Steven Perez

Background: FOP stands as an enigmatic genetic disorder, marked by HO formation and debilitating musculoskeletal abnormalities.^1,6 The dysregulation of ACVR1, alias ALK2, precipitates an aberrant activation cascade, disrupting normal bone morphogenetic protein (BMP) signaling and promoting ectopic ossification.² Current therapeutic options are limited, necessitating innovative approaches to mitigate FOP’s relentless progression.³

Objective: This narrative review endeavors to elucidate the mechanistic underpinnings of FOP pathogenesis, with a particular focus on ALK2 and ACVR1 signaling pathways.² Additionally, it explores emerging therapeutic strategies targeting the dysregulated Activin A pathway, offering potential avenues for effective FOP management.¹

Search Methods: A comprehensive search was conducted utilizing the PubMed database from 2016 to 2020, employing keywords including “Fibrodysplasia Ossificans Progressiva”, “ALK2”, “ACVR1”, “Activin A signaling pathway”, and “Therapeutic interventions”.

Results: Studies reveal the pivotal role of ACVR1 mutations, particularly the R206H variant, in instigating dysregulated BMP signaling and driving HO formation in FOP, as well as the potential therapeutic effects offered from antibodies that bind ot the ALK2 receptor and the Activin A ligand itself.^5,6,7,8,9 The dysregulation of Activin A signaling pathways orchestrates aberrant cellular differentiation, inflammation, and tissue remodeling, further exacerbating FOP’s pathogenesis.³ Emerging therapeutic modalities, such as monoclonal antibodies targeting Activin A, hold promise in mitigating HO progression and alleviating clinical symptoms in FOP patients.^1,3,5,6 Additionally, contrary to the hypothesis, administration of monoclonal antibody JAB0505, which binds to the ALK2 receptor, drastically exacerbated the presence of HO in FOP mice and extended the period of lesion growth.⁶ Conversely, the administration of garetosmab, which binds to the activin A ligand itself, did not have any significant effect on existing HO lesions, but halted the formation of new HO lesions.⁸

Conclusions: The intricate interplay between ALK2 and ACVR1 signaling pathways underscores their significance in FOP pathogenesis.^1,3 Novel therapeutic interventions targeting the dysregulated Activin A pathway offer renewed hope for effective FOP management. Consideration of ALK2 and ACVR1 as potential therapeutic targets paves the way for innovative treatment strategies, offering solace to those afflicted by this debilitating condition. In summary, the elucidation of ALK2 and ACVR1’s roles in FOP pathogenesis represents a significant step forward in understanding this complex disorder.¹ By targeting the dysregulated Activin A pathway, novel therapeutic interventions such as garetosmab, hold promise in ameliorating HO progression and improving clinical outcomes for FOP patients.⁸ As research endeavors continue to unravel the intricacies of FOP’s molecular landscape, the prospect of effective therapeutic interventions grows ever closer, offering hope to individuals grappling with the burdens of this rare and debilitating condition.³

Works Cited:

1. Lin H, Shi F, Gao J, Hua P. The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator. Biosci Rep. 2019;39(8):BSR20190377. Published 2019 Aug 2. doi:10.1042/BSR20190377
2. Seefried L, Banholzer D, Fischer R, et al. Empfehlungen zur Versorgung von Patient:innen mit FOP [Recommendations for the healthcare of patients with FOP]. Orthopadie (Heidelb). 2023;52(11):924-930. doi:10.1007/s00132-023-04425-y
3. Anwar S, Yokota T. Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers. Genes (Basel). 2023;14(12):2162. Published 2023 Nov 30. doi:10.3390/genes14122162
4. Eekhoff EMW, de Ruiter RD, Smilde BJ, et al. Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles. Hum Gene Ther. 2022;33(15-16):782-788. doi:10.1089/hum.2022.023
5. Barruet E, Garcia SM, Wu J, et al. Modeling the ACVR1R206H mutation in human skeletal muscle stem cells. Elife. 2021;10:e66107. Published 2021 Nov 10. doi:10.7554/eLife.66107
6. Lees-Shepard JB, Stoessel SJ, Chandler JT, et al. An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice. J Clin Invest. 2022;132(12):e153795. doi:10.1172/JCI153795
7. Aykul S, Huang L, Wang L, et al. Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1. J Clin Invest. 2022;132(12):e153792. doi:10.1172/JCI153792
8. Di Rocco M, Forleo-Neto E, Pignolo RJ, et al. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med. 2023;29(10):2615-2624. doi:10.1038/s41591-023-02561-8
9. Collins MT. Twists in the fibrodysplasia ossificans progressiva story challenge and expand our understanding of BMP biology. J Clin Invest. 2022;132(12):e160773. doi:10.1172/JCI160773