Elucidation of the mechanism of liver fibrosis by Wnt-b-catenin pathway

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Metropolitan Komagome Hospital (Clinical research laboratory)
• Principal Investigator: Kimura Kiminori 東京都立駒込病院(臨床研究室), 肝臓内科, 部長 (70397339)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 肝硬変 / 肝線維化

Outline of Final Research Achievements

There are no therapeutic agents for HCV cirrhosis, especially decompensated cirrhosis with Child-Pugh (CP) score B, which exists in more than 200,000 people in Japan, and the prognosis is poor. A therapeutic drug (anti-fibrotic drug) for liver cirrhosis has not been put into practical use at present. Recently, it was reported that Wnt signaling is also involved in fibrosis via TGF-b. PRI-724 is a compound developed by Prism Pharma that can inhibit Wnt signaling and selectively inhibit the protein interaction between β-catenin and CREB-binding protein. An antifibrotic effect was also observed by administration of PRI-724 using a fibrotic model using carbon tetrachloride and bile duct ligation. As the mechanism of action of PRI-724, we found that it suppresses the activation of hepatic stellate cells and showed the involvement of Ly-6 Clow macrophages.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

今回研究開発代表者らが提案する低分子化合物PRI-724は、Wnt-β-cateninシグナル阻害剤で、特にCBP-β-cateninシグナルのみを阻害する点が非常に独創的である。すでに、我々は胆汁うっ滞線維化モデルのみならず、HCV Tg miceや四塩化炭素誘導線維化モデル及びコリン欠乏メチオニン減量NASHモデルにおいても、抗線維化治療効果を報告している。本研究の成果により線維化に対する有効な治療薬開発が実現すれば、肝硬変に伴う様々な合併症も改善され、肝不全への進行や肝がんの発症も予防可能となる。肝硬変患者の予後の改善が見込まれ、それに伴う医療費の削減により医療経済的にも貢献できる。