Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva
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 <i>ACVR1</i>, encoding the bone morphogenetic...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-02-01
|
Series: | Biomedicines |
Subjects: | |
Online Access: | https://www.mdpi.com/2227-9059/9/2/213 |
id |
doaj-c3cde98499ca4096b050ad86f43e2375 |
---|---|
record_format |
Article |
spelling |
doaj-c3cde98499ca4096b050ad86f43e23752021-02-20T00:05:23ZengMDPI AGBiomedicines2227-90592021-02-01921321310.3390/biomedicines9020213Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans ProgressivaFrancesc Ventura0Eleanor Williams1Makoto Ikeya2Alex N. Bullock3Peter ten Dijke4Marie-José Goumans5Gonzalo Sanchez-Duffhues6Department de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, SpainCentre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UKDepartment of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, JapanCentre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UKOncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Cardiovascular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Cardiovascular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The NetherlandsFibrodysplasia 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 <i>ACVR1</i>, 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.https://www.mdpi.com/2227-9059/9/2/213activinALK2BMPboneFOPrepurposed drug |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Francesc Ventura Eleanor Williams Makoto Ikeya Alex N. Bullock Peter ten Dijke Marie-José Goumans Gonzalo Sanchez-Duffhues |
spellingShingle |
Francesc Ventura Eleanor Williams Makoto Ikeya Alex N. Bullock Peter ten Dijke Marie-José Goumans Gonzalo Sanchez-Duffhues Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva Biomedicines activin ALK2 BMP bone FOP repurposed drug |
author_facet |
Francesc Ventura Eleanor Williams Makoto Ikeya Alex N. Bullock Peter ten Dijke Marie-José Goumans Gonzalo Sanchez-Duffhues |
author_sort |
Francesc Ventura |
title |
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva |
title_short |
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva |
title_full |
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva |
title_fullStr |
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva |
title_full_unstemmed |
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva |
title_sort |
challenges and opportunities for drug repositioning in fibrodysplasia ossificans progressiva |
publisher |
MDPI AG |
series |
Biomedicines |
issn |
2227-9059 |
publishDate |
2021-02-01 |
description |
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 <i>ACVR1</i>, 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. |
topic |
activin ALK2 BMP bone FOP repurposed drug |
url |
https://www.mdpi.com/2227-9059/9/2/213 |
work_keys_str_mv |
AT francescventura challengesandopportunitiesfordrugrepositioninginfibrodysplasiaossificansprogressiva AT eleanorwilliams challengesandopportunitiesfordrugrepositioninginfibrodysplasiaossificansprogressiva AT makotoikeya challengesandopportunitiesfordrugrepositioninginfibrodysplasiaossificansprogressiva AT alexnbullock challengesandopportunitiesfordrugrepositioninginfibrodysplasiaossificansprogressiva AT petertendijke challengesandopportunitiesfordrugrepositioninginfibrodysplasiaossificansprogressiva AT mariejosegoumans challengesandopportunitiesfordrugrepositioninginfibrodysplasiaossificansprogressiva AT gonzalosanchezduffhues challengesandopportunitiesfordrugrepositioninginfibrodysplasiaossificansprogressiva |
_version_ |
1724260125898702848 |