Development of a breakthrough treatment for Niemann-Pick disease type C liver lesions

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07066
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kumamoto University
• Principal Investigator: Ishitsuka Yoichi 熊本大学, 大学院生命科学研究部(薬), 教授 (70423655)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ニーマン・ピック病C型 / シクロデキストリン / 肝障害 / 脳肝連関 / 薬剤性肝障害 / アセトアミノフェン

Outline of Final Research Achievements

Niemann-Pick disease type C (NPC) is a recessive genetic disorder caused by mutations in NPC1 and NPC2 genes, resulting in liver damage and cholesterol buildup. This study aimed to evaluate the mechanisms of development NPC-related liver disorders and develop therapeutic agents. (1) Intracerebroventricular administration of hydroxypropyl-β-cyclodextrin (HPBCD) to NPC model mice decreased serum transaminase levels and liver tissue's osteoactivin (GPNMB), indicating a link between CNS and liver damage. Identifying molecules involved in this brain-liver connection lays the groundwork for further research on liver pathogenesis. (2) Maltosyl-γ-cyclodextrin (G2GCD), an alternative therapy to HPBCD, was discovered and patented. (3) Experiments with NPC-like cells and mice reported acetaminophen exacerbating hepatotoxicity. Thus, we examined the impact of NPC1 gene mutations on acetaminophen-induced hepatotoxicity, finding no evidence of worsened toxicity in vitro and in vivo models.

Free Research Field

応用薬理学

Academic Significance and Societal Importance of the Research Achievements

未だ病態が解明されておらず治療薬開発が急務な疾患であるNPC肝障害における脳-肝臓連関があることを薬理学的検討から明らかにし、更に新規治療薬候補のG2GCDを見出し、それぞれ論文報告した点で、学術的にも社会的にも極めて意義のある成果である。また、NPCにおけるアセトアミノフェン肝毒性に関する情報を提供し、その臨床使用に際して有益な情報を提示するものであり、社会的意義のある研究成果と考えられる。