| Project/Area Number |
18390215
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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 |
Gastroenterology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YOKOTA Takanori Tokyo Medical and Dental University, Department of Neurology and Neurological Science, Associate Professor (90231688)
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| Co-Investigator(Kenkyū-buntansha) |
AKARI Hirofumi National Institute of Biomedical Innovation, Tsukuba Primate Research Center, 研究リーダー (20294671)
ENOMOTO Nobuyuki Yamanashi University, First Department of Medicine, 教授 (20251530)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,750,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | RNA interference / siRNA / AAV / Tamarin / shRNA / marmoset / GBV-B / Vitamin E / 新世界ザル / カチオニックベクター / C型肝炎 / AAV8 / インターフェロン |
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| Research Abstract |
1) We succeeded in preventing induction of interferon after intravenous administration of siRNA/cationic liposome by chemical modifications including 2'O-methylation, phosphorothionate to siRNA oligonucleotides, resulting in increase the dose up to 20mg/kg. With this new siRNA with chemical modifications, GBV-B inoculated tamarins were treated. However, viral titres were not decreased, although transaminases tended to be decreased.
2)As a new siRNA vector, we use the vitamin E as a carrier molecule of siRNA in vivo which has -a physiological transport pathway to most of organs. The a-tocopherol was covalently bound to anti-sense strand of 27/29 mer siRNA at the 5' end (Toc-siRNA). The 27/29 mer Toc-siRNA was designed to be cleaved by Dicer in the cytosol and to produce 21/21 mer maturated siRNA after releasing a-tocopherol. The anti-oxidant activity of a-tocopherol in Toc-siRNA was abolished. With this new delivery strategy, systemic and intravenous injection of clinically relevant dose (2 mg/kg) of Toc-siRNA targeting apolipoprotein B(apoB) can reduce endogenous apoB mRNA in the liver by about 80%. The down-regulation of apoB was confirmed by the observation of lipid droplets accumulation in the liver as a phenotype. Neither induction of interferons nor other overt side effects were observed in biochemical and pathological analysis. These findings demonstrate the therapeutic potential of a-tocopherol-bound siRNAs for the treatment of disease.
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