Editors' ChoiceCARDIAC REGENERATION

A big shot of small RNAs repairs a broken heart

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Science Translational Medicine  25 Jan 2017:
Vol. 9, Issue 374, eaal4999
DOI: 10.1126/scitranslmed.aal4999

Abstract

Delivery of synthetic microRNAs directly to the damaged heart restores cardiac function and is a new therapeutic opportunity.

Advances in the diagnosis and treatment of ischemic cardiovascular disease have begun to bend the mortality curve, with more patients surviving a heart attack. The trade-off for this increase in acute survival is the growing number of patients that develop heart failure as a result of the ischemic insult to the myocardium. Chronic heart failure is an increasing problem on a global scale for which there are limited treatment options. Therapies that regenerate damaged cardiac muscle are highly sought after, but even the most promising stem cell delivery therapies show only modest improvements in heart function over time. In parallel, microRNAs have emerged as essential regulators of cardiac development, function, and repair, and have been targeted successfully in preclinical studies to repair damaged myocardium. Although RNA-based therapies that inhibit microRNA function have shown promising results in early trials in humans, microRNA replacement therapy has been hampered by the limited delivery options available.

To address these challenges, Lesizza et al. took advantage of two known proregenerative microRNAs and evaluated novel delivery methods to test their therapeutic potential. The authors first evaluated the toxicity and efficiency of microRNA delivery in vitro in cardiomyocytes using commercially available lipid-based transfection cocktails, selecting several for in vivo characterization. In addition to ensuring the efficient overexpression of microRNAs-199a-3p and -590-3p, the authors made the important observation that delivery of these synthetic microRNAs to cardiac tissue in mice resulted in down-regulation of their expected target genes, which confirmed that the proregenerative microRNAs functioned as expected in vivo. In a mouse model of myocardial infarction (MI), intracardiac delivery of either miR-199a-3p or miR-590-3p after MI significantly improved ventricular function and reduced the size of the damaged area within the myocardium.

Importantly, these benefits were seen after a single injection of the microRNA-lipid cocktail and persisted for up to 8 weeks, although the microRNA only remained in the tissue for a maximum of 12 days post-injection. This is a significant improvement over other microRNA delivery methods that use viruses or vectors that persist for weeks or months in host cells. Overall, this approach could be an important step toward harnessing the reparative power of microRNAs, bypassing the use of autologous stem cell therapy and its varying viability and regenerative capacity, and integrating the potential for improved safety and efficacy of therapies that aim to regenerate the damaged heart.

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