Format

Send to

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

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

Author information

1
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.
2
Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France.
3
Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USA.
4
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
5
Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
6
Genethon, 91000 Evry, France.
7
Neuromuscular Physiology and Evaluation Lab, Institut de Myologie, 75651 Paris, France.
8
Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
9
Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
10
Audentes Therapeutics, San Francisco, CA 94108, USA.
11
Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98019, USA.
12
Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA.
13
Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA.
14
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.
15
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
16
Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France; Institut de Myologie, University Pierre and Marie Curie, 75005 Paris, France.
17
Genethon, 91000 Evry, France; INSERM, UMR_S951, 91002 Evry, France. Electronic address: abujbello@genethon.fr.
18
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.

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.

KEYWORDS:

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

PMID:
28237839
PMCID:
PMC5383631
DOI:
10.1016/j.ymthe.2017.02.004
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center