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Introduction: Heterotopic ossification (HO), acquired or hereditary, is a diverse pathological condition defined by the production of extraskeletal bone in muscles, soft tissues, and connective tissues. Acquired HO is relatively prevalent and develops mostly in response to trauma, although its etiology is unknown. Genetic forms provide insight into the pathobiological mechanisms of this disorder. Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary form of HO that can have a significant impact on affected individuals. FOP steadily weakens affected subjects and increases their risk of death., Areas Covered: The U.S. Food and Drug Administration has recently approved the retinoid palovarotene as the first compound to treat heterotopic ossification in patients with FOP. This review provides a comprehensive overview of current and potential future pharmacotherapeutic options and their modes of action. The online databases PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched using the terms 'heterotopic ossification' and 'fibrodysplasia ossificans progressiva' or synonyms, with a special focus over the last 5 years of publications., Expert Opinion: Approval of palovarotene, as the first retinoid indicated for reduction in the volume of new HO, may revolutionize the therapeutic landscape. However, long-term safety and efficacy data for palovarotene are currently lacking.

Rare diseases and conditions have thus far received relatively less attention in the field of precision/personalized medicine than common chronic diseases. There is a dire need for orphan drug discovery and therapeutics in ways that are informed by the precision/personalized medicine scholarship. Moreover, people with rare conditions, when considered collectively across diseases worldwide, impact many communities. In this overarching context, Activin A Receptor Type 1 (ACVR1) is a transmembrane kinase from the transforming growth factor-β superfamily and plays a critical role in modulating the bone morphogenetic protein signaling. Missense variants of the ACVR1 gene result in modifications in structure and function and, by extension, abnormalities and have been predominantly linked with two rare conditions: fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. We report here an extensive bioinformatic analyses assessing the pool of 50,951 variants and forecast seven highly destabilizing mutations (R206H, G356D, R258S, G328W, G328E, R375P, and R202I) that can significantly alter the structure and function of the native protein. Protein-protein interaction and ConSurf analyses revealed the crucial interactions and localization of highly deleterious mutations in highly conserved domains that may impact the binding and functioning of the protein. cBioPortal, CanSAR Black, and existing literature affirmed the association of these destabilizing mutations with posterior fossa ependymoma, uterine corpus carcinoma, and pediatric brain cancer. The current findings suggest these deleterious nonsynonymous single nucleotide polymorphisms as potential candidates for future functional annotations and validations associated with rare conditions, further aiding the development of precision medicine in rare diseases.

The diagnosis of fibrodysplasia ossificans progressiva is missed or delayed because of its insidious precursors, especially in uncharacteristic cases. Fibrodysplasia ossificans progressiva, which mostly displayed the mutation c.617G > A, p.R206H, is characterized by congenital malformation of the great toe and progressive extra-skeletal ossification of ligaments, tendons and muscles. The mutation c.774G > C, p.R258S (HGVS: NC_000002.11:g.158626896 C > G) in activin A receptor type I is an infrequent etiology of fibrodysplasia ossificans progressiva and can present different clinical features. Awareness of these multiple clinical features will help endocrinologists in the early diagnosis of fibrodysplasia ossificans progressiva. We report a case of fibrodysplasia ossificans progressiva with the activin A receptor type I mutation c.774G > C, p.R258S, which was diagnosed before its ossifying period., (© 2024. The Author(s).)

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objectives: Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by IL-1β. This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy., Methods: Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient and describe 3 additional patients, from two medical centres., Results: All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced a resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales., Conclusion: This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing the formation of new HO., Funding: RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Case: A 62-year-old woman receiving romosozumab for 3 months underwent extreme lateral interbody fusion (XLIF) for lumbar degenerative spondylolisthesis. From 1 week after surgery, she experienced gradually increasing pain from the right groin to the front of the thigh. Examination revealed ossifying myositis in bilateral psoas major muscles. Etidronate treatment was initiated, improving pain after 4 days. Computed tomography showed lesion disappearance by 3 months after surgery., Conclusion: We report a rare case of myositis ossificans in bilateral psoas major muscles following XLIF surgery, possibly influenced by intraoperative manipulation and romosozumab treatment. Etidronate administration may be effective, as with heterotopic ossification., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C372)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2 R206H . In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2 R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2 R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2 R206H with high affinity, inhibiting signaling from ALK2 R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2 R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2 R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2 R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized., Purpose of Review: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP., Future Perspectives: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.

