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Cardiopulmonary and Neurologic Dysfunctions in Fibrodysplasia Ossificans Progressiva
Open AccessReview

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

1
Department de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Spain
2
Centre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
3
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
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 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; Williams, Eleanor; Ikeya, Makoto; Bullock, Alex N.; ten Dijke, Peter; Goumans, Marie-José; Sanchez-Duffhues, Gonzalo. 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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