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Genes Nov 2023Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective... (Review)
Review
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 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 impede progress in the broader field of medical research into ultra-rare conditions.
Topics: Humans; Myositis Ossificans; Proteomics; Rare Diseases; Ossification, Heterotopic; Bone and Bones
PubMed: 38136984
DOI: 10.3390/genes14122162 -
Scientific Reports Dec 2023Flexion-type pediatric humeral supracondylar fractures are rare, and the reduction technique remains contradictory. A minimally invasive technique using percutaneous...
Flexion-type pediatric humeral supracondylar fractures are rare, and the reduction technique remains contradictory. A minimally invasive technique using percutaneous leverage reduction combined with an external fixator was described to achieve satisfactory reduction and avoid the open reduction in this study. The operation and clinical results of patients treated with this technique were retrospectively compared with traditional closed reduction. From January 2013 to January 2018, children diagnosed with displaced flexion-type humeral supracondylar fractures were included in this study. Patients were treated with closed reduction (Group A) or minimally invasive reduction technique (Group B). The external fixator fixation was then applied. The demographic information, as well as the clinical and functional results of the operation, were retrospectively reviewed and evaluated. There were twenty-two patients, ten in Group A and twelve in Group B. The mean duration of the operation in Group A was more prolonged than Group B (59 min versus 46 min, p < 0.001). No infection, nonunion, myositis ossificans, neurovascular injury or other complications related to the operation were observed by the time the fractures healed. During an average 36 months follow-up time, almost all children achieved good to excellent results except for one fair in Group A according to the MEPS and the Flynn criteria. This study introduced a safe and efficient minimally invasive technique for displaced flexion-type supracondylar humerus fractures. With the assistance of mosquito forceps, this leverage technique might achieve similar satisfactory clinical outcomes as traditional closed reduction but with a shorter surgical duration.
Topics: Child; Humans; Retrospective Studies; Humeral Fractures; External Fixators; Humerus; Fracture Fixation, Internal; Treatment Outcome
PubMed: 38097631
DOI: 10.1038/s41598-023-48158-6 -
Journal of Medical Case Reports Dec 2023Fibrodysplasia ossificans progressiva (FOP) as a rare and heritable disorder with the infrequent genetic transmission of the condition is a catastrophic disorder of...
BACKGROUND
Fibrodysplasia ossificans progressiva (FOP) as a rare and heritable disorder with the infrequent genetic transmission of the condition is a catastrophic disorder of heterotopic ossification (HO) and a cause of extraskeletal bone formation in humans. Given the lack of effective treatment for this disease, the important point is to avoid aggravating factors such as bone biopsy, surgery, and intramuscular injection.
CASE PRESENTATION
In this report, we present a 52-year-old female patient, Kurdish ethnic, suspected to FOP who had a surgical intervention on the second toe of the right foot, which subsequently, it caused further deterioration of the disease in the person including necrosis and amputation of the distal phalanx of the second toe.
CONCLUSIONS
Although, based on our investigation and the available scientific evidence, surgery may a cause for faster progression and worsening of the FOP disorder, but its proof requires further studies.
Topics: Female; Humans; Middle Aged; Myositis Ossificans; Ossification, Heterotopic; Toes; Bone and Bones
PubMed: 38044456
DOI: 10.1186/s13256-023-04253-w -
BMC Medical Research Methodology Nov 2023The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an...
BACKGROUND
The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design.
METHODS
PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies.
RESULTS
Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes.
CONCLUSIONS
A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development.
TRIAL REGISTRATION
NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Prospective Studies; Rare Diseases; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic
PubMed: 37957586
DOI: 10.1186/s12874-023-02080-7 -
Imaging Science in Dentistry Sep 2023Fibrodysplasia ossificans progressiva is a rare hereditary disorder characterized by progressive heterotopic ossification in muscle and connective tissue, with few...
Fibrodysplasia ossificans progressiva is a rare hereditary disorder characterized by progressive heterotopic ossification in muscle and connective tissue, with few reported cases affecting the head and neck region. Although plain radiographic findings and computed tomography features have been well documented, limited reports exist on magnetic resonance findings. This report presents 2 cases of fibrodysplasia ossificans progressiva, one with limited mouth opening due to heterotopic ossification of the lateral pterygoid muscle and the other with restricted neck movement due to heterotopic ossification of the platysma muscle. Clinical findings of restricted mouth opening or limited neck movement, along with radiological findings of associated heterotopic ossification, should prompt consideration of fibrodysplasia ossificans progressiva in the differential diagnosis. Dentists should be particularly vigilant with patients diagnosed with fibrodysplasia ossificans progressiva to avoid exposure to diagnostic biopsy and invasive dental procedures.
PubMed: 37799735
DOI: 10.5624/isd.20230069 -
Nature Medicine Oct 2023Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2... (Randomized Controlled Trial)
Randomized Controlled Trial
Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .
Topics: Adult; Humans; Myositis Ossificans; Positron Emission Tomography Computed Tomography; Ossification, Heterotopic
PubMed: 37770652
DOI: 10.1038/s41591-023-02561-8 -
Biomolecules Sep 2023Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal...
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 () 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 (ACVR1) and artificial miRNAs targeting Activin A and its receptor ACVR1 ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of 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 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.
Topics: Animals; Humans; Mice; Activin Receptors, Type I; Activins; Dependovirus; Myositis Ossificans; Osteogenesis
PubMed: 37759764
DOI: 10.3390/biom13091364 -
Pediatric Rheumatology Online Journal Aug 2023Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic...
Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic ossification. Since flares of the disease are associated with inflammation, it is assumed that JAK inhibitors can control active FOP due to blocking multiple signaling pathways.
Topics: Humans; Myositis Ossificans; Patients; Piperidines; Inflammation; Rare Diseases
PubMed: 37644581
DOI: 10.1186/s12969-023-00856-1 -
Orthopadie (Heidelberg, Germany) Nov 2023Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the... (Review)
Review
BACKGROUND
Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible.
AIM OF THE RECOMMENDATIONS
This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.
Topics: Humans; Myositis Ossificans; Mutation; Ossification, Heterotopic; Bone Morphogenetic Proteins; Delivery of Health Care
PubMed: 37603129
DOI: 10.1007/s00132-023-04425-y -
German Medical Science : GMS E-journal 2023Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant rare disease characterized by foot deformities and concomitant heterotopic ossifications....
Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant rare disease characterized by foot deformities and concomitant heterotopic ossifications. Theoretically, in the absence of early diagnosis and medication, the patient's outcome will be poor. The patients are usually diagnosed at an early age. Hence, encountering a non-treated and terminal-period patient is rare. Our case was unique because it showed the clinical picture and atypical radiological distribution of a 20-year-old, terminally ill untreated female patient. She had hallux valgus, heterotopic ossifications and multiple osteochondromas that were detected in the right clavicula, the posterior arch of the 9 rib, the bilateral tibia and fibula. Atypically, heterotopic ossifications were not present in the soft tissues of the neck. Hand deformity, cardiac anomaly, or mental retardation was not observed. It was a sporadic case. The presentation with neurological symptoms was also atypical.
Topics: Humans; Female; Young Adult; Adult; Myositis Ossificans; Arthrogryposis; Bunion; Clavicle; Clonal Hematopoiesis
PubMed: 37599859
DOI: 10.3205/000326