Modifying VEGF-A mRNA by combinatorial optimization to enhance therapeutic efficacy for myocardial infarction.

Vascular endothelial growth factor A (VEGF-A) is a highly specific endothelial cell mitogen that critically regulates angiogenesis and vascular network formation. While VEGF-A mRNA administration enables dose-dependent protein expression and therapeutic angiogenesis without genomic integration, unmodified mRNA suffers from rapid degradation and inherent immunogenicity, which substantially limits its therapeutic potential. In this study, we designed and synthesized a combinatorially optimized modified VEGF-A mRNA construct, designated Km10566, engineered to enhance translational efficiency and reduce immunogenicity through strategic incorporation of modified nucleosides. In vitro transcription (IVT) assays demonstrated that Km10566 yields substantially increased VEGF-A protein expression compared to unmodified counterparts. Following intracardiac administration in a rat model of myocardial infarction, a single dose of Km10566 formulated in citrate saline buffer significantly improved left ventricular ejection fraction (LVEF) and reduced myocardial fibrosis at 21 days post-treatment. Pharmacodynamic analysis confirmed sustained VEGF-A expression and enhanced vascularization in the ischemic myocardium. These findings establish Km10566 as a promising therapeutic candidate for cardiac repair and support its further evaluation in preclinical and clinical development.