Drug development of fibrodysplasia ossificans progressiva (FOP) focused on constitutive activation of FOP-ACVR1

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15617
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: ZHAO CHENGZHU 京都大学, iPS細胞研究所, 特定研究員 (50778678)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 進行性骨化性線維異形成症 / FOP / mTOR

Outline of Final Research Achievements

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by progressive heterotopic ossification (HO) of soft tissues. Most people with FOP carry an activating mutation in the gene ACVR1, which encodes a type I receptor for bone morphogenetic proteins. In this study, we established a phenotypic assay-based high-throughput screening (HTS) system utilizing a chondrogenic ATDC5 cell line that stably expresses FOP-ACVR1. After HTS of 5,000 small-molecule compounds, we identified two hit compounds that are effective at suppressing the enhanced chondrogenesis of FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and suppressed the heterotopic ossification (HO) of multiple model mice. Furthermore, we revealed that one of the hit compounds is an mTOR signaling modulator that indirectly inhibits mTOR signaling. Our results demonstrate that these hit compounds could contribute to future drug repositioning and the mechanistic analysis of mTOR signaling.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

FOP 病態の進行には長年進行を止める根本的な治療法が存在しない。本研究では先行研究の in vitro 病態再現系の解析で得られた治療薬候補化合物の異所性骨形成に対する治療効果をFOPモデルマウスを用いて評価した。さらに、治療効果を示した候補化合物の作用機序の解明を行い、新しい病態メカニズム発見および治療薬の開発に資することが期待される。