Molecular analysis of chemical chaperone effect on lysosomal storage diseases

• Project/Area Number: 23591498
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tottori University
• Principal Investigator: HIGAKI Katsumi 鳥取大学, 生命機能研究支援センター, 准教授 (90294321)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ライソゾーム病 / 脂質代謝異常 / 脳疾患 / 治療法開発 / シャペロン / 蛋白質分解 / シグナル伝達 / 小児神経 / 細胞内輸送 / ファブリー病 / 小児神経疾患 / 脂質代謝異常症 / ケミカルシャペロン / コレステロール / 小胞体 / モデルマウス / リン脂質

Research Abstract

I investigated the intracellular molecular mechanisms of chemical chaperone compounds to the lysosomal storage diseases. Co-crystal structural analysis of chaperone compound with lysoosmal enzyme protein identified a potent hydrogen bound in human alpha-galactosidase A protein. I also investigated the synergetic effect of the proteostasis regulator with the chaperone compound. Cultured fibroblasts analyses also found that the effect of treatment or washout of chaperone compounds on alpha-galactosidase enzyme activities as well as substrate accumulation. These results provided us important insights applicable to develop new chaperone compounds for other lysosomal diseases.

Research Products

• [Journal Article] Targeted delivery of pharmacological chaperones for Gaucher disease to marophages by a mannosylated cyclodextrin carrier (2014)
  • Author(s): Rodriguez-Lavado J, de la Mata M, Jimenez-Blanco J, Garcia-Moreno MI, Benito JM, Diaz-Quintana A, Sanchez-Alcazar JA, Higaki K, Nanba E, Ohno K, Suzuki Y, Ortiz Mellet C, Garcia Fernandez JM
  • Journal Title: Org Biomol Chem Volume: 12 Pages: 2289-2301
• [Journal Article] Targeted delivery of pharmacological chaperones for Gaucher disease to marophages by a mannosylated cyclodextrin carrier. (2014)
  • Author(s): Rodriguez-Lavado J
  • Journal Title: Org Biomol Chem Volume: 12 Issue: 14 Pages: 2289-2301
  • DOI: 10.1039/c3ob42530d
  • Peer Reviewed
• [Journal Article] Two candidate molecules for chemical chaperone therapy for GM1-gangliosidosis (2013)
  • Author(s): Higaki K, Ninomiya H, Suzuki Y, Nanba E
  • Journal Title: Future Med Chem Volume: 5 Pages: 1551-1558
• [Journal Article] A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM_1 gangliosidosis (2013)
  • Author(s): Takai T, Higaki K, Aguilar-Moncayo M, Mena-Barragán T, Hirano Y, Yura K, Yu L, Ninomiya H, García-Moreno I, Sakakibara Y, Ohno K, Nanba E, Ortiz Mellet C, García Fernández JM, Suzuki Y
  • Journal Title: Mol Ther Volume: 21 Pages: 526-532
• [Journal Article] The chaperone activity and toxicity of ambroxol on GD cells and normal mice (2013)
  • Author(s): Luan Z, Li L, Higaki K, Nanba E, Suzuki Y, Ohno K
  • Journal Title: Brain Dev Volume: 35 Pages: 317-322
• [Journal Article] Two candidate molecules for chemical chaperone therapy for GM1-gangliosidosis. (2013)
  • Author(s): Higaki K
  • Journal Title: Future Med Chem Volume: 5 Issue: 13 Pages: 1551-1558
  • DOI: 10.4155/fmc.13.123
  • Peer Reviewed
• [Journal Article] The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice (2013)
  • Author(s): Luan Z,Li LinjingHigaki K, Nanba.E,Suzuki Y, Ohno K
  • Journal Title: Brain Dev Volume: 35 Issue: 4 Pages: 3170322-3170322
  • DOI: 10.1016/j.braindev.2012.05.008
  • Peer Reviewed
• [Journal Article] A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 - gangliosidosis (2013)
  • Author(s): Takai T, Higaki K, Aguilar-Moncayo M, Mena-Barragan T, Hirano Y, Yura K, Yu L, Ninomiya H, M. Garcia-Moreno I,Sakakibara Y, Ohno K, Nanba E, Ortiz Mellet C, Jose M. Fernandez G, Suzuki Y
  • Journal Title: Mol Ther Volume: 21 Issue: 3 Pages: 526-532
  • DOI: 10.1038/mt.2012.263
  • Peer Reviewed
