LNA-mediated microRNA silencing in non-human primates

microRNAs ( miRNAs) are small regulatory RNAs that are important in development and disease(1-3) and therefore represent a potential new class of targets for therapeutic intervention(4). 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.