Azuma J, Taniyama Y, Takeya Y, Iekushi K, Aoki M, Dosaka N, Matsumoto K, Nakamura T, Ogihara T, Morishita R
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Gene Ther. 2006 Aug;13(16):1206-13. doi: 10.1038/sj.gt.3302740. Epub 2006 Apr 20.
Impairment of cardiac function in ischemic cardiomyopathy has been postulated to be due to the decrease in blood flow and increase in collagen synthesis. Therefore, an approach to alter them directly by means of a growth factor may open up a new therapeutic concept in ischemic cardiomyopathy. From this viewpoint, hepatocyte growth factor (HGF) is a unique growth factor with angiogenic and antifibrotic effects. Thus, we examined the feasibility of gene therapy using HGF plasmid DNA for ischemic cardiomyopathy. Human HGF plasmid DNA at a dose of 0.4 or 4 mg was injected into ischemic myocardium of pigs induced by ameroid constrictor with the NOGA system. At 1 month after injection, the ischemic area was significantly reduced in the HGF group, accompanied by a significant increase in capillary density and regional myocardial perfusion in the ischemic area (P<0.01). In contrast, a significant decrease in fibrotic area was observed in the HGF group, associated with a significant decrease in collagen I, III and TGF-beta synthesis as compared to the control group (P<0.01). Consistently, cardiac function was significantly improved in the 4 mg HGF group as compared to the control group (P<0.05). Overall, the present in vivo experiments demonstrated that intramyocardial injection of human HGF plasmid DNA in ischemic cardiomyopathy resulted in a significant improvement in cardiac function through an increase in blood flow and decrease in fibrosis. These favorable outcomes suggest potential utility to treat patients with ischemic heart disease using HGF gene transfer. Currently, a phase I study using human HGF plasmid DNA is ongoing to test the validity of this concept.
缺血性心肌病中心脏功能受损被认为是由于血流减少和胶原蛋白合成增加所致。因此，通过生长因子直接改变这些因素的方法可能为缺血性心肌病开辟新的治疗理念。从这个角度来看，肝细胞生长因子（HGF）是一种具有血管生成和抗纤维化作用的独特生长因子。因此，我们研究了使用HGF质粒DNA对缺血性心肌病进行基因治疗的可行性。采用NOGA系统将剂量为0.4或4mg的人HGF质粒DNA注入由阿梅里德缩窄器诱导的猪缺血心肌中。注射后1个月，HGF组的缺血面积显著减小，同时缺血区域的毛细血管密度和局部心肌灌注显著增加（P<0.01）。相比之下，HGF组的纤维化面积显著减小，与对照组相比，I型、III型胶原蛋白和转化生长因子-β的合成显著减少（P<0.01）。同样，与对照组相比，4mg HGF组的心脏功能显著改善（P<0.05）。总体而言，目前的体内实验表明，在缺血性心肌病中，心肌内注射人HGF质粒DNA可通过增加血流和减少纤维化显著改善心脏功能。这些良好结果提示使用HGF基因转移治疗缺血性心脏病患者具有潜在的应用价值。目前，一项使用人HGF质粒DNA的I期研究正在进行，以验证这一概念的有效性。
