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21 results on '"Service of Clinical Trials and Databases"'

1. High urinary ferritin reflects myoglobin iron evacuation in DMD patients

Author: Jeremy Rouillon, Hervé Puy, Katell Peoc'h, Thomas Voit, Brenda Wong, Thibaud Lefebvre, Jérôme Ausseil, Vincent Puy, Laurent Servais, Aleksandar Zocevic, Paul Fogel, Fedor Svinartchouk, Zoubida Karim, Jérôme Denard, Raed Daher, Centre de recherche et d'applications sur les thérapies géniques (CRATG), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS)-Généthon, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université de Picardie Jules Verne (UPJV), Laboratory of Excellence GR-Ex ' The red cell : from genesis to death ', PRES Sorbonne Paris Cité, CHU Amiens-Picardie, Service de Biochimie et de Biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Faculté de Pharmacie, Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center, Service of Clinical Trials and Databases, Institut de Myologie, Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Faculté de Pharmacie
Subjects: 0301 basic medicine, Male, Antibody microarray, Duchenne muscular dystrophy, Urinary ferritin, Urine, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antibody array, MESH: Child, Child, Genetics (clinical), Kidney, MESH: Cytokines, MESH: Iron, biology, Myoglobin, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, medicine.anatomical_structure, Neurology, MESH: Young Adult, Child, Preschool, Biomarker (medicine), Cytokines, Dystrophin, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, MESH: Myoglobin, Urinary system, Iron, MESH: Ferritins, 03 medical and health sciences, Young Adult, Internal medicine, medicine, MESH: Muscular Dystrophy, Duchenne, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, MESH: Male, Ferritin, Muscular Dystrophy, Duchenne, 030104 developmental biology, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pediatrics, Perinatology and Child Health, Ferritins, biology.protein, MESH: Biomarkers, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract: International audience; Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the dystrophin gene leading to the absence of the normal dystrophin protein. The efforts of many laboratories brought new treatments of DMD to the reality, but ongoing and forthcoming clinical trials suffer from absence of valuable biomarkers permitting to follow the outcome of the treatment day by day and to adjust the treatment if needed. In the present study the levels of 128 urinary proteins including growth factors, cytokines and chemokines were compared in urine of DMD patients and age related control subjects by antibody array approach. Surprisingly, statistically significant difference was observed only for urinary ferritin whose level was 50 times higher in young DMD patients. To explain the observed high urinary ferritin content we analysed the levels of iron, iron containing proteins and proteins involved in regulation of iron metabolism in serum and urine of DMD patients and their age-matched healthy controls. Obtained data strongly suggest that elevated level of urinary ferritin is functionally linked to the renal management of myoglobin iron derived from leaky muscles of DMD patients. This first observation of the high level of ferritin in urine of DMD patients permits to consider this protein as a new urinary biomarker in muscular dystrophies and sheds light on the mechanisms of iron metabolism and kidney functioning in DMD.
Published: 2020
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2. Can global muscle segmentation detect changes in neuromuscular disorders using quantitative nuclear magnetic resonance imaging?

Author: Reyngoudt, Harmen, Marty, Benjamin, Boisserie, Jean-Marc, Louër, Julien Le, Koumako, Cedi, Baudin, Pierre-Yves, Wong, Brenda, Stojkovic, Tanja, Behin, Anthony, Gidaro, Teresa, Servais, Laurent, Allenbach, Yves, Benveniste, Olivier, Carlier, Pierre, Laboratoire RMN AIM-CEA, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Organ Modeling through Extraction, Representation and Understanding of Medical Image Content (GALEN), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Ecole Centrale Paris, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service of Clinical Trials and Databases, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Laboratoire Spécification et Vérification [Cachan] (LSV), and École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience
Published: 2019
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3. X-linked myotubular myopathy: A prospective international natural history study

Author: A. Hernandez, Andrea Gangfuß, V. Chê, Adele D'Amico, Rémi Bellance, Laurent Servais, Capucine de Lattre, Basil T. Darras, E. Gargaun, James J. Dowling, Teresa Gidaro, C. Lilien, Ulrike Schara, A. Daron, Ana Buj-Bello, H. Landy, Jean-Marie Cuisset, Carole Vuillerot, Jean-Yves Hogrel, S. Fontaine, Jean-Michel Arnal, Valérie Biancalana, Michèle Mayer, M. Annoussamy, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Advanced BC.org, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Neuromuscular Physiology and Evaluation Laboratory, Service of Clinical Trials and Databases, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Vital capacity, medicine.medical_specialty, Neuromuscular disease, Adolescent, [SDV]Life Sciences [q-bio], Population, Medizin, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Longitudinal Studies, Prospective Studies, education, Prospective cohort study, Child, education.field_of_study, business.industry, Exhalation, Infant, Middle Aged, medicine.disease, X-linked myotubular myopathy, 3. Good health, 030104 developmental biology, Phenotype, Child, Preschool, Breathing, Disease Progression, Neurology (clinical), business, 030217 neurology & neurosurgery, Natural history study, Follow-Up Studies, Myopathies, Structural, Congenital
Abstract: ObjectivesBecause X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures.MethodsWe designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored.ResultsForty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti–adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.ConclusionsOur data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population.ClinicalTrials.gov identifierNCT02057705.
Published: 2019
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4. Phenotypic and genomic characterization of Becker dystrophy patients with 45 to 55 exons deletion

Author: Gargaun, Elena, Yaou, Rabah Ben, Guibaud, Marine, Solé, Guilhem, Tiffreau, Vincent, Laforet, Pascale, Parent, Michel, Bassez, Guillaume, Vanhulle, Catherine, Servais, Laurent, Lacombe, Pascal, Pedespan, Jean-Michel, Kettaneh, Adrien, Roche, Corinne, Gaillard, Dominique, Sacconi, Sabrina, Faivre, Laurence, Nadaj-Pakleza, Alexandra, Vallat, Jean Michel, Laroche, Cécile, Moing, Anne-Gaëlle Le, Durigneux, Julien, Themar-Noel, Christine, Negrier, Marie Laure, Espil-Taris, Caroline, Boucher, Elise, Delaubier, Anne, Guillou, Claire, Cuisset, Jean Marie, Urtizberea, Andoni, Eymard, Bruno, Boland, Anne, Deleuze, Jean François, Salgado, David, Krahn, Martin, Levy, Nicolas, Blesius, Alexia, Leturcq, France, Pietri-Rouxel, France, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Reference des Maladies Neuromusculaires - Atlantique Occitanie Caraïbe (CRMN - AOC), CHU Lille, Pathologie Nord Unilabs, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie néonatale et réanimation - neuropédiatrie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service of Clinical Trials and Databases, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Vichy], CH Vichy, Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Maintenance Myélinique et Neuropathies Périphériques (MMNP), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, Service de Pédiatrie médicale [CHU Limoges], Pediatric Neurology Department, University Hospital, Ang ers, France, 87, avenue Raymond-Poincaré, 75116 Paris, parent, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Bordeaux (UB), Hôpital Marin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset CEPH, Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Internationales Servier [Suresnes] (IRIS), and Hôpital Cochin [AP-HP]
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Becker muscular dystrophy (BMD) is an X linked disorder with 1/30000 life births incidence and is characterized by a progressive muscular dystrophy with or without cardiomyopathy. We present a population of 49 BMD patients with a DMD gene in-phase deletion of exons 45 to 55 (BMDdel45-55). Interestingly, emerging regulatory actors as lncRNA are localized in introns 44 and 55 (Bovolenta et al., 2012). Thus, the specific neo-introns of each patient could create or modify the lncRNA and/or RNA non-coding sequences. The objective of this study is to identify modifier factors involved in phenotypic variability in BMDdel45-55 patients. As described in literature, 63% of Duchenne patients are eligible to a multiexon skipping therapy by skipping exons 45 to 55.We performed (i) a phenotypic characterization of 49 patients, (ii) a lncRNA profile in 40/49patients and (iii) a WGS in 19/49patients. We have established the profile of lncRNA presence at genomic level in healthy subjects, muscle biopsies of BMDdel45-55 and DMD patients and human immortalized myoblasts displaying a deletion of 45-52 exons in DMD gene (Myo-45-52).In our cohort 22% of patients have dilatative cardiomyopathy, interestingly in 51% the first signs age was
Published: 2019