Here, we report the clinical pharmacology data from LUMINA-1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty-four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double-blind 28-week treatment period, followed by a 28-week open-label treatment period with garetosmab, and subsequent open-label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure-response analyses for efficacy and safety were performed with trough concentrations (C trough ) of garetosmab prior to dosing. Steady-state PK was reached 12-16 weeks after the first dose of garetosmab, with mean (standard deviation) C trough of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti-garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration-time profiles between patients who did and did not experience epistaxis or death. The comparative exposure-response analyses demonstrated no association between C trough and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target-mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial., (© 2023 Regeneron Pharmaceuticals, Inc and The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), a type I bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity of FOP-variant ACVR1 (ACVR1 FOP ) and/or hyperactivation by BMPs, it was later shown that HO in FOP requires activation of ACVR1 FOP by Activin A. Inhibition of Activin A completely prevents HO in FOP mice, indicating that Activin A is an obligate driver of HO in FOP, and excluding a key role for BMPs in this process. This discovery led to the clinical development of garetosmab, an investigational antibody that blocks Activin A. In a phase 2 trial, garetosmab inhibited new heterotopic bone lesion formation in FOP patients. In contrast, antibodies to ACVR1 activate ACVR1 FOP and promote HO in FOP mice. Beyond their potential clinical relevance, these findings have enhanced our understanding of FOP's pathophysiology, leading to the identification of fibroadipogenic progenitors as the cells that form HO, and the discovery of non-signaling complexes between Activin A and wild type ACVR1 and their role in tempering HO, and are also starting to inform biological processes beyond FOP.

Background: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design., Methods: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-‍1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies., Results: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes., Conclusions: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development., Trial Registration: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014)., (© 2023. The Author(s).)

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 ., (© 2023. The Author(s).)

Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic ossification. Since flares of the disease are associated with inflammation, it is assumed that JAK inhibitors can control active FOP due to blocking multiple signaling pathways., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Activin A receptor type I (ACVR1), a transmembrane serine/threonine kinase, belongs to the transforming growth factor-β superfamily, which signals via phosphorylating the downstream effectors and SMAD transcription factors. Its central role in several biological processes and intracellular signaling is well known. Genetic variation in ACVR1 has been associated with a rare disease, fibrodysplasia ossificans progressive, and its somatic alteration is reported in rare cancer diffuse intrinsic pontine glioma. Furthermore, altered expression or variation of ACVR1 is associated with multiple pathologies such as polycystic ovary syndrome, congenital heart defects, diffuse idiopathic skeletal hyperostosis, posterior fossa ependymoma and other malignancies. Recent advancements have witnessed ACVR1 as a potential pharmacological target, and divergent promising approaches for its therapeutic targeting have been explored. This review highlights the structural and functional characteristics of receptor ACVR1, associated signaling pathways, genetic variants in several diseases and cancers, protein-protein interaction, gene expression, regulatory miRNA prediction and potential therapeutic targeting approaches. The comprehensive knowledge will offer new horizons and insights into future strategies harnessing its therapeutic potential., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1-2/3-6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1-2/3-6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7-53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 10 3  mm 3 with palovarotene 10/5 mg; 1.3 × 10 3  mm 3 with palovarotene 5/2.5 mg; 18.0 × 10 3  mm 3 with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

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., (© 2022. The Author(s).)

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP., Methods: The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include 18 F NaF PET activity and patient reported outcome measures., Discussion: Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients., Trial Registration: EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL ., Clinicaltrials: gov , NCT04307953 . Registered 13 March 2020., (© 2022. The Author(s).)

