Abstract

MicroRNA (miRNA) inhibition is a promising therapeutic strategy in several disease indications. MRG-110 is a locked nucleic acid-based antisense oligonucleotide that targets miR-92a-3p and experimentally was shown to have documented therapeutic effects on cardiovascular disease and wound healing. To gain first insights into the activity of anti-miR-92a in humans, we investigated miR-92a-3p expression in several blood compartments and assessed the effect of MRG-110 on target derepression. Healthy adults were randomly assigned (5:2) to receive a single intravenous dose of MRG-110 or placebo in one of seven sequential ascending intravenous dose cohorts ranging from 0.01 to 1.5 mg/kg body weight. MiR-92a-3p whole blood levels were time and dose dependently decreased with half-maximal inhibition of 0.27 and 0.31 mg/kg at 24 and 72 h after dosing, respectively. In the high-dose groups, >95% inhibition was detected at 24–72 h postinfusion and significant inhibition was observed for 2 weeks. Similar inhibitory effects were detected in isolated CD31+ cells, and miR-92a-3p expression was also inhibited in extracellular vesicles in the high-dose group. Target derepression was measured in whole blood and showed that ITGA5 and CD93 were increased at a dose of 1.5 mg/kg. Single-cell RNA sequencing of peripheral blood cells revealed a cell type-specific derepression of miR-92a targets. Together this study demonstrates that systemic infusion of anti-miR-92a efficiently inhibits miR-92a in the peripheral blood compartment and derepresses miR-92a targets in humans.

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Information & Authors

Information

Published In

cover image Nucleic Acid Therapeutics
nucleic acid therapeutics
Volume 30Issue Number 6December 2020
Pages: 335 - 345
PubMed: 32707001

History

Published online: 4 December 2020
Published in print: December 2020
Published ahead of print: 20 July 2020
Accepted: 18 June 2020
Received: 16 April 2020

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Authors

Affiliations

Wesley Tyler Abplanalp*
Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.
German Center for Cardiovascular Research (DZHK), Frankfurt, Germany.
Ariane Fischer*
Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.
David John
Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.
Andreas M. Zeiher
German Center for Cardiovascular Research (DZHK), Frankfurt, Germany.
Cardio-Pulmonary Institute (CPI), Frankfurt, Germany.
Willy Gosgnach
CentEX Biotechnology, Institut de Recherche SERVIER, Paris, France.
Helene Darville
CentEX Biotechnology, Institut de Recherche SERVIER, Paris, France.
Rusty Montgomery
miRagen Therapeutics, Inc., Boulder, Colorado, USA.
Linda Pestano
miRagen Therapeutics, Inc., Boulder, Colorado, USA.
Guillaume Allée
Center for Therapeutic Innovation Cardiovascular and Metabolic Disease, Institut de Recherches Internationales SERVIER, Paris, France.
Isabelle Paty
Center for Therapeutic Innovation Cardiovascular and Metabolic Disease, Institut de Recherches Internationales SERVIER, Paris, France.
Francoise Fougerousse
Center for Therapeutic Innovation Cardiovascular and Metabolic Disease, Institut de Recherches Internationales SERVIER, Paris, France.
Stefanie Dimmeler [email protected]
Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.
German Center for Cardiovascular Research (DZHK), Frankfurt, Germany.
Cardio-Pulmonary Institute (CPI), Frankfurt, Germany.

Notes

*
These authors contributed equally to this work.
Address correspondence to: Stefanie Dimmeler, PhD, Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany [email protected]

Author Disclosure Statement

S.D. and A.Z. have a patent on miR-92a targeting in cardiovascular disease. S.D. has a research contract with Servier and is scientific advisor of miRagen Therapeutics. W.G., H.D., G.A., I.P., F.F. are employees of Servier, R.M. and L.P. are employees of miRagen Therapeutics. All other authors have no competing financial interests.

Funding Information

The study was supported by the German Center for Cardiovascular Research (DZHK), the Leducq Network MIRVAD, and the Rolf M. Schwiete foundation.

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