RARE DISEASE
Fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva
Synonyms: FOP, Myositis ossificans progressiva, Stone man syndrome
Synonyms: FOP, Myositis ossificans progressiva, Stone man syndrome
Synonyms: FOP, Myositis ossificans progressiva, Stone man syndrome
Drug discovery
16
drugs
With orphan designations
Overview
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant disorder caused by ACVR1 gene mutations, leading to progressive heterotopic ossification of muscles, tendons, and ligaments. Hallmark features include congenital great toe malformations and episodic flare-ups triggered by trauma or illness, culminating in irreversible bone formation. Median survival is ~40 years, with thoracic insufficiency as the leading cause of mortality [1][2][6][13].
Therapies
Acute flares: Short-course high-dose corticosteroids within 24 hours of flare onset [2][5].
Prophylaxis: Avoid trauma/intramuscular injections; respiratory support (e.g., incentive spirometry) [7][14].
Emerging therapies: Palovarotene (BMP/ACVR1 inhibitor), CRISPR-Cas9 gene editing, and small-molecule kinase inhibitors in clinical trials [3][19].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare skin diseases
Research Papers
505 drug discovery papers about Fibrodysplasia ossificans progressiva, with 6 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
505 drug discovery papers about Fibrodysplasia ossificans progressiva, with 6 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | Palovarotene impact on fibrodysplasia ossificans progressiva (FOP): data from month 48 of the phase III MOVE trial.
Palovarotene is approved in several countries for reducing heterotopic ossification (HO) in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare, severely debilitating, genetic disorder. Approval was based on interim phase III MOVE trial (NCT03312634) analyses at month 18 (IA3), the most complete dataset considering subsequent clinical holds for futility and study restart; however, long-term data remain limited. We report exploratory, post hoc analyses of once daily palovarotene over the 48-mo MOVE trial, including time on and off treatment. The primary efficacy outcome was annualized change in new HO volume, per low-dose whole-body CT. Safety was assessed throughout. Post-baseline HO volume measurements were available for 97 palovarotene-treated patients from MOVE and 101 untreated patients from a natural history study (NHS; NCT02322255). Across 48 mo, mean annualized new HO volume was numerically lower (46.4%) in palovarotene-treated patients compared with untreated patients; however, this difference was not significant (nominal p = .0585). In patients who paused and stopped or paused and restarted palovarotene, mean annualized new HO volume appeared lower when patients received palovarotene compared with when they did not (significance not assessed). The proportions of patients with new HO and number of affected body regions were similar in palovarotene-treated patients and untreated patients (significance not assessed); flare-up rates were consistent with published literature. Adverse events were predominantly retinoid-associated mucocutaneous events. In 80 patients aged <18 yr in MOVE, palovarotene treatment occurred for a mean (SD) of 166.0 (75.2) wk; 24 (30.0%), all aged <14 yr, had premature physeal closure events. Computational analyses showed a significantly increased risk of radiographically-observed, asymptomatic new-onset vertebral deformities with palovarotene treatment. Overall, these exploratory analyses reaffirm the MOVE IA3 findings but should be interpreted with caution; potential efficacy must be weighed against the safety profile of palovarotene, particularly in growing patients. Clinical trial registration number: NCT03312634 (MOVE), NCT02322255 (NHS), and NCT02279095 (phase II OLE).
2026-08-12 | [Oral cavity sanitation in progressive form of ossificating dysplasia].
A clinical case of successful oral cavity sanitation using general anesthesia in a patient with a rare genetic disease, progressive fibrodysplasia ossificans progressiva (PFO), is presented. Special attention is paid to the technical features of performing oral cavity sanitation and general anesthesia in the context of progressive phenomena of false ankylosis of maxillofacial structures with a total lack of mouth opening function. An individualized algorithm of actions is selected at the stage of endotracheal anesthesia with nasotracheal intubation, oral cavity sanitation, and subsequent rehabilitation. The presented case demonstrates the existence of problematic patients, the lack of information about them in the medical community, and the importance of interdisciplinary collaboration between dentists, pediatricians, orthopedists, traumatologists, anesthesiologists, and other specialists to optimize treatment outcomes and prevent potential risks in the management of patients with FOP. The positive treatment outcome indicates a significant improvement in the patient's quality of life and the absence of complications.
2026-07-03 | Single-Cell dissection of fibrodysplasia ossificans progressiva identifies SPP1 as a mediator of macrophage-fibroadipogenic progenitors crosstalk.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by gain-of-function mutations in ACVR1/ALK2, leading to progressive heterotopic ossification (HO) through endochondral bone formation. Inflammatory flare-ups often precede new ossification events, but the cellular and molecular mechanisms linking immune responses to progenitor cell fate remain incompletely understood. Here, using a tamoxifen-inducible Acvr1R206H mouse model of FOP and a reproducible muscle injury protocol, we combined single-cell RNA sequencing with in vitro assays to dissect early events during lesion formation. We identified an expansion of macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in FOP mice, with both populations exhibiting inflammatory and osteochondrogenic transcriptional signatures. Cell-cell interaction analysis revealed a self-reinforcing network of cytokine signaling among MPs and a prominent MP-FAP communication axis centred on SPP1. Functional studies confirmed that SPP1 enhanced FAP osteogenic differentiation and that its inhibition partially reversed this phenotype in vitro and attenuated HO in vivo. Our findings highlight the critical role of inflammatory MPs in shaping the fate of resident stromal mesenchymal progenitors (e.g. FAP) and suggest that early immune-stromal interactions set the stage for HO. Targeting this immune-mesenchymal crosstalk may represent a potential complementary strategy for preventing or mitigating disease progression in FOP.
2026-05-31 | USP24-dependent STAT2 stabilization mediates physiologic and pathologic bone formation.
Osteoblast development must be precisely regulated, as insufficient bone formation results in low bone mass and skeletal fragility, whereas excessive osteogenesis drives heterotopic ossification (HO), the ectopic formation of bone in soft tissues. Here, we identify the deubiquitinating enzyme ubiquitin-specific peptidase 24 (USP24) as a key regulator of both physiological and pathological ossification. USP24 is highly expressed in skeletal tissues, where it promotes osteoblast development by stabilizing STAT2 through deubiquitination. Loss of USP24 reduces osteoblast differentiation and bone formation, an effect mirrored by STAT2 deficiency. Beyond physiologic bone, USP24 and STAT2 are also strongly expressed in heterotopic bones from patients with HO. In a fibrodysplasia ossificans progressiva (FOP) mouse model, recombinant adeno-associated virus (rAAV)-mediated silencing of Usp24 markedly diminished HO pathogenesis and reduced STAT2 protein levels in HO lesions. Consistently, USP24 deficiency attenuated activin A-induced bone morphogenetic protein (BMP) signaling and osteogenesis, with comparable effects observed upon Stat2 silencing. Together, these findings uncover a previously unrecognized role for USP24-STAT2 signaling in osteoblast differentiation and HO, highlighting bone-targeted USP24-STAT2 inhibition as a potential therapeutic strategy for pathologic bone formation.
2026-05-19 | Navigating Fibrodysplasia Ossificans Progressiva (FOP): Insights into Diagnosis, Management and Therapeutic Advancements
Fibrodysplasia ossificans progressiva(FOP), famously known as stoneman syndrome is a lesser-known clinical entity. This condition begins its clinical presentation at birth. Delay in diagnosis or wrong diagnosis leads to unnecessary procedures which leads to worsening of the condition. The goal of this article is to review the existing literature on epidemiology, clinical presentation and relevant aspects for the diagnosis and treatment options for FOP. In addition, we also briefed about the ongoing research activities on this condition. FOP classically presents as congenital bilateral great toe deformity and early onset progressive heterotrophic ossification that can result in a deformed secondary skeleton. There occur several flare-ups during lifetime that can be triggered by seemingly minor trauma such as intramuscular immunisation, influenza-like viral illnesses, pulmonary infections, blunt muscle trauma, muscle fatigue, etc. There are no known predilection or risk factors for occurrence of this disease. Since August 2023, Sohonos (palovarotene) capsules have been approved by the U.S. Food and Drug Administration (FDA) to reduce the volume of extra-skeletal bone formation, or new heterotopic ossification, in adults and children with FOP who are 8 years of age or older for females and 10 years of age or older for males. Ongoing clinical trials are evaluating additional therapies, such as Garetosmab and Saracatinib, for their potential to manage flare-ups and prevent new heterotopic ossification.
proteins
2025-05-26 | Combined rapamycin and mesenchymal stem/stromal cells derived from induced pluripotent stem cells-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by extraskeletal heterotopic ossification (HO). The underlying mechanism is the aberrant activation of bone morphogenetic protein (BMP) signaling caused by a point mutation in the ACVR1 gene. Although FOP is an ultra-rare disease, its symptoms severely impair patients' daily activities and quality of life. Furthermore, the HO is also observed in broader clinical contexts, including major surgeries and trauma, highlighting the significance of its study. We have previously reported that rapamycin suppressed Activin-A-triggered progression of cartilage formation in FOP mice. We recently found that the ACVR2B-Fc fusion protein produced by mesenchymal stem/stromal cells derived from induced pluripotent stem cells (iMSCs) attenuates BMP signaling activated by Activin-A and BMP-9 in FOP patient-derived iMSCs. Transplantation of ACVR2B-Fc-producing iMSCs (iMSC2B-Fc/Luci) reduces primary HO in FOP mice. In this study, we found that intraperitoneal administration of rapamycin reduced primary HO in a dose-dependent manner in FOP-ACVR1R206H transgenic mice. A low concentration of rapamycin (0.3 mg/kg, 5 times/wk) efficiently suppressed chondrogenesis. The combination of iMSC2B-Fc/Luci transplantation with low concentration of rapamycin significantly reduced primary and recurrent HO. Rapamycin improved cell survival in transplanted iMSC2B-Fc/Luci cells by attenuating chemokine secretion, likely resulting in improved ACVR2B-Fc fusion protein production. Our results suggest that combining stem cell therapy and rapamycin can reduce primary HO and surgery-induced HO.
