title: Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs.
abstract: X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.
authors.affiliation: Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Mack
authors.affiliation: Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poulard
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Goddard
authors.affiliation: Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Latournerie
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Snyder
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Grange
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Elverman
authors.affiliation: Genethon, 91000 Evry, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Denard
authors.affiliation: Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Veron
authors.affiliation: Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France.
authors.forename: Laurine
authors.initials: L
authors.lastname: Buscara
authors.affiliation: Genethon, 91000 Evry, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Le Bec
authors.affiliation: Neuromuscular Physiology and Evaluation Lab, Institut de Myologie, 75651 Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Hogrel
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Annie G
authors.initials: AG
authors.lastname: Brezovec
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
authors.affiliation: Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Fujun
authors.initials: F
authors.lastname: Liu
authors.affiliation: Audentes Therapeutics, San Francisco, CA 94108, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Callaghan
authors.affiliation: Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98019, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Gopal
authors.affiliation: Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA.
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Kelly
authors.affiliation: Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Strande
authors.affiliation: Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
authors.affiliation: The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France; Institut de Myologie, University Pierre and Marie Curie, 75005 Paris, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France. Electronic address: abujbello@genethon.fr.
authors.forename: Ana
authors.initials: A
authors.lastname: Buj-Bello
authors.affiliation: Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USA. Electronic address: mkc8@uw.edu.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Childers
mesh_terms: D000818:Animals; D001706:Biopsy; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D005684:Gait; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000493:pharmacokinetics; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D053208:Kaplan-Meier Estimate; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D020914:Myopathies, Structural, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D020127:Recovery of Function; D012018:Reflex; D012129:Respiratory Function Tests; D014018:Tissue Distribution; D019076:Transgenes / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin
keywords: adeno-associated virus; canine; centronuclear; gene therapy; muscle; myopathy; myotubular; myotubularin; neuromuscular; pediatric