5. Caractérisation phénotypique et génomique des patients Becker avec délétion des exons 45-55

Author: Gargaun, Elena, Yaou, Rabah Ben, Solé, Guilhem, Tiffreau, Vincent, Laforet, Pascale, Parent, Michel, Bassez, Guillaume, Stojkovic, Tanya, Vanhulle, Catherine, Servais, Laurent, Lacombe, Pascal, Pedespan, Jean-Michel, Kettaneh, Adrien, Roche, Corinne, Gaillard, Dominique, Sacconi, Sabrina, Faivre, Laurence, Nadaj-Pakleza, Alexandra, Vallat, Jean Michel, Laroche, Cécile, Moing, Anne-Gaëlle Le, Durigneux, Julien, Themar-Noel, Christine, Negrier, Marie Laure, Espil-Taris, Caroline, Boucher, Elise, Delaubier, Anne, Guillou, Claire, Cuisset, Jean Marie, Urtizberea, Andoni, Eymard, Bruno, Boland, Anne, Deleuze, Jean François, Salgado, David, Krahn, Martin, Levy, Nicolas, Blesius, Alexia, Leturcq, France, Pietri-Rouxel, France, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie néonatale et réanimation - neuropédiatrie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service of Clinical Trials and Databases, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bordeaux Ségalen [Bordeaux 2], Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Vichy], CH Vichy, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), CHU Nice, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institute of Developmental Biology and Cancer (IBDC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Maintenance Myélinique et Neuropathies Périphériques (MMNP), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, Service de Pédiatrie médicale [CHU Limoges], Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), 87, avenue Raymond-Poincaré, 75116 Paris, parent, University Hospital, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Bordeaux (UB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Biochimie et Génétique Moléculaire, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP]
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; La dystrophie musculaire de Becker (BMD) est une pathologie liée à l’X qui se caractérise par une dégénérescence des muscles squelettiques et/ou associée à une cardiomyopathie. Les patients Becker BMDdel45-55 présentent une délétion “en phase” des exons 45 à 55 dans le gène DMD. Les introns 44 et 55 qui bordent cette délétion contiennent des séquences régulatrices comme des long-non-coding ARN (lncRNA). Chaque patient BMDdel45-55 présente un point de cassure différent et donc un neo-intron unique avec potentiellement des modifications dans les séquences de lncRNA.L’objectif du projet est d’établir une caractérisation génomique d’une cohorte unique de patients BMDdel45-55 et d’étudier des facteurs impliqués dans leur variabilité phénotypique.Nous avons réalisé (i)une caractérisation phénotypique chez 49 patients, (ii)un séquençage du génome entier chez 19/49 patients et (iii)une étude des lncRNA chez 38/49 patients. Nous avons établi le profil des lncRNA dans des myoblastes immortalisés des sujets sains et DMD avec une délétion des exons 45-52 (Myo-45-52).L’étude phénotypique de notre population identifie une cardiomyopathie dilatée (22%), des difficultés à la marche/course (46%), la fatigabilité (34%). Dans 51% l’âge d’apparition des premiers signes est
Published: 2019

