Chemical chaperone therapy for brain pathology in G <sub>M1</sub> -gangliosidosis

  • Junichiro Matsuda
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Osamu Suzuki
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Akihiro Oshima
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Yoshie Yamamoto
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Akira Noguchi
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Kazuhiro Takimoto
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Masayuki Itoh
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Yuji Matsuzaki
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Yosuke Yasuda
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Seiichiro Ogawa
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Yuko Sakata
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Eiji Nanba
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Katsumi Higaki
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Yoshimi Ogawa
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Lika Tominaga
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Kousaku Ohno
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Hiroyuki Iwasaki
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Hiroshi Watanabe
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Roscoe O. Brady
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...
  • Yoshiyuki Suzuki
    Department of Veterinary Science, and Division of Experimental Animal Research, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Central Research Laboratories, Seikagaku Corporation, 3-1253 Tateno, Higashi-Yamato, Tokyo 207-0021, Japan; Department of Biosciences...

抄録

<jats:p> We synthesized a galactose derivative, <jats:italic>N-</jats:italic> octyl-4-epi-β-valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, β-galactosidosis (G <jats:sub>M1</jats:sub> -gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal β-galactosidase <jats:italic>in vitro</jats:italic> . 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. Short-term oral administration of NOEV to a model mouse of juvenile G <jats:sub>M1</jats:sub> -gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of G <jats:sub>M1</jats:sub> and G <jats:sub>A1</jats:sub> in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass biochemical analysis did not show the substrate reduction observed histochemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement. </jats:p>

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