XLMTM dog transcriptome remodeling by gene therapy

Gene therapy using recombinant adeno-associated virus (rAAV) vectors is an attractive approach to treat neuromuscular disorders resulting from single gene mutations. Despite encouraging results in large animal models and in recent clinical trials, gene therapy is sometimes considered a “hit-or-miss” technology, because the exact molecular mechanisms driving disease rescue remain elusive, and biomarkers of rAAV corrective impact in target cells are missing. In this study, the complete rescue of X-linked myotubular myopathy (XLMTM) after gene therapy in dogs was used as a model to develop analytical tools and help decipher the impact of the treatment on the muscle transcriptome. RNA-sequencing was performed on samples from two different muscles (Biceps femoris and Vastus lateralis) in a pre-existing colony of 13 dogs that were included in a dose-finding study published in 2017 (Mack D.L. et al.,Molecular Therapy 2017 Apr 5;25(4):839-854).