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1. Capsid-specific removal of circulating antibodies to adeno-associated virus vectors

Author

Benoit Delache, Bérangère Bertin, Jack-Yves Deschamps, Virginie Latournerie, Carole Masurier, Christian Leborgne, Sophie Moullec, Olivier Benveniste, Roger Le Grand, Philippe Moullier, Fanny Collaud, Sylvie Boutin, Otto Wilhelm Merten, Philippe Veron, Laetitia van Wittenberghe, Yves Fromes, Nathalie Dereuddre-Bosquet, Federico Mingozzi, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Atlantic Gene Therapies [Nantes], Centre de Boisbonne [Nantes], Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by Genethon. It was also supported by the European Union, ERC-2013-CoG Consolidator Grant, grant agreement number 617432 (MoMAAV, to F.M.), European Union’s research and innovation program under Grant Agreements No. 667751 (Myocure, to F.M.) and No. 755225 (CureCN, to F.M. and O.M.), E-Rare2 grant SMART-HaemoCare (to F.M.). This work was also supported by the 'Investissements d’Avenir' programs managed by the ANR under reference ANR-11-INBS-0008 funding the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay-aux-Roses, France), and ANR-10-EQPX-02–01 funding the FlowCyTech facility (IDMIT, Fontenay-aux-Roses, France)., ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), ANR-10-EQPX-0002,FlowCyTech,Plateforme de phénotypage en Mass cytométrie pour l'analyse multiparamétrique de biomarqueurs complexes de l'efficacité de nouvelles stratégies thérapeutiques ou vaccinales(2010), European Project: 617432,EC:FP7:ERC,ERC-2013-CoG,MOMAAV(2014), European Project: 667751,H2020,H2020-PHC-2015-two-stage,MYOCURE(2016), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-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), Bodescot, Myriam, Infrastructures - Infrastructure nationale pour la modélisation des maladies infectieuses humaines - - IDMIT2011 - ANR-11-INBS-0008 - INBS - VALID, Equipements d'excellence - Plateforme de phénotypage en Mass cytométrie pour l'analyse multiparamétrique de biomarqueurs complexes de l'efficacité de nouvelles stratégies thérapeutiques ou vaccinales - - FlowCyTech2010 - ANR-10-EQPX-0002 - EQPX - VALID, Molecular signatures and Modulation of immunity to Adeno-Associated Virus vectors - MOMAAV - - EC:FP7:ERC2014-07-01 - 2019-06-30 - 617432 - VALID, Development of an innovative gene therapy platform to cure rare hereditary muscle disorders - MYOCURE - - H20202016-01-01 - 2019-12-31 - 667751 - VALID, Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre de Recherche en Myologie

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, medicine.medical_treatment, viruses, Genetic Vectors, lcsh:Medicine, medicine.disease_cause, Antibodies, Viral, Virus, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Capsid, In vivo, Medicine, Animals, Humans, Vector (molecular biology), lcsh:Science, Adeno-associated virus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Multidisciplinary, biology, Molecular medicine, business.industry, lcsh:R, Gene Transfer Techniques, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Plasmapheresis, Translational research, Dependovirus, Virology, Antibodies, Neutralizing, 3. Good health, Titer, 030104 developmental biology, Preclinical research, 030220 oncology & carcinogenesis, Immunoglobulin G, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, lcsh:Q, Antibody, business
Abstract

Neutralizing antibodies directed against adeno-associated virus (AAV) are commonly found in humans. In seropositive subjects, vector administration is not feasible as antibodies neutralize AAV vectors even at low titers. Consequently, a relatively large proportion of humans is excluded from enrollment in clinical trials and, similarly, vector redosing is not feasible because of development of high-titer antibodies following AAV vector administration. Plasmapheresis has been proposed as strategy to remove anti-AAV antibodies from the bloodstream. Although safe and relatively effective, the technology has some limitations mainly related to the nonspecific removal of all circulating IgG. Here we developed an AAV-specific plasmapheresis column which was shown to efficiently and selectively deplete anti-AAV antibodies without depleting the total immunoglobulin pool from plasma. We showed the nearly complete removal of anti-AAV antibodies from high titer purified human IgG pools and plasma samples, decreasing titers to levels that allow AAV vector administration in mice. These results provide proof-of-concept of a method for the AAV-specific depletion of neutralizing antibodies in the setting of in vivo gene transfer.

