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Fibrodysplasia Ossificans Progressiva A Blueprint For Metamorphosis

Leo Migdal
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fibrodysplasia ossificans progressiva a blueprint for metamorphosis

The most important milestone in understanding a genetic disease is the identification of the causative mutation. However, such knowledge is often insufficient to decipher the pathophysiology of the disorder or to effectively treat those affected. Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling, genetic disease of progressive heterotopic endochondral ossification (HEO) enabled by missense mutations that promiscuously and provisionally activate ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor,... While activating mutations of the ACVR1/ALK2 receptor are necessary, disease activity and progression also depend on altered cell and tissue physiology. Recent findings identify inflammatory and immunological factors, vascular-derived mesenchymal stem cells, and a hypoxic lesional microenvironment that trigger, promote, and enable episodic progression of FOP in the setting of the genetic mutation. Effective therapies for FOP will need to consider these seminal pathophysiologic interactions.

An early blueprint for the metamorphosis. In FOP, connective tissue injury leads to… Our research integrity and auditing teams lead the rigorous process that protects the quality of the scientific record Authors for correspondence (Frederick.Kaplan@uphs.upenn.edu; Shore@mail.med.upenn.edu) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the... Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of connective tissue metamorphosis.

It is characterized by malformation of the great (big) toes during embryonic skeletal development and by progressive heterotopic endochondral ossification (HEO) postnatally, which leads to the formation of a second skeleton of heterotopic bone. Individuals with these classic clinical features of FOP have the identical heterozygous activating mutation (c.617G>A; R206H) in the gene encoding ACVR1 (also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Disease activity caused by this ACVR1 mutation also depends on altered cell and tissue physiology that can be best understood in the context of a high-fidelity animal model. Recently, we developed such a knock-in mouse model for FOP (Acvr1R206H/+) that recapitulates the human disease, and provides a valuable new tool for testing and developing effective therapies. The FOP knock-in mouse and other models in Drosophila, zebrafish, chickens and mice provide an arsenal of tools for understanding BMP signaling and addressing outstanding questions of disease mechanisms that are relevant not only... Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of connective tissue metamorphosis.

It is characterized by malformation of the great (big) toes during embryonic skeletal development and by progressive heterotopic endochondral ossification (HEO; see Box 1 for glossary) postnatally, leading to the formation of a second... Although FOP is an extremely rare disease and the most severe form of HEO in humans, its lessons are relevant to every common, non-genetic form of HEO, such as that which occurs after soft... In addition, disease mechanisms revealed by FOP might be harnessed and exploited to create new skeletal elements for regenerative medicine in individuals with fracture non-unions, failed spine fusions, traumatic bone loss or congenital agenesis... Aggressive fibromatosis: an aggressive tumor-like condition characterized by fibrous tissue proliferation First prospective study to assess the association of fibrodysplasia ossificans progressive (FOP) flare-ups and extra-skeletal bone growth (heterotopic ossification or HO) with functional impairment PARIS, France, 28 September 2022 – Ipsen (Euronext: IPN; ADR: IPSEY) today announced the publication of its Natural History Study (NHS) of FOP in Genetics in Medicine, the official journal of the American College...

This is the first time a global, prospective, longitudinal evaluation of FOP has been carried out, with data collected over a period of 36 months. Findings demonstrated the debilitating impact and progressive nature of the disease, with the greatest progression of new heterotopic ossification (HO; or bone growth that takes place outside of the normal skeletal system in joints... “Natural history studies are essential to understanding ultra-rare diseases with high unmet need like FOP, increasing our knowledge around the natural course of disease, diagnoses, monitoring techniques, potential biomarkers and new outcome measures,” said... Robert Pignolo, Professor of Geriatric Medicine, Mayo Clinic, USA. “This is the first study of its kind following the progression of FOP over three years. These results demonstrate the significant impact of the disease on people living with FOP.

Furthermore, it will facilitate the evaluation of meaningful endpoints in the development of new therapies, which are critically needed for individuals with FOP.” Results from the NHS demonstrated at month 36, across the whole study population, a mean of 2.6 body regions with new HO; this was highest (3.9) in those aged between two and eight years... However, although individuals aged 25 – 65 years had the lowest new HO volume at annual visits, approximately 70% continued to accumulate new HO across the duration of the study. These data confirmed the progressive nature of FOP with characteristic patterns of growth, starting in younger individuals initially across the upper and mid-torso, progressing into hip and lower-leg regions, and with accumulation of HO... The assessment of flare-ups showed, 82 (71.9%) individuals experienced a total of 229 flare-ups, most commonly in the upper back (17.9%), hip (14.8%) and shoulder (10.9%). Individuals between the ages of two and eight years, were most likely to report more than one flare-up throughout the study duration.

For those who experienced flare-ups, the most common symptoms were pain and soft tissue swelling. Imaging at the site of the flare-up revealed HO occurring at the time of the flare-up, with many individuals going on to experience new HO in the following 12 weeks.1

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The most important milestone in understanding a genetic disease is the identification of the causative mutation. However, such knowledge is often insufficient to decipher the pathophysiology of the disorder or to effectively treat those affected. Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling, genetic disease of progressive heterotopic endochondral ossification (HEO) enabled by m...

An Early Blueprint For The Metamorphosis. In FOP, Connective Tissue

An early blueprint for the metamorphosis. In FOP, connective tissue injury leads to… Our research integrity and auditing teams lead the rigorous process that protects the quality of the scientific record Authors for correspondence (Frederick.Kaplan@uphs.upenn.edu; Shore@mail.med.upenn.edu) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial...

It Is Characterized By Malformation Of The Great (big) Toes

It is characterized by malformation of the great (big) toes during embryonic skeletal development and by progressive heterotopic endochondral ossification (HEO) postnatally, which leads to the formation of a second skeleton of heterotopic bone. Individuals with these classic clinical features of FOP have the identical heterozygous activating mutation (c.617G>A; R206H) in the gene encoding ACVR1 (a...

It Is Characterized By Malformation Of The Great (big) Toes

It is characterized by malformation of the great (big) toes during embryonic skeletal development and by progressive heterotopic endochondral ossification (HEO; see Box 1 for glossary) postnatally, leading to the formation of a second... Although FOP is an extremely rare disease and the most severe form of HEO in humans, its lessons are relevant to every common, non-genetic form of HEO, such as th...

This Is The First Time A Global, Prospective, Longitudinal Evaluation

This is the first time a global, prospective, longitudinal evaluation of FOP has been carried out, with data collected over a period of 36 months. Findings demonstrated the debilitating impact and progressive nature of the disease, with the greatest progression of new heterotopic ossification (HO; or bone growth that takes place outside of the normal skeletal system in joints... “Natural history s...