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AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

Jean-Baptiste Dupont, Jianjun Guo, Michael W. Lawlor, Robert W. Grange, John T. Gray, Ana Buj-Bello, Martin K. Childers, David L. Mack
doi: https://doi.org/10.1101/499384
Jean-Baptiste Dupont
1Departments of Rehabilitation Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
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Jianjun Guo
3Audentes Therapeutics, San Francisco, CA 94108, USA.
7Present address: Clinical NGS Group, Thermo Fisher Scientific, South San Francisco, CA 94080, USA.
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Michael W. Lawlor
4Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Robert W. Grange
5Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
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John T. Gray
3Audentes Therapeutics, San Francisco, CA 94108, USA.
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Ana Buj-Bello
6Généthon, INSERM UMR S951, Université Evry Val-d’Essone, Université Paris-Saclay, 91000 Evry, France.
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Martin K. Childers
1Departments of Rehabilitation Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
8Present address: AskBio, Chapel Hill, NC 27514, USA.
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David L. Mack
1Departments of Rehabilitation Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
2Department of Bioengineering, University of Washington, Seattle, WA 98109, USA.
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  • For correspondence: dmack21@uw.edu
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Abstract

Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Previous work from our laboratory on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrects structural abnormalities within the muscle and restores contractile function, with affected dogs surviving more than four years post injection. This exceptional therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology, and to what extent the whole muscle transcriptome is restored to normal after gene transfer. Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously-described canine cohort showing dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice, but also identified new transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created new metrics to pinpoint potential biomarkers of disease progression and correction.

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Posted December 17, 2018.
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AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy
Jean-Baptiste Dupont, Jianjun Guo, Michael W. Lawlor, Robert W. Grange, John T. Gray, Ana Buj-Bello, Martin K. Childers, David L. Mack
bioRxiv 499384; doi: https://doi.org/10.1101/499384
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AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy
Jean-Baptiste Dupont, Jianjun Guo, Michael W. Lawlor, Robert W. Grange, John T. Gray, Ana Buj-Bello, Martin K. Childers, David L. Mack
bioRxiv 499384; doi: https://doi.org/10.1101/499384

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