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1. Long-term effects of systemic gene therapy in a canine model of myotubular myopathy

Author

Alan H. Beggs, Robert W. Grange, Ana Buj-Bello, Valerie E. Kelly, Matthew Elverman, Michael W. Lawlor, Martin K. Childers, Melissa A. Goddard, Anthony P. Marsh, Jessica M. Snyder, David L. Mack, Karine Poulard, Hui Meng, 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, Genomics Program and Division of Genetics, Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Généthon, Laboratoire d'Astrophysique de Marseille (LAM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Centre National d'Études Spatiales [Toulouse] (CNES), Wake Forest University, 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), Généthon, Evry, and École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, Pathology, Physiology, Myotubularin, muscle, Genetic enhancement, viruses, medicine.disease_cause, 0302 clinical medicine, Transduction, Genetic, Longitudinal Studies, Respiratory system, Adeno-associated virus, myotubular myopathy, Glucuronidase, Adenosine Triphosphatases, Neurologic Examination, [SDV.BA]Life Sciences [q-bio]/Animal biology, Dependovirus, Protein Tyrosine Phosphatases, Non-Receptor, gene therapy, 3. Good health, Female, medicine.symptom, Myopathies, Structural, Congenital, medicine.medical_specialty, Neuromuscular disease, Transgene, canine, adeno-associated virus, Biology, gait, Virus, 03 medical and health sciences, Cellular and Molecular Neuroscience, Dogs, Physiology (medical), medicine, Animals, Humans, Muscle, Skeletal, Gait Disorders, Neurologic, [SDV.GEN]Life Sciences [q-bio]/Genetics, Muscle weakness, Genetic Therapy, neuromuscular disease, medicine.disease, NAD, Respiration Disorders, Disease Models, Animal, Microscopy, Electron, 030104 developmental biology, Mutation, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Introduction X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years. Methods We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression. Results Four years following AAV-mediated gene therapy, gait, respiratory performance, neurological function and pathology in AAV-infused XLMTM dogs remained comparable to their healthy littermate controls despite a decline in VCN and muscle strength. Conclusions AAV-mediated gene transfer of MTM1 in young XLMTM dogs results in long-term expression of myotubularin transgene with normal muscular performance and neurological function in the absence of muscle pathology. These findings support a clinical trial in patients. Muscle Nerve 56: 943–953, 2017

Published
2017

2. Prolonged benefit from systemic rAAV8 in a canine model of myotubular myopathy

Author

Karine Poulard, David L. Mack, Michael W. Lawlor, Hui Meng, Jessica M. Snyder, Federico Mingozzi, Melissa A. Goddard, Virginie Latournerie, Robert W. Grange, Anna Buj-Bello, Matthew Elverman, Philippe Veron, Alan H. Beggs, Martin K. Childers, 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
0303 health sciences, Pathology, medicine.medical_specialty, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, Myotubular Myopathy, Medicine, Neurology (clinical), business, Canine model, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2016

3. 498. Prolonged Benefit from Systemic rAAV8 in a Canine Model of Myotubular Myopathy

Author

Matthew Elverman, Michael W. Lawlor, Robert W. Grange, David L. Mack, Christine Le Bec, Karine Poulard, Jessica M. Snyder, Federico Mingozzi, Philippe Veron, Hui Meng, Melissa A. Goddard, Fulvio Mavilio, Laurine Buscara, Samia Martin, Alan H. Beggs, Anna Buj-Bello, Martin K. Childers, Virginie Latournerie, 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, Neuromuscular disease, Neurological function, 03 medical and health sciences, Neurological assessment, 0302 clinical medicine, Gene replacement, Internal medicine, Drug Discovery, Genetics, medicine, Myotubular Myopathy, Respiratory function, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Gait, 030220 oncology & carcinogenesis, Cardiology, Molecular Medicine, business, Canine model
Abstract

Body: Mutations in MTM1 result in X-linked myotubular myopathy (XLMTM), a rare neuromuscular disease that causes devastating muscular weakness in affected children, often fatal in the first years of life. A naturally occurring MTM1 mutation in Labrador retrievers provides unprecedented opportunity to assess MTM1 gene replacement strategies. Here, we report clinical and physiological outcomes more than 3 years after a single intravenous infusion of AAV8-MTM1 in two dogs. Readouts include neurological assessment, limb strength, gait, respiratory function, and histology. Results (Fig 1Fig 1) are shown in comparison to age-matched littermates, and indicate that a single infusion of AAV8-MTM1 can markedly prolong life and achieve near normal levels of neurological function, strength, gait, and respiratory function for more than 3 years in MTM1 mutant dogs.View Large Image | Download PowerPoint Slide