2024-03-18 | iMSC-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva
Abstract Background Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP. Methods In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSC ACVR2B-Fc ), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1 R206H , female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSC ACVR2B-Fc on BMP signaling pathways and HO development, respectively. Results We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs. Conclusions These results offer a new perspective for treating FOP through stem cell therapy.
2023-02-14 | TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGFβ1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGFβ1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNFα and IL6 produced negligible levels of Activin A and TGFβ1 in both cell groups. We present for the first time TGFβ1 as a triggering factor of Activin A production in FOP. As TGFβ1 can promote the induction of the main driver of FOP, TGFβ1 could also be considered a possible therapeutic target in FOP treatment.
2023-02-01 | Interleukin 6 promotes BMP9-induced osteoblastic differentiation through Stat3/mTORC1 in mouse embryonic fibroblasts
Interleukin 6 (IL-6) plays a dual role in regulating bone metabolism, although the concrete mechanism is unclear. Bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic inducers, and a promising alternative for bone tissue engineering. The relationship between IL-6 and BMP9 in osteogenic differentiation remains to be elucidated, and the osteoblastic potential of BMP9 needs to be enhanced to overcome certain shortcomings of BMP9. In this study, we used real-time PCR, western blot, immunofluorescent stain, fetal limb culture and cranial defects repair model to explore the IL-6 role in BMP9-induced osteogenic differentiation in mouse embryonic fibroblasts (MEFs). We found that the rat serum level of IL-6 was increased in the dexamethasone-induced osteoporosis model, and IL-6 expression was detectable in several progenitor cells and MEFs. BMP9 upregulated IL-6 in MEFs, and the BMP9-induced osteoblastic markers were elevated by IL-6, but reduced by IL-6 knockdown. BMP9 and/or IL-6 both activated mTOR, and the IL-6 effect on BMP9-induced osteoblastic markers and bone formation were reduced greatly by mTOR inhibition. Raptor was up-regulated by IL-6 and/or BMP9 specifically, and the osteoblastic markers induced by IL-6 and/or BMP9 were reduced by Raptor knockdown. Meanwhile, Stat-3 was activated by IL-6 and/or BMP9, and the increase of Raptor or osteoblastic markers by IL-6 and/or BMP9 were reduced by Stat-3 inhibition. The Raptor promoter activity was regulated by p-Stat-3. Our finding suggested that IL-6 can promote the BMP9 osteoblastic potential, which may be mediated through activating Stat-3/mTORC1 pathway.
2022-11-30 | Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification.
Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild-type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild-type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally overexpress human wild-type ACVR1. Injury-induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild-type receptor were targeted to Tie2-positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1R206H/+ mice was rescued by constitutive ACVR1 overexpression, and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive overexpression of ACVR1 also provided protection from spontaneous abnormal skeletogenesis, and the incidence and severity of injury-induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 overexpression functions cell-autonomously by reducing osteogenic signaling in response to activin A. We propose that ACVR1 overexpression inhibits HO by decreasing the abundance of ACVR1(R206H)-containing signaling complexes at the cell surface while increasing the representation of activin-A-bound non-signaling complexes comprised of wild-type ACVR1. © 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).
gene therapies
2026-02-16 | Advances in genetic and pharmacological therapeutic strategies for fibrodysplasia ossificans progressiva
A very rare, severe genetic condition known as fibrodysplasia ossificans progressiva (FOP) is characterized by progressive heterotopic ossification of soft tissues caused on by mutations in the ACVR1 gene, particularly R206H, which results in abnormal BMP signalling. This condition causes severe mobility limitations and life-threatening complications. The goal of this review is to thoroughly examine current developments in stem cell, pharmacologic, and genetic therapy for FOP and assess their potential for translation in clinical settings. Current understanding highlights that mutant ACVR1 receptors respond abnormally to Activin A, triggering pathological ossification. Innovations such as CRISPR-Cas9 gene editing, antisense oligonucleotides, and RNA interference show promise in correcting or silencing these mutations. Several Pharmacological advances include saracatinib (evaluated in Phase II studies), garetosmab (anti-Activin A antibody with early clinical data), and palovarotene which received FDA approval in August 2023 for reducing HO in FOP. Though post-marketing data highlight ongoing concerns regarding growth-plate toxicity and long-term skeletal safety. However, significant translational challenges persist, including limited long-term safety data, heterogeneous patient responses, and gaps between preclinical success and clinical efficacy. Stem cell therapies using MSCs and iPSCs offer regenerative potential and personalized modeling platforms. Smart drug delivery devices and precision medicine techniques guided by biomarkers improve therapy targeting and monitoring. Although there are still issues with delivery, safety, and long-term effectiveness, a mix of targeted medications, gene-based treatments, and cutting-edge technology is opening the door to precision and combination therapies, which provide patients with FOP fresh hope for better results.
2025-09-03 | Fibrodysplasia ossificans progressiva: molecular genetic causes, clinical and morphological characteristics, and therapeutic approaches to treatment
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic disorder with a prevalence of approximately 1 case per 1.5–2.0 million individuals. The primary cause of the disease lies in mutations of the ACVR1 gene, which encodes the homonymous receptor involved in the regulation of bone histogenesis. The most common genetic variant is the 617GA single nucleotide substitution (R206H, rs121912678), resulting in the replacement of arginine with histidine. This variant is observed in over 95% of all registered patients with fibrodysplasia ossificans progressiva. The mutation disrupts intracellular signaling, leading to the formation of abnormal heterotopic bone tissue in muscles, tendons, and ligaments. The clinical presentation may vary: some patients experience additional symptoms presumably associated with rare mutations in other domains of the ACVR1 receptor. Despite active research, the exact precursor cells responsible for pathological osteogenesis remain unidentified. Scientists hypothesize the involvement of multiple cell types, including mesenchymal stem cells and endothelial cells. Currently, no effective treatment exists for fibrodysplasia ossificans progressiva, underscoring the urgent need for novel therapeutic targets. Gene therapy, successfully employed in other monogenic disorders, represents a promising direction. Several experimental approaches, including targeted inhibitors of the ACVR1 signaling pathway, are undergoing preclinical and clinical trials.
2024-05-23 | Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases.
Adeno-associated viral (AAV) vectors have emerged as crucial tools in advancing gene therapy for skeletal diseases, offering the potential for sustained expression with low postinfection immunogenicity and pathogenicity. Preclinical studies support both the therapeutic efficacy and safety of these vectors, illustrating the promise of AAV-mediated gene therapy. Emerging technologies and innovations in AAV-mediated gene therapy strategies, such as gene addition, gene replacement, gene silencing, and gene editing, offer new approaches to clinical application. Recently, the increasing preclinical applications of AAV to rare skeletal diseases, such as fibrodysplasia ossificans progressiva (FOP) and osteogenesis imperfecta (OI), and prevalent bone diseases, such as osteoporosis, bone fracture, critical-sized bone defects, and osteoarthritis, have been reported. Despite existing limitations in clinical use, such as high cost and safety, the AAV-mediated gene transfer platform is a promising approach to deliver therapeutic gene(s) to the skeleton to treat skeletal disorders, including those otherwise intractable by other therapeutic approaches. This review provides a comprehensive overview of the therapeutic advancements, challenges, limitations, and solutions within AAV-based gene therapy for prevalent and rare skeletal diseases.
2023-09-08 | AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human ACVR1R206H (Acvr1R206H/+) while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1opt) and artificial miRNAs targeting Activin A and its receptor ACVR1R206H ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of Acvr1R206H/+ skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in Acvr1R206H/+ mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP.