• [Journal Article] Conformationally-Locked N-Glycosides with Selectiveβ-Glycosidase Inhibitory Activity : Identification of a New Non-Iminosugar-Type Pharmacological Chaperone for Gaucher Disease (2012)
  • Author(s): Castella J, Risquez R, Cruz D, Higaki K, Nanba E, Ohno K, Suzuki Y, Diaz Y, Ortiz Mellet C, García Fernández JM, Castellon S
  • Journal Title: J Med Chem Volume: 55 Pages: 6857-6865
• [Journal Article] Tuning glycosidase inhibition through aglycone interactions : Pharmacological chaperones for Fabry disease and GM1 gangliosidosis (2012)
  • Author(s): Aguilar-Moncayo M, Takai T, Higaki K, Mena-Barragán T, Hirano Y, Yura K, Li L, Yu Y, Ninomiya H, García-Moreno MI, Ishii S, Sakakibara Y, Ohno K, Nanba E, Ortiz Mellet C, García Fernández JM, Suzuki Y
  • Journal Title: Chem Commun Volume: 48 Pages: 6514-6516
• [Journal Article] Therapeutic chaperone effect of N-octyl-4-epi-β-valienamine on murine GM1-gangliosidosis (2012)
  • Author(s): Suzuki Y, Ichinomiya S, Kurosawa M, Matsuda D, Ogawa S, Iida M, Kubo T, Tabe M, Itoh M, Higaki K, Nanba E, Ohno K
  • Journal Title: Mol Genet Metab Volume: 106 Pages: 92-98
• [Journal Article] Therapeutic chaperone effect of N-octyl 4-epi-β-valienamine on murine G(M1)-gangliosidosis (2012)
  • Author(s): Suzuki Y, Ichinomiya S, Kurosawa M, Matsuda J,Ogawa S, Iida M, Kubo T, Tabe M, Itoh M, Higaki K, Nanba E,Ohno K
  • Journal Title: Mol Genet Metab Volume: 106 Issue: 1 Pages: 92-98
  • DOI: 10.1016/j.ymgme.2012.02.012
  • Peer Reviewed
• [Journal Article] Tuning glycosidase inhibition through aglycone interactions: Pharmacological chaperones for Fabry disease and GM1gangliosidosis (2012)
  • Author(s): Aguilar-Moncayo M, Takai T, Higaki K, Mena-Barragan T, Hirano Y, Yura K, Li L, Yu Y, Ninomiya H, Garcia-Moreno I, Ishii S, Sakakibara Y, Ohno K, Nanba E, Ortiz Mellet C, Garcia Fernandez JM, Suzuki Y:
  • Journal Title: Chem Commun Volume: 48 Issue: 52 Pages: 6514-6516
  • DOI: 10.1039/c2cc32065g
  • Peer Reviewed
• [Journal Article] Conformationally-locked N-glycosides with selective β-glucosidase inhibitory activity: Identification of a new non-iminosugar-type pharmacological chaperone for Gaucher disease (2012)
  • Author(s): Castilla J, Risquez R. Cruz D,Higaki K, Nanba E, Ohno K, Suzuki Y, Diaz Y, Ortiz Mellet C, Carcia Fernandez JM, Castillon
  • Journal Title: J Med Chem Volume: 55 Issue: 15 Pages: 6857-6865
  • DOI: 10.1021/jm3006178
  • Peer Reviewed
• [Journal Article] An"exacerbate-reverse"strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick type C disease (2011)
  • Author(s): Munkacsi AB, Chen FW, Brinkman MA, Higaki K, Gutiérrez GD, Chaudhari J, Layer JV, Tong A, Bard M, Boone C, Ioannou YA, Sturley SL
  • Journal Title: J Biol Chem Volume: 286 Pages: 23842-23851
• [Journal Article] Lysosomal accumulation of Trk protein in brain of GM1-gangliosidosis mouse and its restoration by chemical chaperone (2011)
  • Author(s): Takamura A, Higaki K, Ninomiya H, Takai T, Matsuda J, Iida M, Ohno K, Suzuki Y, Nanba E
  • Journal Title: J Neurochem Volume: 118 Pages: 399-406
• [Journal Article] Lysosomal storage causes cellular dysfunction in mucolipidosis II skin fibroblasts (2011)
  • Author(s): Otomo T, Higaki K, Nanba E, Ozono K, Sakai N
  • Journal Title: J Biol Chem Volume: 286 Pages: 35283-35290
• [Journal Article] Chemical chaperone therapy : chaperone effect on mutant enzyme and cellular pathophysiology inβ-galactosidase deficiency (2011)
  • Author(s): Higaki K, Li L, Bahrudin U, Okuzawa S, Takamura A, Yamamoto K, Adachi K, Paraguison RC, 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: Hum Mutat Volume: 32 Pages: 843-852
• [Journal Article] Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency (2011)
