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 (Tmax 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<0.05 vs vehicle) and improvement (+6.6%, p<0.05) in left ventricular ejection fraction (LVEF) 8 days post-injection, respectively. To explore effects of bc-mRNA further out from the acute cardiac injury, Lanyu mini pigs underwent a permanent occlusion of the LAD coronary artery, and 7 days post MI, randomised to epicardial injection of vehicle or 1 or 10 mg bc-mRNA (n=8/group) and followed for 2 months. Serial assessments revealed a dose-dependent improvement (5.6%±2.3 and 7.2%±1.6% absolute difference vs pre-injection (43±1.4% and 43±0.7%), P<0.001) in LVEF and a significant reduction in infarct size and fibrosis vs vehicle. Invasive hemodynamic analysis showed a significant increase of inotropic function and maximal pressure development over time, preload recruitable stroke work and compliance in bc-mRNA-treated pigs.
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.
Author Disclosures: L. Carlsson: Employment; Significant; Employed by AstraZeneca. Ownership Interest; Significant; Stock owner AstraZeneca. C.Y. Yen: None. Y. Wang: None. R. Lin: None. A.H. Lo: None. C. Chen: None. J. Clarke: None. T. Albery: Employment; Significant; Employed by AstraZeneca. M. Antonsson: Employment; Significant; Employed by AstraZeneca. K. Jennbacken: Employment; Significant; Employed by AstraZeneca. E. Johansson: Employment; Significant; Employed by AstraZeneca. G. Linhardt: Employment; Significant; Employed by AstraZeneca. S. Martinsson: Employment; Significant; Employed by AstraZeneca. M. Palmér: Employment; Significant; Employed by AstraZeneca. K. Woods: Employment; Significant; Employed by AstraZeneca. K.R. Chien: Research Grant; Significant; Research grant from AstraZeneca. Ownership Interest; Significant; Moderna Therapeutics equity/founder. Consultant/Advisory Board; Significant; AstraZeneca consultancy & advisory, Moderna Therapeutics consultancy & advisory. P.C. Hsieh: Research Grant; Significant; AstraZeneca. Ownership Interest; Significant; Stock (spouse) ReVasgen Inc.. Consultant/Advisory Board; Significant; Consultancy ReVasgen Inc. R. Fritsche-Danielson: Employment; Significant; Employed by AstraZeneca.
- © 2016 by American Heart Association, Inc.