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Frederick S. Kaplan - One of the best experts on this subject based on the ideXlab platform.

  • whole body computed tomography versus dual energy x ray absorptiometry for assessing heterotopic ossification in Fibrodysplasia Ossificans Progressiva
    Calcified Tissue International, 2021
    Co-Authors: Sarah E Warner, Frederick S. Kaplan, Robert J. Pignolo, Edward C Hsiao, Maja Di Rocco, Carmen Cunto, Stacy E Smith, K Harnett, Donna R Grogan, Harry K Genant
    Abstract:

    Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare genetic disorder that leads to heterotopic ossification (HO), resulting in progressive restriction of physical function. In this study, low-dose, whole-body computed tomography (WBCT) and dual energy X-ray absorptiometry (DXA) were evaluated to determine the preferred method for assessing total body burden of HO in patients with FOP. This was a non-interventional, two-part natural history study in patients with FOP (NCT02322255; date of registration: December 2014). In Part A (described here), WBCT and DXA scans were individually assessed for HO presence and severity across 15 anatomical regions. All images were independently reviewed by an expert imaging panel. Ten adult patients were enrolled across four sites. The sensitivity to HO presence and severity varied considerably between the two imaging modalities, with WBCT demonstrating HO in more body regions than DXA (76/138 [55%] versus 47/113 [42%]) evaluable regions). Inability to evaluate HO presence, due to overlapping body regions (positional ambiguity), occurred less frequently by WBCT than by DXA (mean number of non-evaluable regions per scan 1.2 [standard deviation: 1.5] versus 2.4 [1.4]). Based on the increased sensitivity and decreased positional ambiguity of low-dose WBCT versus DXA in measuring HO in patients with FOP, low-dose WBCT was chosen as the preferred imaging for measuring HO. Therefore, low-dose WBCT was carried forward to Part B of the natural history study, which evaluated disease progression over 36 months in a larger population of patients with FOP.

  • Prevalence of Fibrodysplasia Ossificans Progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization
    'Springer Science and Business Media LLC', 2021
    Co-Authors: Robert J. Pignolo, Edward C Hsiao, Geneviève Baujat, David Lapidus, Adam Sherman, Frederick S. Kaplan
    Abstract:

    Abstract Background Fibrodysplasia Ossificans Progressiva (FOP), an ultra-rare, progressive, and permanently disabling disorder of extraskeletal ossification, is characterized by episodic and painful flare-ups and irreversible heterotopic ossification in muscles, tendons, and ligaments. Prevalence estimates have been hindered by the rarity of FOP and the heterogeneity of disease presentation. This study aimed to provide a baseline prevalence of FOP in the United States, based on contact with one of 3 leading treatment centers for FOP (University of Pennsylvania, Mayo Clinic, or University of California San Francisco), the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) membership list, or the IFOPA FOP Registry through July 22, 2020. Results Patient records were reviewed, collected, and deduplicated using first and last name initials, sex, state, and year of birth. A Kaplan–Meier survival curve was applied to each individual patient to estimate the probability that he or she was still alive, and a probability-weighted net prevalence estimate was calculated. After deduplication, 373 unique patients were identified in the United States, 294 of whom who were not listed as deceased in any list. The average time since last contact for 284 patients was 1.5 years. Based on the application of the survival probability, it is estimated that 279 of these patients were alive on the prevalence date (22 July 2020). An adjusted prevalence of 0.88 per million US residents was calculated using either an average survival rate estimate of 98.4% or a conservative survival rate estimate of 92.3% (based on the Kaplan–Meier survival curve from a previous study) and the US Census 2020 estimate of 329,992,681 on prevalence day. Conclusions This study suggests that the prevalence of FOP is higher than the often-cited value of 0.5 per million. Even so, because inclusion in this study was contingent upon treatment by the authors, IFOPA membership with confirmed clinical diagnosis, and the FOP Registry, the prevalence of FOP in the US may be higher than that identified here. Thus, it is imperative that efforts be made to identify and provide expert care for patients with this ultra-rare, significantly debilitating disease

  • druggable targets clinical trial design and proposed pharmacological management in Fibrodysplasia Ossificans Progressiva
    Expert opinion on orphan drugs, 2020
    Co-Authors: Robert J. Pignolo, Frederick S. Kaplan
    Abstract:

    Introduction: Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare genetic disorder characterized by heterotopic ossification, congenital skeletal abnormalities especially of the great toes...

