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Angiopoietin-1 gene therapy for acute myocardial infarction

血管生成素-1基因治疗急性心肌梗死

基本信息

批准号：
15590761
负责人：
ITO Yoshinori
金额：
$ 2.24万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590761/
关键词：
Gene Therapy Myocardial Infarction Ischemic Heart Disease Viral Vector Angiopoietin-1 VEGF 間葉系幹細胞

项目摘要

In acute myocardial infarction (AMI), prognosis and the mortality rate are closely related to the infarct size, and the progression of post-infarction cardiac failure. Angiogenic gene-therapy has presented a new approach for the treatment of AMI. Angiopoietin-1 (Ang1) is a critical angiogenic factor for vascular maturation and enhances vascular endothelial growth factor (VEGF)-induced angiogenesis in a complementary manner. We hypothesized that gene-therapy of Angl for AMI might promote angiogenesis cooperatively with intrinsic VEGF.To evaluate the therapeutic effects of Angi in AMI, we employed a rat AMI model, and adenoviral Angi gene transfer to the heart. A significant increase in capillary density, and reduction in infarct size were noted in the infarct hearts with adenoviral Angi gene treatment. Furthermore, Angl group showed significantly higher cardiac performance. The adenoviral delivery Angi during the acute phase of myocardial infarction would be feasible to attenuate the pr … More ogression of cardiac dysfunction in the rat model without unfavorable effects. However, adverse effects of adenoviral vector might be concern for clinical use of Angl gene therapy for AIVII. For this purpose, we evaluated naked plasmid injection and Sendai virus vector (SeVV) as an alternative gene delivery method of adenoviral vector. In our results, transgene expression mediated by naked CA promoter-based plasmid injection and SeVV were shown to be quite efficient in the heart. Similarly with adenoviral Angl gene therapy, Angi gene delivery for infarct heart utilizing SeVV or naked plasmid injection clearly promoted myocardial angiogenesis and reduced the infarct size resulting in the prevention of remodeling. Especially, SeVV'mediated Angi gene therapy demonstrated early recovery (within 3 days) of ischemic event. Furthermore transplantation of bone marrow mesenchymal stem cells (MSC) modified with Angl gene was more efficient for the recovery of ischemia in comparison with gene therapy or MSCs transplantation alone.Naked plasmid or Sendai virus vector encoding angiopoietin-1 gene would be safe and useful therapeutic option for acute myocardial infarction. Less

急性心肌梗死（AMI）的预后和死亡率与梗死面积、梗死后心力衰竭的进展密切相关。血管生成基因治疗为急性心肌梗死的治疗提供了新的途径。血管生成素-1（Ang 1）是血管成熟的关键血管生成因子，并以互补的方式增强血管内皮生长因子（VEGF）诱导的血管生成。我们假设Angi对AMI的基因治疗可能与内在的VEGF协同促进血管生成。为了评估Angi对AMI的治疗效果，我们采用大鼠AMI模型，并将腺病毒Angi基因转移到心脏。在用腺病毒Angi基因治疗的梗塞心脏中注意到毛细血管密度的显著增加和梗塞面积的减小。此外，Angl组显示出显著更高的心脏性能。在心肌梗死急性期应用腺病毒载体介导的Angi治疗可减轻心肌梗死后心肌细胞的凋亡， ...更多信息在大鼠模型中的心功能不全的进展，而没有不利的影响。然而，腺病毒载体的不良反应可能是临床应用Angl基因治疗AIVII的关注点。为此，我们评估裸质粒注射和仙台病毒载体（SeVV）作为腺病毒载体的替代基因递送方法。在我们的研究结果中，裸CA启动子为基础的质粒注射和SeVV介导的转基因表达被证明是相当有效的心脏。与腺病毒Angl基因治疗类似，利用SeVV或裸质粒注射的梗死心脏的Angi基因递送明显促进心肌血管生成并减少梗死面积，从而防止重塑。特别是，SeVV介导的Angi基因治疗显示缺血事件的早期恢复（3天内）。Angl基因修饰的骨髓间充质干细胞（MSCs）移植治疗急性心肌梗死的疗效优于单纯基因治疗或MSCs移植，Angl基因修饰的裸质粒或仙台病毒载体可能是治疗急性心肌梗死的安全有效的方法。少