Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages.

Highlights

  • Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic musculoskeletal disease (OMIM: #135100)

  • FOP progresses by episodic formation of ectopic bone, that arises from endochondral bone formation at extraskeletal sites including muscles, tendons, ligaments, and fascia

  • We will discuss the aberrant signal transduction pathways altered by mutations in ACVR1/activin receptorlike kinase 2 (ALK2) and briefly review the existing in vitro platforms to screen for novel drugs and genes with therapeutic potential in FOP

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Summary

Introduction

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic musculoskeletal disease (OMIM: #135100). In addition to the progressive immobility, other life-threatening complications include severe weight loss following ankylosis of the jaw, affecting opening of the mouth and eating, as well as pneumonia and right-sided heart failure resulting from deformation in the thorax. This makes breathing complicated and leads to the development of thoracic insufficiency syndrome [3]. In this manuscript, we will discuss the aberrant signal transduction pathways altered by mutations in ACVR1/ALK2 and briefly review the existing in vitro platforms to screen for novel drugs and genes with therapeutic potential in FOP. We will introduce the existing treatments under clinical investigation and focus on drug repositioning as an alternative promising approach with potential benefits in the field of rare diseases

Aberrant TGF-β Signalling Underlies FOP
In Vitro Research Platforms Resembling FOP
Repurposed Drugs for FOP
Drug Repurposing versus De Novo Drug Development
Preclinical Candidates
Saracatinib
Rapamycin
Findings
Conclusions and Perspectives
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