Development of a new molecular therapeutic drug for brain pathology in lysosomal storage diseases

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 14207106
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 応用薬理学・医療系薬学
• Research Institution: International University of Health and Welfare
• Principal Investigator: SUZUKI Yoshiyuki International University of Health and Welfare, School of Health Science, Professor, 保健学部, 教授 (90010389)
• 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
• Project Period (FY): 2002 – 2004
• Keywords: chemical chaperone therapy / β-galactosidase / G_<M1>-gangliosidosis / competitive inhibitor / genetically engineered mouse / N-octyl-4-epi-β-valianamine / lysosomal disease

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.

Research Products

• [Journal Article] ライソゾーム病に対するケミカルシャペロン療法 (2005)
  • Author(s): 鈴木義之
  • Journal Title: 小児科 45 Pages: 2313-2320
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease (2004)
  • Author(s): Lin H, Sugimoto Y, Ohsaki Y, Ninomiya H, Oka A, Taniguchi M, Ida H, Eto Y, Ogawa S, Matsuzaki Y, Sawa M, Inoue T, Higaki K, Nanba E, Ohno K, Suzuki Y
  • Journal Title: Biochim Biophys Acta 1689 Pages: 219-228
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Convenient synthesis and evaluation of glycosidase inhibitory activity of α- and β-galactose-type valienamines, and some N-alkyl derivatives (2004)
  • Author(s): Ogawa S, Sakata Y, Ito N, Watanabe M, Kabayama K, Itoh M, Korenaga T
  • Journal Title: Bioorg Med Chem 12 Pages: 995-1002
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Chromosomal mapping and zygosity check of transgene based on flanking genome sequences determined by genomic walking (2004)
  • Author(s): Noguchi A, Takekawa N, Einarsdottir T, Koura M, Noguchi Y, Takano K, Yamamoto Y, Matsuda J, Suzuki O
  • Journal Title: Exp Anim 53 Pages: 103-111
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease (2004)
  • Author(s): Lin H, Sugimoto Y, Ohsaki Y, Ninomiya H, Oka A, Taniguchi M, Ida H, Eto Y, Ogawa S, Matsuzaki Y, Sawa M, Inoue T, Higaki K, Nanba E, Ohno K, Suzuki Y
  • Journal Title: Biochem Biophys Acta 1689 Pages: 219-228
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Skeletal muscle FOXO1 (FKHR)-transgenic mice have less skeletal muscle mass, down-regulated type I (slow twitch/red muscle) fiber genes, and impaired glycemic control (2004)
  • Author(s): Kamei Y, Miura S, Suzuki M, Kai Y, Mizukami J, Taniguchi T, Mochida K, Hata T, Matsuda J, Aburatani H, Nishino I, Ezaki O
  • Journal Title: J Biol Chem 279 Pages: 41114-41123
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chromosomal mapping and zygosity check of transgenes based on flanking genome sequences determined by genomic walking. (2004)
  • Author(s): Noguchi A, Takekawa N, Einarsdottir T, Koura M, Noguchi Y, Takano K, Yamamoto Y, Matsuda J, Suzuki O
  • Journal Title: Exp Anim 53 Pages: 103-111
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and glycosidase inhibitory activity of some N-substituted 5a-carba-β-fuco-and β-galactopyranosylamines, and selected derivatives (2004)
  • Author(s): Ogawa S, Fujieda S, Sakata Y, Ishizaki M, Hisamatsu S, Okazaki K, Ooki Y, Mori M, Itoh M, Korenaga T
  • Journal Title: Bioorg Med Chem 12 Pages: 6569-6579
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of 5a-carbahexopyranoses and hexopyramosylamines, as well as 5a,5a'-dicarbadisaccharides, from 3,8-dioxatricyclo[4.2.1.0^<2,4>]nonan-9-ol : glycosidase inhibitory activity of N-substituted 5a-carba-□-gluco- and □-galactopyranosylamines, and derivative thereof (2004)
  • Author(s): Ogawa S, Funayama S, Okazaki K, Ishizuka F, Sakata Y, Doi F
  • Journal Title: Bioorg Med Chem 14 Pages: 5183-5188
