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7 results on '"Duchenne Parent Project"'

1. Delivery of oligonucleotide‐based therapeutics: challenges and opportunities

Author

Annemieke Aartsma-Rus, Marisol Montolio, Gisela Gaina, Camilla Foged, Suzan M. Hammond, Alejandro Garanto, David R. Jones, Lourdes R. Desviat, Giuseppina Covello, Sabine Krause, Magdalena Guzowska, Virginia Arechavala-Gomeza, Sven Even F. Borgos, Willeke M. C. van Roon-Mom, Taavi Lehto, Sandra Alves, Ronald A.M. Buijsen, Michela A. Denti, Aurélie Goyenvalle, Rob W.J. Collin, Irina Holodnuka, Lucia Echevarria, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), DFF-4184-00422 20577, 446002002 Foundation Fighting Blindness, FFB: PPA-0517-0717-RAD Fundación Ramón Areces Horizon 2020 Framework Programme, H2020: 721058, 761104 Muscular Dystrophy UK, MDUK Medical Research Council, MRC Institut National de la Santé et de la Recherche Médicale, Inserm Eesti Teadusagentuur, ETAg: PSG226 Ikerbasque, Basque Foundation for Science Prinses Beatrix Spierfonds Instituto de Salud Carlos III, ISCIII: CPII17/00004 Ministerio de Ciencia e Innovación, MICINN: PID2019-105344RB-I00 Duchenne Parent Project Hersenstichting: DR-2018-00253 Friedrich-Baur-Stiftung European Regional Development Fund, ERDF Algemene Nederlandse Vereniging ter voorkoming van Blindheid, ANVVB Landelijke Stichting voor Blinden en Slechtzienden, LSBS Stichting Retina Fonds: 2015-31, 2018-21 Stichting Blinden-Penning Ministerul Cercetării şi Inovării, MCI: 31N/2016/PN 16.22.02.05, PTDC/BBB-BMD/6301/2014, This work was supported by funding from Cooperation of Science and Technology (COST) Action CA17103 (networking grant to V.A-G). V.A-G holds a Miguel Servet Fellowship from the ISCIII [grant reference CPII17/00004] that is part-funded by the European Regional Development Fund (ERDF/FEDER) and also acknowledges funding from Ikerbasque (Basque Foundation for Science). S.M.H is funded by the Medical Research Council and Muscular Dystrophy UK. A.A-R receives funding from amongst others the Duchenne Parent Project, Spieren voor Spieren, the Prinses Beatrix Spierfonds, Duchenne UK and through Horizon2020 project BIND. A.G and R.W.J.C are supported by several foundations including the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Stichting Blinden-Penning, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Oogfonds Nederland, Stichting Macula Degeneratie Fonds, and Stichting Retina Nederland Fonds (who contributed through UitZicht 2015-31 and 2018-21), together with the Rotterdamse Stichting Blindenbelangen, Stichting Blindenhulp, Stichting tot Verbetering van het Lot der Blinden, Stichting voor Ooglijders, and Stichting Dowilvo, as well as the Foundation Fighting Blindness USA, grant no. PPA-0517-0717-RAD. R.A.M.B is supported by Hersenstichting Nederland Grant DR-2018-00253. G.G. is supported by Ministry of Research and Innovation in Romania/National Program 31N/2016/PN 16.22.02.05. S.A is supported by Project PTDC/BBB-BMD/6301/2014 (Funda??o para a Ci?ncia e a Tecnologia?MCTES, Portugal). L.R.D. is supported by Fundaci?n Ram?n Areces Grant XVII CN and Spanish Ministry of Science and Innovation (MICINN, grant PID2019-105344RB-I00). T.L is supported by Estonian Research Council grant PSG226. S.K is supported by the Friedrich-Baur-Stiftung. C.F is funded by The Danish Council for Independent Research, Technology and Production Sciences (grant number DFF-4184-00422). W.vRM is supported by ZonMw Programme Translational Research 2 [Project number 446002002], Campaign Team Huntington and AFM Telethon [Project number 20577]. S.E.B is supported by the H2020 projects B-SMART, Grant number 721058, and REFINE, Grant number 761104. A.T.G is supported by the Institut National de la sant? et la recherche m?dicale (INSERM) and the Association Monegasque contre les myopathies (AMM). L.E. is founded by the Association Monegasque contre les myopathies (AMM)., UAM. Departamento de Biología Molecular, Ministerio de Ciencia y Tecnología (España), Instituto de Salud Carlos III, Ikerbasque Basque Foundation for Science, Medical Research Council (UK), Duchenne UK, Foundation Fighting Blindness, Netherlands Brain Foundation, Ministerio de Ciencia e Innovación (España), Fundação para a Ciência e a Tecnologia (Portugal), and Fundación Ramón Areces

