Batkai Sandor, Spannbauer Andreas, Viereck Janika, Genschel Celina, Rump Steffen, Traxler Denise, Riesenhuber Martin, Lukovic Dominika, Zlabinger Katrin, Hasimbegovic Ena, Thum Thomas, Gyöngyösi Mariann
Research and Development, Cardior Pharmaceuticals GmbH, Hollerithallee 20, Hannover 30419, Germany.
Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria.
Eur Heart J Imaging Methods Pract. 2025 Aug 4;3(2):qyaf088. doi: 10.1093/ehjimp/qyaf088. eCollection 2025 Jul.
Cardiac miR-132 has been proposed as a target for heart failure (HF) therapy. CDR132L, a rationally designed synthetic oligonucleotide inhibitor of miR-132 has proved pre-clinical efficacy in non-ischaemic and ischaemic large animal HF models. The safety and tolerability of CDR132L were tested in chronic HF patients in a Phase 1b study (NCT04045405) and is currently being tested in a Phase 2 trial in post-MI HF patients (NCT05350969). The aim of the current study was to gain further data on myocardial function and efficacy of CDR132L by analysing left ventricular (LV) and atrial (LA) wall motion by serial cardiac magnetic resonance (cMRI) strain imaging in a clinically relevant large animal (pig) model of chronic HF.
Animals (15 per group) were randomized 1-month post-MI and received five intravenous (i.v.) monthly treatments with CDR132L (5 mg/kg) or placebo and were followed up for 6-month post-MI. LV and LA strain parameters were deteriorated after MI over time but significantly ameliorated by CDR132L treatment, compared with placebo. Strain parameters showed significant correlations with pharmacodynamic measures such as ejection fraction, NT-proBNP, and cardiac interstitial fibrosis in remodelling hearts 6 months post-MI.
LV and LA motion and contractility were improved by repeated monthly dosing of CDR132L in a large animal model of HF with reduced ejection fraction model with first dose given one month post-MI. The results highlight the translational value and usability of MRI-based cardiac strain imaging in HF drug development and support further clinical development of CDR132L.
心脏miR-132已被提议作为心力衰竭（HF）治疗的靶点。CDR132L是一种经合理设计的miR-132合成寡核苷酸抑制剂，已在非缺血性和缺血性大型动物HF模型中证明了临床前疗效。在一项1b期研究（NCT04045405）中对慢性HF患者进行了CDR132L的安全性和耐受性测试，目前正在对心肌梗死后HF患者进行2期试验（NCT05350969）。本研究的目的是通过在慢性HF的临床相关大型动物（猪）模型中，通过连续心脏磁共振（cMRI）应变成像分析左心室（LV）和心房（LA）壁运动，获得关于CDR132L心肌功能和疗效的进一步数据。
动物（每组15只）在心肌梗死后1个月随机分组，每月接受5次静脉注射（i.v.）CDR132L（5mg/kg）或安慰剂治疗，并在心肌梗死后随访6个月。随着时间的推移，心肌梗死后左心室和左心房应变参数恶化，但与安慰剂相比，CDR132L治疗显著改善。在心肌梗死后6个月的重塑心脏中，应变参数与诸如射血分数、NT-proBNP和心脏间质纤维化等药效学指标显著相关。
在射血分数降低的HF大型动物模型中，心肌梗死后1个月给予首剂，每月重复给药CDR132L可改善左心室和左心房的运动及收缩性。结果突出了基于MRI的心脏应变成像在HF药物开发中的转化价值和实用性，并支持CDR132L的进一步临床开发。