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Design and synthesis of carba-sugars of biological interest (2004)
  • Author(s): Ogawa S
  • Journal Title: Trends Glycosci Glycotechnol 16 Pages: 33-53
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] υ^^--Galactosidase deficiency (υ^^--galactosidosis) : G_<M1>-Gangliosidosis and Morquio B disease (2004)
  • Author(s): Suzuki Y, Oshima A, Nanba E
  • Journal Title: The Metabolic and Molecular Bases of Inherited Disease, 8th ed, <http://genetics.accessmedicine.com/>(Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds))(McGraw-Hill, New York)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chemical chaperone therapy for brain pathology in G_<M1>-gangliosidosis (2003)
  • Author(s): Matsuda J, Suzuki O, Oshima A, Yamamoto Y, Noguchi A, Takimoto K, Itoh M, Matsuzaki Y, Yasuda Y, Ogawa S, Sakata Y, Nanba E, Higaki K, Ogawa Y, Tominaga L, Ohno K, Iwasaki H, Watanabe H, Brady RO, Suzuki Y
  • Journal Title: Proc Natl Acad Sci USA 100 Pages: 15912-15917
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Chemical chaperone therapy for brain pathology in G_<M1>-gangliosidosis (2003)
  • Author(s): Matsuda J, Suzuki O, Oshima A, Yamamoto Y, Noguchi A, Takimoto K, Itoh M, Matsuzaki Y, Yasuda Y, Ogawa S, Sakata Y, Nanba E, Higaki K, Ogawa Y, Tominaga L, Ohno K, Iwasaki H, Watanabe H Brady RO, Suzuki Y
  • Journal Title: Proc Natl Acad Sci USA 100 Pages: 15912-15917
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Attenuation of ganglioside G_<M1> accumulation in the brain of G_<M1> gangliosidosis mice by neonatal intravenous gene transfer (2003)
  • Author(s): Takaura N, Yagi T, Maeda M, Nanba E, Oshima A, Suzuki Y, Yamano T, Tanaka A
  • Journal Title: Gene Ther 10 Pages: 1487-1493
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulatory sequence elements of mouse GLUT4 gene expression in adipose tissues (2003)
  • Author(s): Miura S, Tsunoda N, Ikeda S, Kai Y, Ono M, Maruyama K, Takahashi M, Mochida K, Matsuda J, Lane MD, Ezaki O
  • Journal Title: Biochem Biophys Res Commun 312 Pages: 277-284
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antisense in vivo knockdown of synaptotagmin I and synapsin I by HVJ-liposome mediated gene transfer modulates ischemic injury of hippocampus in opposing ways (2003)
  • Author(s): Iwakuma M, Anzai T, Kobayashi S, Ogata M, Kaneda Y, Ohno K, Saji M
  • Journal Title: Neurosci Res 45 Pages: 285-296
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chemical modification of the β-glucocerebrosidase inhibitor N-octyl-β-valienamine : Synthesis and biological evaluation of 4-epimeric and 4-O-(β-D-galactopyranosyl) derivatives (2002)
  • Author(s): Ogawa S, Matsunaga YK, Suzuki Y
  • Journal Title: Bioorg Med Chem 10 Pages: 1967-1972
  • Description: 「研究成果報告書概要(和文)」より
• [Book] The Metabolic and Molecular Bases of Inherited Disease, 8th ed,<http://genetics.accessmedicine.com/>(Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds)) (2004)
  • Author(s): Suzuki Y, Oshima A, Nanba E
  • Publisher: McGraw-Hill, New York(Online version)
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 糖脂質代謝異常症治療剤 (2002)
  • Inventor(s): 鈴木 義之, 難波 栄二, 松田 潤一郎
  • Industrial Property Rights Holder: 生化学工業株式会社
  • Industrial Property Number: 特願2002-260534号
  • Filing Date: 2002-09-05
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] Carba-sugar amine derivatives and treatments for disorder of glycolipid metabolism containing the same as the active ingredient (2002)
  • Inventor(s): 小川 誠一郎, 鈴木 義之, 難波 栄二, 松田 潤一郎, 大野 耕策
  • Industrial Property Rights Holder: 生化学工業株式会社
  • Industrial Property Number: PCT/JP02/08882, 米国(10/793857), カナダ(2459887), オーストラリア(2002328402), ヨーロッパ(全加盟国)(02762961.7)
  • Filing Date: 2002-09-02
  • Description: 「研究成果報告書概要(和文)」より