Gene therapy for cardiovascular diseases : Development of newvector and evaluation of clinical strategy

心血管疾病的基因治疗：新载体的开发和临床策略的评估

• 批准号: 09357006
• 负责人: TOSHIO Ogihara
• 金额: $ 18.37万
• 依托单位: OSAKA University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09357006/
• 关键词: Gene therapy; HVJ-liposome method; vector; restenosis; atherosclerosis; NFkB; decoy oligonucleotides; 血管新生; HGF; 閉塞性動脈硬化症; 心筋梗塞; E2F; アンチセンス

To develop gene therapy for cardiovascular diseases, we focused on HVJ-liposome method as an efficient and safe gene delivery system. We reported that HVJ-liposome method has low cytotoxicity and is a suitable system for transfection of gene or oligonucleotides into vessels and hearts.We developed new strategies as treatments of cardiovascular diseases using this system. We showed the possibility of the therapy with gene modified grafted myocytes, and also reported that transfection of NFkB decoy oligonucleotides into hearts via coronary artery resulted in beneficial response to ischemic heart disease. Moreover, we reported the possibility of gene therapy for angiopathy after heart transplantation.For vessel diseases, we showed the effect of transfection of P21 gene, AP-1 decoy, prostacyclin gene, or NFkB decoy on restenosis after angioplasty, using HVJ-liposome method. Also we reported the usefulness of rybozyme against apolipoprotein (a) for atherosclerosis.Based on these results, we have already performed a clinical trial for restenosis after angioplasty using E2F decoy oligonucleotides, and now we are planning a new treatment for restenosis using NFkB decoy. To enhance the effects of these strategies, we are studying about the application of HVJ-liposome system now.

为了发展心血管疾病的基因治疗，我们将重点放在作为一种高效、安全的基因递送系统的HVJ-脂质体方法上。我们报道了HVJ-脂质体方法具有低的细胞毒性，是一种适合于将基因或寡核苷酸导入血管和心脏的系统，我们开发了利用该系统治疗心血管疾病的新策略。我们证明了用基因修饰的移植心肌细胞进行治疗的可能性，也报道了通过冠状动脉将NFkB诱骗寡核苷酸导入心脏可以对缺血性心脏病产生有益的反应。此外，我们还报道了基因治疗心脏移植后血管病变的可能性。对于血管疾病，我们使用HVJ-脂质体方法，展示了P21基因、AP-1诱骗物、前列环素基因或NFkB诱骗物对血管成形术后再狭窄的影响。基于这些结果，我们已经进行了使用E2F诱骗寡核苷酸治疗血管成形术后再狭窄的临床试验，现在我们正在计划使用NFkB诱骗治疗再狭窄的新方法。为了加强这些策略的效果，我们正在研究HVJ-脂质体系统的应用。

项目成果

Morishita R, Yamada S, Yamamoto K, Tomita N, Kida I, Sakurabayashi I, Kikuchi A, Kaneda Y, Lawn R, Higaki J, Ogihara T.: "Novel therapeutic strategy for atherosclerosis : ribozyme oligonucleotides against apolipoprotein (a) selectively inhibit apolipoprot

Morishita R、Yamada S、Yamamoto K、Tomita N、Kida I、Sakurabayashi I、Kikuchi A、Kaneda Y、Lawn R、Higaki J、Ogihara T.：“动脉粥样硬化的新治疗策略：针对载脂蛋白（a）的核酶寡核苷酸选择性抑制

Morishita R, Nishii T,: "Angiotensinogen gene activating elements regulate blood pressure in the brain"Circulation Research. 85. 257-263 (1999)

Morishita R，Nishii T，：“血管紧张素原基因激活元件调节大脑血压”循环研究。

Morishita R, Hayashi S,: "Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease : down-regulation of HGF in response to hypoxia in vascular cells"Circulasion. 100. II301-II308 (1999)

Morishita R，Hayashi S，：“肝细胞生长因子（一种新型血管生成生长因子）在外周动脉疾病中的潜在作用：血管细胞缺氧时 HGF 的下调”循环。

Morishita R,Ogihara T,: "Dzau VJ.Role of AP-1 complex in angiotensin II-mediated transforming growth factor-β expression and growth of smooth muscle cells : using decoy approach against AP-1 binding site."Biochemical Biophysics Research Communication. 43.

Morishita R，Ogihara T，：“Dzau VJ。AP-1 复合物在血管紧张素 II 介导的转化生长因子-β 表达和平滑肌细胞生长中的作用：使用针对 AP-1 结合位点的诱饵方法。”生化生物物理学研究通讯.43.

Aoki M, Morishita R, Higaki J, Moriguchi A, Hayashi S, Matsushita H, Kida I, Tomita N, Sawa Y, Kaneda Y, Ogihara T.: "Survival of grafts of genetically modified cardiac myocytes transfected with FITC-labeled oligodeoxynucleotides and β-galactosidase gene

Aoki M、Morishita R、Higaki J、Moriguchi A、Hayashi S、Matsushita H、Kida I、Tomita N、Sawa Y、Kaneda Y、Ogihara T.：“用 FITC 标记的寡脱氧核苷酸转染的转基因心肌细胞移植物的存活率和β-半乳糖苷酶基因