Inhibition of mutant activin A type-1 receptor ACVR1 (ALK2) signaling by small-molecule drugs is a promising therapeutic approach to treat fibrodysplasia ossificans progressiva (FOP), an ultra-rare disease leading to progressive soft tissue heterotopic ossification with no curative treatment available to date. Here, we describe the synthesis and in vitro characterization of a novel series of 2-aminopyrazine-3-carboxamides that led to the discovery of Compound 23 showing excellent biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and a favorable in vitro ADME profile., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Palovarotene (Sohonos™) is an orally bioavailable selective retinoic acid receptor (RAR)γ agonist being developed by Ipsen for the reduction of heterotopic ossification (HO) formation in patients with fibrodysplasia ossificans progressiva (FOP). By binding to RARγ, palovarotene inhibits bone morphogenetic protein and SMAD 1/5/8 signalling: interfering with these pathways prevents chondrogenesis and ultimately HO by permitting normal muscle tissue repair or regeneration to occur. Palovarotene received its first approval on 21 January 2022 to reduce the formation of HO in adults and children aged 8 years and above for females and 10 years and above for males with FOP in Canada. This article summarizes the milestones in the development of palovarotene leading to this first approval., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The compassionate use of available medications with unproven efficacy is often in conflict with their clinical evaluation in placebo-controlled clinical trials. For ultra-rare diseases where no approved treatments exist, such as fibrodysplasia ossificans progressiva (FOP), routine clinical trial enrollment for available medications may be difficult to achieve. Therefore adaptive methods of evaluation are often desirable. Off-on-off-on (O4) approaches offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment. Here we report three children with classic FOP who had recalcitrant flare-ups of the back and who had been treated with an O4 regimen of imatinib. In all three children, fewer flare-ups, decreased swelling and improved function with activities of daily living were reported by the parents and treating physician when the children were "on" imatinib than when they were "off" imatinib. The median time to improvement on imatinib was 2-3 weeks. The anecdotal O4 experience with imatinib reported here in three children with FOP who had recalcitrant flare-ups of the back supports the design of a brief placebo controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP. A tool to prospectively measure and quantitate flare-up symptoms is presently being developed and validated and will be used for such a study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Balanced signal transduction is crucial in tissue patterning, particularly in the vasculature. Heterotopic ossification (HO) is tightly linked to vascularization with increased vessel number in hereditary forms of HO, such as Fibrodysplasia ossificans progressiva (FOP). FOP is caused by mutations in the BMP type I receptor ACVR1 leading to aberrant SMAD1/5 signaling in response to ActivinA. Whether observed vascular phenotype in human FOP lesions is connected to aberrant ActivinA signaling is unknown. Blocking of ActivinA prevents HO in FOP mice indicating a central role of the ligand in FOP. Here, we established a new FOP endothelial cell model generated from induced pluripotent stem cells (iECs) to study ActivinA signaling. FOP iECs recapitulate pathogenic ActivinA/SMAD1/5 signaling. Whole transcriptome analysis identified ActivinA mediated activation of the BMP/NOTCH pathway exclusively in FOP iECs, which was rescued to WT transcriptional levels by the drug candidate Saracatinib. We propose that ActivinA causes transcriptional pre-patterning of the FOP endothelium, which might contribute to differential vascularity in FOP lesions compared to non-hereditary HO.

Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder with heterotopic ossification (HO) in soft tissues. The abnormal activation of bone morphogenetic protein (BMP) signaling by a mutant activin receptor-like kinase-2 (ALK2) leads to the development of HO in FOP patients, and, thus, BMP signaling inhibitors are promising therapeutic applications for FOP. In the present study, we screened extracts of 188 Indonesian marine invertebrates for small molecular inhibitors of BMP-induced alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation in a C2C12 cell line stably expressing ALK2(R206H) (C2C12(R206H) cells), and identified five marine sponges with potent ALP inhibitory activities. The activity-guided purification of an EtOH extract of marine sponge Dysidea sp. (No. 256) resulted in the isolation of dysidenin ( 1 ), herbasterol ( 2 ), and stellettasterol ( 3 ) as active components. Compounds 1 - 3 inhibited ALP activity in C2C12(R206H) cells with IC 50 values of 2.3, 4.3, and 4.2 µM, respectively, without any cytotoxicity, even at 18.4-21.4 µM. The direct effects of BMP signaling examined using the Id1WT4F-luciferase reporter assay showed that compounds 1 - 3 did not decrease the reporter activity, suggesting that they inhibit the downstream of the Smad transcriptional step in BMP signaling.

