SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

Objectives
Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).
Methods
BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.
Results
12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.
Conclusions
Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

研究目标
脊髓性肌萎缩症（Spinal Muscular Atrophy, SMA）的临床研究面临三大挑战：一是监测疾病活动度并预测疾病进展，二是设计可快速评估候选疗法的临床试验，三是阐明该病的分子致病机制与病理后果。经过验证的SMA运动功能与非运动功能生物标志物，可为解决上述难题提供有效工具。本研究的目标分为两点：其一，依托免疫测定平台，从SMA生物标志物（Biomarkers for SMA, BforSMA）研究队列中发掘新型标志物；其二，在一项多中心自然病史研究（Natural History Study, NHS）采集的独立SMA患者队列中，对候选生物标志物进行验证。
研究方法
本研究通过免疫测定法对BforSMA研究的129份血浆样本进行分析，以筛选与SMA运动功能相关的新型分析物。本次使用的免疫测定法，涵盖了此前通过色谱法筛选出的最优候选生物标志物。我们选取了35种生物标志物，在另一项SMA自然病史研究的独立队列中开展验证，该队列包含158份1型、2型及3型SMA患者样本。我们对候选生物标志物与多项运动功能评分量表、肺功能、神经生理学指标、肌力及生活质量评估指标的相关性进行了检验。此外，本研究采用托比特模型（Tobit model）预测SMA运动功能评分。
研究结果
在35种候选SMA生物标志物中，有12种与运动功能呈显著相关性（p<0.05），另有1种分析物接近显著性水平。此外，还有多种分析物与SMA非运动功能结局指标存在关联。从上述35种生物标志物中，我们筛选出27种，纳入商用SMA生物标志物检测组合（SMA-MAP），用于后续与运动功能及其他功能指标的相关性分析。
研究结论
通过独立队列完成的生物标志物发掘与验证工作，得到了一组与SMA运动功能及其他疾病活动度指标显著相关的生物标志物。本研究已开发出商用SMA-MAP生物标志物检测组合，可在其他SMA样本集与干预性临床试验中开展进一步测试。未来的研究方向包括：评估该检测组合在其他神经肌肉疾病中的应用价值、验证其对实验性SMA疗法的药效学响应能力，以及预测SMA患者随时间推移的功能变化情况。