Future Of Fibrodysplasia Ossificans Progressiva Wiley Online Library

Leo Migdal

-Dec 5, 2025, 4:38 PM

future of fibrodysplasia ossificans progressiva wiley online library

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... 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. Keywords: ACVR1/ALK2 gene; Extraskeletal bone formation; fibrodysplasia ossificans progressiva; heterotopic ossification; palovarotene.

Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies.

We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that... Keywords: ACVR1; antisense therapy; bone morphogenetic proteins (BMPs); clinical trial design for ultra-rare diseases; fibrodysplasia ossificans progressiva (FOP); genetic therapy; heterotopic ossification; targeted therapy; ultra-rare disorders. T.Y. is a co-founder and shareholder of OligomicsTx Inc., which aims to commercialize antisense technology. S.A.

declares that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Schematic overview of the human ACVR1 gene, its molecular architecture, and mutational landscape… Canonical and aberrant BMP signaling and FOP. The canonical and aberrant activin A-mediated… Correspondence: E Marelise W Eekhoff, Department of Internal Medicine section Endocrinology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands, Tel +31 204440588, Email emw.eekhoff@amsterdamumc.nl Received 2022 Jan 29; Accepted 2022 Apr 2; Collection date 2022.

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Fibrodysplasia ossificans progressiva (FOP), sometimes known as myositis ossificans progressiva, is an ultra-rare disease in which bone is formed in muscular tissue, tendons and ligaments.

This is known as heterotopic ossification (HO). FOP is caused by a heterozygous mutation in the highly conserved ACVR1/ALK2 gene which affects about 1 in 1.5–2 million individuals. At birth, patients with the predominant R206H mutation only exhibit a bilateral hallux valgus. During childhood, heterotopic bone formation develops in a typical pattern, affecting the axial muscles first before appendicular body parts are involved. HO can start spontaneously but is often elicited by soft tissue trauma or medical procedures. After soft tissue injury, an inflammatory process called a flare-up can start, followed by the formation of HO.

HO leads to a limited range of motion, culminating in complete ankylosis of nearly all joints. As a result of HO surrounding the thorax, patients often suffer from thoracic insufficiency syndrome (TIS). TIS is the most common cause of a limited life expectancy for FOP patients, with a median life expectancy of 56 years. Management is focused on preventing soft-tissue injury that can provoke flare-ups. This includes prevention of iatrogenic damage by biopsies, intramuscular injections and surgery. Anti-inflammatory medication is often started when a flare-up occurs but has a poor basis of evidence.

Several forms of potential treatment for FOP are being researched in clinical trials. Progression of the disease is monitored using CT and 18F-NaF PET/CT combined with functional assessments. Patients are regularly evaluated for frequently occurring complications such as restrictive lung disease. Here, we review the current management, monitoring and treatment of FOP. Keywords: fibrodysplasia ossificans progressiva, heterotopic ossification, activin A receptor type 1, treatment strategies Background: Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant ultra-rare disease characterized by progressive episodic multi-focal heterotopic ossification of skeletal muscle, ligaments, tendons, and fascia.

Comprehensive characterization and understanding of the natural disease history of FOP, including mortality, comorbidities, and medication use, is currently limited. Objective: This systematic review, which we believe is the first of its kind, aims to synthesize current knowledge on the morbidity, mortality, and medication use associated with FOP. Methods: A systematic literature review (SLR) was conducted utilizing various databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials, the Trip database, and National Institute for Health and Care Excellence documents. The search was limited to studies involving humans, but was not restricted based on language. The studies used reported at least one of the following outcomes: mortality, comorbidity, and medication use; any clinical trials that were solely designed to evaluate a symptomatic treatment for FOP, such as flare-ups and... Two independent reviewers reviewed and selected the included studies of the review, and extraction was done by one reviewer with cross-check performed by the other person.

The Joanna Briggs Institute Critical Appraisal Checklist, specifically designed for studies reporting prevalence data, was used to assess the quality of studies. The SLR was registered on Prospero (CRD42022366914). Results: In total, 32 publications were selected for review. These studies included a wide range of participants age (0.1-78 years), study duration (1 day-33 years), and sample size (3-299 patients). Ten studies reported information on mortality, 26 studies reported on comorbidities, and 12 reported information on medication use. The three organ systems most affected by the conditions studied were, in order of severity, the cardiovascular (40-70%), skeletal (50-65%), and respiratory (20-42%).

Conclusions: Although FOP is an ultra-rare disease, the available literature demonstrates that it is associated with excess morbidity and mortality. Our review synthesized all available published estimates of epidemiologic landscape of FOP and demonstrates the need for future work to better understand this rare disease.

Future Of Fibrodysplasia Ossificans Progressiva Wiley Online Library

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