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

Ariana Foinquinos, Sandor Batkai, Celina Genschel, Janika Viereck, Steffen Rump, Mariann Gyöngyösi, Denise Traxler, Martin Riesenhuber, Andreas Spannbauer, Dominika Lukovic, Natalie Weber, Katrin Zlabinger, Ena Hašimbegović, Johannes Winkler, Jan Fiedler, Seema Dangwal, Martin Fischer, Jeanne de la Roche, Daniel Wojciechowski, Theresia Kraft, Rita Garamvölgyi, Sonja Neitzel, Shambhabi Chatterjee, Xiaoke Yin, Christian Bär, Manuel Mayr, Ke Xiao and Thomas Thum ()
Additional contact information
Ariana Foinquinos: Hannover Medical School
Sandor Batkai: Hannover Medical School
Celina Genschel: Hannover Medical School
Janika Viereck: Hannover Medical School
Steffen Rump: CARDIOR Pharmaceuticals GmbH
Mariann Gyöngyösi: Medical University of Vienna
Denise Traxler: Medical University of Vienna
Martin Riesenhuber: Medical University of Vienna
Andreas Spannbauer: Medical University of Vienna
Dominika Lukovic: Medical University of Vienna
Natalie Weber: Hannover Medical School
Katrin Zlabinger: Medical University of Vienna
Ena Hašimbegović: Medical University of Vienna
Johannes Winkler: Medical University of Vienna
Jan Fiedler: Hannover Medical School
Seema Dangwal: Hannover Medical School
Martin Fischer: Hannover Medical School
Jeanne de la Roche: Hannover Medical School
Daniel Wojciechowski: Hannover Medical School
Theresia Kraft: Hannover Medical School
Rita Garamvölgyi: University of Kaposvár
Sonja Neitzel: Axolabs GmbH
Shambhabi Chatterjee: Hannover Medical School
Xiaoke Yin: University of London
Christian Bär: Hannover Medical School
Manuel Mayr: University of London
Ke Xiao: Hannover Medical School
Thomas Thum: Hannover Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14349-2

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