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（Nature），doi:10.1038/nature06783，Joacim Elmén, Sakari Kauppinen
Lindholm1, Maj Hedtjärn1, Henrik Frydenlund Hansen1, Urs Berger4, Steven Gullans3, Phil Kearney1, Peter Sarnow2, Ellen Marie Straarup1 & Sakari Kauppinen1,5
Santaris Pharma, Bøge Allé 3, DK-2970 Hørsholm, Denmark
Department of Microbiology and Immunology, 299 Campus Drive, Stanford University School of Medicine, Stanford, California 94305, USA
RxGen Inc, 100 Deepwood Drive, Hamden, Connecticut 06517, USA
UB-in situ, PO Box 463, Natick, Massachusetts 01760, USA
Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
These authors contributed equally to this work.
Correspondence to: Sakari Kauppinen1,5 Correspondence and requests for materials should be addressed to S.K. (Email: ).
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.
