Efficiency and Target Derepression of Anti-miR-92a: Results of a First in Human Study

Nucleic Acid Ther. 2020 Dec;30(6):335-345. doi: 10.1089/nat.2020.0871. Epub 2020 Jul 20.

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.

Keywords: anti-miR; first in human; miR-92a; single cell sequencing.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antagomirs / administration & dosage
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / pathology
  • Cell Lineage / genetics
  • Extracellular Vesicles / drug effects
  • Extracellular Vesicles / genetics
  • Female
  • Humans
  • Integrins / genetics*
  • Male
  • Membrane Glycoproteins / genetics*
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • Middle Aged
  • Oligonucleotides / administration & dosage*
  • Oligonucleotides, Antisense / administration & dosage
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Receptors, Complement / genetics*
  • Wound Healing / drug effects
  • Wound Healing / genetics
  • Young Adult

Substances

  • Antagomirs
  • ITGA5 protein, human
  • Integrins
  • MIRN92 microRNA, human
  • Membrane Glycoproteins
  • MicroRNAs
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Receptors, Complement
  • complement 1q receptor
  • locked nucleic acid