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Muscle Nerve. 2017 Nov;56(5):943-953. doi: 10.1002/mus.25658. Epub 2017 May 22.

Long-term effects of systemic gene therapy in a canine model of myotubular myopathy.

Author information

1
Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
2
Department of Physiology and Pharmacology, School of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.
3
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
4
Department of Comparative Medicine, University of Washington, Campus Box 357340, Seattle, Washington, USA.
5
Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
6
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
7
Généthon, INSERM UMR S951, Evry, France.
8
Department of Health and Exercise Science, Wake Forest University, Winston-Salem, North Carolina, USA.
9
Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.

Abstract

INTRODUCTION:

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.

KEYWORDS:

adeno-associated virus; canine; gait; gene therapy; muscle; myotubular myopathy; neuromuscular disease

PMID:
28370029
PMCID:
PMC5620115
DOI:
10.1002/mus.25658
[Indexed for MEDLINE]
Free PMC Article

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