Published
2020
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2. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients

Author

Olivier Boyer, Fabienne Jouen, Virginie Latournerie, Carole Masurier, Marcelo Simon Sola, Federico Mingozzi, Diana Desgue, Severine Charles, Philippe Veron, Aliénor Quéré, Elisa Masat, Christian Leborgne, Elodie Pignot, Sylvie Boutin, Fanny Collaud, Généthon, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), 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), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), 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), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Généthon, Evry, Centre de recherche et d'applications sur les thérapies géniques (CRATG), Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Centre National de la Recherche Scientifique (CNRS), 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), 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, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Immunologie moléculaire et biothérapies innovantes, École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Genethon, Laboratoire des Sciences de l'Information et des Systèmes (LSIS), and Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, AAV humoral immunity, Adolescent, Duchenne muscular dystrophy, Genetic enhancement, [SDV]Life Sciences [q-bio], viruses, Immunology, Genetic Vectors, Duchenne Muscular Dystrophy, Biology, medicine.disease_cause, Antibodies, Viral, Virus, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene therapy, Seroepidemiologic Studies, medicine, Humans, Longitudinal Studies, Seroconversion, Adeno-associated virus, ComputingMilieux_MISCELLANEOUS, Immunosuppression Therapy, Antibody titer, Age Factors, Dependovirus, medicine.disease, Antibodies, Neutralizing, 3. Good health, Immunity, Humoral, Muscular Dystrophy, Duchenne, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunoglobulin G, Humoral immunity, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, 030215 immunology
Abstract

International audience; Adeno-associated virus (AAV) vectors are promising candidates for gene therapy and have been explored as gene delivery vehicles in the treatment of Duchenne Muscular Dystrophy (DMD). Recent studies showed compelling evidence of therapeutic efficacy in large animal models following the intravenous delivery of AAV vectors expressing truncated forms of dystrophin. However, to translate these results to humans, careful assessment of the prevalence of anti-AAV neutralizing antibodies (NAbs) is needed, as presence of preexisting NABs to AAV in serum have been associated with a drastic diminution of vector transduction. Here we measured binding and neutralizing antibodies against AAV serotype 1, 2, and 8 in serum from children and young adults with DMD (n = 130). Results were compared with to age-matched healthy donors (HD, n = 113). Overall, approximately 54% of all subjects included in the study presented IgG to AAV2, 49% to AAV1, and 41% to AAV8. A mean of around 80% of IgG positive sera showed neutralizing activity with no statistical difference between DMD and HD. NAb titers for AAV2 were higher than AAV1, and AAV8 in both populations studied. Older DMD patients (13-24 years old) presented significantly lower anti-AAV8 IgG4 subclass. Anti-AAV antibodies were found to be decreased in DMD patients subjected to a 6-month course of corticosteroids and in subjects receiving a variety of immunosuppressive drugs including B cell targeting drugs. Longitudinal follow up of humoral responses to AAV over up to 6 years showed no change in antibody titers, suggesting that in this patient population, seroconversion is a rare event in humans.

Published
2018
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3. 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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4. 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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5. Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy

Author

Melissa A. Goddard, Mandy Lockard, Christelle Moal, Alan H. Beggs, Fulvio Mavilio, Jane Barber, Thomas Soker, David L. Mack, Nathalie Daniele, Carole Masurier, J. Koudy Williams, Philippe Moullier, Christel Rivière, Anna Buj-Bello, Robert W. Grange, Karine Poulard, Samia Martin, Xuan Guan, T. Jamet, C. Hammer, Laetitia van Wittenberghe, Alban Vignaud, R. Joubert, Martin K. Childers, Mark E. Furth, Michael W. Lawlor, Branden E. Rider, Erin Mitchell, Jonathan Doering, Wake Forest University, Biorobotics Lab (University of Washington), University of Washington [Seattle], Généthon, Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Virginia Tech [Blacksburg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-Université d'Évry-Val-d'Essonne (UEVE), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Coeur, Muscle et Vaisseaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1089, Laboratoire de Thérapie Génique, Université de Nantes (UN), Genomics Program and Division of Genetics, Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, 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, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Recherches Avicoles (SRA), Institut National de la Recherche Agronomique (INRA), 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), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Association française contre les myopathies (AFM-Téléthon), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Pathology, Myotubularin, Genetic enhancement, [SDV]Life Sciences [q-bio], medicine.disease_cause, Congenital, Mice, Non-Receptor, Mice, Knockout, Mutation, Muscle Weakness, Medicine (all), [SDV.BA]Life Sciences [q-bio]/Animal biology, Animals, Dependovirus, Diaphragm, Dogs, Genetic Therapy, Genetic Vectors, Genotype, HEK293 Cells, Humans, Muscle Contraction, Myopathies, Structural, Congenital, Protein Tyrosine Phosphatases, Non-Receptor, Disease Models, Animal, General Medicine, X-linked myotubular myopathy, 3. Good health, Knockout mouse, Systemic administration, Myopathies, medicine.symptom, medicine.medical_specialty, Knockout, Biology, Article, Immune system, Structural, medicine, Animal, Muscle weakness, medicine.disease, Disease Models, Immunology, Protein Tyrosine Phosphatases
Abstract

International audience; Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology, and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged life span to more than 1 year in the absence of toxicity or a humoral or cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small- and large-animal models, and provide proof of concept for future clinical trials in XLMTM patients.

