Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

Ventura, Francesc; Williams, Eleanor; Ikeya, Makoto; Bullock, Alex N.; ten Dijke, Peter; Goumans, Marie-José; Sanchez-Duffhues, Gonzalo

doi:10.3390/biomedicines9020213

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Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

⁴,

⁵

and

Gonzalo Sanchez-Duffhues

^5,*

Department de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain

Centre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK

Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

⁴

Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands

⁵

Department of Cell and Chemical Biology, Cardiovascular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands

Author to whom correspondence should be addressed.

Academic Editor: Roberto Ravazzolo

Biomedicines 2021, 9(2), 213; https://doi.org/10.3390/biomedicines9020213

Received: 11 January 2021 / Revised: 8 February 2021 / Accepted: 15 February 2021 / Published: 19 February 2021

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)

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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. View Full-Text

Keywords: activin; ALK2; BMP; bone; FOP; repurposed drug; signal transduction; TGF-β

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MDPI and ACS Style

Ventura, F.; Williams, E.; Ikeya, M.; Bullock, A.N.; ten Dijke, P.; Goumans, M.-J.; Sanchez-Duffhues, G. Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva. Biomedicines 2021, 9, 213. https://doi.org/10.3390/biomedicines9020213

AMA Style

Ventura F, Williams E, Ikeya M, Bullock AN, ten Dijke P, Goumans M-J, Sanchez-Duffhues G. Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva. Biomedicines. 2021; 9(2):213. https://doi.org/10.3390/biomedicines9020213

Chicago/Turabian Style

Ventura, Francesc, Eleanor Williams, Makoto Ikeya, Alex N. Bullock, Peter ten Dijke, Marie-José Goumans, and Gonzalo Sanchez-Duffhues. 2021. "Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva" Biomedicines 9, no. 2: 213. https://doi.org/10.3390/biomedicines9020213

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