Based on recent success in using modified RNA in clinical applications, we tested the safety, feasibility, and efficacy of direct delivery of citrate-saline-formulated mRNA into an 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 (1 mg) and high (7.5 mg) doses of citrate-saline-formulated vascular endothelial growth factor (VEGF)-A₁₆₅ mRNA were administered in the study. LacZ mRNA and citrate-saline buffer were used as controls. Ten intramyocardial injections (200 μL each) of the mRNAs or citrate-saline buffer were given endovascularly into the hibernating ischemic myocardium using the NOGA catheter. Positron emission tomography 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 time point. Thirty-five days after the mRNA transfers, pigs were sacrificed, and infarct size and general histology were analyzed. LacZ mRNA pigs were sacrificed 24 h after the transduction. Citrate-saline-formulated mRNA delivery into the ischemic myocardium with endovascular injection catheter did not lead to meaningful transduction with the translation of VEGF-A₁₆₅, nor therapeutic effects in the heart. VEGF-A₁₆₅ mRNA showed no statistically significant improvements in left ventricular ejection fraction (LVEF), cardiac output, myocardial perfusion, infarct size, collateral growth, or capillary area in the study groups. However, there was a trend in the high-dose group toward an improved LVEF and cardiac output at rest. No significant adverse effects were observed. In conclusion, the NOGA/Myostar injection catheter system is ineffective in delivering citrate-saline-formulated mRNAs into the heart muscle with the doses and methods used in a porcine chronic myocardial ischemia model.

中文翻译：

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在猪慢性心肌缺血模型中，使用机电映射和注射导管将柠檬酸盐-盐水配制的 mRNA 递送到心肌中不会产生治疗效果

基于最近在临床应用中使用修饰 RNA 的成功，我们测试了使用机电标测和注射导管系统 (NOGA/Myostar) 将柠檬酸盐-盐水配制的 mRNA 直接递送到冬眠缺血性心肌的安全性、可行性和有效性在猪慢性心肌缺血模型中。 使用放置在左冠状动脉前降支中的瓶颈支架在家猪 ( n = 24)中诱导慢性缺血。低剂量（1 毫克）和高剂量（7.5 毫克）柠檬酸盐配制的血管内皮生长因子 (VEGF)-A ₁₆₅在研究中施用了mRNA。LacZ mRNA 和柠檬酸盐缓冲液用作对照。使用 NOGA 导管将 10 次心肌内注射（每次 200 μL）mRNA 或柠檬酸盐-盐水缓冲液经血管内注射到冬眠的缺血心肌中。正电子发射断层扫描¹⁵在缺血诱导后 7 天和 mRNA 递送后 28 天进行 O-放射性水成像，以测量定量心肌血液灌注。在每个时间点获得冠状动脉造影、左心室功能测量和临床化学。mRNA 转移后 35 天，处死猪，分析梗塞面积和一般组织学。转导后 24 小时处死 LacZ mRNA 猪。用血管内注射导管将柠檬酸盐配制的 mRNA 递送到缺血心肌中并没有导致有意义的转导与 VEGF-A ₁₆₅的翻译，也没有在心脏中产生治疗效果。血管内皮生长因子-A ₁₆₅在研究组中，mRNA 在左心室射血分数 (LVEF)、心输出量、心肌灌注、梗死面积、侧枝生长或毛细血管面积方面没有显示出统计学上的显着改善。然而，高剂量组有改善静息时 LVEF 和心输出量的趋势。没有观察到明显的不良反应。总之，NOGA/Myostar 注射导管系统在用猪慢性心肌缺血模型中使用的剂量和方法将柠檬酸盐-盐水配制的 mRNA 输送到心肌中是无效的。