{"title":"脊髓肌肉萎缩症生物标志物的最新进展。","authors":"Megan G Pino, Kelly A Rich, Stephen J Kolb","doi":"10.1177/11772719211035643","DOIUrl":null,"url":null,"abstract":"<p><p>The availability of disease modifying therapies for spinal muscular atrophy (SMA) has created an urgent need to identify clinically meaningful biomarkers. Biomarkers present a means to measure and evaluate neurological disease across time. Changes in biomarkers provide insight into disease progression and may reveal biologic, physiologic, or pharmacologic phenomena occurring prior to clinical detection. Efforts to identify biomarkers for SMA, a genetic motor neuron disease characterized by motor neuron degeneration and weakness, have culminated in a number of putative molecular and physiologic markers that evaluate biological media (eg, blood and cerebrospinal fluid [CSF]) or nervous system function. Such biomarkers include <i>SMN2</i> copy number, SMN mRNA and protein levels, neurofilament proteins (NFs), plasma protein analytes, creatine kinase (CK) and creatinine (Crn), and various electrophysiology and imaging measures. <i>SMN2</i> copy number inversely correlates with disease severity and is the best predictor of clinical outcome in untreated individuals. SMN mRNA and protein are commonly measured in the blood or CSF of patients receiving SMA therapies, particularly those aimed at increasing SMN protein expression, and provide insight into current disease state. NFs have proven to be robust prognostic, disease progression, and pharmacodynamic markers for SMA infants undergoing treatment, but less so for adolescents and adults. Select plasma proteins are altered in SMA individuals and may track response to therapy. CK and Crn from blood correlate with motor function and disease severity status and are useful for predicting which individuals will respond to therapy. Electrophysiology measures comprise the most reliable means for monitoring motor function throughout disease course and are sensitive enough to detect neuromuscular changes before overt clinical manifestation, making them robust predictive and pharmacodynamic biomarkers. Finally, magnetic resonance imaging and muscle ultrasonography are non-invasive techniques for studying muscle structure and physiology and are useful diagnostic tools, but cannot reliably track disease progression. Importantly, biomarkers can provide information about the underlying mechanisms of disease as well as reveal subclinical disease progression, allowing for more appropriate timing and dosing of therapy for individuals with SMA. Recent therapeutic advancements in SMA have shown promising results, though there is still a great need to identify and understand the impact of biomarkers in modulating disease onset and progression.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"16 ","pages":"11772719211035643"},"PeriodicalIF":3.4000,"publicationDate":"2021-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bb/b8/10.1177_11772719211035643.PMC8371741.pdf","citationCount":"0","resultStr":"{\"title\":\"Update on Biomarkers in Spinal Muscular Atrophy.\",\"authors\":\"Megan G Pino, Kelly A Rich, Stephen J Kolb\",\"doi\":\"10.1177/11772719211035643\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The availability of disease modifying therapies for spinal muscular atrophy (SMA) has created an urgent need to identify clinically meaningful biomarkers. Biomarkers present a means to measure and evaluate neurological disease across time. Changes in biomarkers provide insight into disease progression and may reveal biologic, physiologic, or pharmacologic phenomena occurring prior to clinical detection. Efforts to identify biomarkers for SMA, a genetic motor neuron disease characterized by motor neuron degeneration and weakness, have culminated in a number of putative molecular and physiologic markers that evaluate biological media (eg, blood and cerebrospinal fluid [CSF]) or nervous system function. Such biomarkers include <i>SMN2</i> copy number, SMN mRNA and protein levels, neurofilament proteins (NFs), plasma protein analytes, creatine kinase (CK) and creatinine (Crn), and various electrophysiology and imaging measures. <i>SMN2</i> copy number inversely correlates with disease severity and is the best predictor of clinical outcome in untreated individuals. SMN mRNA and protein are commonly measured in the blood or CSF of patients receiving SMA therapies, particularly those aimed at increasing SMN protein expression, and provide insight into current disease state. NFs have proven to