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.

中文翻译：

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AAV 介导的基因转移在 X 连锁肌管肌病的犬模型中恢复了正常的肌肉转录组。

已经启动了多项使用重组腺相关病毒 (rAAV) 载体治疗神经肌肉疾病的临床试验，包括杜氏和肢带型肌营养不良症、脊髓性肌萎缩症和最近的 X 连锁肌管肌病 (XLMTM)。我们之前对 XLMTM 犬模型的研究表明，单次 rAAV8-cMTM1 全身输注可纠正肌肉内的结构异常并恢复收缩功能，受影响的狗在注射后存活超过 4 年。这种显着的治疗效果为鉴定 XLMTM 病理学的下游分子驱动因素以及基因转移后整个肌肉转录组恢复正常的程度提供了独特的机会。在此处，RNA 测序用于检查先前描述的犬群中股二头肌和股外侧肌的转录组，该群在 rAAV8-cMTM1 基因转移后显示出剂量依赖性临床改善。我们的分析证实了先前在 XLMTM 小鼠中观察到的几个失调基因，但也确定了与 XLMTM 病理学相关的转录本。我们展示了 XLMTM 转录组重构和基因转移后基因表达的剂量依赖性正常化，并创建了指标来确定疾病进展和纠正的潜在生物标志物。