Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
CARDIOR Pharmaceuticals GmbH, Feodor-Lynen-Str. 15, 30625, Hannover, Germany.
Nat Commun. 2020 Jan 31;11(1):633. doi: 10.1038/s41467-020-14349-2.
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.
尽管针对主要的全球神经激素失调的药物治疗已被证实有效，但心力衰竭（HF）仍是一种日益严重的流行疾病，负担不断增加。缺乏针对心肌细胞水平的机械性治疗方法。microRNAs（miRNA）是转录调节剂，也是疾病进展的关键驱动因素。我们之前的研究表明，miR-132 是驱动病理性心肌细胞生长的必要和充分条件，这是心脏不良重构的标志。因此，miR-132 可能成为 HF 治疗的靶点。在这里，我们进一步报道了优化的、合成的锁核酸反义寡核苷酸抑制剂（antimiR-132）的作用机制和转化证据的深入了解。我们在各种模型中揭示了该化合物的治疗效果，包括 HF 的临床相关性很强的猪模型。我们证明了该化合物具有良好的药代动力学、安全性、耐受性、剂量依赖性 PK/PD 关系以及针对 antimiR-132 治疗方案的高临床潜力。
