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Sci Transl Med. 2013 Nov 20;5(212):212ra162. doi: 10.1126/scitranslmed.3006840.

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

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Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Santaris Pharma, DK-2970, Hørsholm, Denmark.
Department of Haematology, Aalborg University Hospital, DK-2450 Copenhagen SV, Denmark.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
RxGen, Inc., 100 Deepwood Dr., Hamden, CT 06517, USA.
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Department of Cell and Developmental Biology, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, PO Box 24144, Doha, Qatar.
Contributed equally


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.

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