  • Author(s): HigakKLi L,Bahrudin U, Okuzawa S,Takamura A, Yamamoto K, Adachi K, Paraguison RC, 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: Hum Mutat Volume: 32 Issue: 7 Pages: 843-852
  • DOI: 10.1002/humu.21516
  • Peer Reviewed
• [Journal Article] Lysosomal accumulation of Trk protein in brain of GM1-gangliosidosis mouse and its restoration by chemical chaperone. (2011)
  • Author(s): Takamura A,Higaki K,Ninomiaya H,Takai T, Matsuda J, Iida M, Ohno K, Suzuki Y, Nanba E
  • Journal Title: J Neurochem Volume: 118 Issue: 3 Pages: 399-406
  • DOI: 10.1111/j.1471-4159.2011.07310.x
  • Peer Reviewed
• [Journal Article] Lysosomal storage causes cellular dysfunction In mucolipidosis II skin fibroblasts (2011)
  • Author(s): Otomo T
  • Journal Title: J Biol Chem Volume: 286(40) Issue: 40 Pages: 35283-35290
  • DOI: 10.1074/jbc.m111.267930
  • Peer Reviewed
• [Journal Article] An "exacerbate-reverse" strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick C disease. (2011)
  • Author(s): Munkacsi AB
  • Journal Title: J Biol Chem Volume: 286 Issue: 27 Pages: 23842-23851
  • DOI: 10.1074/jbc.m111.227645
  • Peer Reviewed
• [Presentation] Comparison of two Chaperone candidates for treatment of GM1-gangliosidosis (2013)
  • Author(s): Takai T, Higaki K, Suzuki Y, Nanba E
  • Organizer: The 3^<rd> Asian Congress for Inherited Metabolic Diseases / The 55^<th> Annual Meeting for The Japanese Society for Inherited Metabolic Diseases
  • Place of Presentation: Chiba
  • Year and Date: 2013-11-29
• [Presentation] NOEV treatment option for Japansese late-onset Krabbe disease (2013)
  • Author(s): Hossain MA, Higaki K, Nanba E, Suzuki Y, Ozono K, Sakai N
  • Organizer: The 3^<rd> Asian Congress for Inherited Metabolic Diseases / The 55^<th> Annual Meeting for The Japanese Society for Inherited Metabolic Diseases
  • Place of Presentation: Chiba
  • Year and Date: 2013-11-29
• [Presentation] β-ガラクトシダーゼ欠損症に対するシャペロン治療薬の開発 (2013)
  • Author(s): 難波栄二,檜垣克美,髙井知子,由良敬,榊原康文, Carmen Ortiz Mellet, Jose M. Garcia Fernandez,鈴木義之
  • Organizer: 第58回日本人類遺伝学会
  • Place of Presentation: 仙台
  • Year and Date: 2013-11-21
• [Presentation] Comparison of two Chaperone candidates for treatment of GM1-gangliosidosis. (2013)
  • Author(s): Takai T
  • Organizer: The 3rd Asian Congress for Inherited Metabolic Diseases / The 55th Annual Meeting for The Japanese Society for Inherited Metabolic Diseases.
  • Place of Presentation: Tokyo
• [Presentation] NOEV treatment option for Japansese late-onset Krabbe disease. (2013)
  • Author(s): Hossain MA
  • Organizer: The 3rd Asian Congress for Inherited Metabolic Diseases / The 55th Annual Meeting for The Japanese Society for Inherited Metabolic Diseases.
  • Place of Presentation: Tokyo
• [Presentation] ヒトI51T変異β-ガラクトシダーゼに有効な新規ケミカルシャペロン化合物の解析 (2012)
  • Author(s): 髙井知子,檜垣克美, Ortiz Mellet C, García Fernández JM,大野耕策,鈴木義之,難波栄二
  • Organizer: 第54回日本先天代謝異常学会
  • Place of Presentation: 岐阜
  • Year and Date: 2012-11-16
• [Presentation] ライソゾーム病に対するシャペロン化合物の開発 (2012)
  • Author(s): 檜垣克美
  • Organizer: 第1回日本シャペロン療法研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-11-11
• [Presentation] ファブリー病ならびにGM1-ガングリオシドーシスに対する新しいシャペロン治療薬の開発 (2012)
  • Author(s): 難波栄二,檜垣克美,髙井知子, Yu Yi,大野耕策,鈴木義之
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-26
• [Presentation] A novel chaperone compound for G_<M1>-gangliosidosis (2012)
  • Author(s): Takai T, Higaki K, Ortiz Mellet C, García Fernández JM, Ohno K, Suzuki Y, Nanba E
  • Organizer: 第17回日本ライソゾーム病研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-06
• [Presentation] シャペロン療法の開発戦略 (2011)
  • Author(s): 檜垣克美
  • Organizer: 第53回 日本先天代謝異常学会総会 シンポジウム3 シャペロン療法
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-26
