Abstract 15533: A Biocompatible Chemically Modified mRNA Drives Sustained VEGF-A Protein Production, Human Endothelial Angiogenesis and Epicardial Progenitor Expansion, and Reduces Infarct Size and Partially Reverses Global Cardiac Dysfunction When Intracardially Injected One Week Post-Myocardial Infarction in the Pig

Introduction: Synthetic chemically modified RNA (mRNA) is a potential cardiac therapeutic platform, but requires lipid carriers for efficient in vivo transfection. Herein, we report a biocompatible VEGF-A mRNA (bc-mRNA), that drives the cardiac specific, efficient, and sustained production of functionally active VEGF-A protein, and in a pig model decreases scarring and partially reverses global cardiac function, even 1 week post-myocardial infarction (MI). Methods and Results: Transfection of VEGF-A mRNA in human cells drives robust VEGF-A protein production over 32h, (peak 8h) which is fully functional, i.e., phosphorylation of the VEGFR2/Akt/e-NOS, human endothelial cell angiogenesis, and expansion of human epicardial progenitors. Intracardiac injection of bc-mRNA in vivo caused a rapid (T max 3-6h) and sustained (8 days) production of VEGF-A in mouse, rat and pig. A single intracardiac injection of bc-mRNA (150 or 1800 μg, n=19) during acute MI in rats revealed cardiac protection, with significant reduction in cardiac troponin I day 1 (4.1±0.58 vs 6.7±0.91 ng/mL, P Conclusions: At one week post MI, a single injection of biocompatible VEGF-A mRNA drives sustained, functional protein levels, and markedly improves cardiac function in a clinically relevant large animal model, suggesting feasibility of partially reversing cardiac dysfunction in patients post MI.