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.
Highlights
Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden
Transgenic mice overexpressing the miR-212/132 cluster develop pathological cardiac remodeling and die prematurely from progressive HF2. Using both knockout and antisense strategies, we have shown miR-132 to be both necessary and sufficient to drive the pathological growth of cardiomyocytes in a murine model of left ventricular pressure overload[2]
We propose that miR-132 may serve as a therapeutic target in HF therapy
Summary
Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Expression levels were restored in cardiac tissue form TG animals receiving antimiR-132 treatment (Fig. 2j).
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