Gene Therapy in the Cardiovascular Disease

心血管疾病的基因治疗

• 批准号: 09044299
• 负责人: OGIHARA Toshio
• 金额: $ 3.71万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044299/
• 关键词: gene therapy; HGF; decoy; restenosis; peripheral arterial disease; アンチセンス; ベクター

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.

近年来，基因治疗已成为心血管疾病治疗的热点。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，针对细胞增殖所必需的转录因子E2F的诱饵导致转染后长达8周的新生内膜形成的完全抑制。采用猪冠状动脉球囊损伤模型。使用水凝胶导管转染E2F诱饵ODN导致显著抑制新生内膜形成。目前，我们计划开展利用E2F诱饵基因治疗血管成形术后再狭窄的临床试验，或者，我们也关注利用人肝细胞生长因子（HGF）基因治疗血管新生的策略。转染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。因此，我们提供了直接的体内证据，HGF基因诱导血管生成在大鼠缺血后肢模型。基于这些发现，我们向大坂大学提交了使用HGE治疗外周动脉疾病的人类基因治疗临床方案。

项目成果

Morishita R,Aoki M,: "Kluwer Academic Publishers" Gene therapy for myocardial infarction., 531-550 (1998)

Morishita R，Aoki M，：“Kluwer 学术出版社”心肌梗塞的基因治疗。，531-550（1998）

Aoki M,Morishita R,Muraishi A,Moriguchi A,Sugimoto T,Maeda K,Dzau VJ,Kaneda Y,Higaki J,Ogihara T.: "Efficient in vivo gene transfer into heart in rat myocardial infarction model using HVJ (Henagglutinating Virus of Japan )-liposome method." J Mol Cell Car

Aoki M、Morishita R、Muraishi A、Moriguchi A、Sugimoto T、Maeda K、Dzau VJ、Kaneda Y、Higaki J、Ogihara T.：“使用 HVJ（Henagglutinating 病毒）将体内基因有效转移到大鼠心肌梗死模型的心脏中

Hayashi S,Morishita R,: "In vivo transfer of gene and oligodeoxynucleotides into skin of fetal rats by incubation in amniotic fluid" Gene Therapy. 3. 878-885 (1996)

Hayashi S，Morishita R，：“通过在羊水中孵育，将基因和寡脱氧核苷酸体内转移到胎鼠皮肤中”基因治疗。

Suzuki J: "Prevention of graft coronary arteriosclerosis by antisense cdk 2 kinase oligonucleotide." Nature Medicine. 3. 900-903 (1997)

Suzuki J：“通过反义 cdk 2 激酶寡核苷酸预防移植物冠状动脉硬化。”

Morishita R: "Role of AP-1 complex in angiotensin II-mediated transforming growth factor-β expression and growth of smooth muscles cells:using decoy approach against AP-1 binding site" Biochemical Biophysics Research Communication. (in press).

Morishita R：“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（正在出版）。