be robust prognostic, disease progression, and pharmacodynamic markers for SMA infants undergoing treatment, but less so for adolescents and adults. Select plasma proteins are altered in SMA individuals and may track response to therapy. CK and Crn from blood correlate with motor function and disease severity status and are useful for predicting which individuals will respond to therapy. Electrophysiology measures comprise the most reliable means for monitoring motor function throughout disease course and are sensitive enough to detect neuromuscular changes before overt clinical manifestation, making them robust predictive and pharmacodynamic biomarkers. Finally, magnetic resonance imaging and muscle ultrasonography are non-invasive techniques for studying muscle structure and physiology and are useful diagnostic tools, but cannot reliably track disease progression. Importantly, biomarkers can provide information about the underlying mechanisms of disease as well as reveal subclinical disease progression, allowing for more appropriate timing and dosing of therapy for individuals with SMA. 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引用次数: 0
摘要
随着脊髓性肌萎缩症(SMA)疾病调整疗法的出现,人们迫切需要确定具有临床意义的生物标志物。生物标志物是测量和评估神经系统疾病的一种手段。生物标志物的变化可帮助人们深入了解疾病的进展,并揭示临床检测之前发生的生物、生理或药理现象。SMA 是一种遗传性运动神经元疾病,以运动神经元变性和乏力为特征,为确定 SMA 的生物标记物所做的努力最终产生了许多可评估生物介质(如血液和脑脊液 [CSF])或神经系统功能的假定分子和生理标记物。这些生物标志物包括 SMN2 拷贝数、SMN mRNA 和蛋白水平、神经丝蛋白(NFs)、血浆蛋白分析物、肌酸激酶(CK)和肌酐(Crn)以及各种电生理学和成像测量。SMN2 拷贝数与疾病严重程度成反比,是预测未经治疗者临床结局的最佳指标。在接受 SMA 治疗(尤其是旨在增加 SMN 蛋白表达的治疗)的患者的血液或脑脊液中,通常会测量 SMN mRNA 和蛋白,从而了解当前的疾病状态。事实证明,对于接受治疗的 SMA 婴儿来说,NFs 是强有力的预后、疾病进展和药效学标志物,但对于青少年和成人来说,NFs 的作用则较弱。某些血浆蛋白在 SMA 患者中会发生改变,并可跟踪治疗反应。血液中的 CK 和 Crn 与运动功能和疾病严重程度相关,有助于预测哪些患者将对治疗产生反应。电生理学测量是监测整个病程中运动功能的最可靠方法,其灵敏度足以在明显临床表现之前检测到神经肌肉变化,因此是强有力的预测和药效生物标记物。最后,磁共振成像和肌肉超声是研究肌肉结构和生理学的非侵入性技术,是有用的诊断工具,但不能可靠地跟踪疾病的进展。重要的是,生物标志物可提供有关疾病潜在机制的信息,并揭示亚临床疾病进展,从而为 SMA 患者提供更适当的治疗时机和剂量。最近在 SMA 治疗方面取得的进展已显示出良好的效果,但仍亟需确定和了解生物标志物在调节疾病发病和进展方面的影响。
The availability of disease modifying therapies for spinal muscular atrophy (SMA) has created an urgent need to identify clinically meaningful biomarkers. Biomarkers present a means to measure and evaluate neurological disease across time. Changes in biomarkers provide insight into disease progression and may reveal biologic, physiologic, or pharmacologic phenomena occurring prior to clinical detection. Efforts to identify biomarkers for SMA, a genetic motor neuron disease characterized by motor neuron degeneration and weakness, have culminated in a number of putative molecular and physiologic markers that evaluate biological media (eg, blood and cerebrospinal fluid [CSF]) or nervous system function. Such biomarkers include SMN2 copy number, SMN mRNA and protein levels, neurofilament proteins (NFs), plasma protein analytes, creatine kinase (CK) and creatinine (Crn), and various electrophysiology and imaging measures. SMN2 copy number inversely correlates with disease severity and is the best predictor of clinical outcome in untreated individuals. SMN mRNA and protein are commonly measured in the blood or CSF of patients receiving SMA therapies, particularly those aimed at increasing SMN protein expression, and provide insight into current disease state. NFs have proven to be robust prognostic, disease progression, and pharmacodynamic markers for SMA infants undergoing treatment, but less so for adolescents and adults. Select plasma proteins are altered in SMA individuals and may track response to therapy. CK and Crn from blood correlate with motor function and disease severity status and are useful for predicting which individuals will respond to therapy. Electrophysiology measures comprise the most reliable means for monitoring motor function throughout disease course and are sensitive enough to detect neuromuscular changes before overt clinical manifestation, making them robust predictive and pharmacodynamic biomarkers. Finally, magnetic resonance imaging and muscle ultrasonography are non-invasive techniques for studying muscle structure and physiology and are useful diagnostic tools, but cannot reliably track disease progression. Importantly, biomarkers can provide information about the underlying mechanisms of disease as well as reveal subclinical disease progression, allowing for more appropriate timing and dosing of therapy for individuals with SMA. Recent therapeutic advancements in SMA have shown promising results, though there is still a great need to identify and understand the impact of biomarkers in modulating disease onset and progression.