The activin-like kinases are a family of kinases that play important roles in a variety of disease states. Of this class of kinases, ALK2, has been shown by a gain-of-function to be the primary driver of the childhood skeletal disease fibrodysplasia ossificans progressiva (FOP) and more recently the pediatric cancer diffuse intrinsic pontine glioma (DIPG). Herein, we report our efforts to identify a novel imidazo[1,2-a]pyridine scaffold as potent inhibitors of ALK2 with good in vivo pharmacokinetic properties suitable for future animal studies., Competing Interests: Declaration of Competing Interest The authors: D.W.E., C.W.L., C.C.H., and C.R.H. have received funding and royalties from La Jolla Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease characterized by heterotopic ossification (HO) in soft tissues and caused by a mutation of the ACVR1A/ALK2 gene. Activin-A is a key molecule for initiating the process of HO via the activation of mTOR, while rapamycin, an mTOR inhibitor, effectively inhibits the Activin-A-induced HO. However, few reports have verified the effect of rapamycin on FOP in clinical perspectives., Methods: We investigated the effect of rapamycin for different clinical situations by using mice conditionally expressing human mutant ACVR1A/ALK2 gene. We also compared the effect of rapamycin between early and episode-initiated treatments for each situation., Results: Continuous, episode-independent administration of rapamycin reduced the incidence and severity of HO in the natural course of FOP mice. Pinch-injury induced HO not only at the injured sites, but also in the contralateral limbs and provoked a prolonged production of Activin-A in inflammatory cells. Although both early and injury-initiated treatment of rapamycin suppressed HO in the injured sites, the former was more effective at preventing HO in the contralateral limbs. Rapamycin was also effective at reducing the volume of recurrent HO after the surgical resection of injury-induced HO, for which the early treatment was more effective., Conclusion: Our study suggested that prophylactic treatment will be a choice of method for the clinical application of rapamycin for FOP.

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder marked by painful, recurrent flare-ups and heterotopic ossification (HO) in soft and connective tissues, which can be idiopathic or provoked by trauma, illness, inflammation, or surgery. There are currently no effective treatments for FOP, or for patients with FOP who must undergo surgery. Palovarotene, an investigational retinoic acid receptor-γ agonist, offers a potential avenue to prevent HO formation., Case Presentation: The patient is a 32 year-old male, who at age 29 enrolled in a study evaluating palovarotene to prevent HO formation in FOP. One year after starting palovarotene, he fell resulting in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received palovarotene at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Imaging 12 weeks after surgery showed new bridging HO at the site of intramedullary rod insertion and distal screw. Nine months after the left hip fracture, the patient had a second fall resulting in a subdural hematoma, left parietal bone fracture, and right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. Palovarotene 20 mg/day was started at fracture occurrence and continued for 4 weeks, then reduced to 10 mg/day for 8 weeks. HO also formed near the insertion site of the intramedullary rod. No HO developed at the right distal intramedullary rod. After each fracture, the patient had prolonged recurrent flare-ups around the hips., Conclusion: Surgery is only rarely considered in FOP due to the high risks of procedural complications and potential for inducing HO. This case emphasizes the risks of increased flare activity and HO formation from injury and surgery in patients with FOP. The efficacy of HO prevention by palovarotene could not be assessed; however, our observation that palovarotene can be administered in an individual with FOP following surgery with no negative impact on clinical fracture healing, osteointegration, or skin healing will help facilitate future trials testing the role of palovarotene as a therapy for HO.

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling heritable connective tissue disease that is difficult to treat. This study seeks to explore the clinical characteristics, clinical manifestations, treatment and prognosis of FOP to provide a clinical basis for its early diagnosis and treatment., Methods: Twenty-six children with FOP were retrospectively analyzed in terms of their onset, clinical manifestations, auxiliary examinations and treatment., Results: Among the 26 cases, the youngest age of manifestation of mass was 8 days after birth, and the average age was 3 years and 2 months. The peak age was 2-5 years old. Inflammatory mass and toe-finger deformity are the main early clinical manifestations of the disease. These inflammatory masses often lead to hard osteogenic deposits that initially mainly involve the central axis, such as the neck (22/26, 84.6%), back (20/26, 76.9%), and head (13/26, 50%). Toe-finger deformity mainly manifests as symmetrical great toe deformity, or short and deformed thumb and little finger. The diagnosis of FOP requires typical clinical manifestations or ACVR1 gene detection. The main therapeutic drugs for FOP include glucocorticoids and non-steroidal anti-inflammatory drugs. Although not compliant with the recommended medical management of FOP, in our clinical practice children with uncontrollable illness could be treated using a variety of immunosuppressive agents in combination., Conclusions: FOP is a rare autosomal dominant heritable disease. The main clinical manifestations observed in this study were recurrent inflammatory mass and toe-finger deformity. If the diagnosis and treatment are not performed in a timely manner, serious complications are likely to affect the prognosis. Therefore, early diagnosis and active treatment should be performed.

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.