Subjects
safety, 0301 basic medicine, Medicine (General), Computer science, [SDV]Life Sciences [q-bio], Aptamer, Gene Expression, Review, Computational biology, QH426-470, Small Interfering, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, R5-920, 0302 clinical medicine, Chemical Biology, Marketed products, Genetics, Cost of goods, Antisense, RNA, Small Interfering, Genetica Humana, Antisense Oligonucleotides, oligonucleotides, Oligonucleotide, RNA therapeutics, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Oligonucleotides, Antisense, Biología y Biomedicina / Biología, RNA Biology, preclinical models, Doenças Genéticas, 3. Good health, 030104 developmental biology, delivery, Nanoparticles, Oligonucleotides, Antisense oligonucleotides, RNA, Molecular Medicine, Synthetic Biology & Biotechnology, 030217 neurology & neurosurgery
Abstract

Nucleic acid‐based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid‐based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics., Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics.

Published
2021
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2. The FibromiR miR-214-3p Is Upregulated in Duchenne Muscular Dystrophy and Promotes Differentiation of Human Fibro-Adipogenic Muscle Progenitors

Author

Claude J. Dechesne, Georges Vassaux, Julien Fassy, Virginie Magnone, Claudine Moratal, Nicolas Nottet, Noémie Clément, Nicolas Pottier, Pascal Peraldi, Nicole Arrighi, Romain Larrue, Kevin Lebrigand, Sandy Fellah, Bernard Mari, Christian Dani, Nicolas Pons, Grégoire Savary, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 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)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), This work was supported by funds from Institut National de la Santé et de la Recherche Médicale (Inserm), Centre National de la Recherche Scientifique (CNRS), the « Association Française contre les Myopathies, AFM (through grant HuMusmiR #17708 and a PhD fellowship for CM), the French Government (Agence Nationale de Recherche, ANR) ANR-PRCI FIBROMIR, the Investments for the Future LABEX SIGNALIFE (ANR-11-LABX-0028- 551 01), the Netherland Duchenne Parent Project and ITMO Cancer Aviesan (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Science and Health) within the framework of the Cancer Plan (Plan Cancer 2018 ARN non-codants en cancérologie: du fondamental au translationnel n° 18CN045)., ANR-18-CE92-0009,FIBROMIR,MicroARN et Interactions Epithélio-Mesenchymateuses dans les Pathologies Pulmonaires(2018), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), RUIZ, Caroline, APPEL À PROJETS GÉNÉRIQUE 2018 - MicroARN et Interactions Epithélio-Mesenchymateuses dans les Pathologies Pulmonaires - - FIBROMIR2018 - ANR-18-CE92-0009 - AAPG2018 - VALID, and Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID

