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, Thomas Thum
Nature Communications2020
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.
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