–320 (2005)

    Article  CAS  ADS  PubMed  Google Scholar 

  10. Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006)

    Article  CAS  ADS  Google Scholar 

  11. Eisenberg, I. et al. Distinctive patterns of microRNA expression in primary muscular disorders. Proc. Natl Acad. Sci. USA 104, 17016–17021 (2007)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  12. Esquela-Kerscher, A. & Slack, F. J. Oncomirs—microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006)

    Article  CAS  Google Scholar 

  13. He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  14. Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309, 1577–1581 (2005)

    Article  CAS  ADS  PubMed  Google Scholar 

  15. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005)

    Article  CAS  ADS  PubMed  Google Scholar 

  16. Pedersen, I. M. et al. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449, 919–922 (2007)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  17. Triboulet, R. et al. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 315, 1579–1582 (2007)

    Article  CAS  ADS  PubMed  Google Scholar 

  18. van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007)

    Article  CAS  ADS  PubMed  Google Scholar 

  19. Yang, B. et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nature Med. 13, 486–491 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. Randall, G. et al. Cellular cofactors affecting hepatitis C virus infection and replication. Proc. Natl Acad. Sci. USA 104, 12884–12889 (2007)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  21. Krutzfeldt, J. et al. Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res. 35, 2885–2892 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Elmen, J. et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res. 10.1093/nar/gkm1113 (2007)

  23. Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005)

    Article  CAS  ADS  PubMed  Google Scholar 

  24. Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80.1–R80.16 (2004)

    Article  Google Scholar 

  25. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005)

    Article  CAS  PubMed  Google Scholar 

Download references


All primate studies were performed at the St Kitts Biomedical Research Foundation, St Kitts, West Indies. We thank A. Konge, A. Koustrup, B. Nordbo, H. W. Høvring, J. J. Jørgensen, K. R. Nielsen, L. Bang, H. Brostrøm, O. Olsen, R. Sølberg, U. Steinmeier, J. Staruk, C. Kent, E. Nisbett, M. Struharik and R. Valles for technical assistance. This study was supported by grants from the Danish National Advanced Technology Foundation, the Danish Medical Research Council and the Lundbeck Foundation (to S.K.) and by grants from the National Institutes of Health (to P.S.). The Wilhelm Johannsen Centre for Functional Genome Research was established by the Danish National Research Foundation.

Author Contributions J.E. and M. Lindow contributed equally to this study. J.E., M. Lindow, M. Lawrence, U.B., S.O., M.H., A.P., S.S. and E.M.S. performed experiments and contributed data. H.F.H. performed the synthesis of all oligonucleotides. J.E., M. Lindow, M. Lawrence, M. Lindholm, H.F.H., P.K., S.G., P.S., E.M.S. and S.K. designed experiments and discussed the data. S.K. supervised the study and wrote the paper together with J.E. and M. Lindow.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Sakari Kauppinen.

Ethics declarations

Competing interests

J.E., M. Lindow, A.P., S.O., M. Lindholm, M.H., H.F.H., P.K., E.M.S. and S.K. are employees of Santaris Pharma, a clinical stage biopharmaceutical company that develops RNA-based therapeutics.

Supplementary information

Supplementary Information 1

The file contains extensive Supplementary Information detailing the primate study and the data collected. (PDF 2781 kb)

Supplementary Information 2

The file contains Supplementary Figures 1-4 with Legends and Supplementary Methods. (PDF 5183 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Elmén, J., Lindow, M., Schütz, S. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing