Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR

Veerle Rottiers, Susanna Obad, Andreas Petri, Robert McGarrah, Marie W. Lindholm, Joshua C. Black, Sumita Sinha, Robin J. Goody, Matthew S. Lawrence, Andrew S. DeLemos, Henrik F. Hansen, Steve Whittaker, Steve Henry, Rohn Brookes, Hani Najafi, Raymond T. Chung, Johnathan R. Whetstine, Robert E. Gerszten, Sakari Kauppinen, Anders M. Näär

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

MicroRNAs (miRNAs) regulate many aspects of human biology. They target mRNAs for translational repression or degradation through base pairing with 3′ untranslated regions, primarily via seed sequences (nucleotides 2 to 8 in the mature miRNA sequence). A number of individual miRNAs and miRNA families share seed sequences and targets, but differ in the sequences outside of the seed. miRNAs have been implicated in the etiology of a wide variety of human diseases and therefore represent promising therapeutic targets. However, potential redundancy of different miRNAs sharing the same seed sequence and the challenge of simultaneously targeting miRNAs that differ significantly in nonseed sequences complicate therapeutic targeting approaches. We recently demonstrated effective inhibition of entire miRNA families using seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiRs in short-term experiments in mammalian cells and in mice. However, the long-term efficacy and safety of this approach in higher organisms, such as humans and nonhuman primates, have not been determined. We show that pharmacological inhibition of the miR-33 family, key regulators of cholesterol/lipid homeostasis, by a subcutaneously delivered 8-mer LNA-modified antimiR in obese and insulin-resistant nonhuman primates results in derepression of miR-33 targets, such as ABCA1, increases circulating high-density lipoprotein cholesterol, and is well tolerated over 108 days of treatment. These findings demonstrate the efficacy and safety of an 8-mer LNA-antimiR against an miRNA family in a nonhuman primate metabolic disease model, suggesting that this could be a feasible approach for therapeutic targeting of miRNA families sharing the same seed sequence in human diseases.

Original languageEnglish
Article number212ra162
JournalScience Translational Medicine
Volume5
Issue number212
DOIs
Publication statusPublished - 20 Nov 2013

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MicroRNAs
Primates
Seeds
Pharmacology
Primate Diseases
Safety
Metabolic Diseases
3' Untranslated Regions
Base Pairing
HDL Cholesterol
Homeostasis
Therapeutics
Cholesterol
Insulin
Lipids
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Rottiers, V., Obad, S., Petri, A., McGarrah, R., Lindholm, M. W., Black, J. C., ... Näär, A. M. (2013). Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR. Science Translational Medicine, 5(212), [212ra162]. https://doi.org/10.1126/scitranslmed.3006840

Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR. / Rottiers, Veerle; Obad, Susanna; Petri, Andreas; McGarrah, Robert; Lindholm, Marie W.; Black, Joshua C.; Sinha, Sumita; Goody, Robin J.; Lawrence, Matthew S.; DeLemos, Andrew S.; Hansen, Henrik F.; Whittaker, Steve; Henry, Steve; Brookes, Rohn; Najafi, Hani; Chung, Raymond T.; Whetstine, Johnathan R.; Gerszten, Robert E.; Kauppinen, Sakari; Näär, Anders M.

In: Science Translational Medicine, Vol. 5, No. 212, 212ra162, 20.11.2013.

Research output: Contribution to journalArticle

Rottiers, V, Obad, S, Petri, A, McGarrah, R, Lindholm, MW, Black, JC, Sinha, S, Goody, RJ, Lawrence, MS, DeLemos, AS, Hansen, HF, Whittaker, S, Henry, S, Brookes, R, Najafi, H, Chung, RT, Whetstine, JR, Gerszten, RE, Kauppinen, S & Näär, AM 2013, 'Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR', Science Translational Medicine, vol. 5, no. 212, 212ra162. https://doi.org/10.1126/scitranslmed.3006840
Rottiers, Veerle ; Obad, Susanna ; Petri, Andreas ; McGarrah, Robert ; Lindholm, Marie W. ; Black, Joshua C. ; Sinha, Sumita ; Goody, Robin J. ; Lawrence, Matthew S. ; DeLemos, Andrew S. ; Hansen, Henrik F. ; Whittaker, Steve ; Henry, Steve ; Brookes, Rohn ; Najafi, Hani ; Chung, Raymond T. ; Whetstine, Johnathan R. ; Gerszten, Robert E. ; Kauppinen, Sakari ; Näär, Anders M. / Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR. In: Science Translational Medicine. 2013 ; Vol. 5, No. 212.
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AU - Henry, Steve

AU - Brookes, Rohn

AU - Najafi, Hani

AU - Chung, Raymond T.

AU - Whetstine, Johnathan R.

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