Preclinical development of a miR-132 inhibitor for heart failure treatment

Nat Commun. 2020 Jan 31;11(1):633. doi: 10.1038/s41467-020-14349-2.


Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • Female
  • Gene Expression Regulation
  • Genetic Therapy / methods*
  • Heart Failure / genetics*
  • Heart Failure / metabolism
  • Heart Failure / therapy*
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Myocytes, Cardiac / metabolism
  • Oligonucleotides, Antisense / genetics*
  • Oligonucleotides, Antisense / metabolism
  • Oligonucleotides, Antisense / pharmacokinetics
  • Swine


  • MicroRNAs
  • Oligonucleotides, Antisense