Development of New Therapeutic Agents for Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP, MIM #135100) is a rare genetic disorder of heterotopic endochondral ossification, resulting in transformation of soft tissue into episodic bone formation. Currently, no effective treatment for FOP has been established. The causative heterozygous genetic mutations have been identified in either the intracellular glycine-serine-rich (GS) domain or kinase domain of ALK2 (Activin-like kinase-2, also known as Activin A receptor type I, ACVR1), a type I receptor of bone morphogenetic proteins (BMP). Cumulative studies support that these mutations abnormally activate BMP signaling in a ligandindependent manner by reducing the ALK2 interaction with the negative regulator FKBP12, whereas others argue a ligand-dependent BMP signaling activation in FOP. Nevertheless, in either the ligand-independent or ligand-dependent model, ALK2 receptor activation is essential for heterotopic ossification in FOP. Thus targeting ALK2 likely represents an effective treatment for FOP. In this article, we critically review the recent progress on therapeutic strategies, with a focus on development of small molecule ALK2 inhibitors to suppress BMP signaling for FOP treatment.