Development of novel allosteric chaperone therapy for lysosomal storage diseases

• Project/Area Number: 21K07821
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• 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): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: シャペロン / アロステリック / ライソゾーム / 低分子化合物 / 治療法開発 / 中枢神経障害 / 低分子物質 / 変異酵素 / ライソゾーム病 / 蛋白質構造異常 / 脳疾患

Outline of Research at the Start

ライソゾーム病に対し、標的酵素の活性中心部以外のアロステリック部位に結合し、酵素安定化活性を示す新規シャペロン化合物（アロステリックシャペロン）の基礎開発研究を行う。化合物の変異型特異的シャペロン効果、および作用機序、細胞病態に対する効果を明らかにすることで、ライソゾーム病に対する新たな治療法開発に応用する。

Outline of Final Research Achievements

In this study, we explored the candidate chaperone compounds’ effects for beta-galactosidase deficiency and Gaucher disease in in vitro and cultured cell experiments. All the compounds showed no specific substrate competitive inhibition activity in vitro. And they showed enzyme enhancement activity in mutation specific manner in cultured cells. When cell treated with both chaperone and purified human normal beta-Glucosidase, synergetic effect was observed. In addition, chaperone for Gaucher disease showed restoration of mitochondrial abnormality in mutant GBA1 expressed cells. These results provided us important insights into efficacy of these compounds as candidate for chaperone therapy in the future.

Academic Significance and Societal Importance of the Research Achievements

遺伝性ライソゾーム病の脳病態に有効な治療法の開発が求められている現状に対し、薬理的シャペロン療法は有効な治療アプローチで、その開発研究は重要である。また、副反応の低い新しい治療法の開発は、将来的なシャペロン療法の応用のためも有用な知見を示すことができた。

Research Products

• [Journal Article] sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease. (2022)
  • Author(s): Gonzalez-Cuesta M, Herrera-Gonza;lez I, Garcia-Moreno MI, Ashmus RA, Vocadlo DJ, Garcia Fernandez JM, Nanba E, Higaki K, Ortiz Mellet C.
  • Journal Title: J Enzyme Inhib Med Chem Volume: 37 Issue: 1 Pages: 1364-1374
  • DOI: 10.1080/14756366.2022.2073444
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann?Pick disease type C without hearing loss (2022)
  • Author(s): Yamada Y, Miwa T, Nakashima M, Shirakawa A, Ishii A, Namba N, Kondo Y, Takeo T, Nakagata N, Motoyama K, Higashi T, Arima H, Kurauchi Y, Seki T, Katsuki H, Okada Y, Ichikawa A, Higaki K, Hayashi K, Minami K, Yoshikawa N, Ikeda R, Ishikawa Y, Kajii T, Tachii K, Takeda H, Orita Y, Matsuo M, Irie T, Ishitsuka Y
  • Journal Title: Biomedicine & Pharmacotherapy Volume: 155 Pages: 113698-113698
  • DOI: 10.1016/j.biopha.2022.113698
  • Peer Reviewed / Open Access
• [Journal Article] Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins increases safety margin in treatment of Niemann-Pick disease type C (2021)
  • Author(s): Yamada Yusei et al.
  • Journal Title: British Journal of Pharmacology Volume: 178 Issue: 13 Pages: 2727
  • DOI: 10.1111/bph.15464
  • URL: https://localhost/en/publications/bf79e28f-26c1-44f7-911c-ccda22d44960
  • Peer Reviewed