Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs

Mol Ther. 2017 Apr 5;25(4):839-854. doi: 10.1016/j.ymthe.2017.02.004. Epub 2017 Feb 22.


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.

Keywords: adeno-associated virus; canine; centronuclear; gene therapy; muscle; myopathy; myotubular; myotubularin; neuromuscular; pediatric.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy
  • Dependovirus / classification
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Disease Progression
  • Dogs
  • Gait
  • Gene Expression
  • Genetic Therapy* / adverse effects
  • Genetic Therapy* / methods
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Genetic Vectors / genetics*
  • Genetic Vectors / pharmacokinetics
  • Immunity, Cellular
  • Immunity, Humoral
  • Kaplan-Meier Estimate
  • Muscle Strength
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscle, Skeletal / ultrastructure
  • Myopathies, Structural, Congenital / diagnosis
  • Myopathies, Structural, Congenital / genetics*
  • Myopathies, Structural, Congenital / mortality
  • Myopathies, Structural, Congenital / therapy
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Recovery of Function
  • Reflex
  • Respiratory Function Tests
  • Tissue Distribution
  • Transgenes / genetics
  • Transgenes / immunology
  • Treatment Outcome


  • Protein Tyrosine Phosphatases, Non-Receptor
  • myotubularin