  • longitudinal patient reported mobility assessment in Fibrodysplasia Ossificans Progressiva fop
    Bone, 2017
    Co-Authors: Frederick S. Kaplan, Mona Al Mukaddam, Robert J. Pignolo
    Abstract:

    Abstract Background Fibrodysplasia Ossificans Progressiva (FOP) is a rare, disabling genetic disorder characterized by episodic soft tissue swelling (flare-ups) that leads to progressive heterotopic ossification and restricted joint mobility. Methods Here we present the first longitudinal patient-reported mobility assessment (PRMA) in FOP based on a simple evaluation tool. At initial presentation and follow-up (1–11 year span; median: 6 year span), 64 patients (36 females; 28 males) with classic FOP completed a questionnaire designed to rapidly assess mobility at 15 sites (three axial; six upper limb, and six lower limb). In order to validate this instrument, twenty-one of 64 patients (33%) underwent a cumulative analogue joint involvement scale (CAJIS) evaluation by two physicians within six months of their second self-assessment. Results We found that: 1) mobility changes were episodic and regional, occurring first in the neck and trunk, followed by the upper limbs and finally the lower limbs; 2) interval improvements in mobility did occur, most notably in the lower limbs (18%), and less so in the upper limbs (12%) and trunk (3%), and 3) patient-reported mobility assessments correlate highly (R2 = 0.81) with physician-reported CAJIS evaluations. Conclusion This is the first longitudinal PRMA in FOP and provides a simple and valid tool that can be used in the design and evaluation of clinical trials in this progressively disabling disease.

  • palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human acvr1 r206h Fibrodysplasia Ossificans Progressiva fop mutation
    Journal of Bone and Mineral Research, 2016
    Co-Authors: Salin A Chakkalakal, Frederick S. Kaplan, Kenta Uchibe, Michael R Convente, Deyu Zhang, Aris N Economides, Maurizio Pacifici, Masahiro Iwamoto, Eileen M Shore
    Abstract:

    Fibrodysplasia Ossificans Progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans and causes skeletal deformities, movement impairment, and premature death. Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1R206H, that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO. We showed previously that the retinoic acid receptor γ (RARγ) agonist palovarotene effectively inhibited HO in injury-induced and genetic mouse models of the disease. Here we report that the drug additionally prevents spontaneous HO, using a novel conditional-on knock-in mouse line carrying the human ACVR1R206H mutation for classic FOP. In addition, palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates when given to lactating mothers. Importantly, palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP. © 2016 American Society for Bone and Mineral Research.

Eileen M Shore - One of the best experts on this subject based on the ideXlab platform.

  • palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human acvr1 r206h Fibrodysplasia Ossificans Progressiva fop mutation
    Journal of Bone and Mineral Research, 2016
    Co-Authors: Salin A Chakkalakal, Frederick S. Kaplan, Kenta Uchibe, Michael R Convente, Deyu Zhang, Aris N Economides, Maurizio Pacifici, Masahiro Iwamoto, Eileen M Shore
    Abstract:

    Fibrodysplasia Ossificans Progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans and causes skeletal deformities, movement impairment, and premature death. Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1R206H, that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO. We showed previously that the retinoic acid receptor γ (RARγ) agonist palovarotene effectively inhibited HO in injury-induced and genetic mouse models of the disease. Here we report that the drug additionally prevents spontaneous HO, using a novel conditional-on knock-in mouse line carrying the human ACVR1R206H mutation for classic FOP. In addition, palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates when given to lactating mothers. Importantly, palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP. © 2016 American Society for Bone and Mineral Research.