Subjects
0301 basic medicine, Male, Duchenne muscular dystrophy, Muscle Development, microRNA (miRNA), 0302 clinical medicine, Fibrosis, Adipocytes, Medicine, Biology (General), Child, Myofibroblasts, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Adipogenesis, Stem Cells, Cell Differentiation, General Medicine, Middle Aged, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], transforming growth factor beta (TGFβ), Female, Fibroblast Growth Factor 2, Myofibroblast, Signal Transduction, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, QH301-705.5, Population, Article, Transforming Growth Factor beta1, 03 medical and health sciences, Downregulation and upregulation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Humans, Receptor, Fibroblast Growth Factor, Type 1, Progenitor cell, education, Muscle, Skeletal, Base Sequence, business.industry, Gene Expression Profiling, fibrosis, Skeletal muscle, medicine.disease, fibro-adipogenic progenitor (FAP), Muscular Dystrophy, Duchenne, MicroRNAs, 030104 developmental biology, FGFR1, Gene Expression Regulation, Duchenne muscular dystrophy (DMD), Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Fibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFβ1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several “FibromiRs”, was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFβ1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFβ1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR » miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFβ axis, opening new avenues for the treatment of DMD.

Published
2021
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3. Aldehyde dehydrogenases contribute to skeletal muscle homeostasis in healthy, aging, and Duchenne muscular dystrophy patients

Author

Cyril Catelain, Stéphane Blot, Pierre Joanne, Jean-Thomas Vilquin, Onnik Agbulut, Jessy Etienne, Isabel Punzón, Stéphanie Riveron, Jérémy Lafable, Alexandra Clarissa Bayer, 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), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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 National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by the DIM-STEMPOLE from Région Ile-de-France(J.E.),theAssociationFrançaisecontrelesMyopathies (AFM, C.C., S.R., and J.L.), and by grants from the Duchenne Parent Project from the Netherlands (DPP), from the Ligue contre la Cardiomyopathie, and from the Agence de Biomédecine., 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), California Institute for Quantitative Biosciences [Berkeley] (QB3-Berkeley), University of California [Berkeley], University of California-University of California, Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Vilquin, Jean-Thomas, 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)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Duchenne muscular dystrophy, medicine.medical_specialty, Cell type, Aging, lcsh:Diseases of the musculoskeletal system, [SDV]Life Sciences [q-bio], Aldehyde dehydrogenase, Dog model, Skeletal muscle, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:QM1-695, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Internal medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Myocyte, Orthopedics and Sports Medicine, Non‐human primate, ComputingMilieux_MISCELLANEOUS, biology, business.industry, lcsh:Human anatomy, Original Articles, medicine.disease, Non-human primate, [SDV] Life Sciences [q-bio], ALDH1A1, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Myogenic, 030220 oncology & carcinogenesis, biology.protein, CD146, Original Article, lcsh:RC925-935, Stem cell, business, Human
Abstract

International audience; BACKGROUND:Aldehyde dehydrogenases (ALDHs) are key players in cell survival, protection, and differentiation via the metabolism and detoxification of aldehydes. ALDH activity is also a marker of stem cells. The skeletal muscle contains populations of ALDH-positive cells amenable to use in cell therapy, whose distribution, persistence in aging, and modifications in myopathic context have not been investigated yet.METHODS:The Aldefluor® (ALDEF) reagent was used to assess the ALDH activity of muscle cell populations, whose phenotypic characterizations were deepened by flow cytometry. The nature of ALDH isoenzymes expressed by the muscle cell populations was identified in complementary ways by flow cytometry, immunohistology, and real-time PCR ex vivo and in vitro. These populations were compared in healthy, aging, or Duchenne muscular dystrophy (DMD) patients, healthy non-human primates, and Golden Retriever dogs (healthy vs. muscular dystrophic model, Golden retriever muscular dystrophy [GRMD]).RESULTS:ALDEF+ cells persisted through muscle aging in humans and were equally represented in several anatomical localizations in healthy non-human primates. ALDEF+ cells were increased in dystrophic individuals in humans (nine patients with DMD vs. five controls: 14.9 ± 1.63% vs. 3.6 ± 0.39%, P = 0.0002) and dogs (three GRMD dogs vs. three controls: 10.9 ± 2.54% vs. 3.7 ± 0.45%, P = 0.049). In DMD patients, such increase was due to the adipogenic ALDEF+ /CD34+ populations (11.74 ± 1.5 vs. 2.8 ± 0.4, P = 0.0003), while in GRMD dogs, it was due to the myogenic ALDEF+ /CD34- cells (3.6 ± 0.6% vs. 1.03 ± 0.23%, P = 0.0165). Phenotypic characterization associated the ALDEF+ /CD34- cells with CD9, CD36, CD49a, CD49c, CD49f, CD106, CD146, and CD184, some being associated with myogenic capacities. Cytological and histological analyses distinguished several ALDH isoenzymes (ALDH1A1, 1A2, 1A3, 1B1, 1L1, 2, 3A1, 3A2, 3B1, 3B2, 4A1, 7A1, 8A1, and 9A1) expressed by different cell populations in the skeletal muscle tissue belonging to multinucleated fibres, or myogenic, endothelial, interstitial, and neural lineages, designing them as potential new markers of cell type or of metabolic activity. Important modifications were noted in isoenzyme expression between healthy and DMD muscle tissues. The level of gene expression of some isoenzymes (ALDH1A1, 1A3, 1B1, 2, 3A2, 7A1, 8A1, and 9A1) suggested their specific involvement in muscle stability or regeneration in situ or in vitro.CONCLUSIONS:This study unveils the importance of the ALDH family of isoenzymes in the skeletal muscle physiology and homeostasis, suggesting their roles in tissue remodelling in the context of muscular dystrophies.

