The study was published in Frontiers in Cardiovascular Medicine (doi:10.3389/fcvm.2021.592362) by an international group of scientists from Stanford University School of Medicine (USA), the University Medical Center Utrecht (The Netherlands) and Shanghai University (China).[1]

In their publication, Lei et al. investigate the molecular mechanisms of two microRNAs, miR-132 and miR-212, in modulating cardiomyocyte contractility, which is impaired in the pathological progression of heart failure. Using both hypertrophic heart failure mice models and human cardiac tissue, the researchers could show that an up-regulation of miR-132 in heart failure impairs cardiac contractile function by targeting SERCA2a. This important protein is involved in the regulation of calcium handling in the heart and in maintaining the regular heart contraction-relaxation cycles. Dysregulated calcium handling is assumed to play a central role in limited cardiac function. The results suggest that inhibition of miR-132 can be a promising therapeutic approach to improve cardiac function in heart failure patients.

The findings are supported by a previous publication of a team of scientists from the Cardiovascular Research Institute, National University of Singapore (Singapore), in Molecular Therapy in 2020 (doi:10.1016/j.ymthe.2020.04.006).[2] In this publication, the authors show that upregulation of both miR-132 and miR-212 in an in vivo transverse aortic constriction (TAC) mouse model leads to pathological hypertrophy – an effect that can be reversed by therapeutic miRNA antagonists.

"We are delighted about the growing body of evidence that miR-132 plays a crucial role in the development of heart failure," said Prof. Thomas Thum, CSO of Cardior Pharmaceuticals. "Our approach of blocking miR-132 and thereby halting the process of cardiac disease has now been validated by a number of independent research groups worldwide. In our own studies, we have shown that our lead compound CDR132L not only regulates SERCA2a, but a number of key targets in cardiac remodelling. Based on the recently reported promising Phase Ib data of CDR132L, we are committed to provide heart failure patients with a first-ever causal treatment approach in the next years."

Cardior expects to initiate a clinical Phase II trial with CDR132L later this year.

About CDR132L

CDR132L is an antisense oligonucleotide developed by Cardior Pharmaceuticals inhibiting the microRNA-132 (miR-132), a non-coding microRNA that regulates cardiac hypertrophy and remodeling in cardiomyocytes by targeting well-defined pathways.

miR-132 is a regulatory master switch to control cardiac function and a promising, causal therapeutic target in heart failure therapy. Expression of miR-132 is increased in various pathological cardiac conditions in both animals and humans, and previous preclinical studies have shown that miR-132 is essential for driving the pathological growth of cardiomyocytes.

In a randomized, double-blind, placebo-controlled, dose-escalating Phase Ib study CDR132L showed excellent safety and tolerability, linear dose-dependent pharmacokinetic (PK) and promising pharmacodynamic (PD) properties in heart failure (HF) patients on guideline directed medication. The study design combined dose escalation with repeat dosing (day 1 and 28) at 4 dose levels. 28 patients received CDR132L or placebo (5:2 randomized in 4 cohorts) via short-term (15 min.) intravenous infusions.

[1] Lei Z, Wahlquist C, el Azzouzi H, Deddens JC, Kuster D, van Mil A, Rojas-Munoz A, Huibers MM, Mercola M, de Weger R, Van der Velden J, Xiao J, Doevendans PA and Sluijter JPG (2021). miR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a. Front. Cardiovasc. Med. 8:592362. doi: 10.3389/fcvm.2021.592362

[2] Lavenniah A, Luu TDA, Li YP, Lim TB, Jiang J, Ackers-Johnson M, Foo RS (2020). Engineered Circular RNA Sponges Act as miRNA Inhibitors to Attenuate Pressure Overload-Induced Cardiac Hypertrophy. Mol Ther. Jun 3;28(6):1506-1517. doi: 10.1016/j.ymthe.2020.04.006.