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

基因治疗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、血管旁路移植物闭塞、移植冠状动脉血管病变、心肌梗死，对于这些疾病还不存在已知的有效疗法。最近，已经报道了使用VEGF（血管内皮生长因子）基因转移的治疗性血管生成在患有严重肢体缺血和心肌缺血的人类患者中的功效。因此，使用血管生成生长因子的治疗性血管生成策略应被考虑用于治疗严重肢体缺血或心肌梗死患者。从这个角度出发，我们集中在一个新的血管生成因子，肝细胞生长因子（HGF）。虽然HGF最初被认为是肝细胞最有效的促有丝分裂原，但我们在兔后肢模型中发现了HGF的有效血管生成特性。因此，我们计划使用肌内注射法进行人体临床试验。 ...更多信息 y注射裸人HGF质粒（0.5mg × 4）两次。目前，在6例常规治疗失败的PAD（n = 3）或Buerger（n = 3）患者中进行了HGF基因转移，这些患者分级为方丹III或IV级。6例患者中5例疼痛减轻（视觉模拟评分> 1cm），有效率为83%。5例患者ABI（踝关节压力指数）增加> 0.1（有效率为100%），而1例患者由于严重钙化而未能从基因治疗前测量API。此外，2例患者的TPI（脚趾压力指数）也增加（有效率为100%），而另外3例患者由于缺血性溃疡而未能从基因治疗前测量TPI。目前，无法在所有患者中检测到严重不良反应。虽然目前的数据仍然是初步的，初步的临床结果与裸肝细胞生长因子质粒DNA转移似乎是有用的，作为唯一的治疗PAD。此外，我们证实了HGF在刺激心肌侧支形成中的强血管生成活性。基于这些发现，我们提交了使用HGF治疗慢性心力衰竭的人体临床试验。少

项目成果

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

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

Taniyama Y, Morishita R, Aoki M, Nakagami H, Yamamoto K, Yamazaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T: "Therapeutic anglogenesis Induced by human hepatocyte growth factor gene in rat and rabbit hind limb ischemfa models: preclinical study for

Taniyama Y、Morishita R、Aoki M、Nakagami H、Yamamoto K、Yamazaki K、Matsumoto K、Nakamura T、Kaneda Y、Ogihara T：“在大鼠和兔后肢缺血模型中由人肝细胞生长因子基因诱导的治疗性血管生成：临床前

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