Published
2020
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4. Evaluation of an exercise-enabling control interface for powered wheelchair users: a feasibility study with Duchenne muscular dystrophy

Author

Joan Lobo-Prat, Julita Medina-Cantillo, Carme Torras, Nariman Sharifrazi, Antonio Rodríguez-Fernández, David J. Reinkensmeyer, Josep M. Font-Llagunes, Aure Enkaoua, Duchenne Parent Project, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Universitat Politècnica de Catalunya. Doctorat en Enginyeria Biomèdica, Universitat Politècnica de Catalunya. Departament d'Enginyeria Mecànica, Institut de Robòtica i Informàtica Industrial, Universitat Politècnica de Catalunya. BIOMEC - Biomechanical Engineering Lab, and Universitat Politècnica de Catalunya. ROBiri - Grup de Robòtica de l'IRI

Subjects
Male, Computer science, Duchenne muscular dystrophy, Controller (computing), Interface (computing), 01 natural sciences, 010104 statistics & probability, 0302 clinical medicine, Wheelchair, Pediatric, Assistive Technology, Rehabilitation, Exercise Therapy, Driving performance, Arm, Electric wheelchairs, Powered wheelchair, Duchenne/ Becker Muscular Dystrophy, Distròfia muscular, Adult, medicine.medical_specialty, Adolescent, Intellectual and Developmental Disabilities (IDD), Control (management), Biomedical Engineering, Health Informatics, Physical exercise, Bioengineering, Sitting, lcsh:RC321-571, 03 medical and health sciences, Physical medicine and rehabilitation, Rare Diseases, Enginyeria mecànica [Àrees temàtiques de la UPC], Clinical Research, Joystick, medicine, Humans, 0101 mathematics, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Cadires de rodes elèctriques, Leg, Research, Neurosciences, medicine.disease, Duchenne, Muscular dystrophy, Brain Disorders, Muscular Dystrophy, Duchenne, Physical Rehabilitation, Wheelchairs, Musculoskeletal, Feasibility Studies, Rare disease, 030217 neurology & neurosurgery
Abstract