2023-07-28 | Novel Therapeutic Targets for Fibrodysplasia Ossificans Progressiva: Emerging Strategies and Future Directions
Fibrodysplasia ossificans progressiva (FOP), also known as Stoneman syndrome, is a rare genetic disorder characterized by abnormal bone development caused by activating mutations of the ACVR1 gene. FOP affects both the developmental and postnatal stages, resulting in musculoskeletal abnormalities and heterotopic ossification. Current treatment options for FOP are limited, emphasizing the need for innovative therapeutic approaches. Challenges in the development of management criteria for FOP include difficulties in recruitment due to the rarity of FOP, disease variability, the absence of reliable biomarkers, and ethical considerations regarding placebo-controlled trials. This narrative review provides an overview of the disease and explores emerging strategies for FOP treatment. Gene therapy, particularly the CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9) system, holds promise in treating FOP by specifically targeting the ACVR1 gene mutation. Another gene therapy approach being investigated is RNA interference, which aims to silence the mutant ACVR1 gene. Small molecule inhibitors targeting glycogen synthase kinase-3β and modulation of the bone morphogenetic protein signaling pathway are also being explored as potential therapies for FOP. Stem cell-based approaches, such as mesenchymal stem cells and induced pluripotent stem cells, show potential in tissue regeneration and inhibiting abnormal bone formation in FOP. Immunotherapy and nanoparticle delivery systems provide alternative avenues for FOP treatment.
oligonucleotides
2026-06-29 | Precision RNAi for Fibrodysplasia Ossificans Progressiva: a combinatorial, unimolecular, allele selective approach.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder caused by a dominant mutation in the ACVR1 gene (R206H, 97% of cases), leading to debilitating heterotopic ossification (HO) characterized by abnormal bone growth triggered by inflammatory flare-ups. Here, we report the development of disease-modifying, allele-selective small interfering RNA (siRNA) targeting ACVR1 R206H . Allele selectivity is essential as wildtype ACVR1 is crucial for many functions including skeletal homeostasis and development. When conjugated to docosanoic acid (DCA), administration of the fully modified ACVR1 siRNA, either alone or in combination with an siRNA targeting IL1B (a key regulator of inflammation), results in profound reduction of HO using both responsive (post-trauma) and preventative (pre-trauma) intervention strategies in a murine FOP model. Notably, the combination therapy outperforms modulation of either target alone. We also describe the chemical engineering of a new class of lipophilic divalent siRNAs that target both pathways with a single compound, demonstrating superior muscle accumulation and therapeutic efficacy. siRNA treatment inhibits key signaling pathways (e.g. inflammatory, WNT, Notch, Hedgehog, and TGF-β), within muscle-resident fibroadipogenic progenitors (FAPs), leading to a significant reduction in cartilage, bone, and connective tissue formation. This work establishes a foundation for the development of disease-modifying treatments for FOP and offers a platform for targeting other musculoskeletal disorders involving multi-pathway dysregulation.
2026-06-22 | Single-base 2'OMe-modified LNA and MOE gapmers selectively silence ACVR1 R206H in fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder caused by gain-of-function mutations in ACVR1, most commonly c.617G>A (R206H), leading to progressive heterotopic ossification. In this study, we developed novel antisense gapmers selectively targeting the mutant ACVR1 R206H transcript while sparing the wild-type allele. We engineered locked nucleic acid (LNA) and 2'-O-methoxyethyl (MOE) gapmers incorporating a single 2'-O-methyl (2'OMe) modification at gap position 2. This is hypothesized to synergize with the wild-type sequence mismatch to restrict RNase H1 cleavage, limiting wild-type degradation while preserving mutant target engagement. In FOP patient-derived fibroblasts carrying the endogenous ACVR1 R206H mutation and in murine-derived C2C12 cells ectopically expressing ACVR1 R206H constructs, 2'OMe-modified gapmers demonstrated robust and preferential suppression of ACVR1 R206H at both RNA and protein levels. Gapmer treatment also reduced osteogenic differentiation, as shown by decreased alkaline phosphatase and Alizarin Red S staining, and lower expression of osteogenic markers. In wild-type mice, 2'OMe modification was associated with higher apparent gapmer levels in skeletal muscle and tendon and lower hepatic and renal stress marker readouts. These findings provide preliminary proof-of-concept that a single-base chemical modification can modulate allele selectivity and biodistribution of gapmers targeting ACVR1 R206H . Further studies in disease-relevant FOP models will be needed to establish therapeutic efficacy and long-term safety.
2022-11-29 | Functional Testing of Bone Morphogenetic Protein (BMP) Pathway Variants Identified on Whole-Exome Sequencing in a Patient with Delayed-Onset Fibrodysplasia Ossificans Progressiva (FOP) Using ACVR1R206H -Specific Human Cellular and Zebrafish Models.
Bone morphogenetic protein (BMP) signaling is critical in skeletal development. Overactivation can trigger heterotopic ossification (HO) as in fibrodysplasia ossificans progressiva (FOP), a rare, progressive disease of massive HO formation. A small subset of FOP patients harboring the causative ACVR1R206H mutation show strikingly mild or delayed-onset HO, suggesting that genetic variants in the BMP pathway could act as disease modifiers. Whole-exome sequencing of one such patient identified BMPR1AR443C and ACVR2AV173I as candidate modifiers. Molecular modeling predicted significant structural perturbations. Neither variant decreased BMP signaling in ACVR1R206H HEK 293T cells at baseline or after stimulation with BMP4 or activin A (AA), ligands that activate ACVR1R206H signaling. Overexpression of BMPR1AR443C in a Tg(ACVR1-R206Ha) embryonic zebrafish model, in which overactive BMP signaling yields ventralized embryos, did not alter ventralization severity, while ACVR2AV173I exacerbated ventralization. Co-expression of both variants did not affect dorsoventral patterning. In contrast, BMPR1A knockdown in ACVR1R206H HEK cells decreased ligand-stimulated BMP signaling but did not affect dorsoventral patterning in Tg(ACVR1-R206Ha) zebrafish. ACVR2A knockdown decreased only AA-stimulated signaling in ACVR1R206H HEK cells and had no effect in Tg(ACVR1-R206Ha) zebrafish. Co-knockdown in ACVR1R206H HEK cells decreased basal and ligand-stimulated signaling, and co-knockdown/knockout (bmpr1aa/ab; acvr2aa/ab) decreased Tg(ACVR1-R206Ha) zebrafish ventralization phenotypes. Our functional studies showed that knockdown of wild-type BMPR1A and ACVR2A could attenuate ACVR1R206H signaling, particularly in response to AA, and that ACVR2AV173I unexpectedly increased ACVR1R206H -mediated signaling in zebrafish. These studies describe a useful strategy and platform for functionally interrogating potential genes and genetic variants that may impact the BMP signaling pathway. © 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).
2022-06-06 | Allele-Selective LNA Gapmers for the Treatment of Fibrodysplasia Ossificans Progressiva Knock Down the Pathogenic ACVR1R206H Transcript and Inhibit Osteogenic Differentiation.
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by episodic heterotopic ossification. The median life span of people with this disorder is ∼40 years, and currently, there is no effective treatment available. More than 95% of cases are caused by a recurrent mutation (c.617G>A; R206H) of Activin A receptor, type I (ACVR1)/Activin receptor-like kinase-2 (ALK2), a bone morphogenetic protein type I receptor. The mutation renders ACVR1 responsive to activin A, which does not activate wild-type ACVR1. Ectopic activation of ACVR1R206H by activin A induces heterotopic ossification. Since ACVR1R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of mutated ACVR1. To accomplish this goal, we developed locked nucleic acid (LNA) gapmers. These are short DNA oligonucleotides with LNA modification at both ends. They induce targeted mRNA degradation and specific knockdown of gene expression. We demonstrated that some of these gapmers efficiently knocked down ACVR1R206H expression at RNA levels, while ACVR1WT was mostly unaffected in human FOP fibroblasts. Also, the gapmers suppressed osteogenic differentiation induced by ACVR1R206H and activin A. These gapmers may be promising drug candidates for FOP. This novel strategy will also pave the way for antisense-mediated therapy of other autosomal dominant disorders.
2018-08-31 | Morpholino-Mediated Exon Skipping Targeting Human ACVR1/ALK2 for Fibrodysplasia Ossificans Progressiva
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive heterotopic ossification. More than 95% of cases are caused by a recurrent mutation (617G>A; R206H) of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. Recent studies revealed that ACVR1R206H induces heterotopic ossification by aberrant activation in response to activin A. Because ACVR1R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of ACVR1 in patients. Here, we describe a method to reduce ACVR1 expression in FOP patient cells by exon skipping in ACVR1 mRNAs using phosphorodiamidate morpholino oligomers (PMOs). This strategy can be applied to the screen to select antisense oligomers to knockdown not only ACVR1 but also genes which cause other autosomal-dominant genetic diseases.
other
2026-09-28 | Efficacy and safety of garetosmab, an activin A-blocking antibody, in fibrodysplasia ossificans progressiva (OPTIMA): a randomised, double-blind, placebo-controlled, phase 3 trial.
