MiR-132 inhibition improves myocardial strain in a large animal model of chronic left ventricular adverse remodelling.

Abstract

Aims: 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.

Methods and results: 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.

Conclusion: 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.