Background: Powered wheelchairs are an essential technology to support mobility, yet their use is associated with a high level of sedentarism that can have negative health effects for their users. People with Duchenne muscular dystrophy (DMD) start using a powered wheelchair in their early teens due to the loss of strength in their legs and arms. There is evidence that low-intensity exercise can help preserve the functional abilities of people with DMD, but options for exercise when sitting in a powered wheelchair are limited. Methods: In this paper, we present the design and the feasibility study of a new version of the MOVit device that allows powered-wheelchair users to exercise while driving the chair. Instead of using a joystick to drive the wheelchair, users move their arms through a cyclical motion using two powered, mobile arm supports that provide controller inputs to the chair. The feasibility study was carried out with a group of five individuals with DMD and five unimpaired individuals. Participants performed a series of driving tasks in a wheelchair simulator and on a real driving course with a standard joystick and with the MOVit 2.0 device. Results: We found that driving speed and accuracy were significantly lowered for both groups when driving with MOVit compared to the joystick, but the decreases were small (speed was 0.26 m/s less and maximum path error was 0.1 m greater). Driving with MOVit produced a significant increase in heart rate (7.5 bpm) compared to the joystick condition. Individuals with DMD reported a high level of satisfaction with their performance and comfort in using MOVit. Conclusions: These results show for the first time that individuals with DMD can easily transition to driving a powered wheelchair using cyclical arm motions, achieving a reasonable driving performance with a short period of training. Driving in this way elicits cardiopulmonary exercise at an intensity found previously to produce health-related benefits in DMD., This research has been partially supported by Grant 17.008 funded by Duchenne Parent Project Netherlands, and by the Juan de la Cierva Formación postdoctoral fellowship FJCI-2017-31754, which is funded by the Spanish Ministry of Science and Innovation (MCI)-Agencia Estatal de Investigación (AEI) along with the European Regional Development Fund (ERDF).

Published
2020
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5. Rescue of nonsense mutations by amlexanox in human cells

Author

Fabrice Lejeune, Jieshuang Jia, Sara Gonzalez-Hilarion, Dieter C. Gruenert, Benoit Deprez, Kamel Mamchaoui, Nadège Debreuck, Vincent Mouly, Gonzague Berte, Terence Beghyn, Médecine cellulaire et molécualire, PRES Université Lille Nord de France-Institut de Biologie de Lille-IFR 142, Biostructures et Decouverte de Medicament, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Pôle de Recherche Interdisciplinaire sur le Médicament (PRIM), Faculté de Pharmacie, Institut de Myologie, 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), 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), Laboratory Medicine, Institute for Human Genetics-Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research-Helen Diller Family Comprehensive Cancer Center [San Francisco]-University of California, Department of Pediatrics, University of Vermont College of Medicine, This work was supported by Inserm Avenir program, the Association Française contre les Myopathies, Vaincre la Mucoviscidose, la Fondation pour la Recherche Médicale, la Ligue Régionale du Nord-Pas-de-Calais contre le Cancer and l'Institut Pasteur de Lille. SGH is supported by a grant Inserm/Région Nord-Pas-de-Calais. JJ is supported by a grant from Vaincre la mucoviscidose. KM and VM received funding from TREAT-NMD (contract LSHM-CT-2006-036825) from the European Commission 6th FP, the ANR Genopath-INAFIB, the Duchenne Parent Project Netherlands, CNRS, INSERM, University Pierre and Marie Curie, Parents Project of Monaco, and European Parent Project. DCG is supported by funds from CF Research, Inc and Pennsylvania CF, Inc., 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), University of Vermont [Burlington], Institute for Human Genetics-Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research-Helen Diller Family Comprehensive Cancer Center [San Francisco]-University of California (UC), and BMC, Ed.

Subjects
Cell Survival, Blotting, Western, Nonsense mutation, Mutant, nonsense mutation, Aminopyridines, Cystic Fibrosis Transmembrane Conductance Regulator, Fluorescent Antibody Technique, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Cell Line, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, NMD, Genetics(clinical), Pharmacology (medical), Genetics (clinical), 030304 developmental biology, Medicine(all), Genetics, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Research, lcsh:R, RNA, General Medicine, Human genetics, mRNA surveillance, Nonsense Mediated mRNA Decay, 3. Good health, Cell biology, Blot, small molecules, NMD/nonsense mutation/readthrough/RNA/small molecules, Codon, Nonsense, Cell culture, Amlexanox, 030220 oncology & carcinogenesis, readthrough, HeLa Cells, Protein Binding, medicine.drug
Abstract

