Sasano Tetsuo, Kikuchi Kan, McDonald Amy D, Lai Shenghan, Donahue J Kevin
Heart and Vascular Research Center, MetroHealth Hospital, Case Western Reserve University School of Medicine, Cleveland, OH 44109, USA.
J Mol Cell Cardiol. 2007 May;42(5):954-61. doi: 10.1016/j.yjmcc.2007.02.004. Epub 2007 Feb 14.
Myocardial gene therapy continues to show promise as a tool for investigation and treatment of cardiac disease. Progress toward clinical approval has been slowed by limited in vivo delivery methods. We investigated the problem in a porcine model, with an objective of developing a method for high efficiency, homogeneous myocardial gene transfer that could be used in large mammals, and ultimately in humans. Eighty-one piglets underwent coronary catheterization for delivery of viral vectors into the left anterior descending artery and/or the great cardiac vein. The animals were followed for 5 or 28 days, and then transgene efficiency was quantified from histological samples. The baseline protocol included treatment with VEGF, nitroglycerin, and adenosine followed by adenovirus infusion into the LAD. Gene transfer efficiency varied with choice of viral vector, with use of VEGF, adenosine, or nitroglycerin, and with calcium concentration. The best results were obtained by manipulation of physical parameters. Simultaneous infusion of adenovirus through both left anterior descending artery and great cardiac vein resulted in gene transfer to 78+/-6% of myocytes in a larger target area. This method was well tolerated by the animals. We demonstrate targeted, homogeneous, high efficiency gene transfer using a method that should be transferable for eventual human usage.
心肌基因治疗作为一种用于研究和治疗心脏病的工具，仍展现出前景。体内递送方法有限减缓了临床批准的进程。我们在猪模型中研究了这一问题，目标是开发一种可用于大型哺乳动物并最终用于人类的高效、均匀的心肌基因转移方法。81只仔猪接受冠状动脉导管插入术，以便将病毒载体输送到左前降支动脉和/或大心静脉。对这些动物进行了5天或28天的跟踪，然后从组织学样本中对转基因效率进行量化。基线方案包括用血管内皮生长因子（VEGF）、硝酸甘油和腺苷进行治疗，随后将腺病毒注入左前降支。基因转移效率因病毒载体的选择、VEGF、腺苷或硝酸甘油的使用以及钙浓度而异。通过控制物理参数获得了最佳结果。同时通过左前降支动脉和大心静脉注入腺病毒，可使较大目标区域内78±6%的心肌细胞发生基因转移。该方法在动物中耐受性良好。我们展示了一种靶向、均匀、高效的基因转移方法，该方法最终应可转化用于人类。
