Gene Therapy in the Cardiovascular Disease

近年来，基因治疗已成为心血管疾病治疗领域的研究热点。血管成形术后再狭窄是基因治疗的主要靶点之一。为了实现对新生内膜形成的完全抑制，我们已经确定了细胞周期调节蛋白作为靶点。应用诱骗策略调控疾病相关基因的转录具有重要的治疗潜力。因此，针对转录因子E2F的诱骗对细胞增殖至关重要，导致在转染后8周完全抑制新生内膜的形成。我们还采用了猪冠状动脉球囊损伤模型。经水凝胶导管转染人E2F诱骗ODN后，可明显抑制新生内膜的形成。目前，我们计划开始使用E2F诱骗基因治疗血管成形术后再狭窄的人类基因治疗试验。另外，我们还重点研究了利用人肝细胞生长因子(HGF)基因治疗血管生成的策略。转导HGF基因的大鼠后肢血管数明显增多。增加，伴随着血流量的显著增加。为HGF基因诱导大鼠后肢缺血模型血管生成提供了直接的体内证据。基于这些发现，我们向大阪大学提交了使用HGE治疗外周动脉疾病的人类基因治疗的临床方案。

Recently, gene therapy has been center of interests in the treatment of cardiovascular disease. One of major targets for gene therapy is restenosis after angioplasty. To achieve the complete inhibition of neointimal formation, we have identified cell cycle regulatory proteins as a target. Application of decoy strategy to regulate the transcription of disease-related genes has important therapeutic potentials. Thus, decoy against transcription factor E2F that is essential for cell proliferation resulted in the complete inhibition of neointimal formation up to 8 weeks after transfection. We also employed porcine coronary artery balloon injury model. Transfection of E2F decoy ODN using hydrogel catheter resulted in a significant inhibition of neointimal formation. Currently, we plan to start human gene therapy trial using E2F decoy to treat restenosis after angioplasty.Alternatively, we also focused on the therapeutic angiogenesis strategy using human hepatocyte growth factor (HGF) gene. Number of vessels in rat hindlimb transfected with HGF gene was significantly. increased, accompanied by a significant increase in blood flow. Thus, we provided direct in vivo evidence for angiogenesis induced by HGF gene in rat ischemic hindlimb model. Based upon these findings, we submitted the clinical protocol of human gene therapy using HGE to treat peripheral arterial disease to Osaka University.