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M3RNA Drives Targeted Gene Delivery in Acute Myocardial Infarction

Myocardial infarction occurs every 36 s or nearly 1 million times in the United States. The treatment of acute myocardial infarction (AMI) has been revolutionized with coronary reperfusion ensuring over 96% in-hospital survival. There has, however, been a paucity in technological advancement in the...

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Bibliographic Details
Published in:Tissue engineering. Part A 2019-01, Vol.25 (1-2), p.145-158
Main Authors: Singh, Raman Deep, Hillestad, Matthew L., Livia, Christopher, Li, Mark, Alekseev, Alexey E., Witt, Tyra A., Stalboerger, Paul G., Yamada, Satsuki, Terzic, Andre, Behfar, Atta
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Language:English
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Summary:Myocardial infarction occurs every 36 s or nearly 1 million times in the United States. The treatment of acute myocardial infarction (AMI) has been revolutionized with coronary reperfusion ensuring over 96% in-hospital survival. There has, however, been a paucity in technological advancement in the field of acute coronary syndrome, with nearly 30% of individuals progressing toward heart failure after AMI. This has engendered a pandemic of ischemic heart failure worldwide, mandating the development of off-the-shelf regenerative interventions, including gene-encoded therapies, capable to acutely target the injured myocardium. However, the main challenge in realizing gene-encoded therapy for AMI has been the inadequate induction of gene expression following intracoronary delivery. To address this challenge, we, in this study, report the use of synthetic modified messenger RNA, engineered to reduce lag time. Termed M 3 RNA (microencapsulated modified messenger RNA), this platform achieved expeditious induction of protein expression in cell lines (HEK293, human dermal and cardiac fibroblasts) and primary cardiomyocytes. Expression was documented as early as 2–4 h and lasted up to 7 days without impact on electromechanical coupling, as tracked by patch clamp electrophysiology and calcium imaging in transfected cardiomyocytes. In vivo , firefly luciferase (FLuc) and mCherry M 3 RNA myocardial injections in mice using ∼100 nm nanoparticles yielded targeted and temporally restricted expression of FLuc protein within 2 h, and sustained for 72 h as assessed by Xenogen and mCherry expression using immunofluorescence. In a porcine model of myocardial infarction, protein expression targeted to the area of injury was demonstrated following intracoronary delivery of alginate carrying M 3 RNA encoding mCherry. M 3 RNA thus enables rapid protein expression in primary cardiomyocytes and targeted expression in mouse and porcine hearts. This novel technology, capable of inducing rapid simultaneous protein expression, offers a platform to achieve targeted gene-based therapies in the setting of AMI.
ISSN:1937-3341
1937-335X
DOI:10.1089/ten.tea.2017.0445