Basic research for clinical treatment of neuropathic Gaucher disease by chemical chhaperones

• Project/Area Number: 20390297
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tottori University
• Principal Investigator: OHNO Kousaku Tottori University, 医学部, 教授 (70112109)
• Co-Investigator(Renkei-kenkyūsha): SUGIURA Titose 鳥取大学, 医学部・附属病院, 講師 (90325027) ; INOUE Takehiko 鳥取大学, 医学部・附属病院, 助教 (80346361)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2010: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2009: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: ゴーシェ病 / シャペロン / 経口治療薬 / モデルマウス / リソゾーム

Research Abstract

There are no effective treatment for neurological manifestations in Gaucher disease. We found N-octyl-β-valienamine (NOV) could increase the protein level and enzyme activity of F213I mutant GBA in culture cells. We have tried to establish a model mouse expressing F213I protein, but failed to establish the mice. The NOV effects on normal mice were evaluated. No adverse effect was observed and GBA activity increased with increasing NOV dose in tissues. We also found new compounds, bicyclic nojirimycin analogues, show a chemical chaperone activity on mutant GBAs.

Research Products

• [Journal Article] Chemical chaperone therapy : chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency. (2011)
  • Author(s): Higaki K, Li L, Udin Bahrudin, Okuzawa S, Takamura A, Yamamoto K, Adachi K, Rubigilda C. Paraguison, Takai T, Ikehata H, Tominaga L, Hisatome I, Iida M, Ogawa S, Matsuda J, Ninomiya H, Sakakibara Y, Ohno K, Suzuki Y, Nanba E.
  • Journal Title: Human Mutation. in press
  • Peer Reviewed
• [Journal Article] The effect of N-octyl-β-valienamine on β-glucosidase activity in tissues of normal mice. (2010)
  • Author(s): Luan Z, Ninomiya H, Ohno K, Ogawa S, Kubo T, Iida M, Suzuki Y.
  • Journal Title: Brain Dev 32(10) Pages: 805-809
  • NAID: 10029559648
  • Peer Reviewed
• [Journal Article] A fluorescent SP2-iminosugar with pharmacological chaperone activity for Gaucher disease : Cellular uptake and intracellular distribution studies. (2010)
  • Author(s): Luan Z, Higaki K, Aguilar-Moncayo M, Li L, Ninomiya H, Nanba E, Ohno K, Garcia-Moreno M, Mellet CO, Fernandez JMG, Suzuki Y.
  • Journal Title: ChemBioChem 11(17) Pages: 2453-2464
  • Peer Reviewed
• [Journal Article] Chemical chaperone therapy : Luciferase assay for screening of b-galactosidase mutations. (2010)
  • Author(s): Li L, Higaki K, Ninomiya H, Luan Z, Iida M, Ogawa S, Suzuki Y, Nanba E, Ohno K.
  • Journal Title: Mol Genet Metab 101(4) Pages: 364-369
  • Peer Reviewed
• [Journal Article] The pharmacological chaperone effect of N-octyl-beta-valienamine on human mutant acid beta-glucosidases. (2010)
  • Author(s): Luan Z, Li L, Ninomiya H, Ohno K, Ogawa S, Kubo T, Iida M, Suzuki Y.
  • Journal Title: Blood Cells Mot Dis. 44(1) Pages: 48-54
  • Peer Reviewed
• [Journal Article] ライソゾーム病の治療シャペロン療法 (2010)
  • Author(s): 大野耕策
  • Journal Title: 血液フロンティア 20(4) Pages: 69-77
• [Journal Article] The effect of N-octyl-β-valienamine on β-glucosidase activity in tissues of normal mice (2010)
  • Author(s): Luau Z
  • Journal Title: Brain Dev Volume: 32 Pages: 805-809
  • Peer Reviewed
• [Journal Article] A fluorescent SP2-iminosugar with pharmacological chaperone activity for Gaucher disease : Cellular uptake and intracellular distribution studies (2010)
  • Author(s): Luan Z
  • Journal Title: ChemBioChem Volume: 11 Pages: 2453-2464
  • Peer Reviewed
• [Journal Article] Chemical chaperone therapy : Luciferase assay for screening of b-galactosidase mutations (2010)
  • Author(s): Li L
  • Journal Title: Mol Genet Metab Volume: 101 Pages: 364-369
  • Peer Reviewed
• [Journal Article] The pharmacological chaperone effect of N-octyl-beta-valienamine on human mutant acid beta-glucosidases (2010)
  • Author(s): Luan Z
  • Journal Title: Blood Cells Mol Dis Volume: 44 Pages: 48-54
  • Peer Reviewed
• [Journal Article] The pharmacological chaperone effect of N-octyl-beta-vallienamine on human mutant acid beta-glucosidases (2010)
  • Author(s): Luan Z
  • Journal Title: Blood Cells Mol Dis 44 Pages: 48-54
