Candidate Proteins, Metabolites and Transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study
Candidate Proteins, Metabolites and Transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study
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DOI：
10.1371/journal.pone.0035462
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发表时间：
2012-04-27
期刊：
影响因子：
3.7
通讯作者：
Plasterer, Thomas
中科院分区：
文献类型：
--
作者：
Finkel, Richard S.;Crawford, Thomas O.;Plasterer, Thomas
背景：脊髓性肌萎缩症(SMA)是由运动神经元存活基因1(SMN1)纯合子突变引起的一种神经退行性运动神经元疾病。基因产物SMN蛋白在所有组织的RNA生物合成中发挥作用。在人类中，一个几乎相同的基因SMN2通过产生少量全长SMN蛋白来拯救原本致命的表型。SMN2拷贝数与疾病严重程度呈负相关。寻找其他新的生物标记物可以指导临床试验设计和确定新的治疗靶点。目的：使用无偏倚的蛋白质组、代谢组学和转录组方法确定与SMA疾病严重程度相关的新候选生物标记物。材料和方法：对108名2-12岁经基因证实的SMA儿童进行横断面单一评估，显示出广泛的疾病严重程度，并选择与SMA类型和目前的功能能力相关的因素，与年龄无关。使用蛋白质组、代谢组学和转录组发现平台对这些患者和22名年龄匹配的健康对照组的血液和尿液样本进行询问。结果：共有200个候选生物标志物与MHFMS评分相关：97个血浆蛋白、59个血浆代谢物(9个氨基酸、10个游离脂肪酸、12个脂类和28个GC/MS代谢物)和44个尿代谢物。没有与MHFMS相关的转录本。讨论：在这项横断面研究中，鉴定了“BforSMA”(SMA的生物标记物)、候选蛋白质和代谢物标记物。没有确定候选转录生物标记物。进一步挖掘这一丰富的数据集可能会对相关的SMA相关病理生理学和生物网络关联产生重要的见解。还需要更多的前瞻性研究来证实这些发现，证明随着疾病进展对变化的敏感性，并评估对临床试验设计的潜在影响。
Background: Spinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets.Objective:: To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches.Materials and Methods:: A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2-12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures.Results: A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS.Discussion: In this cross-sectional study, "BforSMA" (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with disease progression, and assess potential impact on clinical trial design.