6. Nusinersen versus sham control in later-onset spinal muscular atrophy

Author: Vogt, Sibylle, Krueger, Marcus, Pechmann, Astrid, Rippberger, Bianca, Eckenweiler, Matthias, Schara, Ulrike, Koelbel, Heike, Andres, Barbara, Rupprich, Katrin, Gangfuss, Andrea, Jachertz, Philipp, Della Marina, Adela, Sponemann, Nina, Pane, Markia, Palermo, Concetta, Piastra, Marco, Fanelli, Lavinia, de Sanctis, Roberto, Genovese, Orazio, Antonaci, Laura, Pera, Maria Carmela, Lamendola, Priscilla, Messina, Sonia, Vita, Gianluca, Di Bella, Vincenzo, Sframeli, Maria, Rosa, Matteo, Barcellona, Costanza, Distefano, Maria Grazia, Cavallaro, Filippo, Versaci, Antonio, de Luca, Francesco, Vita, Giuseppe, Nacimento Osorio, Andres, Tizzano, Eduardo, Ortez Gonzalez, Carlos Ignacio, Ortigoza Escobar, Juan Dario, Colomer Oferil, Juame, Medina Cantillo, Julita, Febrer Rotger, Anna, Vigo Morancho, Meritxell, Eldblom, Johanneh, Darin, Niklas, Kroksmark, Anna Karin, Lindstedt, Asa, Michael, Eva, Kimber, Eva, Wahlgren, Lisa, Chan, Sophelia Hoi-Shan, Chim, Stella, Chiu, Joseph, Ho, Alvin Chi Chung, Ip, Jing Kun Janice, Lam, Wendy Wai Man, Ng, Maggie Chui-San, Wan, Connie, Wong, Virginia Chun Nei, Yue, Yvonne, Arakawa, Reiko, Yamauchi, Akemi, Nagata, Satoru, Ito, Yasushi, Nakatsukasa, Hidetsugu, Takeshita, Akiko, Hirasawa, Kyoko, Ikai, Tetsuo, Eto, Kaoru, Otamni, Yui, Takeshima, Yasuhiro, Fukuda, Noroki, Tanaka, Yasuhiro, Shimomura, Hideki, Lee, Tomoko, Shibano, Takayuki, Mercuri, E., Tachikawa, Tomohiro, Darras, B. T., Chae, Jong-Hee, Chiriboga, C. A., Lim, Byung Chan, Day, J. W., Shin, Hyung-Ik, Campbell, C., Kim, Soo Yeon, Connolly, A. M., Choi, Sun Ah, Iannaccone, S. T., Son, Woo Sung, Kirschner, J., Jo, Hyemi, Kuntz, N. L., Chun, Seong Min, Saito, K., Kim, Hyuna, Shieh, P. B., Tulinius, M., Mazzone, E. S., Montes, J., Bishop, K. M., Yang, Q., Foster, R., Gheuens, S., Bennett, C. F., Farwell, W., Schneider, E., de Vivo, D. C., Finkel, R. S., Bradley, Walter G., Kaufmann, Petra, Dickson, Patricia I., Reingold, Stephen C., Davis, Charles S., Arredondo, Kristen, Castro, Diana, Cowie, Margaret, Farrow-Gillespie, Alan, Hebert, Andrew, Kauk, Melissa, Miller, Nancy, Nelson, Leslie, Spain, Thomas, Cappell, Joshua, Constantinescu, Andrei, Cruz, Rosangel, Dastgir, Jahannaz, de Vivo, Darryl, Dunaway, Sally, Engelstad, Kristin, Khandji, Alexander G., Kramer, Samantha, Marra, Jonathan, Popolizio, Molly, Salazar, Rachel, Weimer, Louis H., Aziz-Zaman, Sonya, Lamarca, Nicole, Ghosh, Partha, Al-Ghamdi, Fouad, Liew, Wendy, Graham, Robert, Berde, Charles, Sethna, Navil, Koka, Anjali, Wang, Luke, Laine, Regina, Souris, Michelle, Ordonez, Grace, Harrington, Timothy, Szelag, Heather, Pasternak, Amy, Mirek, Elizabeth, Quigley, Janet, Finkel, Richard, Berry, Debbie, Civitello, Matthew, Endsley, Julie Duke, Eden, Candace, Leon, Wendy, O'Reardon, Kathleen, Sigurdardottir, Laufey, Johnson, Craig, Turner, Jenna, Vega, Melisa, Weber-Guzman, Fabiola, Zinn, Matthias, Rocha, Ana Carolina Tesi, Watson, Karolina, d'Souza, Genevieve, Ramamurthi, R. J., Gee, Richard, Kitsuwa-Lowe, Janis, Hagerman, Katharine, Crasta, Sheela, Welsh, Lesly, Paulose, Shirley, Mcfall, Danielle, Perez, Jennifer, Patnaik, Swetapadma, Sanjanwala, Bharati, Sakamuri, Sarada, Proud, Crystal, Purse, Bona Park, Duong, Trinh Tina, Sampson, Jacinda, Tennekoon, Gihan, Brandsema, John, Glanzman, Allan, Flickinger, Jean, Toms, Michele, Adang, Laura, Stanford, Delores, Mayer, Oscar, Zigmont, Joshua, Chadehumbe, Madeline, Kichula, Elizabeth, Finanger, Erika, Russman, Barry, Roberts, Colin, Frank, Andrea, Benjamin, Danielle, Zilke, Kirsten, Golumbek, Paul T., Zaidman, Craig M., Anand, Pallavi, Gadeken, Rebecca, Siener, Catherine, Kuntz, Nancy, Epstein, Leon, Krueger, Jena, Goldman, Stewart, Krosschell, Kristin, Blomgren, Colleen, Choi, Hyoung Won, Kurz, Jonathan, Parsons, Julie, Janas, Joanne, Yang, Michele, Ballard, Alison, Carry, Terri, Shea, Stephanie, Bielsky, Alan, Booker, Kaylee, Camuto, Alicia, Lord-Halvorson, Sierra, Gibbons, Melissa, Zimmerman, Carl, Allen, Victoria, Fuhr, Peter, Johnson, Hannah, Tran, Vi, Vanderveen, Gina, Shieh, Perry, Fowler, Eileen, Parziale, Nicholas, Rao, Lekha, Skura, Christy, Kelley, Carolyn, Shu, Francy, Oskoui, Maryam, Zielinski, David, Poulin, Chantal, Ingelmo, Pablo Mauricio, Desilets, Sarah Turgeon, Dinunzio, Pamela, Rivera, Gonzalo, Srour, Myriam, Arpin, Stephanie, Goobie, Sharan, Gibson, Paul, Scholtes, Cheryl, Mcdonald, Wendy, Zapata, Eugenio, Nguyen, Cam-Tu Emilie, Servais, Laurent, Gargaun, Elena, Le Moing, Anne-Gaelle, Gidaro, Teresa, Vialle, Raphael, Guye, Marie-Laurence, Lilien, Charlotte, Olliver, Gwenn, Gilabert, Stephanie, Borell, Sabine, Wider, Sabine, Stein, Sabine, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Department of Paediatrics, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Vall d'Hebron University Hospital [Barcelona], CIBER de Enfermedades Raras (CIBERER), Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Seoul National University Hospital, Max-Planck-Institut für Mikrostrukturphysik (MPI-HALLE), Max-Planck-Gesellschaft, The University of Tokyo (UTokyo), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institute of Plasma Physics, Chinese Academy of Sciences (ASIPP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de mécanique des solides (LMS), École polytechnique (X)-Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), CureSMA [Elk Grove Village, IL, USA], Harvard Medical School [Boston] (HMS), Institute for Marine and Antarctic Studies [Hobart] (IMAS), University of Tasmania [Hobart, Australia] (UTAS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, The Open University [Milton Keynes] (OU), Department of Pediatrics, Feinberg School of Medicine, Northwestern University [Evanston]-Northwestern University [Evanston]-Northwestern University, University Hospital Basel [Basel], McGill University Health Center [Montreal] (MUHC), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service of Clinical Trials and Databases, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Oxford, Schara, Ulrike (Beitragende*r), Koelbel, Heike (Beitragende*r), Rupprich, Katrin (Beitragende*r), Gangfuss, Andrea (Beitragende*r), Della Marina, Adela (Beitragende*r), and Sponemann, Nina (Beitragende*r)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], spinal, Medizin, Oligonucleotides, Spinal Muscular Atrophies of Childhood, Pediatrics, law.invention, Age of Onset, Child, Child, Preschool, Double-Blind Method, Female, Humans, Infant, Injections, Spinal, Least-Squares Analysis, Motor Skills, Oligonucleotides, Antisense, Medicine (all), 0302 clinical medicine, age of onset, Randomized controlled trial, law, Clinical endpoint, inglese, injections, Motor skill, motor skills, General Medicine, SMA, Settore MED/26 - NEUROLOGIA, medicine.anatomical_structure, female, Anesthesia, Nusinersen, Spinal, antisense, preschool, Injections, 03 medical and health sciences, least-squares analysis, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Settore MED/41 - ANESTESIOLOGIA, medicine, Antisense, Preschool, business.industry, Spinal muscular atrophy, Motor neuron, medicine.disease, 030104 developmental biology, Age of onset, business, 030217 neurology & neurosurgery
Abstract: Background: Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). Methods: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. Results: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by –1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P Conclusions: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537. opens in new tab.)
Published: 2018
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7. Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches

