LNA-mediated microRNA silencing in non-human primates.
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.
Elmén
Joacim
J
Santaris Pharma, Bøge Allé 3, DK-2970 Hørsholm, Denmark.
Lindow
Morten
M
Schütz
Sylvia
S
Lawrence
Matthew
M
Petri
Andreas
A
Obad
Susanna
S
Lindholm
Marie
M
Hedtjärn
Maj
M
Hansen
Henrik Frydenlund
HF
Berger
Urs
U
Gullans
Steven
S
Kearney
Phil
P
Sarnow
Peter
P
Straarup
Ellen Marie
EM
Kauppinen
Sakari
S
D000818:Animals; D002522:Chlorocebus aethiops / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*
D035683:MicroRNAs; D009841:Oligonucleotides; C477371:locked nucleic acid