  • the natural history of flare ups in Fibrodysplasia Ossificans Progressiva fop a comprehensive global assessment
    Journal of Bone and Mineral Research, 2016
    Co-Authors: Robert J. Pignolo, Eileen M Shore, Christopher Bedfordgay, Moira Liljesthrom, Blythe Durbinjohnson, David M Rocke, Frederick S. Kaplan
    Abstract:

    Fibrodysplasia Ossificans Progressiva (FOP) leads to disabling heterotopic ossification (HO) from episodic flare-ups. However, the natural history of FOP flare-ups is poorly understood. A 78-question survey on FOP flare-ups, translated into 15 languages, was sent to 685 classically-affected patients in 45 countries (six continents). Five hundred patients or knowledgeable informants responded (73%; 44% males, 56% females; ages: 1 to 71 years; median: 23 years). The most common presenting symptoms of flare-ups were swelling (93%), pain (86%), or decreased mobility (79%). Seventy-one percent experienced a flare-up within the preceding 12 months (52% spontaneous; 48% trauma-related). Twenty-five percent of those who had received an intramuscular injection reported an immediate flare-up at the injection site, 84% of whom developed HO. Axial flare-ups most frequently involved the back (41.6%), neck (26.4%), or jaw (19.4%). Flare-ups occurred more frequently in the upper limbs before 8 years of age, but more frequently in the lower limbs thereafter. Appendicular flare-ups occurred more frequently at proximal than at distal sites without preferential sidedness. Seventy percent of patients reported functional loss from a flare-up. Thirty-two percent reported complete resolution of at least one flare-up and 12% without any functional loss (mostly in the head or back). The most disabling flare-ups occurred at the shoulders or hips. Surprisingly, 47% reported progression of FOP without obvious flare-ups. Worldwide, 198 treatments were reported; anti-inflammatory agents were most common. Seventy-five percent used short-term glucocorticoids as a treatment for flare-ups at appendicular sites. Fifty-five percent reported that glucocorticoids improved symptoms occasionally whereas 31% reported that they always did. Only 12% reported complete resolution of a flare-up with glucocorticoids. Forty-three percent reported rebound symptoms within 1 to 7 days after completing a course of glucocorticoids. This study is the first comprehensive global assessment of FOP flare-ups and establishes a critical foundation for the design and evaluation of future clinical trials. © 2015 American Society for Bone and Mineral Research.

  • the natural history of flare ups in Fibrodysplasia Ossificans Progressiva fop a comprehensive global assessment
    Journal of Bone and Mineral Research, 2016
    Co-Authors: Robert J. Pignolo, Eileen M Shore, Christopher Bedfordgay, Moira Liljesthrom, Blythe Durbinjohnson, David M Rocke, Frederick S. Kaplan
    Abstract:

    Fibrodysplasia Ossificans Progressiva (FOP) leads to disabling heterotopic ossification (HO) from episodic flare-ups. However, the natural history of FOP flare-ups is poorly understood. A 78-question survey on FOP flare-ups, translated into 15 languages, was sent to 685 classically-affected patients in 45 countries (six continents). Five hundred patients or knowledgeable informants responded (73%; 44% males, 56% females; ages: 1 to 71 years; median: 23 years). The most common presenting symptoms of flare-ups were swelling (93%), pain (86%), or decreased mobility (79%). Seventy-one percent experienced a flare-up within the preceding 12 months (52% spontaneous; 48% trauma-related). Twenty-five percent of those who had received an intramuscular injection reported an immediate flare-up at the injection site, 84% of whom developed HO. Axial flare-ups most frequently involved the back (41.6%), neck (26.4%), or jaw (19.4%). Flare-ups occurred more frequently in the upper limbs before 8 years of age, but more frequently in the lower limbs thereafter. Appendicular flare-ups occurred more frequently at proximal than at distal sites without preferential sidedness. Seventy percent of patients reported functional loss from a flare-up. Thirty-two percent reported complete resolution of at least one flare-up and 12% without any functional loss (mostly in the head or back). The most disabling flare-ups occurred at the shoulders or hips. Surprisingly, 47% reported progression of FOP without obvious flare-ups. Worldwide, 198 treatments were reported; anti-inflammatory agents were most common. Seventy-five percent used short-term glucocorticoids as a treatment for flare-ups at appendicular sites. Fifty-five percent reported that glucocorticoids improved symptoms occasionally whereas 31% reported that they always did. Only 12% reported complete resolution of a flare-up with glucocorticoids. Forty-three percent reported rebound symptoms within 1 to 7 days after completing a course of glucocorticoids. This study is the first comprehensive global assessment of FOP flare-ups and establishes a critical foundation for the design and evaluation of future clinical trials.