Author: Thomas Voit, R. Joubert, Julie Dumonceaux, Laurent Servais, Caroline Bogni, Michael G. Hanna, Ana Buj-Bello, Tanya Stojkovic, Christophe Hourdé, Rozen Le Panse, Olivier Benvensite, Thierry Maisonobe, Pedro Machado, Francesco Muntoni, Léonard Féasson, Virginie Mariot, Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches Avicoles (SRA), Institut National de la Recherche Agronomique (INRA), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Social and Community Medicine School, University of Bristol [Bristol], Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children [London] (GOSH)-Institute of Child Health, Fédération de Neurophysiologie clinique, GH Pitié-Salpêtrière, Paris, Service of Clinical Trials and Databases, Institut de Myologie, GENETHON, Genethon, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics, University of Cambridge, University of Cambridge [UK] (CAM), Généthon, Evry, Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), UMR9196, Physiologie et Pathologie Moléculaires des Rétrovirus Endogènes et Infectieux, Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Unité de Recherche PPEH, Service de Physiologie Clinique et de l'Exercice, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), The Dubowitz Neuromuscular Centre, Imperial College London, Service de Neurophysiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Généthon, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics [Cambridge], Institute of Child Health-Great Ormond Street Hospital for Children [London] (GOSH), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Unité de recherches Avicoles, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Physiologie et physiopathologie des rétrovirus endogènes et infectieux (RETRO-ENDO), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Neurophysiologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, 0301 basic medicine, Follistatin, Myotubularin, Activin Receptors, Type II, General Physics and Astronomy, Myostatin, Bioinformatics, 0302 clinical medicine, lcsh:Science, Wasting, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Regulation of gene expression, Multidisciplinary, biology, Neuromuscular Diseases, Activin receptor, Middle Aged, Protein Tyrosine Phosphatases, Non-Receptor, musculoskeletal system, 3. Good health, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Myopathies, Structural, Congenital, Adult, Science, Down-Regulation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Downregulation and upregulation, medicine, Animals, Humans, business.industry, Skeletal muscle, General Chemistry, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, biology.protein, lcsh:Q, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin. We also provide in vivo evidence in the congenital myotubular myopathy mouse model (knock-out for the myotubularin coding gene Mtm1) that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect. Our data may explain the poor clinical efficacy of anti-myostatin approaches in several of the clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may inform patient selection and stratification for future trials., Drugs targeting myostatin reverse muscle wasting in animal models, but have limited efficacy in patients. The authors show that the myostatin pathway is downregulated in patients, possibly explaining the poor outcome of anti-myostatin approaches, and that it can be reactivated by correcting disease-causing mutations in mice.
Published: 2017
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8. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Author: Virginie François, Oumeya Adjali, Jean-Yves Hogrel, George Dickson, Thibaut Larcher, Maeva Dutilleul, Taeyoung Koo, Marie Montus, Stéphane Ederhy, Stéphane Blot, M. Allais, Carole Masurier, Alberto Malerba, Marie Devaux, B. Matot, Karim Wahbi, Sophie Moullec, Bernard Gjata, Bodvael Fraysse, Laurent Servais, Fulvio Mavilio, Inès Barthélémy, Pierre G. Carlier, Takis Athanasopoulos, Isabelle Testault, Samia Martin, Jack-Yves Deschamps, Philippe Moullier, Federico Mingozzi, Philippe Veron, Christophe Georger, Johanne Le Duff, Caroline Le Guiner, Thomas Voit, Jean-Laurent Thibaut, U1089, Institut National de la Santé et de la Recherche Médicale (INSERM), Service of Clinical Trials and Databases, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Généthon, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Boisbonne, Atlantic Gene Therapies, Ecole Nationale Vétérinaire Agroalimentaire et de l'Alimentation Nantes Atlantique (ONIRIS), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Royal Holloway, University of London, Laboratoire de Résonance Magnétique Nucléaire (LRMN), Modélisation thérapeutique en neurologie: myologie et biothérapies des myopathies canines, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Chercheur indépendant, Centre Hospitalier Vétérinaire Atlantia, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire des Sciences de l'Information et des Systèmes (LSIS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, University of Wolverhampton, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR1089, Laboratoire de Thérapie Génique, Université de Nantes (UN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Service de Cardiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Université de Toulon (UTLN)-Aix Marseille Université (AMU), École pratique des hautes études (EPHE), Laboratoire RMN, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR 1089, Atlantic Gene Therapies, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Association française contre les myopathies (AFM-Téléthon), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1089, Atlantic Gene Therapies & Genethon, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Recherche et développement [Généthon, Evry] (R & D Généthon), Généthon [Evry], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Subjects: 0301 basic medicine, Male, myopathie de duchenne, Duchenne muscular dystrophy, Genetic enhancement, medicine.medical_treatment, General Physics and Astronomy, Bioinformatics, Dystrophin, Muscular Dystrophy, Vector (molecular biology), Transgenes, Muscular dystrophy, Multidisciplinary, biology, Gene Transfer Techniques, Immunosuppression, Skeletal, Dependovirus, 3. Good health, thérapie génique, Administration, Muscle, Administration, Intravenous, Intravenous, ITGA7, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Neuromuscular disease, Science, Genetic Vectors, Animals, Disease Models, Animal, Dogs, Genetic Therapy, Muscle, Skeletal, Muscular Dystrophy, Animal, Muscular Dystrophy, Duchenne, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Animal, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Duchenne, medicine.disease, 030104 developmental biology, Disease Models, biology.protein, business
Abstract: Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV–microdystrophin gene therapy in DMD patients., Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.
Published: 2017
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9. Rapamycin vs. Placebo for the Treatment of Inclusion Body Myositis: improvement of the 6 min walking distance, a functional scale, the FVC and muscle quantitative MRI

Author: Benveniste, Olivier, Hogrel, Jean-Yves, Annoussamy, Melanie, Bachasson, Damien, Rigolet, Aude, Servais, Laurent, Salem, Joe-Elie, Hervier, Baptiste, Cardinal, Oceane Landon, Mariampillai, Kuberaka, Hulot, Jean-Sebastien, Carlier, Pierre, Allenbach, Yves, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut pour la Recherche sur la Moelle Epinière et l'Encéphale (IRME), Institute of Myology Paris France, Service of Clinical Trials and Databases, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience
Published: 2017

10. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy

Author: Sicot, G, Servais, L, Dinca, DM, Leroy, A, Prigogine, C, Medja, F, Braz, SO, Huguet-Lachon, A, Chhuon, C, Nicole, A, Gueriba, N, Oliveira, R, Dan, B, Furling, D, Swanson, MS, Guerrera, IC, Cheron, G, Gourdon, G, Gomes-Pereira, M, Gomes-Pereira, Mario, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, BLANC - Anomalies précoces dans un modèle murin de la dystrophie myotonique de Steinert : un modèle de la forme congénitale ? - - MODELCDM2010 - ANR-10-BLAN-1121 - BLANC - VALID, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of Neurophysiology and Biomechanics of Movement (LNBM), Université libre de Bruxelles (ULB), Université Sorbonne Paris Cité (USPC), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Florida [Gainesville] (UF), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-BLAN-1121,MODELCDM,Anomalies précoces dans un modèle murin de la dystrophie myotonique de Steinert : un modèle de la forme congénitale ?(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service of Clinical Trials and Databases, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Laboratory of Electrophysiology, University of Mons, 7000 Mons, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Bergmann glia, cerebellum, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, brain, Down-Regulation, neurons, Mice, Transgenic, glutamate, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, transgenic mice, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sciences de l'ingénieur, Article, Glutamate Plasma Membrane Transport Proteins, Mice, Purkinje Cells, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, lcsh:QH301-705.5, myotonic dystrophy, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, astrocytes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, ceftriaxone, Disease Models, Animal, Excitatory Amino Acid Transporter 2, lcsh:Biology (General), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, nervous system, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], GLT1, unstable microsatellite repeats
Abstract: SUMMARY Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels., Graphical Abstract, In Brief Neural dysfunction in myotonic dystrophy is not fully understood. Using a transgenic mouse model of the disease, Sicot et al. find electrophysiological and motor evidence for cerebellar dysfunction in association with pronounced signs of RNA toxicity in Bergmann glia. Upregulation of a defective glial-specific glutamate transporter corrects cerebellum phenotypes.
Published: 2017
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11. Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy

