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Mol Ther. 2019 Nov 11. pii: S1525-0016(19)30500-3. doi: 10.1016/j.ymthe.2019.10.018. [Epub ahead of print]

AAV-Mediated Gene Transfer Restores a Normal Muscle Transcriptome in a Canine Model of X-Linked Myotubular Myopathy.

Author information

1
Department of Rehabilitation Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
2
Audentes Therapeutics, San Francisco, CA 94108, USA.
3
Genethon, INSERM UMR S951, Université Evry Val-d'Essone, Université Paris-Saclay, 91000 Evry, France.
4
Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
5
Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
6
Department of Rehabilitation Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA. Electronic address: dmack21@uw.edu.

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). Our previous work on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrected structural abnormalities within the muscle and restored contractile function, with affected dogs surviving more than 4 years post injection. This remarkable 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 that showed dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice but also identified transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created metrics to pinpoint potential biomarkers of disease progression and correction.

KEYWORDS:

AAV; XLMTM; biomarkers; gene therapy; myotubularin; transcriptome

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