  • Peer Reviewed
• [Journal Article] ライソゾーム病の治療 シャペロン療法 (2010)
  • Author(s): 大野耕策
  • Journal Title: 血液フロンティア 20 Pages: 69-77
• [Journal Article] Chaperone activity of bicyclic nojirimycin analogues for Gaucher mutations in comparison with N-(n-nonyl)deoxynojirimycin. (2009)
  • Author(s): Luan Z, Higaki K, Aguilar-Moncayo M, Ninomiya H, Ohno K, Garcia-Moreno MI, Ortiz Mellet C, Garcia Fernandez JM, Suzuki Y.
  • Journal Title: Chembiochem. 10(17) Pages: 2780-2792
  • Peer Reviewed
• [Journal Article] Chaperone activity of bicyclic nojirimycin analogues for Gaucher mutations in comparison with N-(n-nonyl)deoxynojirimycin (2009)
  • Author(s): Luan Z
  • Journal Title: Chembiochem 10 Pages: 2780-2792
  • Peer Reviewed
• [Journal Article] Brainstem neuropathology in a mouse model of Niemann-Pick disease type C. (2008)
  • Author(s): Luan Z, Saito Y, Miyata H, Ohama E, Ninomiya H, Ohno K.
  • Journal Title: J Neurol Sci. 268(1-2) Pages: 108-116
  • Peer Reviewed
• [Journal Article] Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis. (2008)
  • Author(s): Takamura A, Higaki K, Kajimaki K, Otsuka S, Ninomiya H, Matsuda J, Ohno K, Suzuki Y, Nanba E.
  • Journal Title: Biochem Biophys Res Commun. 367(3) Pages: 616-622
  • Peer Reviewed
• [Journal Article] Brainstem neuropathology in a mouse model of Niemann-Pick disease type C. (2008)
  • Author(s): Luan Z, Saito Y, Miyata H, Ohama E, Ninomiya H, Ohno K.
  • Journal Title: J Neurol Sci 268 Pages: 108-116
  • Peer Reviewed
• [Journal Article] Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis. (2008)
  • Author(s): Takamura A, Bigaki K, Kajimaki K, Otsuka S, Ninomiya H, Natsuda J, Ohno K, Suzuki Y, Nanba E.
  • Journal Title: Biochem Biophys Res Commun 367 Pages: 616-622
  • Peer Reviewed
• [Journal Article] Chemical chaperone therapy : chaperone effect on mutant enzyme and cellular pathophysiology in β -galactosidase deficiency
  • Author(s): Higaki K
  • Journal Title: Human Mutation Volume: (in press)
  • Peer Reviewed
• [Presentation] 遺伝性小児神経疾患の治療について (2011)
  • Author(s): 大野耕策
  • Organizer: 第1回由布院・児湯小児神経学研究会
  • Place of Presentation: 大分
  • Year and Date: 2011-03-18
• [Presentation] ライソゾーム病の新しい低分子治療薬の開発 (2010)
  • Author(s): 大野耕策
  • Organizer: 第15回日本ライソゾーム病研究会
  • Place of Presentation: 東京
  • Year and Date: 2010-12-11
• [Presentation] 医師とともに治療する薬剤業務-遺伝性ライソゾーム病に対する新しい治療と薬剤部との連携- (2010)
  • Author(s): 大野耕策
  • Organizer: 第49回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
  • Place of Presentation: 米子
  • Year and Date: 2010-11-06
• [Presentation] 神経変性疾患と先天代謝異常症 (2010)
  • Author(s): 大野耕策
  • Organizer: 第52回日本先天代謝異常学会
  • Place of Presentation: 大阪
  • Year and Date: 2010-10-23
• [Presentation] Molecular pathology : Gaucherdisease (2010)
  • Author(s): 大野耕策
  • Organizer: シャペロン療法国際シンポジウム
  • Place of Presentation: 米子
  • Year and Date: 2010-07-29
• [Presentation] Chemical chaperone for Gaucher disease (2010)
  • Author(s): 大野耕策
  • Organizer: 第1回アジア先天代謝異常学会議(The 1st ACIMD)
  • Place of Presentation: 福岡
  • Year and Date: 2010-03-09
• [Presentation] リソゾーム病の新しい治療を中心に (2009)
  • Author(s): 大野耕策
  • Organizer: 第4回成育代謝異常症研究会
  • Place of Presentation: 東京
  • Year and Date: 2009-12-04
• [Presentation] ゴーシェ病へのケミカルシャペロン療法 (2009)
  • Author(s): 大野耕策
  • Organizer: 第1回カプアセミナー
  • Place of Presentation: 千葉
  • Year and Date: 2009-08-22
• [Presentation] 遺伝性神経疾患の神経変性機構の解明と治療法の開発 (2009)
  • Author(s): 大野耕策
  • Organizer: 第51回日本小児神経学会総会 会長講演
  • Place of Presentation: 米子
  • Year and Date: 2009-05-28
• [Patent(Industrial Property Rights)] Carba-sugar amine derivativeand glycolipid metabolic disorder treating agent containing the same as active agent (2010)
  • Inventor(s): Ogawa S, SuzukiY, Nanba E, MatsudaJm Ohno K
  • Industrial Property Rights Holder: 生化学工業
  • Acquisition Date: 2010-05-25
  • Overseas
• [Patent(Industrial Property Rights)] Compuestos potenciadores de la actividad de glicosidasas mutantes (2009)
  • Inventor(s): Jose Manuel Garcia Fernandez, Carmen Ortiz Mellet, Yoshiyuki Suzuki, Kousaku Ohno
  • Industrial Property Rights Holder: 鳥取大学、国際医療福祉大学、スペイン・セビリア大学
  • Acquisition Date: 2009-11-05
  • Overseas