Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs - Université d'Évry Access content directly
Journal Articles Molecular Therapy Year : 2017

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

David Mack
  • Function : Author
Virginie Latournerie
  • Function : Author
Jessica Snyder
  • Function : Author
Matthew Elverman
  • Function : Author
Jérôme Denard
Laurine Buscara
  • Function : Author
Christine Le Bec
  • Function : Author
Jean-Yves Hogrel
  • Function : Author
  • PersonId : 901910
Annie Brezovec
  • Function : Author
Hui Meng
  • Function : Author
Fujun Liu
  • Function : Author
Michael O'Callaghan
  • Function : Author
Nikhil Gopal
  • Function : Author
Valerie Kelly
  • Function : Author
Barbara Smith
  • Function : Author
Ana Strande
  • Function : Author
Fulvio Mavilio
Michael Lawlor
  • Function : Author
Ana Buj-Bello
Michael O’callaghan
  • Function : Author
Jennifer Strande
  • Function : Author

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.
Fichier principal
Vignette du fichier
main.pdf (2.97 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive

Dates and versions

hal-02179363 , version 1 (09-11-2023)

Identifiers

Cite

David Mack, Karine Poulard, Melissa Goddard, Virginie Latournerie, Jessica Snyder, et al.. Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs. Molecular Therapy, 2017, 25 (4), pp.839-854. ⟨10.1016/j.ymthe.2017.02.004⟩. ⟨hal-02179363⟩
157 View
8 Download

Altmetric

Share

Gmail Facebook X LinkedIn More