| Project/Area Number |
17390047
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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 |
Medical pharmacy
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| Research Institution | National Institute of Biomedical Innovation |
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Principal Investigator |
MIZUGUCHI Hiroyuki National Institute of Biomedical Innovation, National Institute of Biomedducal Innovation, Laboratory of Gene Transfer and Regulation, Project Leader (50311387)
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| Co-Investigator(Kenkyū-buntansha) |
KAWABATA Kenji National Institute of Biomedducal Innovation, Laboratory of Gene Transfer and Regulation, Senior Research Scientist (50356234)
SAKURAI Fuminori National Institute of Biomedducal Innovation, Laboratory of Gene Transfer and Regulation, Scientist (70370939)
TERAO Keiji National Institute of Biomedducal Innovation, Tsukuba Primates Research Center, 霊長類医科学研究センター, Scientist (30109920)
NAKAMURA Shin-ichiro Research Center of Animal Life Scince, Shiga University of Medical Science, 動物生命科学研究センター, Associate Professor (50307980)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥15,990,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2007: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2006: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2005: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | adenovirus vector / gene therapy / nonhuman primates / CD46 / 受容体 / サイトカイン |
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| Research Abstract |
Adenovirus(Ad) serotype 35(Ad35) vectors are promising gene delivery vehicles. However, the transduction profiles of Ad35 vectors in conventional mice allow a limited estimation of transduction properties of Ad35 vectors due to the restricted expression of the mouse analog of the subgroup B Ad receptor, CD46, in the testis. To properly assess the transduction properties of Ad35 vectors, we performed transduction experiments using cynomolgus monkeys, which ubiquitously express CD46 in a pattern similar to that in humans. In vitro transduction experiments demonstrated that cultured cynomolgus monkey cells were efficiently transduced with Ad35 vectors. By contrast, Ad35 vector-mediated transduction was hardly found in the all organs, although Ad35 vector genomes were detected in vanous organs following intravenous administration. Less severe histopathological abnormalities were found in the Ad35 vector-infused monkeys compared with the conventional Ad serotype 5(Ad5) vector-injected monke
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ys, in which serious tissue damages and inflammatory responses, such as hepatocyte necrosis and lymphatic hyperplasia in the colon, were induced. Both Ad35 and Ad5 vectors caused similar hematological changes(increase in CD3^+ cells, and decreases in CD16^+ cells and CD20^+ cells) in peripheral blood cells postinjection.
Furthermore, Ad35 vectors were locally injected into the organs. Ad35 vectors exhibited unique transduction patterns depending on the organs. Hepatocytes and microglia were mainly transduced with Ad35 vectors after injection into the liver and brain, respectively. Intramuscular injection of Ad35 vectors resulted in transduction of cells which appealed to be fibroblasts and macrophages. Conjunctival epithelial cells express transgene expression following infusion into the vitreous body of eyeball. In these organs, transgene expression was limited to areas around the injection points. Transgene expression was not found in the organs which did not receive Ad35 vector injection. These results suggest that Ad35 vectors would be a preferable gene delivery vehicle by direct administration in the organs. Less
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