Fibrodysplasia Ossificans Progressiva: Molecular Mechanism, Drug Development and Current Clinical Trials

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic human disease characterized by abnormal bone formation in muscle and soft tissues of the patient, due to dysregulated activity of the bone morphogenetic protein (BMP) signaling. Activin A receptor type I (ACVR1), also known as Activin-like kinase 2 (ALK2), is a key BMP type I receptor for the normal BMP signaling transduction. The heterozygous missense mutations in ALK2 are the root cause of FOP, and ALK2R206H accounts for approximately 97% of all FOP cases. Cumulative studies have shown that Activin A, which normally activates TGF - β signaling, can induce the BMP signaling via ALK2 mutated receptor in FOP. In the past decade, multiple therapeutical strategies have been developed and several potential drugs are under clinical trials for FOP now. This article specifically focuses on the recent progress in understanding the molecular mechanism, potential drug development and the clinical trials for FOP treatment.