AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy
| Autor: | David L. Mack, Jean-Baptiste Dupont, Ana Buj-Bello, Michael W. Lawlor, Robert W. Grange, John T. Gray, Jianjun Guo, Martin K. Childers |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Pathology medicine.medical_specialty Gene transfer Spinal muscular atrophy Biology medicine.disease X-linked myotubular myopathy Biceps 3. Good health law.invention Transcriptome 03 medical and health sciences 0302 clinical medicine law Gene expression medicine Recombinant DNA Gene 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/499384 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|