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Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.
Highlights
Fibrodysplasia ossificans progressiva (FOP, OMIM 135100) is a rare genetic condition affecting 1:2,000,000 people
The authors described the suppression of HO formation by treatment with these molecules in vivo, in mice implanted with FOP-induced pluripotent stem cells (iPSC) cells together with a source of Activin A (ActA) [37], providing the basis for a possible repurposing of mTOR inhibitors in the management of FOP
Lesional progenitor cells might integrate other signals from the activated immune system through the toll-like receptor (TLR) pathway that might provide fuel to further amplify the bone morphogenetic proteins (BMPs) signaling by positive cross-talk. This has been observed in stem cells from exfoliated deciduous teeth (SHED cells) from FOP patients, where inflammatory triggers activate the TLR3/TLR4 receptor, further stimulating the BMP signaling through the ECSIT adaptor, which links TLR signaling to the SMAD1/5/8 phosphorylation cascade [71]
Summary
Due to its importance in bone biology and homeostasis, the BMP pathway was already considered a candidate for FOP pathogenesis even before the discovery of ACVR1 as the responsible gene. The potency and the efficacy to block the formation of ectopic bone in vivo might be improved [23] and studies on the toxicity and tolerability of long-term treatment with these molecules should be carefully evaluated in further pre-clinical studies These works have opened the door to the targeting of the BMP dysregulated signaling in FOP by developing a pharmacological approach. Both drugs were tested in vivo in a BMP-induced mouse model of ectopic ossification showing a good reduction in the volume of the newly-formed ossicles in animals treated with perhexiline [34] As this drug is commonly and safely used in the prophylactic treatment of angina, an open-label clinical trial was performed by administrating perhexiline to five FOP patients in order to evaluate the efficacy of this molecule in the management of the disease [35]. The drug was well tolerated, the study did not allow them to draw any conclusion about the clinical utility, if any, of perhexiline [35]
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