2004 Fiscal Year Final Research Report Summary
Angiopoietin-1 gene therapy for acute myocardial infarction
| Project/Area Number |
15590761
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
ITO Yoshinori Sapporo Medical University, Medicine, Instructor, 医学部, 助手 (80332914)
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| Co-Investigator(Kenkyū-buntansha) |
MORIKAWA Masayuki SAPPORO MEDICAL UNIVERSITY, Medicine, Assistant Prof., 医学部, 助教授 (60264537)
HAMADA Hirofumi SAPPORO MEDICAL UNIVERSITY, Medicine, Professor, 医学部, 教授 (00189614)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Gene Therapy / Myocardial Infarction / Ischemic Heart Disease / Viral Vector / Angiopoietin-1 |
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| Research Abstract |
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
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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
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