Synthetic MicroRNAs Stimulate Cardiac Repair.

MicroRNAs (miRNA) are short noncoding doublestranded RNAs that were found in several life forms, such as viruses, plants, animals, and humans. Their main function is to regulate gene translation by post-transcriptional binding of the RNA and prevent ribosomal translation (RNA silencing). miRNAs are important for the regulation of many biological processes in our body, including organ development, maintaining stable, and steady-state function of tissues during adulthood and after injury or disease. Although several miRNAs were found to be beneficial for cardiac regeneration, miRNAs are currently not in clinical use. In 2012, Dr. Mauro Giacca Laboratory showed that human miRNAs can induce neonatal cardiomyocyte proliferation. They identified 40 miRNAs that significantly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. They then selected two of these miRNAs (hsa-miR-590 and hsa-miR-199a) and showed their ability to promote adult cardiomyocytes cell cycle re-entry in vivo. In addition, they showed that in a mouse myocardial infarction (MI) model, delivery of adeno-associated vectors (AAV) encoding hsamiR-590 or hsa-miR-199a induced cardiac regeneration with almost complete recovery of cardiac functional parameters. Although viral-derived vectors such as AAV could be efficient tools to increase miRNAs expression, they have certain limitations that can hamper their use in inducing cardiomyocytes proliferation. The long-term expression using AAV vectors may lead to uncontrolled proliferation of the transfected cells increased cardiomyocytes size and cardiac hypertrophy. A recent report from the same laboratory, by Lesizza et al in Circulation Research, circumvented this problem by using synthetic miRNAs (single-stranded RNAs) in the heart after MI. In their work, they focus on the two key candidate miRNAs mimic (hsa-miR-590-3p and hsa-miR-199a-3p) that show ability to induce cardiomyocytes proliferation and cardiac regeneration when were delivered in AAV9 vector (Figure). In this study, they identify lipid vehicle (RNAiMAX) as the optimal delivery vehicle for delivery of synthetic miRNAs mimic in vitro and in vivo. Pharmacokinetic analysis of the synthetic miRNAs mimic shows activity for ≈12 days with most of the activity disappearing by day 20. In a murine MI model, single synthetic miRNAs mimic administration (hsa-miR-590-3p or hsa-miR-199a-3p) in lipid vehicle resulted in improved cardiac function (increase significantly % Ejection Fraction and % Fractional Shortening) and a significant decrease in scar size and an increase in cardiac wall thickness 8 weeks post-MI. This improvement in cardiac function post-MI was also accompanied by significant increase in survival compared with control miRs (cel-miR-67) post-MI. In addition, Lesizza et al were able to confirm that hsa-miR-590-3p or hsa-miR-199a3p increase adult cardiomyocytes proliferation and reduce apoptosis 12 or 2 days post-MI, respectively.