Abstract 15057: miR-132 Inhibitor CDR 132L Attenuates Cardiac Remodeling by Exhibiting Anti-Fibrotic Effects

Abstract

Introduction: Increased cardiac expression levels of miRNA miR-132 have been associated with pathological cardiac remodeling including cardiac fibrosis. As a selective inhibitor for miR-132, the synthetic antisense oligonucleotide CDR132L, is capable to reverse cellular pathology and restore normal heart function. Pharmacological inhibition of miR-132 as well as genetic knockout has been shown to protect mice from transverse aortic constriction induced cardiac remodeling including interstitial fibrosis. Methods and Results: Treatment effects of CDR132L were investigated in several different pig models of ischemic and non-ischemic heart failure (HF) with the aim to further elucidate CDR132L’s mode of action and confirm species-independent effects on fibrotic remodeling. In a pig model of subacute post myocardial infarction (MI) induced HF, CDR132L was administered on day 3 and day 28 by intravenous (IV) or intracoronary (IC) infusion at doses of 1, 5 and 10 mg/kg and followed until day 56. In a chronic post-MI HF large animal model, beneficial effects were confirmed in a 6-month study comparing 5 monthly and 3 monthly repeated IV administrations of 5 mg/kg CDR132L starting one month post-MI. Further, CDR132L was tested in a porcine model of percutaneous aortic constriction by implantation of a reduction stent in the thoracic aorta and two IC injections of CDR132L on day 0 and day 28 followed for 56 days. As part of the pharmacodynamic analyses in these models, paraffin sections of cardiac tissue from the left ventricular remote region were stained with picrosirius red (PSR) and fibrosis was assessed based on collagen quantity. Analysis of fibrosis in PSR-staining revealed that the degree of interstitial fibrosis was significantly reduced in CDR132L treatment groups compared to placebo between 22% and 61%. Moreover, results of the first-in-human safety and tolerability study of CDR132L in patients with stable HF of ischemic origin (NCT04045405) showed encouraging positive trends for relevant cardiac fibrosis biomarkers. Conclusion: By blocking aberrant miR-132 expression, CDR132L is capable to halt and reverse pathological cardiac remodeling partly due to its anti-fibrotic effects.