Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive, extensive, and irreversible heterotopic ossification (HO) of soft tissues throughout the body, leading to severe disabilities. FOP is caused primarily by mutations in activin A receptor type 1 (ACVR1), also known as activin-like kinase 2 (ALK2), which encodes a receptor belonging to the bone morphogenetic protein (BMP) type I family. However, the continuous and complex process of HO in FOP is not yet fully understood, which has impeded the development of therapeutic drugs. Despite surgical removal of HO, which often results in recurrence and expansion of ossification, there is currently no definitive drug treatment available to completely prevent, halt, or reverse the progression of HO in FOP. Currently, researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates, including saracatinib, palovarotene, and rapamycin. This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs, with the goal of providing insights for further research and the development of new treatment methods.

Keywords: Activin A receptor type 1 (ACVR1); Drug treatment; Fibrodysplasia ossificans progressiva (FOP); Heterotopic ossification (HO); Mechanism.

Fig. 1. Schematic overview of currently known fibrodysplasia ossificans progressiva (FOP) mechanisms (created with BioRender.‍ com). ACTA: activin A; ACVR1: activin A receptor type 1; BMP: bone morphogenetic protein; EV: extracellular vesicle; FKBP12: 12-kDa FK506-binding protein; HIF: hypoxia-inducible factor; IL: interleukin; LCK: lymphocyte-specific protein-tyrosine kinase; mTORC1: mechanistic target of rapamycin complex 1; P: phosphorylation; RABEP1: Rab GTPase-binding effector protein 1, Rabaptin 5; SASP: senescence-associated secretory phenotype; SMAD: mothers against decapentaplegic homolog; Sox9: sex-determining region Y (SRY)‍ -box 9; Src: steroid receptor coactivator; TGF-β: transforming growth factor-β; VEGF: vascular endothelial growth factor; YES: YES proto-oncogene.

Fig. 2. Schematic overview of the drugs and compounds currently used and/or evaluated in the treatment of fibrodysplasia ossificans progressiva (FOP), and their respective effects (created with BioRender.com). ACTA: activing A; ACVR1: activin A receptor type I; BMP: bone morphogenetic protein; HIF1α: hypoxia-inducible factor 1α; IL: interleukin; mTOR: mammalian target of rapamycin; mTORC1: mTOR complex 1; P: phosphorylation; PI3K: phosphoinositide 3-kinase; RAR: retinoic acid receptor; SASP: senescence-associated secretory phenotype; SMAD: mothers against decapentaplegic homolog; TGF-β: transforming growth factor-β.