Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient–patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan^® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFβ and fibrosis pathways in muscle.

中文翻译：

---

与未使用类固醇激素的杜氏肌营养不良症男孩的基线临床严重程度相关的血清生物标志物。

Duchenne 型肌营养不良症 (DMD) 是由肌肉中肌营养不良蛋白的丧失引起的，虽然所有患者都有共同的主要基因和生化缺陷，但临床症状存在相当大的患者-患者变异性。我们试图开发解释观察到的变异的血清蛋白生物标志物的多变量模型，使用功能结果测量作为严重程度的代理。研究了 39 名 4 至 <7 岁未使用类固醇的 DMD 男孩的血清样本，这些男孩参加了一项瓦莫罗龙的临床试验 (NCT02760264)。在 6 周的时间间隔内，对每位参与者进行了四次粗大运动功能评估，并将它们的平均值用作生物标志物模型的响应。加权相关网络分析用于对使用 SOMAscan ^®量化的 1305 种蛋白质进行无监督聚类适体分析来定义高度代表性和连接的蛋白质。获得了多变量生物标志物模型，用于站立时间表现（力量表型；17 种蛋白质）和 6 分钟步行表现（耐力表型；17 种蛋白质），包括一些共享蛋白质。鉴定的蛋白质与 mRNA 表达与来自肌营养不良症患者 ( n  = 28) 和正常对照 ( n = 6）。发现 ERBB4（随着严重程度增加，血液和肌肉减少）、SOD1（随着严重程度增加，肌肉减少和血液增加）和 CNTF（随着严重程度增加，血液和肌肉水平降低）预测临床和组织学严重程度的强关联）。我们表明，DMD 男孩的表现可以通过血清蛋白、与生长和重塑途径相关的近端力量以及以 TGFβ 和肌肉纤维化途径为中心的肌肉耐力进行有效建模。