Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting.

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%-50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [ ¹⁵ O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool.
Competing Interests: Declaration of interests J.R., P.Z., A.R., P.G., C.W., M.N.P., R.F.-D., A.C., and L.-M.G. are employees and stockholders of AstraZeneca. V.A. has received a grant from AstraZeneca. A.S. has received consultancy or speaker fees from Abbott, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, and Pfizer. J.K. has received speaker fees from GE Healthcare, Merck, Lundbeck, Pfizer, Boehringer Ingelheim, and Bayer and consultancy fees from AstraZeneca and GE Healthcare. M.H. has received speaker fees from Siemens Healthcare and GE. K.-L.L. has received advisory fees from AstraZeneca. M.K. is a physician proctor and a member of the medical advisory board for JOMDD, a physician proctor for Peter Duschek, and has received speaker fees from Medtronic and Terumo. A.J. has received consultancy or speaker fees from AstraZeneca, Werfen, Boehringer Ingelheim, Portola, Baxter, and LFB. K.R.C. is an advisor and chair of the External Science Panel for AstraZeneca and a member of the Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Center in Huddinge and receives support for these services, as well as research support through the Karolinska Institutet Center, and is a cofounder and equity holder of Moderna, Inc.
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