Publication Date:
2008-03-28
Description:
microRNAs (miRNAs) are small regulatory RNAs that are important in development and disease and therefore represent a potential new class of targets for therapeutic intervention. Despite recent progress in silencing of miRNAs in rodents, 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elmen, Joacim -- Lindow, Morten -- Schutz, Sylvia -- Lawrence, Matthew -- Petri, Andreas -- Obad, Susanna -- Lindholm, Marie -- Hedtjarn, Maj -- Hansen, Henrik Frydenlund -- Berger, Urs -- Gullans, Steven -- Kearney, Phil -- Sarnow, Peter -- Straarup, Ellen Marie -- Kauppinen, Sakari -- England -- Nature. 2008 Apr 17;452(7189):896-9. doi: 10.1038/nature06783. Epub 2008 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Santaris Pharma, Boge Alle 3, DK-2970 Horsholm, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368051" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cercopithecus aethiops/*genetics
;
Female
;
*Gene Silencing
;
Mice
;
Mice, Inbred C57BL
;
MicroRNAs/*genetics
;
Oligonucleotides/administration & dosage/adverse effects/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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