Published
2014
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6. P.4.3 Intravenous infusion of AAV8–MTM1 prolongs life and ameliorates severe muscle pathology in mouse and dog models of X-linked myotubular myopathy

Author

C. Hammer, M.N. Holder, Christelle Moal, Alan H. Beggs, Melissa A. Goddard, Carole Masurier, T. Soker, Michael W. Lawlor, T. Jamet, Christel Rivière, Jonathan Doering, Philippe Moullier, Karine Poulard, Erin Mitchell, Anna Buj-Bello, C. Martin, Alban Vignaud, K. Poppante, J. Barber, Xuan Guan, Robert W. Grange, Martin K. Childers, R. Joubert, N. Danièle, L. Van Wittenberghe, Mark E. Furth, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon

Subjects
medicine.medical_specialty, Pathology, Myotubularin, Genetic enhancement, Hindlimb, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Skeletal muscle, Muscle weakness, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, X-linked myotubular myopathy, Hypotonia, 3. Good health, Surgery, medicine.anatomical_structure, Neurology, Pediatrics, Perinatology and Child Health, Desmin, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Mutations in the myotubularin gene (MTM1) result in X-linked myotubular myopathy (XLMTM), a fatal pediatric disease of skeletal muscle characterized by small myofibers with frequent central nuclei and abnormal mitochondrial accumulations. Patients with XLMTM typically present with severe hypotonia, muscle weakness and respiratory failure. Previous local studies in Mtm1-mutant mice demonstrated potential efficacy of gene therapy to treat the disease. Here we report long-term survival data in mice and dogs following intravenous delivery of an adeno-associated virus serotype 8 (AAV8) vector expressing myotubularin under the muscle-specific desmin promoter. XLMTM dogs (n = 3) were treated at 8 weeks of age with full-length canine MTM1 cDNA using an AAV8 vector. Affected XLMTM dogs were infused with AAV8–MTM1 (2.5 × 10 13 vg/kg), IV under high pressure into the saphenous vein while a tourniquet was applied around the upper thigh. While AAV8–MTM1 was administered by hindlimb infusion, effects were observed systemically in dogs. Mice were given intravenous AAV8–MTM1 by tail vein injection. In both murine and canine models, myotubularin transgene was expressed in all limb muscles and this translated into marked improvement of contractile force in mice and dogs. All mutant mice, including those injected at a late stage of the disease, survived until the end of the 6-month study. The lifespan of MTM1 mutant dogs that normally survive to 4 months was prolonged beyond 1 year in the first of three treated animals. Two additional treated dogs remain robust and continue to thrive beyond 8 months-of-age. Our findings in these two species provide proof-of-principle that intravenous AAV-mediated myotubularin replacement can rescue the severe phenotype of both small and large animal models of myotubular myopathy.

Published
2013
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7. T.O.4 Development of AAV-gene and protein-based therapies for X-linked myotubular myopathy

Author

D. Armstrong, J. Barber, Carole Masurier, Erin Mitchell, M.N. Holder, Melissa A. Goddard, Jeffrey J. Widrick, Philippe Moullier, Nadia Messaddeq, Anna Buj-Bello, Alan H. Beggs, Christopher R. Pierson, R. Joubert, Karine Poulard, T. Soker, Michael W. Lawlor, T. Jamet, Marissa G. Viola, Mark E. Furth, Martin K. Childers, Xuan Guan, N. Danièle, K. Poppante, Samia Martin, C. Hammer, Christel Rivière, Robert W. Grange, L. Van Wittenberghe, Alban Vignaud, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon

Subjects
medicine.medical_specialty, Myotubularin, Gene mutation, Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Myocyte, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Muscle weakness, Skeletal muscle, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Anatomy, medicine.disease, Congenital myopathy, X-linked myotubular myopathy, 3. Good health, Endocrinology, medicine.anatomical_structure, Neurology, Pediatrics, Perinatology and Child Health, Desmin, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery
Abstract

MTM1 gene mutations cause X-linked myotubular myopathy (XLMTM), a fatal congenital myopathy characterized by small myofibers with frequent central nuclei. XLMTM patients typically present with severe hypotonia, muscle weakness and respiratory failure. Previous intramuscular (IM) injection studies in Mtm1 KO mice demonstrated potential efficacy of gene therapy to treat the disease. We extended these results to a large animal model by testing IM delivery of an AAV8-canine MTM1 vector into the cranial tibialis muscle of dogs with XLMTM. We observed dramatic improvement in strength of treated limb muscles to levels approaching that of age-matched normal littermates. This response was detectable at 1 week post-injection and improvement continued until a terminal measurement at 6 weeks post-injection. Concomitantly, the AAV-injected XLMTM muscles showed substantial increase in mass and myofiber size, and decreases in pathological features. We also utilized the Mtm1 KO mouse to determine the response to systemic intravenous delivery of an AAV serotype 9 vector expressing myotubularin under the muscle-specific desmin promoter. Myotubularin was rapidly and persistently expressed in muscles scattered throughout the body and this translated into robust improvement of skeletal muscle pathology and contractile force, and normalized motor activity of treated mice. Importantly, the lifespans of treated mice, which normally survive ∼7–8 weeks, were prolonged to >6 months. We then evaluated the effects of a targeted protein-replacement agent (3E10Fv-MTM1) injected into the tibialis anterior muscle of Mtm1 KO mice. Injection of 3E10Fv-MTM1 over 2 weeks increased contractile function (p

Published
2012
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