Identification of novel chaperones for neurodegerative mucopolysaccharidoses

• Project/Area Number: 17K10051
• 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, 研究推進機構, 准教授 (90294321)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 治療法開発 / ムコ多糖症 / 脳病態 / 低分子化合物 / 酵素蛋白質 / 蛋白質分解 / 脳疾患 / ライソゾーム / シャペロン / 治療法研究

Outline of Final Research Achievements

We have screened novel small molecular chaperone compounds for mucopolysaccharidoses. In vitro screening identified several candidate compounds for both MPSII and MPSIIIB diseases. Cell culture testing with patients’s derived fibroblasts or mutant enzyme cDNA expression have revealed that some of these compounds enhanced the residual enzyme activities in mutation specific manner. Further pharmacokinetic analyses and drug efficacy evaluations are needed to develop the compounds as novel chaperone therapies for these diseases.

Academic Significance and Societal Importance of the Research Achievements

ムコ多糖症の脳病態に対する、新規シャペロン治療薬の候補化合物の開発は、現時点で有効な治療法の存在しない疾患に対する治療法の開発につながり、意義があるものと考えられる。また、経口投与の可能なシャペロン療法は、酵素補充療法の代替え治療として、開発の意義は高い。さらに、シャペロン化合物の効果の変異特異性は、変異酵素蛋白質構造の構造異常との相関を明らかにすることで、この疾患の蛋白質病態の解明に有用な知見となると考えられた。

Research Products

• [Journal Article] Multivalent Glycoligands With Lectin/Enzyme Dual Specificity: Self-Deliverable Glycosidase Regulators (2019)
  • Author(s): Manuel Gonzalez-Cuesta, David Goyard, Eiji Nanba, Katsumi Higaki, Jose M Garcia-Fernandez, Olivier Renaudet, Carmen Ortiz Mellet
  • Journal Title: Chem Commun Volume: 55 Issue: 85 Pages: 12845-12848
  • DOI: 10.1039/c9cc06376e
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pharmacological Chaperones for the Treatment of α-Mannosidosis (2019)
  • Author(s): Rocio Risquez-Cuadro, Reimi Matsumoto, Fernando Ortega-Caballero, Eiji Nanba, Katsumi Higaki, Jose-Manuel Garcia-Fernandez, Carmen Ortiz-Mellet
  • Journal Title: J Med Chem Volume: 62 Issue: 12 Pages: 5832-5843
  • DOI: 10.1021/acs.jmedchem.9b00153
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Probing the inhibitor versus chaperone properties of sp2-iminosugars towards human b-glucocerebrosidase: a picomolar chaperone for Gaucher disease. (2018)
  • Author(s): Mena-Barragan T, Garcia-Moreno MI, Sevsek A, Okazaki T, Nanba E, Higaki K, Martin MI, Pieters RJ, García Fernandez JM, Ortiz Mellet C
  • Journal Title: Molecules Volume: 23 Issue: 4 Pages: 927-927
  • DOI: 10.3390/molecules23040927
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] (5aR)-5a-C-Pentyl-4-epi-isofagomine: A powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. (2017)
  • Author(s): Front S
  • Journal Title: Eur J Med Chem Volume: 126 Pages: 160-179
  • DOI: 10.1016/j.ejmech.2016.09.095
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat. (2017)
  • Author(s): Munkacsi AB
  • Journal Title: J Biol Chem Volume: 292 Issue: 11 Pages: 4395-4410
  • DOI: 10.1074/jbc.m116.770578
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fluorinated Chaperone-β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease. (2017)
  • Author(s): Garcia-Moreno MI
  • Journal Title: J Med Chem Volume: 60 Issue: 5 Pages: 1829-1842
  • DOI: 10.1021/acs.jmedchem.6b01550
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ライソゾーム病のシャペロン治療の進歩 (2020)
  • Author(s): 檜垣克美
  • Organizer: 第６回市民公開フォーラム
  • Invited
• [Presentation] Chaperone therapy for Lysosomal Storage Diseases (2019)
  • Author(s): Katsumi Higaki
  • Organizer: 2nd Asia-Pacific Lysosomal Conference
  • Int'l Joint Research / Invited
• [Presentation] ライソゾーム病に対する薬理シャペロン療法 (2017)
  • Author(s): 檜垣克美
  • Organizer: 第90回日本生化学会
  • Invited
• [Presentation] シャペロン療法の最新状況 (2017)
  • Author(s): 檜垣克美
  • Organizer: 第22回日本ライソゾーム病研究会
  • Invited
• [Book] Mucopolysaccharidoses Updates (2018)
  • Author(s): Higaki K, Ninomiya H
  • Total Pages: 811
  • Publisher: NOCA Science Publishers
  • ISBN: 9781536139860