1. Santaris Pharma, Bøge Allé 3, DK-2970 Hørsholm, Denmark
2. Department of Microbiology and Immunology, 299 Campus Drive, Stanford University School of Medicine, Stanford, California 94305, USA
3. RxGen Inc, 100 Deepwood Drive, Hamden, Connecticut 06517, USA
4. UB-in situ, PO Box 463, Natick, Massachusetts 01760, USA
5. Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
6. These authors contributed equally to this work.

Correspondence to: Sakari Kauppinen^1,5 Correspondence and requests for materials should be addressed to S.K. (Email: sk@santaris.com).

Abstract

microRNAs (miRNAs) are small regulatory RNAs that are important in development and disease^{1, 2, 3} and therefore represent a potential new class of targets for therapeutic intervention⁴. Despite recent progress in silencing of miRNAs in rodents^{5, 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.

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