Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn−/−;SMN2 and intermediate Smn2B/− SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone’s activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn−/−; SMN2 SMA and Smn+/−; SMN2 healthy mice, we identified molecular targets linked to prednisolone’s ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone’s potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.

中文翻译：

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一种基于转录组学的药物重新定位方法，用于识别具有相似活性的药物，用于治疗脊髓性肌萎缩症 (SMA) 模型中的肌肉病理。

脊髓性肌萎缩症（SMA）是一种由运动神经元（SMN）存活蛋白水平降低引起的遗传性神经肌肉疾病。尽管三种 SMN 增强疗法已获得临床批准，可以显着减缓疾病进展，但不幸的是，它们并不能治愈疾病。因此，能够针对关键 SMA 病理学并支持临床批准的 SMN 依赖性药物的补充 SMN 独立疗法是治疗开发的前沿。我们之前已经证明，泼尼松龙（一种合成糖皮质激素（GC））可以改善严重 Smn−/−;SMN2 和中度 Smn2B/− SMA 小鼠的肌肉健康和存活率。然而，长期服用泼尼松龙会促进肌病。因此，我们希望确定骨骼肌中泼尼松龙靶向的基因和途径，以发现临床批准的药物，预计可以模拟泼尼松龙的活性。对经过症状性泼尼松龙治疗和未治疗的 Smn−/− 的骨骼肌使用 RNA 测序、生物信息学和药物重新定位管道；SMN2 SMA 和 Smn+/-；针对 SMN2 健康小鼠，我们确定了与泼尼松龙改善作用相关的分子靶点，并列出了 580 种具有相似预测活性的候选药物。其中两种候选药物二甲双胍和氧甲氢龙在 SMA 细胞和动物模型中进行了进一步研究，结果强调这些化合物对 SMA 表型的改善作用不如泼尼松龙；然而，许多其他重要的药物靶标仍然存在。总体而言，我们的工作进一步支持了泼尼松龙作为 SMA 第二代疗法的潜力，确定了潜在的 SMA 药物治疗列表，并强调了未来基于转录组学的 SMA 药物重新定位研究的改进。