Background Nonsense mutations are at the origin of many cancers and inherited genetic diseases. The consequence of nonsense mutations is often the absence of mutant gene expression due to the activation of an mRNA surveillance mechanism called nonsense-mediated mRNA decay (NMD). Strategies to rescue the expression of nonsense-containing mRNAs have been developed such as NMD inhibition or nonsense mutation readthrough. Methods Using a dedicated screening system, we sought molecules capable to block NMD. Additionally, 3 cell lines derived from patient cells and harboring a nonsense mutation were used to study the effect of the selected molecule on the level of nonsense-containing mRNAs and the synthesis of proteins from these mutant mRNAs. Results We demonstrate here that amlexanox, a drug used for decades, not only induces an increase in nonsense-containing mRNAs amount in treated cells, but also leads to the synthesis of the full-length protein in an efficient manner. We also demonstrated that these full length proteins are functional. Conclusions As a result of this dual activity, amlexanox may be useful as a therapeutic approach for diseases caused by nonsense mutations.

Published
2012
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6. Immortalized pathological human myoblasts: towards a universal tool for the study of neuromuscular disorders

Author

Vincent Mouly, J. Kim, Francesco Muntoni, Woodring E. Wright, Susanne Philippi, Sergiu C. Blumen, Ahmed Aamiri, Simone Spuler, Gillian Butler-Browne, Soraya Chaouch, James P. Di Santo, Nicolas Lévy, Kamel Mamchaoui, Annie Wolff, Prashanth Kumar Kandalla, Solenne Marie, Anne Bigot, Thomas Voit, Capucine Trollet, Elisa Negroni, Jean Lacau St Guily, 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), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), The Dubowitz Neuromuscular Centre, University College of London [London] (UCL)-Institute of Child Health, Muscle Research Unit, Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association-Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique Médicale et Génomique Fonctionnelle (GMGF), 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)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Hillel Yaffe Medical Center, Department of Cell Biology, University of Texas Southwestern Medical Center [Dallas], Departement de Biologie, Faculté des sciences d'Agadir, This work was supported by the MYORES Network of Excellence (contract 511978) and TREAT-NMD (contract LSHM-CT-2006-036825) from the European Commission 6th FP, MYOAGE (contract HEALTH-F2-2009-223576) from the Seventh FP, the ANR Genopath-INAFIB, the ANR MICRORNAS, MyoGrad (GK1631, German Research Foundation), the Duchenne Parent Project Netherlands, CNRS, INSERM, University Pierre and Marie Curie, AFM (Association Française contre les Myopathies) (including network grant #15123), the Jain Foundation, Parents Project of Monaco, and the European Parent Project., European Project: 223576,EC:FP7:HEALTH,FP7-HEALTH-2007-B,MYOAGE(2009), 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), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]-Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Laboratoire LBCM, BMC, Ed., and Understanding and combating human age-related muscle weakness - MYOAGE - - EC:FP7:HEALTH2009-01-01 - 2013-06-30 - 223576 - VALID

Subjects
lcsh:Diseases of the musculoskeletal system, Duchenne muscular dystrophy, Biology, Bioinformatics, Oculopharyngeal muscular dystrophy, 03 medical and health sciences, 0302 clinical medicine, medicine, Myocyte, Facioscapulohumeral muscular dystrophy, Orthopedics and Sports Medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Muscular dystrophy, Molecular Biology, 030304 developmental biology, 0303 health sciences, Research, Cell Biology, medicine.disease, Transplantation, Congenital muscular dystrophy, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:RC925-935, Function and Dysfunction of the Nervous System, Immortalised cell line, 030217 neurology & neurosurgery
Abstract

Background Investigations into both the pathophysiology and therapeutic targets in muscle dystrophies have been hampered by the limited proliferative capacity of human myoblasts. Isolation of reliable and stable immortalized cell lines from patient biopsies is a powerful tool for investigating pathological mechanisms, including those associated with muscle aging, and for developing innovative gene-based, cell-based or pharmacological biotherapies. Methods Using transduction with both telomerase-expressing and cyclin-dependent kinase 4-expressing vectors, we were able to generate a battery of immortalized human muscle stem-cell lines from patients with various neuromuscular disorders. Results The immortalized human cell lines from patients with Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy type 2B had greatly increased proliferative capacity, and maintained their potential to differentiate both in vitro and in vivo after transplantation into regenerating muscle of immunodeficient mice. Conclusions Dystrophic cellular models are required as a supplement to animal models to assess cellular mechanisms, such as signaling defects, or to perform high-throughput screening for therapeutic molecules. These investigations have been conducted for many years on cells derived from animals, and would greatly benefit from having human cell models with prolonged proliferative capacity. Furthermore, the possibility to assess in vivo the regenerative capacity of these cells extends their potential use. The innovative cellular tools derived from several different neuromuscular diseases as described in this report will allow investigation of the pathophysiology of these disorders and assessment of new therapeutic strategies.