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder resulting in progressive heterotopic ossification of ligaments, tendons, and muscles, leading to disability and early mortality. FOP is caused by heterozygous gain-of-function mutations in the activin receptor type 1A, allowing this receptor to be aberrantly activated by activin A (ActA), which normally inhibits this receptor, thus driving heterotopic bone formation. In preclinical models and an earlier phase 2 trial (LUMINA-1) in FOP, an antibody blocking ActA (garetosmab) prevented heterotopic ossification. We aimed to evaluate the efficacy and safety of garetosmab in adults living with FOP. OPTIMA is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 18 study sites across 16 countries and regions. Participants aged 18 years or older with FOP were randomly assigned (1:1:1) to monthly intravenous placebo, garetosmab 3 mg/kg, or garetosmab 10 mg/kg. Randomisation was stratified by baseline Cumulative Analogue Joint Involvement Scale score and previous participation in the LUMINA-1 study. The primary efficacy and safety endpoints were total number of new heterotopic bone lesions at week 56 and treatment-emergent adverse events of special interest (AESIs) through week 56, analysed in all randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT05394116); the trial is active (completed primary endpoint) but not recruiting participants. Between Nov 21, 2022, and July 4, 2024, 63 participants were enrolled and randomly assigned (placebo, n=21; garetosmab 3 mg/kg, n=19; garetosmab 10 mg/kg, n=23). The mean age was 26·6 years (SD 6·8); 38 (60%) participants were female and 25 (40%) male. 62 participants completed 56 weeks of treatment; one participant in the placebo group discontinued at 53 weeks. The total number of new heterotopic bone lesions was significantly lower with garetosmab: there were 19 lesions with placebo versus one lesion with garetosmab 3 mg/kg (rate ratio vs placebo: 0·06 [95% CI 0·00-0·73]; p=0·027) and two lesions with garetosmab 10 mg/kg (rate ratio vs placebo: 0·10 [0·01-0·76]; p=0·026). Treatment-emergent AESIs occurred in one (5%) of 21 participants receiving placebo, zero of 19 receiving garetosmab 3 mg/kg, and four (17%) of 23 receiving garetosmab 10 mg/kg; all were considered treatment-related. No deaths occurred. Garetosmab substantially reduced the number of new heterotopic bone lesions, providing robust evidence of its potential to be an efficacious and generally well tolerated disease-modifying therapy for FOP. Regeneron Pharmaceuticals.
2026-05-04 | Heterotopic Ossification: Molecular Drivers, Subtype-Specific Mechanisms, and Translational Therapeutic Advances.
Heterotopic ossification (HO), the pathological formation of mature bone in non-skeletal soft tissues (e.g., muscles, tendons), severely impairs patient mobility and quality of life. Despite decades of research, systematic analysis of signaling networks across HO subtypes (acquired traumatic HO, hereditary Fibrodysplasia Ossificans Progressiva (FOP), Progressive Osseous Heteroplasia (POH)) remains insufficient, and clinical therapies suffer from high recurrence and severe side effects. This review synthesizes recent advances in HO pathogenesis: FOP involves gain-of-function activin A receptor type I (ACVR1) mutations (mostly R206H), disrupting bone morphogenetic protein (BMP)/Activin A signaling; POH arises from paternal guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) loss-of-function mutations, derepressing Hedgehog signaling via reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activity; tHO features trauma-induced inflammation/hypoxia activating BMP/transforming growth factor-beta (TGF-β) pathways. Key signaling crosstalk (e.g., BMP-Yes-associated protein (YAP)-Indian hedgehog (IHH)) is integrated, and novel therapies (ACVR1 inhibitors, Activin A antibodies, retinoic acid receptor gamma (RARγ) agonists, adeno-associated virus (AAV)-mediated ACVR1 silencing) are highlighted, with emphasis on subtype-specific efficacy. A stratified, mechanism-based HO management framework is proposed, aiming to accelerate precision therapy development and advance understanding of aberrant tissue regeneration.
2026-04-17 | Gut microbiome-dependent IL-1 signaling is a mediator of ACVR1R206H-driven heterotopic ossification.
Inflammatory diseases cause significant morbidity and mortality, but their pathobiology is often difficult to dissect due to complex genetic-environmental interactions. Genetic forms of heterotopic ossification, such as fibrodysplasia ossificans progressiva (FOP), reduce genetic variability, allowing careful dissection of non-genetic drivers of inflammation. While >95% of FOP patients harbor the ACVR1 R206H mutation, patients exhibit significant variability in disease progression, suggesting a role of environmental drivers. Here, we identify the gut microbiome as a regulator of inflammation-driven HO in FOP. Metagenomic profiling of cohabitating FOP/unaffected sibling pairs revealed a pathogenic gut microbiome profile in FOP patients (Bray-Curtis, p < 0.05). In Pdgfrα-Cre/Acvr1 R206H (FOP) mice, gut microbiome ablation by antibiotics reduced spontaneous HO formation (47.4% reduction, p < 0.05) and reduced plasma IL-1 pathway activity. IL-1β blockade in FOP mice suppressed trauma-induced HO formation. These findings identify a gut microbiome-IL-1-HO axis with modifiable targets for developing treatments for HO and related inflammatory conditions.
2026-04-15 | A bio-inspired computational pipeline for antibody screening and repurposing.
Therapeutic antibody discovery is central to modern drug development, yet conventional methods such as hybridoma and phage display remain slow, inefficient, and costly. Computational approaches including site-saturation mutagenesis often yield limited affinity gains and expression liabilities, while deep learning and generative models expand sequence diversity but suffer from low validation rates. Here, we present a multi-scale computational screening pipeline inspired by key principles of in vivo immune selection. The framework integrates structure-based docking (ZDock), graph neural network-based interaction prediction, and accelerated molecular dynamics (MDs) with metadynamics free-energy profiling to enable high-throughput in silico prioritization of structure-resolved antibodies. Applied to Activin A, a pleiotropic cytokine implicated in fibrosis, oncology, and muscle-wasting disorders, the platform screened ~5000 antibody structures and identified 11 candidates. Experimental validation confirmed two binders, with Ab4 exhibiting sub-nanomolar affinity (KD = 0.38 nM) and potent neutralizing activity, underscoring therapeutic potential in fibrodysplasia ossificans progressiva (FOP) and related diseases. Rather than performing full iterative affinity maturation, the present study focuses on the screening and repurposing stage, with affinity maturation positioned as a prospective extension. This work demonstrates the feasibility of integrating AI-driven interaction prediction with physics-based simulations to accelerate structure-guided antibody screening and repurposing, while conceptually paralleling selected stages of immune selection rather than fully recapitulating immune evolution.
2026-01-07 | Fibrodysplasia ossificans progressiva: from clinical complexity to therapeutic opportunity
Abstract Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare and severely disabling genetic disorder affecting approximately one in two million individuals worldwide. It is characterised by progressive endochondral heterotopic ossification (HO), in which ectopic cartilage formation precedes and directs subsequent bone formation within muscles, tendons, and ligaments. Activating mutations in the ACVR1 gene—most commonly the R206H variant—cause dysregulated bone morphogenetic protein (BMP) signaling through both SMAD-dependent and SMAD-independent pathways, leading to inappropriate osteogenic differentiation. Clinically, FOP presents with congenital great toe malformations and recurrent, painful flare-ups that progressively restrict mobility and cause complications such as thoracic insufficiency, ankylosis, and hearing loss. Early genetic diagnosis is critical to avoid iatrogenic harm. Current treatments rely on corticosteroids and NSAIDs, while Palovarotene—a selective retinoic acid receptor gamma agonist approved by the FDA in 2023—marks a major therapeutic advance despite safety limitations. Our review integrates recent breakthroughs, including Phase 3 Garetosmab results and ongoing trials of STOPFOP, INCB000928, and IPN60130, alongside emerging insights into fibro-adipogenic progenitors and molecular mechanisms of HO. Incorporation of regional case analyses from India, together with global data, strengthens the clinical relevance for low- and middle-income regions where FOP remains underreported. This comprehensive review provides the most current translational perspective on FOP, highlighting the alarming need for continued innovation to improve patient outcomes.
small molecules
2026-09-22 | Palovarotene impact on fibrodysplasia ossificans progressiva (FOP): data from month 48 of the phase III MOVE trial.
