| Project/Area Number |
14207106
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | International University of Health and Welfare |
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Principal Investigator |
SUZUKI Yoshiyuki International University of Health and Welfare, School of Health Science, Professor, 保健学部, 教授 (90010389)
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| Co-Investigator(Kenkyū-buntansha) |
KUROSAWA Mieko International University of Health and Welfare, School of Health Science, Professor, 保健学部, 教授 (30178131)
OHNO Kousaku Tottori University, School of Medicine, Professor, 医学部, 教授 (70112109)
NANBA Eiji Tottori University, Research Center for Bioscience and Technology, Professor, 生命機能研究支援センター, 教授 (40237631)
MATSUDA Junichiro National Institute of Infectious Diseases, Department of Veterinary Science, Division Head, 獣医科学部, 室長 (60181731)
IIDA Masami Seikagaku Corporation, Central Research Laboratories, Investigator, 中央研究所, 研究員
松崎 祐二 生化学工業株式会社, 中央研究所, 研究員
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥49,010,000 (Direct Cost: ¥37,700,000、Indirect Cost: ¥11,310,000)
Fiscal Year 2004: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2003: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2002: ¥22,490,000 (Direct Cost: ¥17,300,000、Indirect Cost: ¥5,190,000)
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| Keywords | chemical chaperone therapy / β-galactosidase / G_<M1>-gangliosidosis / competitive inhibitor / genetically engineered mouse / N-octyl-4-epi-β-valianamine / lysosomal disease / β-ガラクトシダーセ / GM1-ガングリオシドーシス |
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| Research Abstract |
We synthesized a novel galactose derivative, N-octyl-4-epi-β-valienamine(NOEV), for a new molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, β-galactosidosis (G_<M1>-gangliosidosis and Morquio B disease). It has a molecular structure analogous to galactose ; molecular weight is 287.40. It is stable at room temperature, and has limited solubility in water (up to 5 mM), but freely soluble in methanol or dimethylsulfoxide. It is a potent competitive inhibitor of lysosomal (β-galactosidase in vitro. IC50 is 0.2 μM. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. We collected 50 fibroblast strains from β-galactosidase deficiency disorders from all over the world, for testing the NOEV effect in the culture system. More than 3-fold increase was observed in 35% of them. The effect was most prominent in mutations causing juvenile G_<M1>-gangliosidosis, and less effective to those causing infantile or adult G_<M1>-gangliosidosis. So far Morquio B cells did not respond significantly in this assay system. We have established a method of NOEV determination in tissues and blood, and started mouse experiments by oral administration of this compound. Chemical chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
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