Recent Progress in Drug Development for Fibrodysplasia Ossificans Progressiva

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2022 May 10

PMID 35536530

Authors

Xinmiao Meng

Haotian Wang

Jijun Hao

Affiliations

Soon will be listed here.

Abstract

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as Activin-like kinase 2 (ALK2), a type I receptor of Bone Morphogenetic Proteins(BMP). Patients with FOP usually undergo episodic flare-ups and the heterotopic ossification in soft and connective tissues. Molecular mechanism study indicates that Activin A, the ligand which normally transduces Transforming Growth Factor Beta signaling, abnormally activates BMP signaling through ALK2 mutants in FOP, leading to heterotopic bone formation. To date, effective therapies to FOP are unavailable. However, significant advances have recently been made in the development of FOP drugs. In this article, we review the recent advances in understanding the FOP mechanism and drug development, with a focus on the small-molecular and antibody drugs currently in the clinical trials for FOP treatment.

Citing Articles

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Haile A, Azale A, Ayana B Case Rep Orthop. 2025; 2025:2161762.

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Generalized Epileptic Seizures in Fibrodysplasia Ossificans Progressiva Harboring a Recurrent Heterozygous Variant of the Gene (R206H).

Mishima K, Kitoh H, Shiraki A, Sawamura K, Kamiya Y, Matsushita M Case Rep Genet. 2024; 2024:9569275.

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Targeting to BMP9 to restrain flare-up of fibrodysplasia ossificans progressiva.

Li Q, Yuan Q EMBO Mol Med. 2024; 17(1):1-2.

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Fibrodysplasia ossificans progressiva associated with osteochondromatosis: A case report.

Houssni J, Jellal S, Dehayni F, Neftah I, El Haddad S, Allali N Radiol Case Rep. 2024; 20(1):256-260.

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Cellular and Molecular Mechanisms of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva.

Mejias Rivera L, Shore E, Mourkioti F Biomedicines. 2024; 12(4).

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References

Hennequin L, Allen J, Breed J, Curwen J, Fennell M, Green T . N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem. 2006; 49(22):6465-88. DOI: 10.1021/jm060434q. View

Wolken D, Idone V, Hatsell S, Yu P, Economides A . The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva. Bone. 2017; 109:210-217. PMC: 6706059. DOI: 10.1016/j.bone.2017.06.011. View

Botello-Smith W, Alsamarah A, Chatterjee P, Xie C, Lacroix J, Hao J . Polymodal allosteric regulation of Type 1 Serine/Threonine Kinase Receptors via a conserved electrostatic lock. PLoS Comput Biol. 2017; 13(8):e1005711. PMC: 5578689. DOI: 10.1371/journal.pcbi.1005711. View

Engers D, Frist A, Lindsley C, Hong C, Hopkins C . Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective.... Bioorg Med Chem Lett. 2013; 23(11):3248-52. PMC: 3677712. DOI: 10.1016/j.bmcl.2013.03.113. View

Hao J, Ho J, Lewis J, Karim K, Daniels R, Gentry P . In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem Biol. 2009; 5(2):245-53. PMC: 2825290. DOI: 10.1021/cb9002865. View

Wang H, Shore E, Pignolo R, Kaplan F . Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone. 2017; 109:218-224. DOI: 10.1016/j.bone.2017.11.014. View

Petrakou E, Fotopoulos S, Anagnostakou M, Anatolitou F, Samitas K, Semitekolou M . Activin-A exerts a crucial anti-inflammatory role in neonatal infections. Pediatr Res. 2013; 74(6):675-81. DOI: 10.1038/pr.2013.159. View

Groppe J, Shore E, Kaplan F . Functional modeling of the ACVR1 (R206H) mutation in FOP. Clin Orthop Relat Res. 2007; 462:87-92. DOI: 10.1097/BLO.0b013e318126c049. View

Song G, Kim H, Woo K, Baek J, Kim G, Choi J . Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva. J Biol Chem. 2010; 285(29):22542-53. PMC: 2903413. DOI: 10.1074/jbc.M109.094557. View

10.

Rodriguez-Martinez G, Molina-Hernandez A, Velasco I . Activin A promotes neuronal differentiation of cerebrocortical neural progenitor cells. PLoS One. 2012; 7(8):e43797. PMC: 3425505. DOI: 10.1371/journal.pone.0043797. View

11.

Shimono K, Tung W, Macolino C, Chi A, Didizian J, Mundy C . Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med. 2011; 17(4):454-60. PMC: 3073031. DOI: 10.1038/nm.2334. View

12.

Haga N, Nakashima Y, Kitoh H, Kamizono J, Katagiri T, Saijo H . Fibrodysplasia ossificans progressiva: Review and research activities in Japan. Pediatr Int. 2019; 62(1):3-13. DOI: 10.1111/ped.14065. View

13.

Yu P, Hong C, Sachidanandan C, Babitt J, Deng D, Hoyng S . Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2007; 4(1):33-41. PMC: 2727650. DOI: 10.1038/nchembio.2007.54. View

14.

Chaikuad A, Alfano I, Kerr G, Sanvitale C, Boergermann J, Triffitt J . Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem. 2012; 287(44):36990-8. PMC: 3481300. DOI: 10.1074/jbc.M112.365932. View

15.

Loomans H, Andl C . Activin receptor-like kinases: a diverse family playing an important role in cancer. Am J Cancer Res. 2016; 6(11):2431-2447. PMC: 5126264. View

16.

Kaplan F, Zeitlin L, Dunn S, Benor S, Hagin D, Al Mukaddam M . Acute and chronic rapamycin use in patients with Fibrodysplasia Ossificans Progressiva: A report of two cases. Bone. 2017; 109:281-284. DOI: 10.1016/j.bone.2017.12.011. View

17.

Pacifici M . Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial. Bone. 2017; 109:267-275. PMC: 8011837. DOI: 10.1016/j.bone.2017.08.010. View

18.

Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y . Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study. J Clin Pharmacol. 2020; 60(11):1424-1431. PMC: 7586962. DOI: 10.1002/jcph.1638. View

19.

Xie C, Jiang W, Lacroix J, Luo Y, Hao J . Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling. Int J Mol Sci. 2020; 21(18). PMC: 7555472. DOI: 10.3390/ijms21186498. View

20.

Bocciardi R, Bordo D, Di Duca M, Di Rocco M, Ravazzolo R . Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. Eur J Hum Genet. 2008; 17(3):311-8. PMC: 2986177. DOI: 10.1038/ejhg.2008.178. View