Department of Health Outcomes and Administrative Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University-SUNY, Binghamton, NY 13902, USA.
Department of Biomedical Engineering, Watson School of Engineering, Binghamton University-SUNY, Binghamton, NY 13902, USA.
Hum Mol Genet. 2020 Aug 29;29(15):2481-2495. doi: 10.1093/hmg/ddaa132.
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.
杜氏肌营养不良症（DMD）是由于肌肉中的肌营养不良蛋白缺失引起的，虽然所有患者都存在主要基因和生化缺陷，但在临床症状上存在相当大的个体间差异。我们试图开发多变量血清蛋白生物标志物模型，这些模型可以解释观察到的变化，并使用功能结局测量作为严重程度的替代指标。研究了 39 名未经类固醇治疗的 DMD 男孩（4 至<7 岁）的血清样本，这些男孩参与了 vamorolone 的临床试验（NCT02760264）。对每个参与者进行了 4 次为期 6 周的总体运动功能评估，并将其平均值作为生物标志物模型的反应。使用 SOMAscan®适体分析定量的 1305 种蛋白质进行无监督聚类的加权相关网络分析，以定义高度代表性和连接性的蛋白质。使用时间站立表现（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）的生物标志物多变量模型，包括一些共同的蛋白质。鉴定出的蛋白质与肌营养不良症患者（n=28）和正常对照者（n=6）的肌肉组织学严重程度的 mRNA 表达进行了关联测试。发现 ERBB4（随着严重程度的增加，血液和肌肉中的表达都减少）、SOD1（肌肉中减少，血液中增加）和 CNTF（随着严重程度的增加，血液和肌肉中的水平降低）与临床和组织学严重程度具有强烈的关联，具有预测作用。我们表明，DMD 男孩的表现可以通过血清蛋白有效地建模，近端力量与生长和重塑途径相关，而肌肉耐力则集中在 TGFβ和纤维化途径上。
