title: Long-term effects of systemic gene therapy in a canine model of myotubular myopathy.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Elverman
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Goddard
authors.affiliation: Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mack
authors.affiliation: Department of Comparative Medicine, University of Washington, Campus Box 357340, Seattle, Washington, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Snyder
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: Généthon, INSERM UMR S951, Evry, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Buj-Bello
authors.affiliation: Généthon, INSERM UMR S951, Evry, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poulard
authors.affiliation: Department of Health and Exercise Science, Wake Forest University, Winston-Salem, North Carolina, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Marsh
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Grange
authors.affiliation: Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Kelly
authors.affiliation: Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Childers
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D020233:Gait Disorders, Neurologic / Q000209:etiology; D015316:Genetic Therapy; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D020914:Myopathies, Structural, Congenital / Q000150:complications / Q000235:genetics / Q000628:therapy* / Q000662:veterinary; D009243:NAD / Q000378:metabolism; D009460:Neurologic Examination; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000627:therapeutic use*; D012120:Respiration Disorders / Q000209:etiology; D014161:Transduction, Genetic
chemical_list: D009243:NAD; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; D005966:Glucuronidase; D000251:Adenosine Triphosphatases
keywords: adeno-associated virus; canine; gait; gene therapy; muscle; myotubular myopathy; neuromuscular disease