Author: Laurent Servais, Fedor Svinartchouk, Brenda Wong, Jeremy Rouillon, Aleksandar Zocevic, Thomas Voit, Service of Clinical Trials and Databases, Institut de Myologie, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Cité (UPCité), and École Pratique des Hautes Études (EPHE)
Subjects: Male, Gynecology, medicine.medical_specialty, business.industry, Duchenne/*blood/*physiopathology, [SDV]Life Sciences [q-bio], Duchenne muscular dystrophy, Disease progression, Matrix metalloproteinase 9, medicine.disease, 3. Good health, Neurology, Disease Progression, Pediatrics, Perinatology and Child Health, medicine, Humans, Animals, Female, Matrix Metalloproteinase 9/*blood, Muscular Dystrophy, Neurology (clinical), Pediatric Neurology, business, ComputingMilieux_MISCELLANEOUS, Genetics (clinical)
Abstract: Aleksandar Zocevic , Jeremy Rouillon , Brenda Wong , Laurent Servais , Thomas Voit , Fedor Svinartchouk * a Genethon, Evry, France b Division of Pediatric Neurology, Cincinnati Children’s Hospital Medical Center, USA c Service of Clinical Trials and Databases, Institut de Myologie, Paris, France d INSERM UMRS 974, CNRS FRE 3617, UPMC, Paris, France e Institut de Myologie, GH Pitie-Salpetriere, Universite Pierre et Marie Curie-Paris 6, Paris, France * Corresponding author. E-mail address: svinart@genethon.fr (F. Svinartchouk).
Published: 2015
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12. Adeno-Associated Virus Vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne Muscular Dystrophy (DMD)

Author: Le Guiner, Caroline, Servais, Laurent, Montus, Marie, Larcher, Thibaut, Fraysse, Bodvael, Moullec, Sophie, Koo, Taeyoung, Malerba, Alberto, Le Bec, Christine, Hebben, Matthias, Masurier, Carole, Mingozzi, Federico, Adjali, Oumeya, Carlier, Pierre, Hogrel, Jean-Yves, Gjata, Bernard, Cherel, Yan, Athanasopoulos, Takis, Mavilio, Fulvio, Voit, Thomas, Moullier, Philippe, Dickson, George, Généthon, Service of Clinical Trials and Databases, Institut de Myologie, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), UMR 1089, Atlantic Gene Therapies, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Boisbonne, Atlantic Gene Therapies, Ecole Nationale Vétérinaire Agroalimentaire et de l'Alimentation Nantes Atlantique (ONIRIS), Royal Holloway, University of London, Laboratoire RMN, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neuromuscular Physiology and Evaluation Laboratory, University of Wolverhampton, UCL Institute of Child Health, UMR 1089, Atlantic Gene Therapies & Genethon, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Duchenne Muscular Dystrophy (DMD) is a X-linked inherited muscle-wasting disease primarily affecting young boys with a prevalence of 1:5,000. The disease is caused by loss-of-function mutations in the gene encoding for the Dystrophin protein and is characterized by systemic, progressive, irreversible and severe loss of muscle function. Among vector systems that allow efficient in vivo gene transfer, recombinant Adeno-Associated Virus vectors (rAAV) hold great promise and allow very efficient transduction of skeletal and cardiac muscles. However, full-length dystrophin cDNA exceeds the packaging capacity for a single rAAV gene-delivery cassette. Therefore, truncated versions namely micro-dystrophins have been designed and optimized to contain few clinically important regions of the dystrophin protein. We have tested a rAAV2/8 vector encoding a sequence optimised canine micro-dystrophin transgene, driven by a muscle-synthetic Spc512 promoter (rAAV2/8-Spc512-µDys) in a total of 12 Golden Retriever Muscular Dystrophy (GRMD) dogs, the canine model of DMD. Isolated limb perfusion studies using a single administration of vector induced high levels of micro-dystrophin expression in the treated limb (up to 90% dystrophin positive fibres) with significant normalisation of histological, NMR imaging and spectroscopy parameters and muscle strength, without deleterious immune responses. Similarly, single-dose intravascular delivery of the same rAAV2/8-Spc512-µDys, in absence of immunosuppression, led to long-term transduction of distant muscle groups and extended lifespan (up to 2 years). Profound improvement of multiple clinical features was observed, including gait and respiratory parameters and no toxicity or deleterious humoral and/or cell-mediated immune responses were observed. This study demonstrates the safety and long term efficacy of rAAV2/8-Spc5.12-µDys gene therapy in a relevant large-animal models of DMD and paves the way towards human clinical gene therapy using systemic peripheral vein administration of vector, and applicable to all DMD patients regardless of their genotype.
Published: 2016
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13. A Movement Monitor Based on Magneto-Inertial Sensors for Non-Ambulant Patients with Duchenne Muscular Dystrophy: A Pilot Study in Controlled Environment