  • alk2 regulates early chondrogenic fate in Fibrodysplasia Ossificans Progressiva heterotopic endochondral ossification
    Stem Cells, 2014
    Co-Authors: Andria L Culbert, Salin A Chakkalakal, Edwin G Theosmy, Tracy A Brennan, Frederick S. Kaplan, Eileen M Shore
    Abstract:

    Bone morphogenetic protein (BMP) signaling is a critical regulator of cartilage differentiation and endochondral ossification. Gain-of-function mutations in ALK2, a type I BMP receptor, cause the debilitating disorder Fibrodysplasia Ossificans Progressiva (FOP) and result in progressive heterotopic (extraskeletal) endochondral ossification within soft connective tissues. Here, we used murine mesenchymal progenitor cells to investigate the contribution of Alk2 during chondrogenic differentiation and heterotopic endochondral ossification (HEO). Alk2R206H/+ (gain-of-function), Alk2CKO (loss-of-function), and wild-type mouse embryonic fibroblasts were evaluated for chondrogenic potential. Chondrogenic differentiation was accelerated in Alk2R206H/+ cells, due in part to enhanced sensitivity to BMP ligand. In vivo, Alk2R206H/+ cells initiated robust HEO and recruited wild-type cell contribution. Despite expression of other type I BMP receptors (Alk3 and Alk6), chondrogenesis of Alk2CKO cells was severely impaired by absence of Alk2 during early differentiation. Alk2 is therefore a direct regulator of cartilage formation and mediates chondrogenic commitment of progenitor cells. These data establish that at least one effect of ALK2 gain-of-function mutations in FOP patients is enhanced chondrogenic differentiation which supports formation of heterotopic endochondral bone. This establishes ALK2 as a plausible therapeutic target during early chondrogenic stages of lesion formation for preventing heterotopic bone formation in FOP and other conditions. Stem Cells 2014;32:1289–1300

  • Fibrodysplasia Ossificans Progressiva diagnosis management and therapeutic horizons
    Pediatric endocrinology reviews, 2013
    Co-Authors: Robert J. Pignolo, Eileen M Shore, Frederick S. Kaplan
    Abstract:

    Fibrodysplasia Ossificans Progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobility is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVRI/ ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP. The discovery of the FOP gene established a critical milestone in our understanding of FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment of FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is focused on early diagnosis, assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function.

Alex N Bullock - One of the best experts on this subject based on the ideXlab platform.

  • Structure–Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants
    2015
    Co-Authors: Ah Mohedas, Alex N Bullock, Ce Sanvitale, You Wang, Peter Canning, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny
    Abstract:

    There are currently no effective therapies for Fibrodysplasia Ossificans Progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG

  • structure activity relationship of 3 5 diaryl 2 aminopyridine alk2 inhibitors reveals unaltered binding affinity for Fibrodysplasia Ossificans Progressiva causing mutants
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Ah Mohedas, Alex N Bullock, C Sanvitale, You Wang, Peter Canning, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny
    Abstract:

    There are currently no effective therapies for Fibrodysplasia Ossificans Progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity...