Published
2016

4. Gene therapy in monogenic congenital myopathies

Author

Melissa A. Goddard, Xuan Guan, Martin K. Childers, David L. Mack, 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), Wake Forest University, 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, and École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, Genetic enhancement, Myopathy, [SDV]Life Sciences [q-bio], Muscle Proteins, Gene mutation, Bioinformatics, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Gene therapy, Gene replacement, medicine, Animals, Humans, Muscular dystrophy, Molecular Biology, Gene, Muscle disease, business.industry, HEK 293 cells, Gene Transfer Techniques, Treatment options, Genetic Therapy, medicine.disease, 3. Good health, Animal models, 030104 developmental biology, medicine.symptom, business, Myopathies, Structural, Congenital
Abstract

International audience; Current treatment options for patients with monogenetic congenital myopathies (MCM) ameliorate the symptoms of the disorder without resolving the underlying cause. However, gene therapies are being developed where the mutated or deficient gene target is replaced. Preclinical findings in animal models appear promising, as illustrated by gene replacement for X-linked myotubular myopathy (XLMTM) in canine and murine models. Prospective applications and approaches to gene replacement therapy, using these disorders as examples, are discussed in this review.

Published
2016

5. Use of Adeno-Associated Virus to Enrich Cardiomyocytes Derived from Human Stem Cells

Author

Philippe Moullier, Xuan Guan, Stefan Czerniecki, David L. Mack, Zejing Wang, Virginie François, Véronique Blouin, Martin K. Childers, 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), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), and JAULIN, Nicolas

Subjects
viruses, [SDV]Life Sciences [q-bio], Population, Cell, Genetic Vectors, Induced Pluripotent Stem Cells, Gene Expression, Biology, 030204 cardiovascular system & hematology, medicine.disease_cause, Serogroup, Virus, Cell Line, Immunophenotyping, Transduction (genetics), 03 medical and health sciences, 0302 clinical medicine, Genes, Reporter, Transduction, Genetic, medicine, Humans, Myocytes, Cardiac, education, Induced pluripotent stem cell, Adeno-associated virus, Research Articles, Genetics (clinical), 030304 developmental biology, education.field_of_study, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Stem Cells, Gene Transfer Techniques, Cell Differentiation, Cell sorting, Dependovirus, Molecular biology, Immunohistochemistry, Cell biology, [SDV] Life Sciences [q-bio], Viral Tropism, medicine.anatomical_structure, Stem cell, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) show great promise as autologousdonor cells to treat heart disease. A major technical obstacle to this approach is that availableinduction methods often produce heterogeneous cell population with low percentage of cardiomyocytes.Here we describe a cardiac enrichment approach using nonintegrating adeno-associated virus (AAV). Wefirst examined several AAV serotypes for their ability to selectively transduce iPSC-derived cardiomyocytes.Results showed that AAV1 demonstrated the highest in vitro transduction efficiency among sevenwidely used serotypes. Next, differentiated iPSC derivatives were transduced with drug-selectable AAV1expressing neomycin resistance gene. Selection with G418 enriched the cardiac cell fraction from 27% to57% in 2 weeks. Compared with other enrichment strategies such as integrative genetic selection, mitochondrialabeling, or surface marker cell sorting, this simple AAV method described herein bypassesantibody or dye labeling. These findings provide proof of concept for large-scale cardiomyocyte enrichmentby exploiting AAV’s intrinsic tissue tropism

Published
2015

6. Validity of a Neurological Scoring System for Canine X-Linked Myotubular Myopathy

Author

Allison Meisner, Melissa A. Goddard, Jessica M. Snyder, Robert W. Grange, Martin K. Childers, Ian T. Coulter, David L. Mack, 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 d'Astrophysique de Marseille (LAM), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Wake Forest University, 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, École pratique des hautes études (EPHE), and Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Centre National d'Études Spatiales [Toulouse] (CNES)

