MDUK Oxford Neuromuscular Centre, Department of Physiology, Anatomy and Genetics, Oxford, UK.
Hum Mol Genet. 2019 Jul 1;28(13):2189-2200. doi: 10.1093/hmg/ddz049.
Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disorder caused by loss of dystrophin. Several therapeutic modalities are currently in clinical trials but none will achieve maximum functional rescue and full disease correction. Therefore, we explored the potential of combining the benefits of dystrophin with increases of utrophin, an autosomal paralogue of dystrophin. Utrophin and dystrophin can be co-expressed and co-localized at the same muscle membrane. Wild-type (wt) levels of dystrophin are not significantly affected by a moderate increase of utrophin whereas higher levels of utrophin reduce wt dystrophin, suggesting a finite number of actin binding sites at the sarcolemma. Thus, utrophin upregulation strategies may be applied to the more mildly affected Becker patients with lower dystrophin levels. Whereas increased dystrophin in wt animals does not offer functional improvement, overexpression of utrophin in wt mice results in a significant supra-functional benefit over wt. These findings highlight an additive benefit of the combined therapy and potential new unique roles of utrophin. Finally, we show a 30% restoration of wt dystrophin levels, using exon-skipping, together with increased utrophin levels restores dystrophic muscle function to wt levels offering greater therapeutic benefit than either single approach alone. Thus, this combination therapy results in additive functional benefit and paves the way for potential future combinations of dystrophin- and utrophin-based strategies.
杜氏肌营养不良症（DMD）是一种致命的神经肌肉疾病，由肌营养不良蛋白缺失引起。目前有几种治疗方法正在临床试验中，但没有一种方法能实现最大的功能恢复和完全纠正疾病。因此，我们探索了将肌营养不良蛋白的益处与肌联蛋白（肌营养不良蛋白的常染色体同源物）的增加相结合的潜力。肌联蛋白和肌营养不良蛋白可以在同一肌肉膜上共同表达和共定位。野生型（wt）肌营养不良蛋白的水平不会因肌联蛋白的适度增加而受到显著影响，而较高水平的肌联蛋白会减少 wt 肌营养不良蛋白，这表明肌膜上的肌动蛋白结合位点数量有限。因此，肌联蛋白上调策略可能适用于肌营养不良蛋白水平较低、病情较轻的 Becker 患者。虽然 wt 动物中增加的肌营养不良蛋白不能提供功能改善，但 wt 小鼠中肌联蛋白的过表达会导致显著的超功能益处。这些发现强调了联合治疗的附加益处和肌联蛋白的潜在新独特作用。最后，我们通过外显子跳跃显示 wt 肌营养不良蛋白水平恢复了 30%，同时增加肌联蛋白水平可将肌营养不良肌肉功能恢复到 wt 水平，提供比单一方法更大的治疗益处。因此，这种联合治疗可带来附加的功能益处，并为未来基于肌营养不良蛋白和肌联蛋白的策略的潜在组合铺平道路。