  • structure of the bone morphogenetic protein receptor alk2 and implications for Fibrodysplasia Ossificans Progressiva
    Journal of Biological Chemistry, 2012
    Co-Authors: A Chaikuad, I Alfano, Georgina Kerr, C Sanvitale, Jan H Boergermann, J T Triffitt, F Von Delft, S Knapp, Petra Knaus, Alex N Bullock
    Abstract:

    Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant receptor kinase domains escape regulation leading to severely degenerative diseases and represent an important therapeutic target. Fibrodysplasia Ossificans Progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand. To establish structural mechanisms of receptor regulation and to address the effects of FOP mutation, we determined the crystal structure of the cytoplasmic domain of ALK2 in complex with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation. The balance of these effects accounts for the comparable activity of R206H and L196P. Kinase activation in the clinically benign mutant L196P is far weaker than R206H but yields equivalent signals due to the stronger interaction of FKBP12 with R206H. The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling.

Gregory D. Cuny - One of the best experts on this subject based on the ideXlab platform.

  • Structure–Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants
    2015
    Co-Authors: Ah Mohedas, Alex N Bullock, Ce Sanvitale, You Wang, Peter Canning, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny
    Abstract:

    There are currently no effective therapies for Fibrodysplasia Ossificans Progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG

  • structure activity relationship of 3 5 diaryl 2 aminopyridine alk2 inhibitors reveals unaltered binding affinity for Fibrodysplasia Ossificans Progressiva causing mutants
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Ah Mohedas, Alex N Bullock, C Sanvitale, You Wang, Peter Canning, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny
    Abstract:

    There are currently no effective therapies for Fibrodysplasia Ossificans Progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure–activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity...

Renata Bocciardi - One of the best experts on this subject based on the ideXlab platform.

  • peripheral blood mononuclear cell immunophenotyping in Fibrodysplasia Ossificans Progressiva patients evidence for monocyte dnam1 up regulation
    Cytometry Part B-clinical Cytometry, 2018
    Co-Authors: Genny Del Zotto, Serena Cappato, Francesca Giacopelli, Roberto Ravazzolo, Francesca Antonini, Irma Azzari, Claudio Ortolani, Gino Tripodi, Lorenzo Moretta, Renata Bocciardi
    Abstract:

    Background Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by sporadic heterozygous mutations in ACVR1 gene which progressively leads to severe heterotopic ossification. FOP is characterized by episodic flare-ups triggered by different factors such as viral infections, tissue injuries, vaccinations or occurring without a recognizable cause. The sporadic course of the disease, the documented presence of an important inflammatory reaction in early lesions and the partial response to corticosteroids support the idea that the immune system, and in particular the innate component, may play a role in FOP pathogenesis. However, an extensive expression profile of the peripheral blood mononuclear cells (PBMC) of FOP patients has never been done. Methods In the present study, we carried out a wide PBMC immunophenotyping on a cohort of FOP patients and matching controls by multiparametric analysis of the expression of a panel of 37 markers associated with migration, adhesion, inhibition, activation and cell death of circulating immune cells. Results We observed a statistically significant increase of the expression of DNAM1 receptor in patients' monocytes as compared to controls, and little but significant differences in the expression profile of CXCR1 (CD181), CD62L, CXCR4 (CD184) and HL-DR molecules. Conclusions DNAM1 had been previously shown to play a pivotal role in monocyte migration through the endothelial barrier and the increased expression detected in patients' monocytes might suggest a role of this surface receptor during the early phases of FOP flare-ups in which the activation of the immune response is believed to represent a crucial event. This article is protected by copyright. All rights reserved.

  • The Horizon of a Therapy for Rare Genetic Diseases: A "Druggable" Future for Fibrodysplasia Ossificans Progressiva.
    International Journal of Molecular Sciences, 2018
    Co-Authors: Serena Cappato, Francesca Giacopelli, Roberto Ravazzolo, Renata Bocciardi
    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.

  • The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva
    MDPI AG, 2018
    Co-Authors: Serena Cappato, Francesca Giacopelli, Roberto Ravazzolo, Renata Bocciardi
    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