Author: Laurent Servais, Eric Dorveaux, Jean-Yves Hogrel, M. Annoussamy, Anne-Gaëlle Le Moing, Amélie Moraux, David Vissiere, Erwan Gasnier, Andreea Mihaela Seferian, Thomas Voit, CHU Amiens-Picardie, Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Myology Paris France, ENGIE, Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), SYSNAV, Service of Clinical Trials and Databases, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and DESSAIVRE, Louise
Subjects: Male, 030506 rehabilitation, Heredity, Activities of daily living, Inertia, Genetic Linkage, Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], lcsh:Medicine, Hands, Pilot Projects, Duchenne Muscular Dystrophy, Wrist, Muscular Dystrophies, 0302 clinical medicine, Activities of Daily Living, Task Performance and Analysis, Medicine and Health Sciences, Biomechanics, Muscular dystrophy, lcsh:Science, Child, Musculoskeletal System, Reliability (statistics), Forearms, Multidisciplinary, Hand Strength, Physics, Classical Mechanics, Equipment Design, Environment, Controlled, [SDV] Life Sciences [q-bio], Arms, medicine.anatomical_structure, Neurology, X-Linked Traits, Sex Linkage, Physical Sciences, Upper limb, Anatomy, 0305 other medical science, Research Article, Adult, medicine.medical_specialty, Adolescent, Minnesota, Acceleration, Upper Extremity, Motion, Young Adult, 03 medical and health sciences, Physical medicine and rehabilitation, Hand strength, Genetics, medicine, Humans, Muscle Strength, Monitoring, Physiologic, Clinical Genetics, business.industry, lcsh:R, Limbs (Anatomy), Biology and Life Sciences, Reproducibility of Results, medicine.disease, Muscular Dystrophy, Duchenne, Clinical trial, Physical therapy, lcsh:Q, business, Software, 030217 neurology & neurosurgery
Abstract: UNLABELLED:Measurement of muscle strength and activity of upper limbs of non-ambulant patients with neuromuscular diseases is a major challenge. ActiMyo® is an innovative device that uses magneto-inertial sensors to record angular velocities and linear accelerations that can be used over long periods of time in the home environment. The device was designed to insure long-term stability and good signal to noise ratio, even for very weak movements. In order to determine relevant and pertinent clinical variables with potential for use as outcome measures in clinical trials or to guide therapy decisions, we performed a pilot study in non-ambulant neuromuscular patients. We report here data from seven Duchenne Muscular Dystrophy (DMD) patients (mean age 18.5 ± 5.5 years) collected in a clinical setting. Patients were assessed while wearing the device during performance of validated tasks (MoviPlate, Box and Block test and Minnesota test) and tasks mimicking daily living. The ActiMyo® sensors were placed on the wrists during all the tests. Software designed for use with the device computed several variables to qualify and quantify muscular activity in the non-ambulant subjects. Four variables representative of upper limb activity were studied: the rotation rate, the ratio of the vertical component in the overall acceleration, the hand elevation rate, and an estimate of the power of the upper limb. The correlations between clinical data and physical activity and the ActiMyo® movement parameters were analyzed. The mean of the rotation rate and mean of the elevation rate appeared promising since these variables had the best reliability scores and correlations with task scores. Parameters could be computed even in a patient with a Brooke functional score of 6. The variables chosen are good candidates as potential outcome measures in non-ambulant patients with Duchenne Muscular Dystrophy and use of the ActiMyo® is currently being explored in home environment. TRIAL REGISTRATION:ClinicalTrials.gov NCT01611597.
Published: 2016
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14. Adeno-associated virus vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne muscular dystrophy (DMD)

Author: L. Servais, Takis Athanasopoulos, Oumeya Adjali, F Mingozzi, George Dickson, J.Y. Hogrel, Yan Cherel, Pierre G. Carlier, Marie Montus, Taeyoung Koo, T. Voit, Sophie Moullec, Fulvio Mavilio, Philippe Moullier, Bernard Gjata, F. Bodvael, C. Le Guiner, Carole Masurier, Généthon, UMR 1089, Atlantic Gene Therapies, Institut National de la Santé et de la Recherche Médicale (INSERM), Service of Clinical Trials and Databases, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuromuscular Physiology and Evaluation Laboratory, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AIM, Atlantic Gene Therapies, Royal Holloway [University of London] (RHUL), University of Wolverhampton, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Cité (UPCité), University of Florida [Gainesville] (UF), World Muscle Society (WMS). London, INT., Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Paris (UP)
Subjects: 0303 health sciences, business.industry, Genetic enhancement, Duchenne muscular dystrophy, medicine.disease_cause, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Neurology, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, medicine, Cancer research, Neurology (clinical), Vector (molecular biology), business, Adeno-associated virus, Canine model, Genetics (clinical), Function (biology), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract: International audience; Duchenne muscular dystrophy (DMD) is an X-linked inherited muscle-wasting disease primarily affecting young boys with a prevalence of 1:5000. The disease is caused by loss-of-function mutations in the gene encoding for the Dystrophin protein and is characterised by systemic, progressive, irreversible and severe loss of muscle function. Among vector systems that allow efficient in vivo gene transfer, recombinant Adeno Associated Virus vectors (rAAV) hold great promise and result in particular in very efficient transduction of skeletal and cardiac muscles.
Published: 2015
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15. Quantitative NMRI and NMRS identify augmented disease progression after loss of ambulation in forearms of boys with Duchenne muscular dystrophy

Author: Claire, Wary, Noura, Azzabou, Céline, Giraudeau, Julien, Le Louër, Marie, Montus, Thomas, Voit, Laurent, Servais, Pierre, Carlier, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physico-Chimie des Polymères et des Milieux Dispersés (PPMD), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Cité (UPCité), Service of Clinical Trials and Databases, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AIM, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), École pratique des hautes études (EPHE), and Université de Paris (UP)
Subjects: Male, Muscular Dystrophy, Duchenne, Forearm, Adenosine Triphosphate, Magnetic Resonance Spectroscopy, Adolescent, [SDV]Life Sciences [q-bio], Disease Progression, Humans, Child, Magnetic Resonance Imaging
Abstract: International audience; Quantitative NMRI and (31) P NMRS indices are reported in the forearms of 24 patients with Duchenne muscular dystrophy (DMD) (6-18 years, 14 non-ambulant) amenable to exon 53 skipping therapy and in 12 age-matched male controls (CONT). Examinations carried out at 3 T comprised multi-slice 17-echo measurements of muscle water T2 and heterogeneity, three-point Dixon imaging of fat fraction in flexor and extensor muscles (FLEX, EXT), and non-localised spectroscopy of phosphate metabolites. We studied four imaging indices, eight metabolic ratios combining ATP, phosphocreatine, phosphomonoesters and phosphodiesters, the cytosolic inorganic phosphate (Pia ) and an alkaline (Pib ) pool present in dystrophic muscle, and average pH. All indices differed between DMD and CONT, except for muscle water T2 . Measurements were outside the 95th percentile of age-matched CONT values in over 65% of cases for percentage fat signal (%F), and in 78-100% of cases for all spectroscopic indices. T2 was elevated in one-third of FLEX measurements, whereas %pixels > 39 ms and T2 heterogeneity were abnormal in one-half of the examinations. The FLEX muscles had higher fat infiltration and T2 than EXT muscle groups. All indices, except pH, correlated with patient age, although the correlation was negative for T2 . However, in non-ambulant patients, the correlation with years since loss of ambulation was stronger than the correlation with age, and the slope of evolution per year was steeper after loss of ambulation. All indices except Pi/gATP differed between ambulant and non-ambulant patients; however, T2 and %pixels > 39 ms were highest in ambulant patients, possibly owing to the greater extent of inflammatory processes earlier in the disease. All other indices were worse in non-ambulant subjects. Quantitative measurements obtained from patients at different disease stages covered a broad range of abnormalities that evolved with the disease, and metabolic indices were up to 10-fold above normal from the onset, thus establishing a variety of potential markers for future therapy. Copyright (c) 2015 John Wiley & Sons, Ltd.
Published: 2015
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16. Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1

