Evaluation of a serum protein signature as monitoring biomarker for Duchenne muscular dystrophy in a long-term clinical trial with corticosteroids.

IF 3.9 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2026-07-13 DOI:10.1186/s13395-026-00437-2

Chiara Degan, Rebecca A Tobin, Sharon I de Vries, Albert Jiménez-Requena, Amela Peco, Michela Guglieri, Jordi Diaz-Manera, Yuri E M van der Burgt, Bart J M van Vlijmen, Yetrib Hathout, Cristina Al-Khalili Szigyarto, Utkarsh J Dang, Roula Tsonaka, Pietro Spitali

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引用次数: 0

Abstract

Background: Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder for which monitoring biomarkers are urgently needed. We aimed to evaluate whether proteins in serum can accurately monitor patients' function within the duration of a clinical trial.

Methods: In this study, we evaluated longitudinal serum proteins of DMD patients participating in the FOR-DMD clinical trial, comparing daily and intermittent corticosteroid regimens in boys aged 4-8 years at baseline. Using the aptamer-based protein platform SomaScan, we profiled 1500 proteins. Associations between protein levels and motor function outcomes, such as Rise from the Floor Velocity (RFV), 10-Meter Run/Walk Velocity (10MRWV), and North Star Ambulatory Assessment (NSAA), were assessed using linear mixed models. In particular, we explored whether patients with higher protein levels also tended to have better functional scores (across-patients analysis), and whether changes in protein levels within the same patient over time were linked to changes in their functional performance (within-patient analysis). Finally, penalized (lasso) mixed models were applied to evaluate the predictive function of the proteins. The prediction accuracy of the models (evaluated by optimism-corrected Root Mean Squared Error) was compared to that of a simpler model with only age and treatment as predictors.

Results: Across-patients and within-patient analyses revealed consistent associations with three functional tests for a subset of proteins, notably RGMA, ART3, ANTXR2, and CFB. Multivariate models incorporating the proteins significantly associated with at least two tests, improved prediction accuracy by 12% for NSAA, and by 33-35% for RFV and 10MRWV. These models also revealed a subset of proteins that were consistently selected. Quantification of CFB, RGMA, ANTXR2, SERPINF1 and ATP5PF using SomaScan showed strong agreement with measurements obtained using orthogonal methods such as ELISA, MRM-MS and an in-house developed bead-based sandwich immunoassay.

Conclusions: These findings support the utility of serum protein signatures as objective, quantitative tools for monitoring disease progression and treatment response in DMD during clinical visits and clinical trials.

Trial registration: The FOR-DMD clinical trial was registered at ClinicalTrials.gov (registration no. NCT01603407). First submission: 03/04/2012.

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在皮质类固醇长期临床试验中评估血清蛋白标记作为杜氏肌营养不良监测的生物标志物。

背景：杜氏肌营养不良症（DMD）是一种进行性神经肌肉疾病，迫切需要监测生物标志物。我们的目的是评估血清中的蛋白质是否能在临床试验期间准确监测患者的功能。方法：在这项研究中，我们评估了参加FOR-DMD临床试验的DMD患者的纵向血清蛋白，比较了4-8岁男孩在基线时的每日和间歇性皮质类固醇治疗方案。使用基于适配体的蛋白质平台SomaScan，我们分析了1500种蛋白质。使用线性混合模型评估蛋白质水平与运动功能结果（如从地板上升速度（RFV）， 10米跑/走速度（10MRWV）和北极星动态评估（NSAA））之间的关系。特别是，我们探讨了蛋白质水平较高的患者是否也倾向于具有更好的功能评分（跨患者分析），以及同一患者体内蛋白质水平随时间的变化是否与其功能表现的变化有关（患者内分析）。最后，采用惩罚（套索）混合模型来评估蛋白质的预测功能。模型的预测精度（由乐观修正的均方根误差评估）与仅以年龄和治疗作为预测因素的简单模型进行比较。结果：患者间和患者内分析揭示了与一组蛋白质的三种功能测试的一致关联，特别是RGMA、ART3、ANTXR2和CFB。多变量模型纳入了与至少两项测试显著相关的蛋白质，将NSAA的预测准确性提高了12%，将RFV和10MRWV的预测准确性提高了33-35%。这些模型还揭示了一致选择的蛋白质子集。使用SomaScan对CFB、RGMA、ANTXR2、serinf1和ATP5PF的定量结果与使用ELISA、MRM-MS和内部开发的基于头部的三明治免疫分析法等正交方法获得的结果高度一致。结论：这些发现支持血清蛋白特征作为客观、定量的工具，在临床访问和临床试验期间监测DMD的疾病进展和治疗反应。试验注册：FOR-DMD临床试验已在ClinicalTrials.gov 注册(注册号：NCT01603407)。首次提交时间：2012年4月3日。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.