Biocompatible, Purified VEGF-A mRNA Improves Cardiac Function after Intracardiac Injection 1 Week Post-myocardial Infarction in Swine

• Main Authors: Leif Carlsson, Jonathan C. Clarke, Christopher Yen, Francine Gregoire, Tamsin Albery, Martin Billger, Ann-Charlotte Egnell, Li-Ming Gan, Karin Jennbacken, Edvin Johansson, Gunilla Linhardt, Sofia Martinsson, Muhammad Waqas Sadiq, Nevin Witman, Qing-Dong Wang, Chien-Hsi Chen, Yu-Ping Wang, Susan Lin, Barry Ticho, Patrick C.H. Hsieh, Kenneth R. Chien, Regina Fritsche-Danielson
• Format: Article
• Language: English
• Published: Elsevier 2018-06-01
• Series: Molecular Therapy: Methods & Clinical Development
• Online Access: http://www.sciencedirect.com/science/article/pii/S232905011830041X

mRNA can direct dose-dependent protein expression in cardiac muscle without genome integration, but to date has not been shown to improve cardiac function in a safe, clinically applicable way. Herein, we report that a purified and optimized mRNA in a biocompatible citrate-saline formulation is tissue specific, long acting, and does not stimulate an immune response. In small- and large-animal, permanent occlusion myocardial infarction models, VEGF-A 165 mRNA improves systolic ventricular function and limits myocardial damage. Following a single administration a week post-infarction in mini pigs, left ventricular ejection fraction, inotropy, and ventricular compliance improved, border zone arteriolar and capillary density increased, and myocardial fibrosis decreased at 2 months post-treatment. Purified VEGF-A mRNA establishes the feasibility of improving cardiac function in the sub-acute therapeutic window and may represent a new class of therapies for ischemic injury. Keywords: modRNA, mRNA, mRNA, VEGF, heart failure