RT Journal Article
SR Electronic
T1 Pharmacological Inhibition of a MicroRNA Family in Nonhuman Primates by a Seed-Targeting 8-Mer AntimiR
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 212ra162
OP 212ra162
DO 10.1126/scitranslmed.3006840
VO 5
IS 212
A1 Rottiers, Veerle
A1 Obad, Susanna
A1 Petri, Andreas
A1 McGarrah, Robert
A1 Lindholm, Marie W.
A1 Black, Joshua C.
A1 Sinha, Sumita
A1 Goody, Robin J.
A1 Lawrence, Matthew S.
A1 deLemos, Andrew S.
A1 Hansen, Henrik F.
A1 Whittaker, Steve
A1 Henry, Steve
A1 Brookes, Rohn
A1 Najafi-Shoushtari, Seyed Hani
A1 Chung, Raymond T.
A1 Whetstine, Johnathan R.
A1 Gerszten, Robert E.
A1 Kauppinen, Sakari
A1 Näär, Anders M.
YR 2013
UL http://stm.sciencemag.org/content/5/212/212ra162.abstract
AB MicroRNAs (miRNAs) regulate many aspects of human biology. They target mRNAs for translational repression or degradation through base pairing with 3′ untranslated regions, primarily via seed sequences (nucleotides 2 to 8 in the mature miRNA sequence). A number of individual miRNAs and miRNA families share seed sequences and targets, but differ in the sequences outside of the seed. miRNAs have been implicated in the etiology of a wide variety of human diseases and therefore represent promising therapeutic targets. However, potential redundancy of different miRNAs sharing the same seed sequence and the challenge of simultaneously targeting miRNAs that differ significantly in nonseed sequences complicate therapeutic targeting approaches. We recently demonstrated effective inhibition of entire miRNA families using seed-targeting 8-mer locked nucleic acid (LNA)–modified antimiRs in short-term experiments in mammalian cells and in mice. However, the long-term efficacy and safety of this approach in higher organisms, such as humans and nonhuman primates, have not been determined. We show that pharmacological inhibition of the miR-33 family, key regulators of cholesterol/lipid homeostasis, by a subcutaneously delivered 8-mer LNA-modified antimiR in obese and insulin-resistant nonhuman primates results in derepression of miR-33 targets, such as ABCA1, increases circulating high-density lipoprotein cholesterol, and is well tolerated over 108 days of treatment. These findings demonstrate the efficacy and safety of an 8-mer LNA-antimiR against an miRNA family in a nonhuman primate metabolic disease model, suggesting that this could be a feasible approach for therapeutic targeting of miRNA families sharing the same seed sequence in human diseases.