Palovarotene is approved in several countries for reducing heterotopic ossification (HO) in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare, severely debilitating, genetic disorder. Approval was based on interim phase III MOVE trial (NCT03312634) analyses at month 18 (IA3), the most complete dataset considering subsequent clinical holds for futility and study restart; however, long-term data remain limited. We report exploratory, post hoc analyses of once daily palovarotene over the 48-mo MOVE trial, including time on and off treatment. The primary efficacy outcome was annualized change in new HO volume, per low-dose whole-body CT. Safety was assessed throughout. Post-baseline HO volume measurements were available for 97 palovarotene-treated patients from MOVE and 101 untreated patients from a natural history study (NHS; NCT02322255). Across 48 mo, mean annualized new HO volume was numerically lower (46.4%) in palovarotene-treated patients compared with untreated patients; however, this difference was not significant (nominal p = .0585). In patients who paused and stopped or paused and restarted palovarotene, mean annualized new HO volume appeared lower when patients received palovarotene compared with when they did not (significance not assessed). The proportions of patients with new HO and number of affected body regions were similar in palovarotene-treated patients and untreated patients (significance not assessed); flare-up rates were consistent with published literature. Adverse events were predominantly retinoid-associated mucocutaneous events. In 80 patients aged <18 yr in MOVE, palovarotene treatment occurred for a mean (SD) of 166.0 (75.2) wk; 24 (30.0%), all aged <14 yr, had premature physeal closure events. Computational analyses showed a significantly increased risk of radiographically-observed, asymptomatic new-onset vertebral deformities with palovarotene treatment. Overall, these exploratory analyses reaffirm the MOVE IA3 findings but should be interpreted with caution; potential efficacy must be weighed against the safety profile of palovarotene, particularly in growing patients. Clinical trial registration number: NCT03312634 (MOVE), NCT02322255 (NHS), and NCT02279095 (phase II OLE).
2026-08-12 | [Oral cavity sanitation in progressive form of ossificating dysplasia].
A clinical case of successful oral cavity sanitation using general anesthesia in a patient with a rare genetic disease, progressive fibrodysplasia ossificans progressiva (PFO), is presented. Special attention is paid to the technical features of performing oral cavity sanitation and general anesthesia in the context of progressive phenomena of false ankylosis of maxillofacial structures with a total lack of mouth opening function. An individualized algorithm of actions is selected at the stage of endotracheal anesthesia with nasotracheal intubation, oral cavity sanitation, and subsequent rehabilitation. The presented case demonstrates the existence of problematic patients, the lack of information about them in the medical community, and the importance of interdisciplinary collaboration between dentists, pediatricians, orthopedists, traumatologists, anesthesiologists, and other specialists to optimize treatment outcomes and prevent potential risks in the management of patients with FOP. The positive treatment outcome indicates a significant improvement in the patient's quality of life and the absence of complications.
2026-07-03 | Single-Cell dissection of fibrodysplasia ossificans progressiva identifies SPP1 as a mediator of macrophage-fibroadipogenic progenitors crosstalk.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by gain-of-function mutations in ACVR1/ALK2, leading to progressive heterotopic ossification (HO) through endochondral bone formation. Inflammatory flare-ups often precede new ossification events, but the cellular and molecular mechanisms linking immune responses to progenitor cell fate remain incompletely understood. Here, using a tamoxifen-inducible Acvr1R206H mouse model of FOP and a reproducible muscle injury protocol, we combined single-cell RNA sequencing with in vitro assays to dissect early events during lesion formation. We identified an expansion of macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in FOP mice, with both populations exhibiting inflammatory and osteochondrogenic transcriptional signatures. Cell-cell interaction analysis revealed a self-reinforcing network of cytokine signaling among MPs and a prominent MP-FAP communication axis centred on SPP1. Functional studies confirmed that SPP1 enhanced FAP osteogenic differentiation and that its inhibition partially reversed this phenotype in vitro and attenuated HO in vivo. Our findings highlight the critical role of inflammatory MPs in shaping the fate of resident stromal mesenchymal progenitors (e.g. FAP) and suggest that early immune-stromal interactions set the stage for HO. Targeting this immune-mesenchymal crosstalk may represent a potential complementary strategy for preventing or mitigating disease progression in FOP.
2026-05-31 | USP24-dependent STAT2 stabilization mediates physiologic and pathologic bone formation.
Osteoblast development must be precisely regulated, as insufficient bone formation results in low bone mass and skeletal fragility, whereas excessive osteogenesis drives heterotopic ossification (HO), the ectopic formation of bone in soft tissues. Here, we identify the deubiquitinating enzyme ubiquitin-specific peptidase 24 (USP24) as a key regulator of both physiological and pathological ossification. USP24 is highly expressed in skeletal tissues, where it promotes osteoblast development by stabilizing STAT2 through deubiquitination. Loss of USP24 reduces osteoblast differentiation and bone formation, an effect mirrored by STAT2 deficiency. Beyond physiologic bone, USP24 and STAT2 are also strongly expressed in heterotopic bones from patients with HO. In a fibrodysplasia ossificans progressiva (FOP) mouse model, recombinant adeno-associated virus (rAAV)-mediated silencing of Usp24 markedly diminished HO pathogenesis and reduced STAT2 protein levels in HO lesions. Consistently, USP24 deficiency attenuated activin A-induced bone morphogenetic protein (BMP) signaling and osteogenesis, with comparable effects observed upon Stat2 silencing. Together, these findings uncover a previously unrecognized role for USP24-STAT2 signaling in osteoblast differentiation and HO, highlighting bone-targeted USP24-STAT2 inhibition as a potential therapeutic strategy for pathologic bone formation.
2026-05-19 | Navigating Fibrodysplasia Ossificans Progressiva (FOP): Insights into Diagnosis, Management and Therapeutic Advancements
Fibrodysplasia ossificans progressiva(FOP), famously known as stoneman syndrome is a lesser-known clinical entity. This condition begins its clinical presentation at birth. Delay in diagnosis or wrong diagnosis leads to unnecessary procedures which leads to worsening of the condition. The goal of this article is to review the existing literature on epidemiology, clinical presentation and relevant aspects for the diagnosis and treatment options for FOP. In addition, we also briefed about the ongoing research activities on this condition. FOP classically presents as congenital bilateral great toe deformity and early onset progressive heterotrophic ossification that can result in a deformed secondary skeleton. There occur several flare-ups during lifetime that can be triggered by seemingly minor trauma such as intramuscular immunisation, influenza-like viral illnesses, pulmonary infections, blunt muscle trauma, muscle fatigue, etc. There are no known predilection or risk factors for occurrence of this disease. Since August 2023, Sohonos (palovarotene) capsules have been approved by the U.S. Food and Drug Administration (FDA) to reduce the volume of extra-skeletal bone formation, or new heterotopic ossification, in adults and children with FOP who are 8 years of age or older for females and 10 years of age or older for males. Ongoing clinical trials are evaluating additional therapies, such as Garetosmab and Saracatinib, for their potential to manage flare-ups and prevent new heterotopic ossification.
proteins
2025-05-26 | Combined rapamycin and mesenchymal stem/stromal cells derived from induced pluripotent stem cells-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by extraskeletal heterotopic ossification (HO). The underlying mechanism is the aberrant activation of bone morphogenetic protein (BMP) signaling caused by a point mutation in the ACVR1 gene. Although FOP is an ultra-rare disease, its symptoms severely impair patients' daily activities and quality of life. Furthermore, the HO is also observed in broader clinical contexts, including major surgeries and trauma, highlighting the significance of its study. We have previously reported that rapamycin suppressed Activin-A-triggered progression of cartilage formation in FOP mice. We recently found that the ACVR2B-Fc fusion protein produced by mesenchymal stem/stromal cells derived from induced pluripotent stem cells (iMSCs) attenuates BMP signaling activated by Activin-A and BMP-9 in FOP patient-derived iMSCs. Transplantation of ACVR2B-Fc-producing iMSCs (iMSC2B-Fc/Luci) reduces primary HO in FOP mice. In this study, we found that intraperitoneal administration of rapamycin reduced primary HO in a dose-dependent manner in FOP-ACVR1R206H transgenic mice. A low concentration of rapamycin (0.3 mg/kg, 5 times/wk) efficiently suppressed chondrogenesis. The combination of iMSC2B-Fc/Luci transplantation with low concentration of rapamycin significantly reduced primary and recurrent HO. Rapamycin improved cell survival in transplanted iMSC2B-Fc/Luci cells by attenuating chemokine secretion, likely resulting in improved ACVR2B-Fc fusion protein production. Our results suggest that combining stem cell therapy and rapamycin can reduce primary HO and surgery-induced HO.
2024-03-18 | iMSC-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva
Abstract Background Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP. Methods In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSC ACVR2B-Fc ), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1 R206H , female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSC ACVR2B-Fc on BMP signaling pathways and HO development, respectively. Results We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs. Conclusions These results offer a new perspective for treating FOP through stem cell therapy.
2023-02-14 | TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGFβ1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGFβ1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNFα and IL6 produced negligible levels of Activin A and TGFβ1 in both cell groups. We present for the first time TGFβ1 as a triggering factor of Activin A production in FOP. As TGFβ1 can promote the induction of the main driver of FOP, TGFβ1 could also be considered a possible therapeutic target in FOP treatment.
