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

体内基因转移在心血管疾病病理生理学分析和治疗中的应用

• 批准号: 11470163
• 负责人: MORISHITA Ryuichi
• 金额: $ 9.34万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470163/
• 关键词: gene therapy; angiogenesis; ASO; HGF; CAP; endotlelial cells; ASO; 再狭; NFkB; 核酸医薬; E2F; 閉塞性動脈硬化症; 心筋梗塞

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

基因疗法正在成为治疗心血管疾病的潜在策略，例如外周动脉疾病，血管成形术后再狭窄，血管旁路肉体颗粒闭塞，移植冠状动脉血管疾病，心肌梗塞，尚无已知有效疗法。最近，据报道，使用VEGF（血管内皮生长因子）基因转移的治疗性血管生成的有效性在临界肢体缺血和心肌缺血的人类患者中已有报道。这是应考虑使用血管生长因子的热血管生成的策略，以治疗临界肢体缺血或心肌梗塞的患者。从这个角度来看，我们专注于一种新型的血管性生长因子HGF（肝细胞生长因子）。尽管HGF最初被鉴定为肝细胞的最潜在有丝分裂原，但我们发现HGF在兔后肢模型中的潜在血管基特性。根据以下内容，我们计划了使用肌内肌内的人类临床试验……更多地注射了裸体人类HGF质粒（0.5mg x 4）两次。当前，HGF基因转移在6例PAD（n = 3）或Buerger（n = 3）的患者中进行了HGF基因转移，而Fontaine III或IV分级失败了。在6例患者中有5例（功效率为83％），观察到疼痛量表的减少（视觉模拟量表> 1cm）。在5例患者中有5例（疗效率为100％）中观察到ABI的增加（踝关节压力指数）> 0.1，而由于强大的计算，从基因治疗前测量API。此外，在2例患者中有2例（疗效率为100％），TPI（脚趾压力指数）也增加了，而其他3例患者未能从缺血性溃疡引起的基因治疗前测量TPI。目前，尽管目前的数据仍然是初步的，但赤裸裸的HGF质粒DNA转移的初始临床结果似乎是有用的，可作为PAD的唯一治疗。此外，我们还提供了HGF在心肌中副作用形成中的潜在血管生成活性。根据这些发现，我们使用HGF提交了人类临床试验来治疗慢性心力衰竭。较少的

项目成果

Tomita N,Morishita R,Lan HY,Yamamoto K,Hashizume M,Notakae M,Toyosawa K.Fulitani B,Mu W,Nikolic-Paterson DJ,Atkins RC,Kaneda Y,Higaki J,Ogihara T.: "In vivo administration of a nlenr transcription factor-kappaB decoy suppresses experimental crescentic glo

Tomita N，Morishita R，Lan HY，Yamamoto K，Hashizume M，Notakae M，Toyosawa K.Fulitani B，Mu W，Nikolic-Paterson DJ，Atkins RC，Kaneda Y，Higaki J，Ogihara T.：“体内给药

Aoki M,Morishita R,Taniyama Y,Kida I,Moriguchi A,Matsumoto K,Nakamura T,Kaneda Y,Higaki J,Ogihara T.: "Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium : up-regulation of essential transcription factor

Aoki M，Morishita R，Taniyama Y，Kida I，Moriguchi A，Matsumoto K，Nakamura T，Kaneda Y，Higaki J，Ogihara T.：“肝细胞生长因子在非梗塞心肌和梗塞心肌中诱导血管生成：上调

Matsushita H,Morishita R,Aoki M,Tomita N,Taniyama Y,Nakagami H,Shimozato T,Higaki J,Kaneda Y,Ogihara T.: "Transfection of antisense p53 tumor suppressor gene oligodeoxynucleotides into rat carotid artery resulted in abnormal growth of vascular smooth musc

Matsushita H,Morishita R,Aoki M,Tomita N,Taniyama Y,Nakagami H,Shimozato T,Higaki J,Kaneda Y,Ogihara T.：“将反义 p53 肿瘤抑制基因寡脱氧核苷酸转染到大鼠颈动脉中导致血管异常生长

Taniyama Y, Morishita R, Hiraoka K, Aoki M, Nakagami H, Yamasaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model: molecular mechanisms of de

Taniyama Y、Morishita R、Hiraoka K、Aoki M、Nakagami H、Yamasaki K、Matsumoto K、Nakamura T、Kaneda Y、Ogihara T：“大鼠糖尿病后肢缺血模型中人肝细胞生长因子基因诱导的治疗性血管生成：分子机制

Taniyama Y, Tachibana K, Hiraoka K, Namba T, Yamasaki K, Hashiya N, Aoki M, Ogihara T, Yasufumi K, Morishita R: "Local delivery of plasmid DNA into rat carotid artery using ultrasound"Circulation. (in press). (2001)

Taniyama Y、Tachibana K、Hiraoka K、Namba T、Yamasaki K、Hashiya N、Aoki M、Ogihara T、Yasufumi K、Morishita R：“使用超声将质粒 DNA 局部递送至大鼠颈动脉”循环。