Author: Monique Elmaleh-Bergès, Jeanne Lainé, Imen Dorboz, Odile Boespflug-Tanguy, Anne Bertrand, Jean-Hubert Caberg, Giovanni Stevanin, Marie Coutelier, Laurent Servais, Gisèle Bonne, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), laboratoire de génétique humaine, de Duve Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, CHU du Sart-Tilman, Service d'imagerie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), département de physiologie, Université Pierre et Marie Curie - Paris 6 (UPMC), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Unité d'Epileptologie Pédiatrique, Service de Neurologie Pédiatrique et des Maladies Métaboliques, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service of Clinical Trials and Databases, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies neuromusculaires, hôpital de la citadelle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), and Administateur, HAL Sorbonne Université
Subjects: Male, Blotting, Western, Nonsense mutation, Cell Culture Techniques, Mutation, Missense, Cardiomyopathy, Torsin, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Cerebellar Diseases, medicine, Humans, Missense mutation, Genetics(clinical), Exome, Pharmacology (medical), Nuclear membrane, Genetics (clinical), Exome sequencing, 030304 developmental biology, Medicine(all), Dystonia, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Research, HSC70 Heat-Shock Proteins, General Medicine, Fibroblasts, medicine.disease, Immunohistochemistry, Molecular biology, Pedigree, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Cerebellar atrophy, Cardiomyopathies, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Molecular Chaperones
Abstract: Background Dystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association. Methods We used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein. Results We report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in TOR1AIP1. The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine. TOR1AIP1 encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia. In vitro studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms. Conclusions and relevance The pathogenic role of TOR1AIP1 mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the TOR1AIP1 nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0174-9) contains supplementary material, which is available to authorized users.
Published: 2014
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17. Distinctive Serum miRNA Profile in Mouse Models of Striated Muscular Pathologies

Author: Isabelle Nelson, David Israeli, Gisèle Bonne, Paul Fogel, Jérôme Poupiot, Fatima Amor, Marie Montus, Angélique Duvallet, Michel Arock, Nicolas Vignier, Isabelle Richard, Sabine Charrier, Lucie Carrier, Thomas Voit, Laurent Servais, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Généthon, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie moléculaire et biothérapies innovantes (IMBI), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Department of Experimental Pharmacology and Toxicology, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE)-Cardiovascular Research Center, Service of Clinical Trials and Databases, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMRS974, Université Pierre et Marie Curie (Paris 6), Généthon, Evry, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), École pratique des hautes études (EPHE), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Pathology, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Duchenne muscular dystrophy, Disease, Muscular Dystrophies, Mice, 0302 clinical medicine, RNA interference, Genome Databases, Myocyte, MESH: Animals, Muscular dystrophy, 0303 health sciences, MESH: Muscle, Skeletal, Multidisciplinary, biology, medicine.diagnostic_test, Genomics, Gene Therapy, Medicine, Biomarker (medicine), Research Article, musculoskeletal diseases, medicine.medical_specialty, Science, Molecular Genetics, 03 medical and health sciences, Genomic Medicine, microRNA, Biopsy, medicine, Genetics, Animals, Muscle, Skeletal, Biology, MESH: Mice, 030304 developmental biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Comparative Genomics, medicine.disease, MESH: Muscular Dystrophies, Disease Models, Animal, MicroRNAs, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetics of Disease, biology.protein, Creatine kinase, Gene expression, MESH: Disease Models, Animal, Genome Expression Analysis, MESH: MicroRNAs, 030217 neurology & neurosurgery
Abstract: International audience; Biomarkers are critically important for disease diagnosis and monitoring. In particular, close monitoring of disease evolution is eminently required for the evaluation of therapeutic treatments. Classical monitoring methods in muscular dystrophies are largely based on histological and molecular analyses of muscle biopsies. Such biopsies are invasive and therefore difficult to obtain. The serum protein creatine kinase is a useful biomarker, which is however not specific for a given pathology and correlates poorly with the severity or course of the muscular pathology. The aim of the present study was the systematic evaluation of serum microRNAs (miRNAs) as biomarkers in striated muscle pathologies. Mouse models for five striated muscle pathologies were investigated: Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy type 2D (LGMD2D), limb-girdle muscular dystrophy type 2C (LGMD2C), Emery-Dreifuss muscular dystrophy (EDMD) and hypertrophic cardiomyopathy (HCM). Two-step RT-qPCR methodology was elaborated, using two different RT-qPCR miRNA quantification technologies. We identified miRNA modulation in the serum of all the five mouse models. The most highly dysregulated serum miRNAs were found to be commonly upregulated in DMD, LGMD2D and LGMD2C mouse models, which all exhibit massive destruction of striated muscle tissues. Some of these miRNAs were down rather than upregulated in the EDMD mice, a model without massive myofiber destruction. The dysregulated miRNAs identified in the HCM model were different, with the exception of one dysregulated miRNA common to all pathologies. Importantly, a specific and distinctive circulating miRNA profile was identified for each studied pathological mouse model. The differential expression of a few dysregulated miRNAs in the DMD mice was further evaluated in DMD patients, providing new candidates of circulating miRNA biomarkers for DMD.
Published: 2013
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18. High urinary ferritin reflects myoglobin iron evacuation in DMD patients.

Author: Rouillon J, Lefebvre T, Denard J, Puy V, Daher R, Ausseil J, Zocevic A, Fogel P, Peoc'h K, Wong B, Servais L, Voit T, Puy H, Karim Z, and Svinartchouk F
Subjects: Adolescent, Biomarkers metabolism, Child, Child, Preschool, Cytokines urine, Humans, Male, Young Adult, Ferritins urine, Iron metabolism, Muscular Dystrophy, Duchenne urine, Myoglobin metabolism
Abstract: Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the dystrophin gene leading to the absence of the normal dystrophin protein. The efforts of many laboratories brought new treatments of DMD to the reality, but ongoing and forthcoming clinical trials suffer from absence of valuable biomarkers permitting to follow the outcome of the treatment day by day and to adjust the treatment if needed. In the present study the levels of 128 urinary proteins including growth factors, cytokines and chemokines were compared in urine of DMD patients and age related control subjects by antibody array approach. Surprisingly, statistically significant difference was observed only for urinary ferritin whose level was 50 times higher in young DMD patients. To explain the observed high urinary ferritin content we analysed the levels of iron, iron containing proteins and proteins involved in regulation of iron metabolism in serum and urine of DMD patients and their age-matched healthy controls. Obtained data strongly suggest that elevated level of urinary ferritin is functionally linked to the renal management of myoglobin iron derived from leaky muscles of DMD patients. This first observation of the high level of ferritin in urine of DMD patients permits to consider this protein as a new urinary biomarker in muscular dystrophies and sheds light on the mechanisms of iron metabolism and kidney functioning in DMD., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2018
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19. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies.