2023-02-01 | Interleukin 6 promotes BMP9-induced osteoblastic differentiation through Stat3/mTORC1 in mouse embryonic fibroblasts
Interleukin 6 (IL-6) plays a dual role in regulating bone metabolism, although the concrete mechanism is unclear. Bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic inducers, and a promising alternative for bone tissue engineering. The relationship between IL-6 and BMP9 in osteogenic differentiation remains to be elucidated, and the osteoblastic potential of BMP9 needs to be enhanced to overcome certain shortcomings of BMP9. In this study, we used real-time PCR, western blot, immunofluorescent stain, fetal limb culture and cranial defects repair model to explore the IL-6 role in BMP9-induced osteogenic differentiation in mouse embryonic fibroblasts (MEFs). We found that the rat serum level of IL-6 was increased in the dexamethasone-induced osteoporosis model, and IL-6 expression was detectable in several progenitor cells and MEFs. BMP9 upregulated IL-6 in MEFs, and the BMP9-induced osteoblastic markers were elevated by IL-6, but reduced by IL-6 knockdown. BMP9 and/or IL-6 both activated mTOR, and the IL-6 effect on BMP9-induced osteoblastic markers and bone formation were reduced greatly by mTOR inhibition. Raptor was up-regulated by IL-6 and/or BMP9 specifically, and the osteoblastic markers induced by IL-6 and/or BMP9 were reduced by Raptor knockdown. Meanwhile, Stat-3 was activated by IL-6 and/or BMP9, and the increase of Raptor or osteoblastic markers by IL-6 and/or BMP9 were reduced by Stat-3 inhibition. The Raptor promoter activity was regulated by p-Stat-3. Our finding suggested that IL-6 can promote the BMP9 osteoblastic potential, which may be mediated through activating Stat-3/mTORC1 pathway.
2022-11-30 | Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification.
Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild-type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild-type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally overexpress human wild-type ACVR1. Injury-induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild-type receptor were targeted to Tie2-positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1R206H/+ mice was rescued by constitutive ACVR1 overexpression, and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive overexpression of ACVR1 also provided protection from spontaneous abnormal skeletogenesis, and the incidence and severity of injury-induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 overexpression functions cell-autonomously by reducing osteogenic signaling in response to activin A. We propose that ACVR1 overexpression inhibits HO by decreasing the abundance of ACVR1(R206H)-containing signaling complexes at the cell surface while increasing the representation of activin-A-bound non-signaling complexes comprised of wild-type ACVR1. © 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).
gene therapies
2026-02-16 | Advances in genetic and pharmacological therapeutic strategies for fibrodysplasia ossificans progressiva
A very rare, severe genetic condition known as fibrodysplasia ossificans progressiva (FOP) is characterized by progressive heterotopic ossification of soft tissues caused on by mutations in the ACVR1 gene, particularly R206H, which results in abnormal BMP signalling. This condition causes severe mobility limitations and life-threatening complications. The goal of this review is to thoroughly examine current developments in stem cell, pharmacologic, and genetic therapy for FOP and assess their potential for translation in clinical settings. Current understanding highlights that mutant ACVR1 receptors respond abnormally to Activin A, triggering pathological ossification. Innovations such as CRISPR-Cas9 gene editing, antisense oligonucleotides, and RNA interference show promise in correcting or silencing these mutations. Several Pharmacological advances include saracatinib (evaluated in Phase II studies), garetosmab (anti-Activin A antibody with early clinical data), and palovarotene which received FDA approval in August 2023 for reducing HO in FOP. Though post-marketing data highlight ongoing concerns regarding growth-plate toxicity and long-term skeletal safety. However, significant translational challenges persist, including limited long-term safety data, heterogeneous patient responses, and gaps between preclinical success and clinical efficacy. Stem cell therapies using MSCs and iPSCs offer regenerative potential and personalized modeling platforms. Smart drug delivery devices and precision medicine techniques guided by biomarkers improve therapy targeting and monitoring. Although there are still issues with delivery, safety, and long-term effectiveness, a mix of targeted medications, gene-based treatments, and cutting-edge technology is opening the door to precision and combination therapies, which provide patients with FOP fresh hope for better results.
2025-09-03 | Fibrodysplasia ossificans progressiva: molecular genetic causes, clinical and morphological characteristics, and therapeutic approaches to treatment
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic disorder with a prevalence of approximately 1 case per 1.5–2.0 million individuals. The primary cause of the disease lies in mutations of the ACVR1 gene, which encodes the homonymous receptor involved in the regulation of bone histogenesis. The most common genetic variant is the 617GA single nucleotide substitution (R206H, rs121912678), resulting in the replacement of arginine with histidine. This variant is observed in over 95% of all registered patients with fibrodysplasia ossificans progressiva. The mutation disrupts intracellular signaling, leading to the formation of abnormal heterotopic bone tissue in muscles, tendons, and ligaments. The clinical presentation may vary: some patients experience additional symptoms presumably associated with rare mutations in other domains of the ACVR1 receptor. Despite active research, the exact precursor cells responsible for pathological osteogenesis remain unidentified. Scientists hypothesize the involvement of multiple cell types, including mesenchymal stem cells and endothelial cells. Currently, no effective treatment exists for fibrodysplasia ossificans progressiva, underscoring the urgent need for novel therapeutic targets. Gene therapy, successfully employed in other monogenic disorders, represents a promising direction. Several experimental approaches, including targeted inhibitors of the ACVR1 signaling pathway, are undergoing preclinical and clinical trials.
2024-05-23 | Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases.
Adeno-associated viral (AAV) vectors have emerged as crucial tools in advancing gene therapy for skeletal diseases, offering the potential for sustained expression with low postinfection immunogenicity and pathogenicity. Preclinical studies support both the therapeutic efficacy and safety of these vectors, illustrating the promise of AAV-mediated gene therapy. Emerging technologies and innovations in AAV-mediated gene therapy strategies, such as gene addition, gene replacement, gene silencing, and gene editing, offer new approaches to clinical application. Recently, the increasing preclinical applications of AAV to rare skeletal diseases, such as fibrodysplasia ossificans progressiva (FOP) and osteogenesis imperfecta (OI), and prevalent bone diseases, such as osteoporosis, bone fracture, critical-sized bone defects, and osteoarthritis, have been reported. Despite existing limitations in clinical use, such as high cost and safety, the AAV-mediated gene transfer platform is a promising approach to deliver therapeutic gene(s) to the skeleton to treat skeletal disorders, including those otherwise intractable by other therapeutic approaches. This review provides a comprehensive overview of the therapeutic advancements, challenges, limitations, and solutions within AAV-based gene therapy for prevalent and rare skeletal diseases.
2023-09-08 | AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human ACVR1R206H (Acvr1R206H/+) while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1opt) and artificial miRNAs targeting Activin A and its receptor ACVR1R206H ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of Acvr1R206H/+ skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in Acvr1R206H/+ mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP.
2023-07-28 | Novel Therapeutic Targets for Fibrodysplasia Ossificans Progressiva: Emerging Strategies and Future Directions
Fibrodysplasia ossificans progressiva (FOP), also known as Stoneman syndrome, is a rare genetic disorder characterized by abnormal bone development caused by activating mutations of the ACVR1 gene. FOP affects both the developmental and postnatal stages, resulting in musculoskeletal abnormalities and heterotopic ossification. Current treatment options for FOP are limited, emphasizing the need for innovative therapeutic approaches. Challenges in the development of management criteria for FOP include difficulties in recruitment due to the rarity of FOP, disease variability, the absence of reliable biomarkers, and ethical considerations regarding placebo-controlled trials. This narrative review provides an overview of the disease and explores emerging strategies for FOP treatment. Gene therapy, particularly the CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9) system, holds promise in treating FOP by specifically targeting the ACVR1 gene mutation. Another gene therapy approach being investigated is RNA interference, which aims to silence the mutant ACVR1 gene. Small molecule inhibitors targeting glycogen synthase kinase-3β and modulation of the bone morphogenetic protein signaling pathway are also being explored as potential therapies for FOP. Stem cell-based approaches, such as mesenchymal stem cells and induced pluripotent stem cells, show potential in tissue regeneration and inhibiting abnormal bone formation in FOP. Immunotherapy and nanoparticle delivery systems provide alternative avenues for FOP treatment.
oligonucleotides
2026-06-29 | Precision RNAi for Fibrodysplasia Ossificans Progressiva: a combinatorial, unimolecular, allele selective approach.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder caused by a dominant mutation in the ACVR1 gene (R206H, 97% of cases), leading to debilitating heterotopic ossification (HO) characterized by abnormal bone growth triggered by inflammatory flare-ups. Here, we report the development of disease-modifying, allele-selective small interfering RNA (siRNA) targeting ACVR1 R206H . Allele selectivity is essential as wildtype ACVR1 is crucial for many functions including skeletal homeostasis and development. When conjugated to docosanoic acid (DCA), administration of the fully modified ACVR1 siRNA, either alone or in combination with an siRNA targeting IL1B (a key regulator of inflammation), results in profound reduction of HO using both responsive (post-trauma) and preventative (pre-trauma) intervention strategies in a murine FOP model. Notably, the combination therapy outperforms modulation of either target alone. We also describe the chemical engineering of a new class of lipophilic divalent siRNAs that target both pathways with a single compound, demonstrating superior muscle accumulation and therapeutic efficacy. siRNA treatment inhibits key signaling pathways (e.g. inflammatory, WNT, Notch, Hedgehog, and TGF-β), within muscle-resident fibroadipogenic progenitors (FAPs), leading to a significant reduction in cartilage, bone, and connective tissue formation. This work establishes a foundation for the development of disease-modifying treatments for FOP and offers a platform for targeting other musculoskeletal disorders involving multi-pathway dysregulation.