Background: Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Based on evidence, demonstrating a role for interleukin-1β (IL-1β) in other forms of heterotopic ossification, we hypothesized that treating FOP patients with anti-IL-1 agents could help lower the rate of FOP paroxysms and/or limit the symptoms and residual lesions., Case Presentation: A 13.5-year-old Arab boy was diagnosed with FOP. Treatment with anti-inflammatory drugs did not change the disease course. New lumps appeared in a rate of approximately one every 8 days. Treatment with the anti-IL-1 agents anakinra and canakinumab resulted in significantly lower rate of paroxysms (every 22-25 days, of which almost all involved only 2 existing lumps), as well as shorter duration. High levels of IL-1β were found in the patient's plasma samples, collected during a paroxysm that appeared 8 weeks after the last canakinumab dose. In contrast, IL-1β plasma levels were undetectable in the previous three plasma samples, obtained while he was treated with anti-IL-1 agents., Conclusions: Our data demonstrate the efficacy of anti-IL-1 agents in the treatment of a patient with FOP. Results showing the marked increase in IL-1β plasma levels during a paroxysm support a role for IL-1β in the pathogenesis of FOP and further provide the rationale for the use of anti-IL-1 agents in FOP treatment.

Purpose of Review: Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO., Recent Findings: Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease caused by a mutation in the intracellular domain of the activin A receptor type I and is characterized by episodes (flare-ups) of progressive heterotopic endochondral ossification (HO) in the soft tissues. The mutation alone is not sufficient for the occurrence of HO since flare-ups are triggered by inflammation and activation of the innate immune system. A number of cellular and humoral mediators have been implicated in animal and in vitro models. Observations in humans support the inflammatory nature of the condition, but data on the involved mediators are variable. We hypothesize that for induction of flare-ups in patients with FOP increase in at least one of the pro-inflammatory cytokines is both essential and sufficient to trigger the entire process of the inflammatory cells influx resulting in the novel ectopic bone formation and we suggest that C-C motif ligand 5 (CCL5), a pro-inflammatory chemokine also known as Regulated on activation, normal T-cell expressed and secreted (RANTES), might be the key candidate. CCL5 is a chemoattractant for all cellular types implicated in HO and is produced by the cells of the tissue microenvironment at the sites of HO as well as by the pro-inflammatory cellular mediators. CCL5 induces ossification in cultured human pluripotent mesenchymal cells (hMSCs) and in the primary culture of monocytes from FOP patients (but not from their healthy relatives), stimulation with lipopolysaccharide induces CCL5 expression. Finally, in a pilot study we used a panel of 23 cytokines and chemokines to screen the plasma samples of three subjects: a female patient with FOP during a flare-up; a female patient with hyperostosis corticalis generalisata (van Buchem disease), another rare disease characterized by excessive bone formation at the sites where it regularly occurs that does not include inflammatory events; and a healthy woman without bone disorders. There appeared a rather clear-cut signal of a 2-fold higher level of CCL5 in the FOP patient vs. the healthy subject and the van Buchem patient. Evaluation of the hypothesis would require an international prospective study, with main motivation being the lack of a conclusive treatment as the major unmet need in FOP. A treatment targeting CCL5 receptor already exists and is used in HIV-infected patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and significant disability. FOP is progressive and many patients are wheelchair-bound by the 3rd decade of life. FOP is caused by an activating mutation in the ACVR1 gene, which encodes the activin A Type 1 receptor. Aberrant signalling through this receptor leads to abnormal activation of the pSMAD 1/5/8 pathway and triggers the formation of bone outside of the skeleton. There is no curative therapy for FOP; however, exciting advances in novel therapies have developed recently. Here, we review the clinical and translational pharmacology of three drugs that are currently in clinical trials (palovarotene, REGN 2477 and rapamycin) as well as other emerging treatment strategies for FOP., (© 2018 The British Pharmacological Society.)

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Fibrodysplasia ossificans progressiva (FOP) or myositis ossificans, is a genetic disease, with a prevalence of 1 in 2.000.000. It is caused by pathogenic variants in ACVR1 gene and characterized by soft tissue heterotopic ossification, starting in the second decade of life. It is associated to early mortality caused by respiratory complications. It evolves in flare-ups, triggered by soft tissue injuries; therapy is symptomatic, using analgesia, steroids and diphosphonates. We report a 12-year-old female with left renal agenesis, hallux valgus and intellectual disability, presenting with a six months history of thoracic kyphosis, tender nodules in the thorax, and rigidity of right elbow and left knee. Clinical examination revealed dysmorphic facial features. A magnetic resonance showed heterotopic ossification nodules, which was confirmed with spinal radiography. These findings prompted the diagnosis of FOP. Pain treatment was started, and prednisone was used during flare-ups. The ACVR1 gene was analyzed and a pathogenic variant, p. Arg206His, was found, confirming the diagnosis of FOP.

