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The effects of gene replacement therapy on respiratory and gait function in a canine model of X-linked myotubular myopathy

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X-linked myotubular myopathy (XLMTM) is a fatal pediatric disease caused by a deficiency of the protein myotubularin due to mutation of the MTM1 gene on the X chromosome. Affected boys experience profound skeletal muscle weakness and are typically ventilator and wheelchair dependent, with respiratory failure as the leading cause of death. A potential gene therapy has been developed where AAV8 mediates MTM1 replacement. A naturally-occuring canine model of the disease displays a phenotype similar to that seen in patients, including markedly reduced survival, and decreased strength and function in the muscles of the limbs and respiratory system. XLMTM dogs were treated once with AAV8 containing a full length canine MTM1 cDNA under a muscle-specific desmin promoter by three different routes of administration—local intramuscular injection of the hindlimb, isolated perfusion of the hindlimb and systemically. Systemic treatment was carried out at three different doses to determine the minimum effective dose for full preservation of function. Respiratory function and ambulation were measured in these dogs and compared to untreated and normal true control littermates over time. XLMTM dogs treated intramuscularly show improvement only at the site of injection, with no improvement in gait or respiration. However, dogs treated by isolated limb perfusion maintain normal ambulation and respiratory function and continue to survive well after treatment. For dogs treated systemically, mid- and high-dose treatment are associated with maintained respiratory function and continued survival, while measures remain subnormal in low-dose treated dogs. Similarly, ambulation in mid- and high-dose treated dogs approaches normal measures, while low-dose treated dogs more closely resemble their untreated littermates. Measures in the dog sensitive to changes due to the disease or treatment were also identified, including gait speed, stride length, peak inspiratory flow and inspiratory time, which could be useful in the translation of this potential treatment for XLMTM to the clinic.
canine model
centronuclear myopathy
gene therapy
myotubular myopathy
Goddard, Melissa (author)
Childers, Martin K (committee chair)
Kelly, Valerie (committee member)
Grange, Robert (committee member)
Christ, George (committee member)
Marsh, Anthony (committee member)
Mack, David (committee member)
2015-06-23T08:35:53Z (accessioned)
2017-06-22T08:30:08Z (available)
2015 (issued)
Physiology and Pharmacology (discipline)
2017-06-22 (terms)
http://hdl.handle.net/10339/57151 (uri)
en (iso)
Wake Forest University
The effects of gene replacement therapy on respiratory and gait function in a canine model of X-linked myotubular myopathy

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