Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
J Cachexia Sarcopenia Muscle. 2018 Aug;9(4):715-726. doi: 10.1002/jcsm.12304. Epub 2018 Apr 16.
Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs.
A large-scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross-sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits.
Cross-sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over-representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development.
Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.
肌肉活检分析使人们能够描述杜兴氏肌营养不良症（DMD）和贝克肌营养不良症（BMD）的病理生理变化，从而导致临床表型。肌肉组织通常在干预性剂量发现研究中进行研究，以证明所测试药物的体内概念验证和药效学效应。需要更微创的检测手段来客观监测患者的健康状况、肌肉质量和对治疗的反应。特别需要鉴定与临床功能相关并能够预测功能评分的血清生物标志物，以便为患者提供个性化的管理，并支持药物开发计划。
采用大规模蛋白质组学方法来鉴定描述病理生理变化（例如肌肉质量损失）、与临床功能相关、预测疾病里程碑、与体内磁共振光谱数据和肌肉中的抗肌萎缩蛋白水平相关的血清生物标志物。进行了横断面比较，以比较 DMD 患者、BMD 患者和健康对照者。一组 DMD 患者接受了中位数为 4.4 年的随访，以允许根据每年的就诊情况监测个体疾病轨迹。
横断面比较能够鉴定出 10 种能够区分健康对照者、DMD 和 BMD 患者的蛋白质。几种蛋白质（285 种）能够将 DMD 与健康个体区分开来，而 121 种蛋白质能够将 BMD 与 DMD 区分开来；只有 13 种蛋白质能够将 BMD 与健康个体区分开来。血清中特定蛋白质的浓度与 BMD 患者的表现（例如，BMP6 血清水平和肘部弯曲度）或抗肌萎缩蛋白水平（例如 TIMP2）显著相关。对纵向轨迹的分析允许鉴定出 427 种随时间变化而受影响的蛋白质，表明肌肉质量的损失、肌肉被脂肪组织替代以及心脏受累。对纵向数据的过度表达分析允许突出可作为当前临床开发药物药效学生物标志物的蛋白质。
血清蛋白质组学分析不仅能够区分 DMD、BMD 和健康个体，还能够检测与临床功能、抗肌萎缩蛋白水平和疾病进展的显著相关性。
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