Development of a selective inhibitor of Activin and its application in a cancer-bearing mouse model

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07683
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Teikyo University (2022); The University of Tokyo (2019-2021)
• Principal Investigator: Morikawa Masato 帝京大学, 先端総合研究機構, 准教授 (80775833)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: アクチビン / ミオスタチン / フォリスタチン / FSTL3 / 筋ジストロフィー / Fc融合蛋白

Outline of Final Research Achievements

In this research, I have developed a ligand trap against activin and its relatives in the transforming growth factor beta (TGF-β) family, and have evaluated the therapeutic effects in mouse models. I focused on follistatin-like 3 (FSTL3), one of endogenous antagonists against activin, which mainly binds and neutralizes activin and myostatin (also known as GDF8). Using the knobs-into-holes technology, I developed monovalent FSTL3-Fc (mono-FSTL3-Fc) with longer serum half-life. I confirmed that systemic administration of mono-FSTL3-Fc induced muscle fiber hypertrophy and increased muscle mass in young wild-type mice and C57BL/10-mdx mice (a model mouse for human Duchenne muscular dystrophy). Targeting the signaling pathway of myostatin has been regarded as a promising strategy to increase muscle mass in the elderly and in patients. We thus reported that the mono-FSTL3-Fc can be a novel anti-myostatin agent.

Free Research Field

病態医化学

Academic Significance and Societal Importance of the Research Achievements

ミオスタチン経路を阻害することで骨格筋の増加・肥大を目指す「ミオスタチン阻害薬」の開発が積極的に行われてきたが、効果不十分であったり標的外の副作用を生じたため、臨床応用された製剤はない。
本研究の成果である1価FSTL3-Fcは、マウスモデルで先行製剤と同等の骨格筋肥大効果を認めた。また、骨格筋に関係するミオスタチン、アクチビン、GDF11に選択性が高いことから、先行製剤の問題点を解消した新たなミオスタチン阻害薬となりうる。副作用の可能性の低いミオスタチン阻害薬は、進行したがんで認められる悪液質の他、高齢者におけるサルコペニア（加齢性筋肉減弱症）などの骨格筋萎縮症の治療法として有望である。