Subjects
Pathology, medicine.medical_specialty, Myotubularin, [SDV]Life Sciences [q-bio], Disease, Severity of Illness Index, Congenital neuromuscular disorder, 03 medical and health sciences, Dogs, 0302 clinical medicine, Internal medicine, Severity of illness, medicine, Animals, Gait, Research Articles, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Muscle biopsy, Muscle Weakness, medicine.diagnostic_test, business.industry, Muscle weakness, Reproducibility of Results, Genetic Therapy, medicine.disease, Protein Tyrosine Phosphatases, Non-Receptor, Congenital myopathy, X-linked myotubular myopathy, 3. Good health, Disease Models, Animal, medicine.symptom, business, 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract

International audience; A simple clinical neurological test was developed to evaluate response to gene therapy in a preclinical canine model of X-linked myotubular myopathy (XLMTM). This devastating congenital myopathy is caused by mutation in the myotubularin (MTM1) gene. Clinical signs include muscle weakness, early respiratory failure, and ventilator dependence. A spontaneously occurring canine model has a similar clinical picture and histological abnormalities on muscle biopsy compared with patients. We developed a neuromuscular assessment score, graded on a scale from 10 (normal) to 1 (unable to maintain sternal recumbency). We hypothesize that this neurological assessment score correlates with genotype and established measures of disease severity and is reliable when performed by an independent observer. At 17 weeks of age, there was strong correlation between neurological assessment scores and established methods of severity testing. The neurological severity score correctly differentiated between XLMTM and wild-type dogs with good interobserver reliability, on the basis of strong agreement between neurological scores assigned by independent observers. Together, these data indicate that the neurological scoring system developed for this canine congenital neuromuscular disorder is reliable and valid. This scoring system may be helpful in evaluating response to therapy in preclinical testing in this disease model, such as response to gene therapy.

Published
2015

7. G.P.41

Author

Philippe Moullier, Karine Poulard, Alan H. Beggs, Jonathan Doering, Jessica M. Snyder, David L. Mack, M. O’Callaghan, Fulvio Mavilio, Anna Buj-Bello, Melissa A. Goddard, Michael W. Lawlor, Martin K. Childers, Virginie Latournerie, 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, business.industry, Physiology, Skeletal muscle, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hindlimb, Hypotonia, 3. Good health, Surgery, medicine.anatomical_structure, Neurology, Respiratory failure, Pediatrics, Perinatology and Child Health, medicine, Desmin, Neurology (clinical), medicine.symptom, Respiratory system, business, Perfusion, Genetics (clinical), ComputingMilieux_MISCELLANEOUS
Abstract

Mutations in the myotubularin gene (MTM1) result in X-linked myotubular myopathy (XLMTM), a fatal pediatric disease of skeletal muscle characterized by small centrally nucleated myofibers containing abnormal mitochondrial accumulations. Patients typically present with severe hypotonia and respiratory failure. Previous local studies in Mtm1-mutant mice demonstrated potential efficacy of gene therapy to treat the disease. We recently reported that administration of adeno-associated virus serotype 8 (AAV8) vector expressing myotubularin under the muscle-specific desmin promoter, delivered systemically in myotubularin deficient mice and by regional hind limb perfusion in XLMTM dogs, could prolong life and restore muscle function. Here we report initial results of a larger dose escalation study testing the efficacy of AAV8-MTM1 systemic venous infusion in XLMTM dogs. Four groups were studied in a blinded manner: Wild-type or female carrier controls (N = 6); affected dogs given saline only (N = 4); affected dogs given AAV8-MTM1 (5E12 vg/kg) (N = 3) or (2.5E13 vg/kg) (N = 3). AAV8-MTM1 was administered at 10 weeks of age and dogs were followed for 9 months. Efficacy readouts included limb strength, gait, respiratory and neurological assessments at 13, 15, and 17 weeks-of-age, then monthly to 40 weeks-of-age. Results indicate a dose-dependent response to AAV8-MTM1. At the highest AAV dose, we observed marked improvements to near-normal levels in all physiological and clinical parameters tested along with improved survival, whereas the lowest dose provided only modest improvements. Together, these data indicate a dose-response for AAV8-MTM1 on muscle strength, walking speed, neuromuscular function and survival in dogs with myotubularin deficiency.

Published
2014

8. 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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