Preclinical development of a miR-132 inhibitor for heart failure treatment.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
31 01 2020
31 01 2020
Historique:
received:
26
04
2019
accepted:
27
12
2019
entrez:
2
2
2020
pubmed:
2
2
2020
medline:
12
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32005803
doi: 10.1038/s41467-020-14349-2
pii: 10.1038/s41467-020-14349-2
pmc: PMC6994493
doi:
Substances chimiques
MicroRNAs
0
Oligonucleotides, Antisense
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
633Subventions
Organisme : British Heart Foundation
ID : CH/16/3/32406
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/16/14/32397
Pays : United Kingdom
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