Citrate-saline formulated mRNA delivery into the heart muscle with an electromechanical mapping and injection catheter does not lead to therapeutic effects in a porcine chronic myocardial ischemia model.

Based on recent success in using modified RNA in clinical applications, we tested the safety, feasibility, and efficacy of the direct delivery of citrate-saline formulated mRNA into hibernating ischemic heart muscle using an electromechanical mapping and injection catheter system (NOGA/Myostar) in a porcine chronic myocardial ischemia model. Chronic ischemia was induced in domestic pigs (n=24) using a bottleneck stent placed in the left anterior descending coronary artery. Low (1mg) and high (7.5 mg) doses of buffer formulated citrate-saline formulated VEGF-A165 mRNA were administered in the study. lacZ mRNA and saline were used as controls. Ten intramyocardial injections (200 μl each) of the mRNAs or saline were given endovascularly into the hibernating ischemic myocardium using the NOGA catheter. Positron emission tomography (PET) 15O-radiowater imaging was performed 7 days after the induction of ischemia and 28 days after the mRNA delivery to measure quantitative myocardial blood perfusion. Coronary angiography, left ventricular function measurements, and clinical chemistry were obtained at each timepoint. Thirty-five days after the mRNA transfers pigs were sacrificed, and infarct size and general histology were analyzed. LacZ mRNA pigs were sacrificed 24h after the transduction. As a result, citrate-saline formulated mRNA delivery into the ischemic myocardium with endovascular injection catheter did not lead to meaningful transduction with the translation of VEGF-A, nor therapeutics effects in the heart. VEGF-A165 mRNA showed no statistically significant improvements in LVEF, CO, myocardial perfusion, infarct size, collateral growth or capillary area in the study groups. However, there was a trend in the high dose group towards an improved LVEF and CO at rest. No significant adverse effects were observed. In conclusion, Myostar injection catheter system is ineffective in delivering citrate-saline formulated mRNAs into the heart muscle in a porcine chronic myocardial ischemia model.