From mysteries to medicines: drug development for fibrodysplasia ossificans progressive

Abstract

Introduction: Fibrodysplasia ossificans progressiva (FOP) is the most disabling disorder of skeletal metamorphosis in humans and leads to the formation of a second skeleton of heterotopic bone. Presently, there is no effective treatment.

Areas covered: In this review, the authors discuss heterozygous activating mutations in Activin receptor A, type I/ Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that are the genetic cause of FOP and reveal a promising pharmacologic target in the BMP signaling pathway. Despite these germline mutations, episodic disease activation is induced by soft tissue injury and resultant inflammatory triggers that are dependent on responding progenitor cells and a tissue microenvironment that supports heterotopic ossification.

Expert opinion: Here we review opportunities and challenges for the development of effective therapeutics for FOP. There are many potential approaches that may eventually be used to harness FOP. The long-term treatment of FOP is likely to involve not one, but several concomitant approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease.

Keywords: Bone morphogenetic protein receptors; Fibrodysplasia ossificans progressiva; Heterotopic endochondral ossification; Skeletal metamorphosis.

Fig. 1. Schematic Diagram of Skeletal Metamorphosis in FOP

In FOP, muscle cells do not become bone cells. Rather, skeletal muscle tissue is transformed into heterotopic bone through a process of skeletal metamorphosis [4, 56, 65]. The process of HEO in FOP involves two major phases - a catamorphic phase (tissue destruction; left column) followed by an anamorphic phase (tissue formation; right column) of transient fibroproliferative and cartilaginous scaffolds, and their replacement with mature heterotopic bone. The activation of tissue progenitor cells that contribute to the formation of heterotopic bone rather than reparative tissue is central to the process of skeletal metamorphosis [33, 34].

Fig. 2. Action of DM-like STIs vs. RARγ Agonists in BMP Signaling

Dorsomorphin (DM)-like STIs inhibit BMP signaling by effectively blocking the kinase domain of multiple BMP type I receptors (ALK2, ALK3, and ALK6). BMP signaling plays a critical role in the formation and maintenance of many organ systems including, but not limited to the skeleton, skin, lung, bowel, liver, fat, heart, eye, and CNS. The therapeutic efficacy of DM-like STIs will depend largely on their ability to selectively block ALK2 signaling that drives HEO at doses that do not impair BMP signaling through ALK 3 and ALK6. RARγ agonists inhibit BMP signaling downstream of BMP type I receptors in cartilage, skin, and both normotopic as well as ectopic chondrogenesis. The therapeutic efficacy of RARγ agonists in FOP will depend largely on their ability to selectively block ectopic chondrogenesis at tolerable doses.