2026-06-22 | Single-base 2'OMe-modified LNA and MOE gapmers selectively silence ACVR1 R206H in fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder caused by gain-of-function mutations in ACVR1, most commonly c.617G>A (R206H), leading to progressive heterotopic ossification. In this study, we developed novel antisense gapmers selectively targeting the mutant ACVR1 R206H transcript while sparing the wild-type allele. We engineered locked nucleic acid (LNA) and 2'-O-methoxyethyl (MOE) gapmers incorporating a single 2'-O-methyl (2'OMe) modification at gap position 2. This is hypothesized to synergize with the wild-type sequence mismatch to restrict RNase H1 cleavage, limiting wild-type degradation while preserving mutant target engagement. In FOP patient-derived fibroblasts carrying the endogenous ACVR1 R206H mutation and in murine-derived C2C12 cells ectopically expressing ACVR1 R206H constructs, 2'OMe-modified gapmers demonstrated robust and preferential suppression of ACVR1 R206H at both RNA and protein levels. Gapmer treatment also reduced osteogenic differentiation, as shown by decreased alkaline phosphatase and Alizarin Red S staining, and lower expression of osteogenic markers. In wild-type mice, 2'OMe modification was associated with higher apparent gapmer levels in skeletal muscle and tendon and lower hepatic and renal stress marker readouts. These findings provide preliminary proof-of-concept that a single-base chemical modification can modulate allele selectivity and biodistribution of gapmers targeting ACVR1 R206H . Further studies in disease-relevant FOP models will be needed to establish therapeutic efficacy and long-term safety.
2022-11-29 | Functional Testing of Bone Morphogenetic Protein (BMP) Pathway Variants Identified on Whole-Exome Sequencing in a Patient with Delayed-Onset Fibrodysplasia Ossificans Progressiva (FOP) Using ACVR1R206H -Specific Human Cellular and Zebrafish Models.
Bone morphogenetic protein (BMP) signaling is critical in skeletal development. Overactivation can trigger heterotopic ossification (HO) as in fibrodysplasia ossificans progressiva (FOP), a rare, progressive disease of massive HO formation. A small subset of FOP patients harboring the causative ACVR1R206H mutation show strikingly mild or delayed-onset HO, suggesting that genetic variants in the BMP pathway could act as disease modifiers. Whole-exome sequencing of one such patient identified BMPR1AR443C and ACVR2AV173I as candidate modifiers. Molecular modeling predicted significant structural perturbations. Neither variant decreased BMP signaling in ACVR1R206H HEK 293T cells at baseline or after stimulation with BMP4 or activin A (AA), ligands that activate ACVR1R206H signaling. Overexpression of BMPR1AR443C in a Tg(ACVR1-R206Ha) embryonic zebrafish model, in which overactive BMP signaling yields ventralized embryos, did not alter ventralization severity, while ACVR2AV173I exacerbated ventralization. Co-expression of both variants did not affect dorsoventral patterning. In contrast, BMPR1A knockdown in ACVR1R206H HEK cells decreased ligand-stimulated BMP signaling but did not affect dorsoventral patterning in Tg(ACVR1-R206Ha) zebrafish. ACVR2A knockdown decreased only AA-stimulated signaling in ACVR1R206H HEK cells and had no effect in Tg(ACVR1-R206Ha) zebrafish. Co-knockdown in ACVR1R206H HEK cells decreased basal and ligand-stimulated signaling, and co-knockdown/knockout (bmpr1aa/ab; acvr2aa/ab) decreased Tg(ACVR1-R206Ha) zebrafish ventralization phenotypes. Our functional studies showed that knockdown of wild-type BMPR1A and ACVR2A could attenuate ACVR1R206H signaling, particularly in response to AA, and that ACVR2AV173I unexpectedly increased ACVR1R206H -mediated signaling in zebrafish. These studies describe a useful strategy and platform for functionally interrogating potential genes and genetic variants that may impact the BMP signaling pathway. © 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).
2022-06-06 | Allele-Selective LNA Gapmers for the Treatment of Fibrodysplasia Ossificans Progressiva Knock Down the Pathogenic ACVR1R206H Transcript and Inhibit Osteogenic Differentiation.
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by episodic heterotopic ossification. The median life span of people with this disorder is ∼40 years, and currently, there is no effective treatment available. More than 95% of cases are caused by a recurrent mutation (c.617G>A; R206H) of Activin A receptor, type I (ACVR1)/Activin receptor-like kinase-2 (ALK2), a bone morphogenetic protein type I receptor. The mutation renders ACVR1 responsive to activin A, which does not activate wild-type ACVR1. Ectopic activation of ACVR1R206H by activin A induces heterotopic ossification. Since ACVR1R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of mutated ACVR1. To accomplish this goal, we developed locked nucleic acid (LNA) gapmers. These are short DNA oligonucleotides with LNA modification at both ends. They induce targeted mRNA degradation and specific knockdown of gene expression. We demonstrated that some of these gapmers efficiently knocked down ACVR1R206H expression at RNA levels, while ACVR1WT was mostly unaffected in human FOP fibroblasts. Also, the gapmers suppressed osteogenic differentiation induced by ACVR1R206H and activin A. These gapmers may be promising drug candidates for FOP. This novel strategy will also pave the way for antisense-mediated therapy of other autosomal dominant disorders.
2018-08-31 | Morpholino-Mediated Exon Skipping Targeting Human ACVR1/ALK2 for Fibrodysplasia Ossificans Progressiva
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive heterotopic ossification. More than 95% of cases are caused by a recurrent mutation (617G>A; R206H) of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. Recent studies revealed that ACVR1R206H induces heterotopic ossification by aberrant activation in response to activin A. Because ACVR1R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of ACVR1 in patients. Here, we describe a method to reduce ACVR1 expression in FOP patient cells by exon skipping in ACVR1 mRNAs using phosphorodiamidate morpholino oligomers (PMOs). This strategy can be applied to the screen to select antisense oligomers to knockdown not only ACVR1 but also genes which cause other autosomal-dominant genetic diseases.
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2026-09-28 | Efficacy and safety of garetosmab, an activin A-blocking antibody, in fibrodysplasia ossificans progressiva (OPTIMA): a randomised, double-blind, placebo-controlled, phase 3 trial.
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder resulting in progressive heterotopic ossification of ligaments, tendons, and muscles, leading to disability and early mortality. FOP is caused by heterozygous gain-of-function mutations in the activin receptor type 1A, allowing this receptor to be aberrantly activated by activin A (ActA), which normally inhibits this receptor, thus driving heterotopic bone formation. In preclinical models and an earlier phase 2 trial (LUMINA-1) in FOP, an antibody blocking ActA (garetosmab) prevented heterotopic ossification. We aimed to evaluate the efficacy and safety of garetosmab in adults living with FOP. OPTIMA is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 18 study sites across 16 countries and regions. Participants aged 18 years or older with FOP were randomly assigned (1:1:1) to monthly intravenous placebo, garetosmab 3 mg/kg, or garetosmab 10 mg/kg. Randomisation was stratified by baseline Cumulative Analogue Joint Involvement Scale score and previous participation in the LUMINA-1 study. The primary efficacy and safety endpoints were total number of new heterotopic bone lesions at week 56 and treatment-emergent adverse events of special interest (AESIs) through week 56, analysed in all randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT05394116); the trial is active (completed primary endpoint) but not recruiting participants. Between Nov 21, 2022, and July 4, 2024, 63 participants were enrolled and randomly assigned (placebo, n=21; garetosmab 3 mg/kg, n=19; garetosmab 10 mg/kg, n=23). The mean age was 26·6 years (SD 6·8); 38 (60%) participants were female and 25 (40%) male. 62 participants completed 56 weeks of treatment; one participant in the placebo group discontinued at 53 weeks. The total number of new heterotopic bone lesions was significantly lower with garetosmab: there were 19 lesions with placebo versus one lesion with garetosmab 3 mg/kg (rate ratio vs placebo: 0·06 [95% CI 0·00-0·73]; p=0·027) and two lesions with garetosmab 10 mg/kg (rate ratio vs placebo: 0·10 [0·01-0·76]; p=0·026). Treatment-emergent AESIs occurred in one (5%) of 21 participants receiving placebo, zero of 19 receiving garetosmab 3 mg/kg, and four (17%) of 23 receiving garetosmab 10 mg/kg; all were considered treatment-related. No deaths occurred. Garetosmab substantially reduced the number of new heterotopic bone lesions, providing robust evidence of its potential to be an efficacious and generally well tolerated disease-modifying therapy for FOP. Regeneron Pharmaceuticals.
