Application of In vivo Gene Transfer for the Analysis of Pathophysiology and Treatment in the Cardiovascular Disease

基因治疗正在成为一种潜在的治疗心血管疾病的策略，如外周动脉疾病、血管成形术后再狭窄、血管旁路移植闭塞、移植冠状动脉病变、心肌梗死等，但目前尚无有效的治疗方法。最近，血管内皮生长因子(VEGF)基因转移治疗严重肢体缺血和心肌缺血的疗效已有报道。因此，在治疗严重肢体缺血或心肌梗死患者时，应考虑使用血管生成因子进行治疗性血管生成的策略。从这一观点出发，我们重点研究了一种新的血管生成生长因子--肝细胞生长因子。虽然HGF最初被认为是一种最有效的肝细胞有丝分裂原，但我们在兔后肢模型中发现了HGF强大的血管生成特性。因此，我们计划使用肌肉内…进行人体临床试验。注射裸质粒(0.5 mg×4)2次以上。目前，常规治疗失败的6例PAD(n=3)或Buerger(n=3)Fontaine III或IV级患者接受了HGF基因转移。6例患者中有5例疼痛评分下降(视觉模拟评分为1 cm)，有效率为83%。5名患者中有5名患者的踝部压力指数(ABI)和GT；0.1升高(有效率为100%)，而1名患者由于强烈的钙化而未能测量到基因治疗前的API。此外，2例患者的足趾压力指数(TPI)也升高(有效率为100%)，另外3例患者因缺血性溃疡而未能检测到基因治疗前的TPI。目前，无法在所有患者中检测到严重的不良反应。尽管目前的数据仍然是初步的，但裸质粒HGF DNA转移的初步临床结果似乎是PAD的唯一治疗方法。此外，我们还证实了HGF在刺激心肌侧支循环形成方面具有很强的血管生成活性。基于这些发现，我们提交了使用HGF治疗慢性心力衰竭的临床试验。较少

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease such as peripheral arterial disease, restenosis after angioplasty, vascular bypass graft occlusion, transplant coronary vasculopathy, myocardial infarction, for which no known effective therapy exists. Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia and myocardial ischemia. Thus, the strategy for therapeutic angiogenesis using angipgenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. From this viewpoint, we focused on a novel angiogenic growth factor, HGF (hepatocyte growth factor). Although HGF is originally identified as a most potent mitogen for hepatocytes, we found the potent angiogenic property of HGF in rabbit hindlimb model. Accordingly, we planed human clinical trial using intramuscularl … More y injection of naked human HGF plasmid (0.5mg x 4) two times. Currently, HGF gene transfer was performed in 6 patients with PAD (n=3) or Buerger (n=3) graded by Fontaine III or IV who had failed conventional therapy. Reduction of pain scale (>1cm in visual analog scale) was observed in 5 of 6 patients (efficacy rate is 83%). Increase in ABI (Ankle Pressure Index) >0.1 was observed in 5 of 5 patients (efficacy rate is 100%), while 1 patients failed to measure API from before gene therapy due to strong calcification. In addition, TPI (Toe pressure Index) was also Increased in 2 of 2 patients (efficacy rate is 100%), whereas other 3 patients failed to measure TPI from before gene therapy due to ischemic ulcer. Currently, severe adverse effects could not be detected in all patients. Although the present data are still preliminary, the initial clinical outcome with naked HGF plasmid DNA transfer seems to be useful as sole therapy for PAD. In addition, we proved the potent angiogenic activity of HGF in the stimulation of collateral formation in myocardium. Based upon these findings, we submitted human clinical trial using HGF to treat chronic heart failure. Less