Modifying VEGF-A mRNA by Combinatorial Optimization to Enhance Therapeutic Efficacy for Myocardial Infarction

Vascular Endothelial Growth Factor A (VEGF-A) is a mitogen with high endothelial cell specificity, playing a key regulatory role in angiogenesis and vasculature formation. Administration of VEGF-A mRNA can facilitate dose-dependent protein expression, promoting therapeutic angiogenesis without genome modification. However, unmodified VEGF-A mRNA is susceptible to degradation and induces immunogenicity, limiting its efficacy. In this study, we designed and synthesized a carefully modified VEGF-A mRNA construct, designated Km10566, which exhibits enhanced VEGF-A protein expression during in vitro transcription (IVT). Intracardiac injection of Km10566, formulated in a biocompatible citrate saline solution, into a rat model of myocardial infarction resulted in significant improvement in left ventricular ejection fraction (LVEF) and reduced myocardial fibrosis after 21 days. A pharmacodynamic analysis further supports Km10566 as a promising therapeutic candidate, highlighting its potential for further application in preclinical and clinical research.