2026-05-04 | Heterotopic Ossification: Molecular Drivers, Subtype-Specific Mechanisms, and Translational Therapeutic Advances.
Heterotopic ossification (HO), the pathological formation of mature bone in non-skeletal soft tissues (e.g., muscles, tendons), severely impairs patient mobility and quality of life. Despite decades of research, systematic analysis of signaling networks across HO subtypes (acquired traumatic HO, hereditary Fibrodysplasia Ossificans Progressiva (FOP), Progressive Osseous Heteroplasia (POH)) remains insufficient, and clinical therapies suffer from high recurrence and severe side effects. This review synthesizes recent advances in HO pathogenesis: FOP involves gain-of-function activin A receptor type I (ACVR1) mutations (mostly R206H), disrupting bone morphogenetic protein (BMP)/Activin A signaling; POH arises from paternal guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) loss-of-function mutations, derepressing Hedgehog signaling via reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activity; tHO features trauma-induced inflammation/hypoxia activating BMP/transforming growth factor-beta (TGF-β) pathways. Key signaling crosstalk (e.g., BMP-Yes-associated protein (YAP)-Indian hedgehog (IHH)) is integrated, and novel therapies (ACVR1 inhibitors, Activin A antibodies, retinoic acid receptor gamma (RARγ) agonists, adeno-associated virus (AAV)-mediated ACVR1 silencing) are highlighted, with emphasis on subtype-specific efficacy. A stratified, mechanism-based HO management framework is proposed, aiming to accelerate precision therapy development and advance understanding of aberrant tissue regeneration.
2026-04-17 | Gut microbiome-dependent IL-1 signaling is a mediator of ACVR1R206H-driven heterotopic ossification.
Inflammatory diseases cause significant morbidity and mortality, but their pathobiology is often difficult to dissect due to complex genetic-environmental interactions. Genetic forms of heterotopic ossification, such as fibrodysplasia ossificans progressiva (FOP), reduce genetic variability, allowing careful dissection of non-genetic drivers of inflammation. While >95% of FOP patients harbor the ACVR1 R206H mutation, patients exhibit significant variability in disease progression, suggesting a role of environmental drivers. Here, we identify the gut microbiome as a regulator of inflammation-driven HO in FOP. Metagenomic profiling of cohabitating FOP/unaffected sibling pairs revealed a pathogenic gut microbiome profile in FOP patients (Bray-Curtis, p < 0.05). In Pdgfrα-Cre/Acvr1 R206H (FOP) mice, gut microbiome ablation by antibiotics reduced spontaneous HO formation (47.4% reduction, p < 0.05) and reduced plasma IL-1 pathway activity. IL-1β blockade in FOP mice suppressed trauma-induced HO formation. These findings identify a gut microbiome-IL-1-HO axis with modifiable targets for developing treatments for HO and related inflammatory conditions.
2026-04-15 | A bio-inspired computational pipeline for antibody screening and repurposing.
Therapeutic antibody discovery is central to modern drug development, yet conventional methods such as hybridoma and phage display remain slow, inefficient, and costly. Computational approaches including site-saturation mutagenesis often yield limited affinity gains and expression liabilities, while deep learning and generative models expand sequence diversity but suffer from low validation rates. Here, we present a multi-scale computational screening pipeline inspired by key principles of in vivo immune selection. The framework integrates structure-based docking (ZDock), graph neural network-based interaction prediction, and accelerated molecular dynamics (MDs) with metadynamics free-energy profiling to enable high-throughput in silico prioritization of structure-resolved antibodies. Applied to Activin A, a pleiotropic cytokine implicated in fibrosis, oncology, and muscle-wasting disorders, the platform screened ~5000 antibody structures and identified 11 candidates. Experimental validation confirmed two binders, with Ab4 exhibiting sub-nanomolar affinity (KD = 0.38 nM) and potent neutralizing activity, underscoring therapeutic potential in fibrodysplasia ossificans progressiva (FOP) and related diseases. Rather than performing full iterative affinity maturation, the present study focuses on the screening and repurposing stage, with affinity maturation positioned as a prospective extension. This work demonstrates the feasibility of integrating AI-driven interaction prediction with physics-based simulations to accelerate structure-guided antibody screening and repurposing, while conceptually paralleling selected stages of immune selection rather than fully recapitulating immune evolution.
2026-01-07 | Fibrodysplasia ossificans progressiva: from clinical complexity to therapeutic opportunity
Abstract Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare and severely disabling genetic disorder affecting approximately one in two million individuals worldwide. It is characterised by progressive endochondral heterotopic ossification (HO), in which ectopic cartilage formation precedes and directs subsequent bone formation within muscles, tendons, and ligaments. Activating mutations in the ACVR1 gene—most commonly the R206H variant—cause dysregulated bone morphogenetic protein (BMP) signaling through both SMAD-dependent and SMAD-independent pathways, leading to inappropriate osteogenic differentiation. Clinically, FOP presents with congenital great toe malformations and recurrent, painful flare-ups that progressively restrict mobility and cause complications such as thoracic insufficiency, ankylosis, and hearing loss. Early genetic diagnosis is critical to avoid iatrogenic harm. Current treatments rely on corticosteroids and NSAIDs, while Palovarotene—a selective retinoic acid receptor gamma agonist approved by the FDA in 2023—marks a major therapeutic advance despite safety limitations. Our review integrates recent breakthroughs, including Phase 3 Garetosmab results and ongoing trials of STOPFOP, INCB000928, and IPN60130, alongside emerging insights into fibro-adipogenic progenitors and molecular mechanisms of HO. Incorporation of regional case analyses from India, together with global data, strengthens the clinical relevance for low- and middle-income regions where FOP remains underreported. This comprehensive review provides the most current translational perspective on FOP, highlighting the alarming need for continued innovation to improve patient outcomes.
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Drug Discovery Landscape
16 orphan drug designations for Fibrodysplasia ossificans progressiva, including 3 approved therapies.
16 orphan drug designations for Fibrodysplasia ossificans progressiva, including 3 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Saracatinib | small molecules | EMA | Amsterdam UMC Stichting | |
Zilurgisertib | small molecules | EMA | Incyte Biosciences Distribution B.V. | |
Andecaliximab | antibodies | FDA | ashibio Inc | |
Andecaliximab | antibodies | EMA | Regulatory Pharma Net S.r.l. | |
(S)-1-(4-(1-(3,4,5-trimethyloxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide citrate | small molecules | FDA | — | BioCryst Pharmaceuticals, Inc. |
(S)-1-(4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide | small molecules | EMA | — | Biocryst Ireland Limited |
Fidrisertib sesquisuccinate | small molecules | EMA | Ipsen Pharma | |
zilurgisertib [Atebrioz] | small molecules | FDA | Approved | Incyte Corporation |
(R)-tetrahydrofuran-3-yl 4-(6-(5-(4-ethoxy-1-isopropylpiperidin-4-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate sesquisuccinate | small molecules | FDA | Clementia Pharmaceuticals, Inc. | |
garetosmab-grts [Pasatru] | antibodies | FDA | Approved | Regeneron Pharmaceuticals, Inc. |
Human monoclonal antibody against activin A | antibodies | EMA | Regeneron Ireland Designated Activity Company (DAC) | |
3-(4-(8-fluoroquinoline)-Imidazole[1,2-a]pyridine-7-(1-phenyl-4-(1-(4-methyl piperazine) | small molecules | FDA | — | La Jolla Pharmaceutical Company, Inc. |
3-(4-(1,5-Napthrydine)-Imidazole[1,2-a]pyridine-7-(1-phenyl-4-(1-(4-methyl piperazine) | small molecules | FDA | — | La Jolla Pharmaceutical Company, Inc. |
Palovarotene [Sohonos] | small molecules | EMA | Ipsen Pharma | |
palovarotene [Sohonos] | small molecules | FDA | Approved | Ipsen Biopharmaceuticals, Inc. |
4-(6-(4-(piperazin-1-yl)phenyl_pyrazolo[1,5-a]pyrimidin-3-yl)quinoline hydrochloride | small molecules | FDA | — | La Jolla Pharmaceutical Company, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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