Bone disease in the neonatal period has often been regarded as an issue affecting premature infants, or a collection of rare and ultra-rare disorders that most neonatologists will see only once or twice each year, or possibly each decade. The emergence of targeted therapies for some of these rare disorders means that neonatologists may be faced with diagnostic dilemmas that need a rapid solution in order to access management options that did not previously exist. The diagnostic modalities available to the neonatologist have not changed a great deal in recent years; blood tests and radiographs still form the mainstays with other techniques usually reserved for research studies, but rapid access to genomic testing is emergent. This paper provides an update around diagnosis and management of bone problems likely to present to the neonatologist., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs' skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation., Competing Interests: JL, SN, SS, PD, MS, MY No competing interests declared, DG The work was funded, in part, by a sponsored research agreement with Clementia Pharmaceuticals., (© 2018, Lees-Shepard et al.)

Background: Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies., Results: Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions., Conclusions: This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases., Results: Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication., Conclusions: These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1 , encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation., Competing Interests: The authors declare no conflict of interest.

Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure. This Drug Discovery, Development, and Deployment Map (4DM), provides a network view of the process, which will be useful for communication and education to those new to the field, orientation and navigation of individual projects, and prioritization of technology development and re-engineering endeavors to improve efficiency and effectiveness. The 4DM is freely available for utilization, modification, and further development by stakeholders across the translational ecosystem., (© 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Fibrodysplasia Ossificans Progressiva is a rare debilitating disorder of the musculoskeletal system affecting one in two million individuals. It is characterized by progressive extraskeletal ossification of soft tissues resulting in the original skeleton being encased in unyielding new bone leading to disability and ultimately death from cardiorespiratory failure. The present case brings to light the delays and potential pitfalls in diagnosis as a result of the rarity of the condition., Competing Interests: Conflict of interest: None declared

Fibrodysplasia ossificans progressiva is a very rare heritable disease characterized by a progressive heterotopic endochondal ossification, occurring in the first decade of life, and leading thereafter to a severe ankylosis of the spine, limbs and jaw, with a progressive and severe functional disability. To date the cause of the disease remains unknown and no medical treatment has been proved efficient. It has recently been shown that a recurrent mutation in activation domain of the activin-receptor IA (ACVR1), a BMP receptor, could lead to an abnormal signalling pathway of BMP-4 and contribute to the occurrence of the devastating lesions characteristic of the disease., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease of heterotopic endochondral ossification (HEO), and currently no effective therapies are available for this disease. A recurrent causative heterozygous mutation (c.617 G>A; R206H) for FOP was identified in activin receptor type IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor. This mutation aberrantly activates the BMP-Smad1/5/8 signaling pathway and leads to HEO in FOP patients. Here we report development of a soluble recombinant ACVR1-Fc fusion protein by combining the extracellular domain of human wild type ACVR1 and the Fc portion of human immunoglobulin gamma 1 (IgG1). The ACVR1-Fc fusion protein significantly down-regulated the dysregulated BMP signaling caused by the FOP ACVR1 mutation and effectively suppressed chondro-osseous differentiation in a previously described cellular FOP model, human umbilical vein endothelial cells (HUVECs) that were infected with adenovirus-ACVR1 R206H (HUVEC R206H ). This ACVR1-Fc fusion protein holds great promise for prevention and treatment of HEO in FOP and related diseases., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft-tissue swelling (flare-ups) that trigger the ossification process. With the aim of finding a new therapeutic strategy for FOP, we developed a high-throughput screening (HTS) assay to identify inhibitors of ACVR1 gene expression among drugs already approved for the therapy of other diseases. The screening, based on an ACVR1 promoter assay, was followed by an in vitro and in vivo test to validate and characterize candidate molecules. Among compounds that modulate the ACVR1 promoter activity, we selected the one showing the highest inhibitory effect, dipyridamole, a drug that is currently used as a platelet anti-aggregant. The inhibitory effect was detectable on ACVR1 gene expression, on the whole Smad-dependent BMP signaling pathway, and on chondrogenic and osteogenic differentiation processes by in vitro cellular assays. Moreover, dipyridamole reduced the process of heterotopic bone formation in vivo Our drug repositioning strategy has led to the identification of dipyridamole as a possible therapeutic tool for the treatment of FOP. Furthermore, our study has also defined a pipeline of assays that will be useful for the evaluation of other pharmacological inhibitors of heterotopic ossification., (© 2016. Published by The Company of Biologists Ltd.)