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

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 essen...

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Published in:Nature communications Vol. 11; no. 1; pp. 633 - 10
Main Authors: Foinquinos, Ariana, Batkai, Sandor, Genschel, Celina, Viereck, Janika, Rump, Steffen, Gyöngyösi, Mariann, Traxler, Denise, Riesenhuber, Martin, Spannbauer, Andreas, Lukovic, Dominika, Weber, Natalie, Zlabinger, Katrin, Hašimbegović, Ena, Winkler, Johannes, Fiedler, Jan, Dangwal, Seema, Fischer, Martin, de la Roche, Jeanne, Wojciechowski, Daniel, Kraft, Theresia, Garamvölgyi, Rita, Neitzel, Sonja, Chatterjee, Shambhabi, Yin, Xiaoke, Bär, Christian, Mayr, Manuel, Xiao, Ke, Thum, Thomas
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 31.01.2020
Nature Publishing Group
Nature Portfolio
Subjects:
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Animal models
Animals
Antisense oligonucleotides
Cardiomyocytes
Chemical compounds
Congestive heart failure
Drug Evaluation, Preclinical
Drug therapy
Female
Gene Expression Regulation
Genetic Therapy - methods
Heart failure
Heart Failure - genetics
Heart Failure - metabolism
Heart Failure - therapy
Humanities and Social Sciences
Humans
Inhibitors
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
Mode of action
multidisciplinary
Myocytes, Cardiac - metabolism
Nucleic acids
Oligonucleotides, Antisense - genetics
Oligonucleotides, Antisense - metabolism
Oligonucleotides, Antisense - pharmacokinetics
Pandemics
Pharmacokinetics
Pharmacology
Regulators
Safety
Science
Science (multidisciplinary)
Swine
Transcription
ISSN:2041-1723, 2041-1723
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Summary: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. miR-132 was shown to drive pathological cardiac remodeling, a hallmark of heart failure. Here, the authors show that an antisense inhibitor of miR-132 has favourable pharmacokinetics, safety-tolerability and preclinical efficacy in mouse and porcine models of heart failure.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-14349-2