Published
2011
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7. DHPR α1S subunit controls skeletal muscle mass and morphogenesis

Author

Arnaud Ferry, Luis Garcia, Isabelle Marty, Etienne Mouisel, Dominique Baas, Laurent Schaeffer, Alban Vignaud, Christophe Hourdé, Stéphane Vassilopoulos, Thomas Voit, Christel Gentil, 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), Department of Bioengineering and Therapeutic Sciences, University of California [San Francisco] (UCSF), University of California-University of California, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université Paris Descartes - Paris 5 (UPD5), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of bio-engineering and Therapeutic Science, University of California, This work was supported by the Association Franc¸aise contre les Myopathies (AFM), Association Institut de Myologie (AIM), Duchenne Parent Project France (DPPF) and the Association Mone´gasque contre les Myopathies (AMM)., École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), University of California (UC), 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 ), University of California [San Francisco] ( UCSF ), Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), and Roux-Buisson, Nathalie

Subjects
MESH: Organ Size, DHPR α1S, MESH: Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type I, MESH: Base Sequence, Inbred C57BL, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Morphogenesis, Tissue Distribution, MESH: Animals, Cells, Cultured, Mice, Knockout, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Calcium Channels, L-Type, Cultured, Voltage-dependent calcium channel, General Neuroscience, MESH: Muscle Strength, Skeletal, Organ Size, MESH: Protein Subunits, L-Type, Hedgehog signaling pathway, Cell biology, Muscular Atrophy, medicine.anatomical_structure, Biochemistry, MESH: Calcium Channels, Muscle, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Cells, Cultured, exon skipping, autophagy, Calcium Channels, L-Type, Protein subunit, Knockout, Cells, Molecular Sequence Data, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Atrophy, Downregulation and upregulation, MESH: Mice, Inbred C57BL, medicine, Animals, MESH: Autophagy, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Muscle Strength, MESH: Tissue Distribution, skeletal muscle, Muscle, Skeletal, Molecular Biology, MESH: Mice, 030304 developmental biology, Sarcolemma, MESH: Molecular Sequence Data, General Immunology and Microbiology, Base Sequence, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Autophagy, MESH: Muscular Atrophy, Skeletal muscle, medicine.disease, MESH: Morphogenesis, Mice, Inbred C57BL, Protein Subunits, Calcium Channels, 030217 neurology & neurosurgery
Abstract

International audience; The alpha1S subunit has a dual function in skeletal muscle: it forms the L-type Ca(2+) channel in T-tubules and is the voltage sensor of excitation-contraction coupling at the level of triads. It has been proposed that L-type Ca(2+) channels might also be voltage-gated sensors linked to transcriptional activity controlling differentiation. By using the U7-exon skipping strategy, we have achieved long-lasting downregulation of alpha1S in adult skeletal muscle. Treated muscles underwent massive atrophy while still displaying significant amounts of alpha1S in the tubular system and being not paralysed. This atrophy implicated the autophagy pathway, which was triggered by neuronal nitric oxide synthase redistribution, activation of FoxO3A, upregulation of autophagy-related genes and autophagosome formation. Subcellular investigations showed that this atrophy was correlated with the disappearance of a minor fraction of alpha1S located throughout the sarcolemma. Our results reveal for the first time that this sarcolemmal fraction could have a role in a signalling pathway determining muscle anabolic or catabolic state and might act as a molecular sensor of muscle activity.

Published
2009
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