• [Presentation] ベータガラクトシダーゼに対する新規シャペロン候補化合物の解析 (2011)
  • Author(s): 高井知子,檜垣克美, Ortiz Mellet C, Garcia Fernandez J,大野耕策,鈴木義之,難波栄二
  • Organizer: 第53回日本先天代謝異常学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-25
• [Presentation] ファブリー病に対する新規シャペロン候補化合物の解析 (2011)
  • Author(s): Yi Y,檜垣克美, Ortiz Mellet C, Garcia Fernandez J,大野耕策,鈴木義之,難波栄二
  • Organizer: 第53回日本先天代謝異常学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-25
• [Presentation] Chemical chaperone therapy forβ-galactosidase deficiency (2011)
  • Author(s): Higaki K, Ohno K, Suzuki Y, Nanba E
  • Organizer: 12^<th> International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2011-10-13
• [Presentation] ヒト変異β-ガラクトシダーゼに対する新規シャペロン化合物 (2011)
  • Author(s): 高井知子、檜垣克美、鈴木義之、難波栄二
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-22
• [Presentation] Chemical chaperone therapy : chaperone effect on mutant enzyme and cellular pathophysiology inβ-galactosidase deficiency (2011)
  • Author(s): Takai T, Higaki K, Ohno K, Suzuki Y, Nanba E
  • Organizer: Satellite Symposium of Asian Congress for Inherited Metabolic Diseases 2011 Tokyo Meeting on Lysosomal Storage Disease Screening
  • Place of Presentation: Tokyo
  • Year and Date: 2011-08-05
• [Presentation] Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency. (2011)
  • Author(s): Takai T
  • Organizer: Satellite Symposium of Asian Congress for Inherited Metabolic Diseases 2011 Tokyo Meeting on Lysosomal Storage Disease Screening.
  • Place of Presentation: キャンパスイノベーションセンター（東京都）
• [Presentation] ヒト変異β-ガラクトシダーゼに対する新規シャペロン化合物. (2011)
  • Author(s): 高井知子
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都国際会議場（京都市）
• [Presentation] GM1ガングリオシドーシスモデルマウス脳におけるシグナル伝達異常. (2011)
  • Author(s): 檜垣克美
  • Organizer: 第16回日本ライソゾーム病研究会
  • Place of Presentation: 東京慈恵会医科大学（東京都）
• [Presentation] Chemical chaperone therapy for β-galactosidase deficiency. (2011)
  • Author(s): Higaki K
  • Organizer: 12th International Congress of Human Genetics
  • Place of Presentation: Montreal Convention Center（Montreal, Canada）
• [Presentation] ベータガラクトシダーゼに対する新規シャペロン候補化合物の解析. (2011)
  • Author(s): 高井知子
  • Organizer: 第53回 日本先天代謝異常学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉市）
• [Presentation] ファブリー病に対する新規シャペロン候補化合物の解析. (2011)
  • Author(s): Yi Y
  • Organizer: 第53回 日本先天代謝異常学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉市）
• [Presentation] シンポジウム３シャペロン療法, シャペロン療法の開発戦略 (2011)
  • Author(s): 檜垣克美
  • Organizer: 第53回 日本先天代謝異常学会総会(招待講演)
  • Place of Presentation: ホテルニューオータニ幕張（千葉市）
• [Presentation] GM1ガングリオシドーシスモデルマウス脳におけるシグナル伝達異常 (2010)
  • Author(s): 檜垣克美,高村歩美,大野耕策,鈴木義之,難波栄二
  • Organizer: 第16回日本ライソゾーム病シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-09-29
• [Presentation] A novel chaperone compound for GM1-gangliosidosis.
  • Author(s): Takai T
  • Organizer: 第17回日本ライソゾーム病研究会
  • Place of Presentation: 東京プリンスホテル（東京都）
• [Presentation] Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM1-gangliosidosis.
  • Author(s): Yu Y
  • Organizer: 第17回日本ライソゾーム病研究会
  • Place of Presentation: 東京プリンスホテル（東京都）
• [Presentation] ファブリー病ならびにGM1-ガングリオシドーシスに対する新しいシャペロン治療薬の開発.
  • Author(s): 難波栄二
  • Organizer: 第57回日本人類遺伝学会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] ヒトI51T変異&#61538;-ガラクトシダーゼに有効な新規ケミカルシャペロン化合物の解析.
  • Author(s): 髙井知子
  • Organizer: 第54回日本先天代謝異常学会
  • Place of Presentation: じゅろくプラザ（岐阜市）
• [Presentation] ライソゾーム病に対するシャペロン化合物の開発
  • Author(s): 檜垣克美
  • Organizer: 第１回 日本シャペロン療法研究会
  • Place of Presentation: キャンパス・イノベーションセンター東京（東京都）
  • Invited
• [Book] ガングリオシドーシス（Brain Medical） (2012)
  • Author(s): 難波栄二
  • Publisher: メディカルレビュー社
• [Book] GM1-ガングリオシドーシス（先天代謝異常症候群 第2版) (2012)
  • Author(s): 檜垣克美
  • Publisher: 日本臨床社