Author: Rouillon J, Poupiot J, Zocevic A, Amor F, Léger T, Garcia C, Camadro JM, Wong B, Pinilla R, Cosette J, Coenen-Stass AM, Mcclorey G, Roberts TC, Wood MJ, Servais L, Udd B, Voit T, Richard I, and Svinartchouk F
Subjects: Adolescent, Adult, Animals, Biomarkers, Case-Control Studies, Child, Child, Preschool, Connectin blood, Creatine Kinase, Disease Models, Animal, Humans, Mass Spectrometry, Mice, Mice, Inbred mdx, Muscular Dystrophies blood, Muscular Dystrophies therapy, Muscular Dystrophy, Duchenne blood, Muscular Dystrophy, Duchenne metabolism, Treatment Outcome, Young Adult, Blood Proteins metabolism, Connectin metabolism, Muscular Dystrophies metabolism, Proteomics methods
Abstract: Therapy-responsive biomarkers are an important and unmet need in the muscular dystrophy field where new treatments are currently in clinical trials. By using a comprehensive high-resolution mass spectrometry approach and western blot validation, we found that two fragments of the myofibrillar structural protein myomesin-3 (MYOM3) are abnormally present in sera of Duchenne muscular dystrophy (DMD) patients, limb-girdle muscular dystrophy type 2D (LGMD2D) and their respective animal models. Levels of MYOM3 fragments were assayed in therapeutic model systems: (1) restoration of dystrophin expression by antisense oligonucleotide-mediated exon-skipping in mdx mice and (2) stable restoration of α-sarcoglycan expression in KO-SGCA mice by systemic injection of a viral vector. Following administration of the therapeutic agents MYOM3 was restored toward wild-type levels. In the LGMD model, where different doses of vector were used, MYOM3 restoration was dose-dependent. MYOM3 fragments showed lower inter-individual variability compared with the commonly used creatine kinase assay, and correlated better with the restoration of the dystrophin-associated protein complex and muscle force. These data suggest that the MYOM3 fragments hold promise for minimally invasive assessment of experimental therapies for DMD and other neuromuscular disorders., (© The Author 2015. Published by Oxford University Press.)
Published: 2015
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20. Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients.

Author: Le Guiner C, Montus M, Servais L, Cherel Y, Francois V, Thibaud JL, Wary C, Matot B, Larcher T, Guigand L, Dutilleul M, Domenger C, Allais M, Beuvin M, Moraux A, Le Duff J, Devaux M, Jaulin N, Guilbaud M, Latournerie V, Veron P, Boutin S, Leborgne C, Desgue D, Deschamps JY, Moullec S, Fromes Y, Vulin A, Smith RH, Laroudie N, Barnay-Toutain F, Rivière C, Bucher S, Le TH, Delaunay N, Gasmi M, Kotin RM, Bonne G, Adjali O, Masurier C, Hogrel JY, Carlier P, Moullier P, and Voit T
Subjects: Animals, Cohort Studies, Disease Models, Animal, Dogs, Dose-Response Relationship, Drug, Exons, Genetic Therapy, Genetic Vectors administration & dosage, Humans, Infusions, Intravenous, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne physiopathology, RNA, Small Nuclear metabolism, Dependovirus genetics, Dystrophin genetics, Forelimb physiopathology, Muscular Dystrophy, Duchenne therapy, RNA, Small Nuclear genetics
Abstract: Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the dystrophin gene, without curative treatment yet available. Our study provides, for the first time, the overall safety profile and therapeutic dose of a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping to restore a functional in-frame dystrophin transcript, and injected by locoregional transvenous perfusion of the forelimb. Eighteen Golden Retriever Muscular Dystrophy (GRMD) dogs were exposed to increasing doses of GMP-manufactured vector. Treatment was well tolerated in all, and no acute nor delayed adverse effect, including systemic and immune toxicity was detected. There was a dose relationship for the amount of exon skipping with up to 80% of myofibers expressing dystrophin at the highest dose. Similarly, histological, nuclear magnetic resonance pathological indices and strength improvement responded in a dose-dependent manner. The systematic comparison of effects using different independent methods, allowed to define a minimum threshold of dystrophin expressing fibers (>33% for structural measures and >40% for strength) under which there was no clear-cut therapeutic effect. Altogether, these results support the concept of a phase 1/2 trial of locoregional delivery into upper limbs of nonambulatory DMD patients.
Published: 2014
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21. Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy.

Author: Rouillon J, Zocevic A, Leger T, Garcia C, Camadro JM, Udd B, Wong B, Servais L, Voit T, and Svinartchouk F
Subjects: Adolescent, Age Factors, Animals, Biomarkers urine, Blotting, Western, Child, Child, Preschool, Cohort Studies, Connectin genetics, Creatine Kinase, MM Form blood, Dogs, Female, Humans, Male, Mass Spectrometry, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity physiology, Protein Kinases genetics, Protein Kinases urine, Young Adult, Connectin urine, Muscular Dystrophy, Duchenne urine, Proteomics methods
Abstract: Diagnosis of muscular dystrophies is currently based on invasive methods requiring muscle biopsies or blood tests. The aim of the present study was to identify urinary biomarkers as a diagnostic tool for muscular dystrophies. Here, the urinary proteomes of Duchenne muscular dystrophy (DMD) patients and healthy donors were compared with a bottom-up proteomic approach. Label-free analysis of more than 1100 identified proteins revealed that 32 of them were differentially expressed between healthy controls and DMD patients. Among these 32 proteins, titin showed the highest fold change between healthy subjects and DMD patients. Interestingly, most of the sequenced peptides belong to the N-terminal and C-terminal parts of titin, and the presence of the corresponding fragments in the urine of DMD patients was confirmed by Western blot analysis. Analysis of a large cohort of DMD patients and age-matched controls (a total of 104 individuals aged from 3 to 20 years) confirmed presence of the N-ter fragment in all but two patients. In two DMD patients aged 16 and 20 years this fragment was undetectable and two healthy controls of 16 and 19 years with serum CK >800 IU/L demonstrated a low level of the fragment. N- and C-terminal titin fragments were also detected in urine from patients with other muscular dystrophies such as Becker muscular dystrophy and Limb-girdle muscular dystrophy (type 1D, 2D and 2J) but not in neurogenic spinal muscular atrophy. They were also present in urine of dystrophin-deficient animal models (GRMD dogs and mdx mice). Titin is the first urinary biomarker that offers the possibility to develop a simple, non-invasive and easy-to-use test for pre-screening of muscular dystrophies, and may also prove to be useful for the non-invasive follow up of DMD patients under treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)
Published: 2014
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21 results on '"Service of Clinical Trials and Databases"'

1. High urinary ferritin reflects myoglobin iron evacuation in DMD patients

2. Can global muscle segmentation detect changes in neuromuscular disorders using quantitative nuclear magnetic resonance imaging?

3. X-linked myotubular myopathy: A prospective international natural history study

4. Phenotypic and genomic characterization of Becker dystrophy patients with 45 to 55 exons deletion

5. Caractérisation phénotypique et génomique des patients Becker avec délétion des exons 45-55

6. Nusinersen versus sham control in later-onset spinal muscular atrophy

7. Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches

8. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

9. Rapamycin vs. Placebo for the Treatment of Inclusion Body Myositis: improvement of the 6 min walking distance, a functional scale, the FVC and muscle quantitative MRI

10. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy

11. Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy

12. Adeno-Associated Virus Vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne Muscular Dystrophy (DMD)

13. A Movement Monitor Based on Magneto-Inertial Sensors for Non-Ambulant Patients with Duchenne Muscular Dystrophy: A Pilot Study in Controlled Environment

14. Adeno-associated virus vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne muscular dystrophy (DMD)

15. Quantitative NMRI and NMRS identify augmented disease progression after loss of ambulation in forearms of boys with Duchenne muscular dystrophy

16. Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1

17. Distinctive Serum miRNA Profile in Mouse Models of Striated Muscular Pathologies

18. High urinary ferritin reflects myoglobin iron evacuation in DMD patients.

19. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies.

20. Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients.

21. Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy.

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