2007 Fiscal Year Final Research Report Summary
Gene therapy of Hepatitis C using monkey by siRNA
| 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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| Keywords | RNA interference / siRNA / AAV / Tamarin / shRNA / marmoset / GBV-B / Vitamin E |
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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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Research Products
(51 results)
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[Journal Article] Inhibition of hepatitis C virus infection and expression in vivo by recombinant adenovirus expressing short hairpin RNA.2008
Author(s)
Sakamoto N, Tanabe Y, Yokota T, Saito K, Sekine-Osajima Y, Nakagawa M, Itsui Y, Tasaka M, Sakurai Y, Chen CH, Yano M, Ohkoshi S, Aoyagi Y, Maekawa S, Enomoto N, Kohara M, Watanabe M
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Journal Title
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Efficient regulation of viral replication by siRNA in a non - human primate surrogate model for hepatitis C.2007
Author(s)
Ybkota T, Iijima S, Kubodera T, Ishii K, Katakai Y, Ageyama N, Chen YW, Lee YJ, Unno T, Nishina K, Iwasaki Y, Maki N, Mizusawa H, Akari H
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Journal Title
Biochem Biophys Res Com 361
Pages: 294-300
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation.2007
Author(s)
Li Y, Yokota T, Gama V, Yoshida T, Gomez JA, Ishikawa K, Sasaguri H, Cohen HY, Sinclair D A, Mizusawa H, Matsuyama S
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Journal Title
Cell Death Differ 14
Pages: 2058-2067
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] GBV-B as a pleiotropic virus: distribution of GBV-B in extrahepatic tissues in vivo.2007
Author(s)
Ishii K, Iijima S, Kimura N, Lee YJ, Ageyama N Yagi S, Yamaguchi K, Maki N, Mori K, Yoshizaki S, Machida S, Suzuki T, Iwata N, Sata T, Terao K, Miyamura T, Akari H
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Journal Title
Microbes Infect. 9
Pages: 515-521
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Efficient regulation of viral replication by siRNA in a non-human primate surrogate model for hepatitis C.2007
Author(s)
Yokota T, lijima S, Kubodera T, Ishii K, Katakai Y, Ageyama N, Chen YW, Lee YJ, Unno T, Nishina K, Iwasaki Y. Maki N, Mizusawa H, Akari H
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Journal Title
Biochem Biophys Res Com 361
Pages: 294-300
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] GBV-B as a pleiotropic virus : distribution of GBV B in extrahepatic tissues in vivo2007
Author(s)
Ishii K, lijima S, Kimura N, Lee YJ, Ageyama N, Yagi S, Yamaguchi K, Maki N ; Mori K, Yoshizaki S. Machida S, Suzuki T, Iwvata N, Sata T, Terao K. Miyamura T, Akari H.
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Journal Title
Microbes Infect 9
Pages: 515-521
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Inhibition of hepatitis C virus infection and expression in vitro and in vivo by recombinant adenovi us expressing short hairpin RNA
Author(s)
Sakamoto N. Tanabe Y, Yokota T, Saito K, Sekine-Osajima Y, Nakagawa M, Itsui Y, Tasaka M, Sakurai Y Chen CH, Yano M, Ohkoshi S. Aoyagi Y, Maekawa S, Enomoto N, Kohara M, Watanabe M
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Journal Title
J Gastro Hepatol (in press)
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Liver toxicity induced by AAV-delivered short hairpin RNA.2007
Author(s)
Unno T, Kubodera T, Murayama S, Ohira S, Nishina K, Igari T, Eishi Y, Hirai Y, Shimada T, Yokota T, Mizusawa H
Organizer
第13回日本遺伝子治療学会
Place of Presentation
東京
Year and Date
2007-06-30
Description
「研究成果報告書概要(和文)」より
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