title: Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR.
abstract: 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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.|Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Veerle
authors.initials: V
authors.lastname: Rottiers
authors.affiliation: Santaris Pharma, DK-2970, Hørsholm, Denmark.
authors.forename: Susanna
authors.initials: S
authors.lastname: Obad
authors.affiliation: Santaris Pharma, DK-2970, Hørsholm, Denmark.|Department of Haematology, Aalborg University Hospital, DK-2450 Copenhagen SV, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Petri
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: McGarrah
authors.affiliation: Santaris Pharma, DK-2970, Hørsholm, Denmark.
authors.forename: Marie W
authors.initials: MW
authors.lastname: Lindholm
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: RxGen, Inc., 100 Deepwood Dr., Hamden, CT 06517, USA.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Goody
authors.affiliation: RxGen, Inc., 100 Deepwood Dr., Hamden, CT 06517, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: deLemos
authors.affiliation: Santaris Pharma, DK-2970, Hørsholm, Denmark.
authors.forename: Henrik F
authors.initials: HF
authors.lastname: Hansen
authors.affiliation: RxGen, Inc., 100 Deepwood Dr., Hamden, CT 06517, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Whittaker
authors.affiliation: RxGen, Inc., 100 Deepwood Dr., Hamden, CT 06517, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Henry
authors.affiliation: RxGen, Inc., 100 Deepwood Dr., Hamden, CT 06517, USA.
authors.forename: Rohn
authors.initials: R
authors.lastname: Brookes
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.|Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.|Department of Cell and Developmental Biology, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, PO Box 24144, Doha, Qatar.
authors.forename: S Hani
authors.initials: SH
authors.lastname: Najafi-Shoushtari
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Santaris Pharma, DK-2970, Hørsholm, Denmark.|Department of Haematology, Aalborg University Hospital, DK-2450 Copenhagen SV, Denmark.
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.|Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Näär
mesh_terms: D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D011323:Primates
chemical_list: D008076:Cholesterol, HDL; D035683:MicroRNAs