| Project/Area Number |
16390418
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | National Institute of Neuroscience, National Center of Neurology and Psychiatry (2006)
Jichi Medical University (2004-2005) |
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Principal Investigator |
OKADA Takashi National Institute of Neuroscience, National Center of Neurology and Psychiatry, Section Chief, 神経研究所 遺伝子疾患治療研究部, 室長 (00326828)
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| Co-Investigator(Kenkyū-buntansha) |
OZAWA Keiya Jichi Medical University, Department of Medicine, Professor, 医学部内科講座, 教授 (30137707)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2006: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2005: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2004: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | gene / virus / neuronal diseases / biotechnology / 遺伝子治療 / ウイルスベクター / アデノ随判ウイルス / 脳腫瘍 / 脳血管障害 / 動脈硬化症 / IL-10 |
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| Research Abstract |
The adeno-associated virus (AAV) vector is a potentially useful gene transfer vehicle for neurologic gene therapies. The development of novel therapeutic strategies for neurological disorder by using the AAV vector has an increasing impact on gene therapy research. We have developed the production system of the AAV vector and evaluated the utility with various disease models.
1. We developed a large-scale method to produce vectors with an active gassing system that uses large culture vessels to process labor-and cost-effective infection or transfection in a closed system.
2. Interleukin-10 is an anti-inflammatory cytokine that may modulate the atherosclerotic disease process. Intramuscular injection of AAV5-mIL10 into ApoE-deficient mice inhibited atherogenesis through anti-inflammatory and cholesterol-lowering effects.
3. Neuropathological abnormalities associated with Huntington disease, such as insoluble protein accumulation and down-regulation of DARPP-32 expression, were successfully ameliorated in mice by the rAAV-mediated RNAi transduction.
4. The use of HDAC inhibitor should enhance the utility of rAAV-mediated transduction strategies for cancer gene therapy. The superior transduction was related to the proposed histone-associated chromatin form of the rAAV concatemer in transduced cells. In the analysis with subcutaneous tumor models, improved transgene expression as well as therapeutic effect was confirmed in vivo.
5. We developed genetically-modified mesenchymal stem cells that produce progeny vectors encoding HSV-tk, aiming at further augmenting therapeutic efficacy of systemic suicide cancer gene therapy. The tumor tropism and anti-tumor effects of vector-producing MSCs were confirmed by intravascular injection in tumor-bearing nude mice.
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