A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein
A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein
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DOI：
10.1371/journal.pone.0201764
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发表时间：
2018-08-13
期刊：
影响因子：
3.7
通讯作者：
Saito, Kayoko
中科院分区：
文献类型：
--
作者：
Otsuki, Noriko;Arakawa, Reiko;Saito, Kayoko
脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种严重的遗传性神经肌肉疾病，其发病原因是运动神经元存活蛋白（survival motor neuron，SMN）表达不足。已经进行了几项旨在上调SMA患者中SMN蛋白表达的临床试验。为了评估这些靶向SMN的方法的效率，有必要验证SMA患者细胞中的SMN蛋白水平。因此，我们已经开发了一种方法，允许使用成像流式细胞术用< 1.5mL的外周血评估功能性SMN蛋白。与来自对照受试者的细胞相比，来自SMA患者的CD 3+、CD 19+和CD 33 ++细胞中SMN蛋白的表达显着降低。在CD33（++）细胞斑点分析中，SMA患者的SMN斑点强度与对照组相比显著降低。因此，SMN斑点暗示细胞核中存在功能性SMN蛋白。据我们所知，我们的研究结果是第一次证明在新鲜分离的外周血细胞中存在功能性SMN蛋白。我们预计，SMN斑点分析将成为评价和监测治疗干预的主要终点分析，SMN将作为SMA患者治疗疗效的可靠生物标志物。
Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by insufficiency of functional survival motor neuron (SMN) protein. Several clinical trials have been conducted with the aim of upregulating the expression of the SMN protein in SMA patients. In order to evaluate the efficiency of these SMN-targeted approaches, it has become necessary to verify SMN protein levels in the cells of SMA patients. Accordingly, we have developed a method allowing the evaluation of the functional SMN protein with < 1.5mL of peripheral blood using imaging flow cytometry. The expression of SMN protein in CD3+, CD19+, and CD33++ cells obtained from SMA patients, was significantly reduced compared with that in cells from control subjects. In spot analysis of CD33(++) cells, the intensities of SMN spots were significantly reduced in SMA subjects, when compared with that in controls. Therefore, SMN spots implied the presence of functional SMN protein in the cell nucleus. To our knowledge, our results are the first to demonstrate the presence of functional SMN protein in freshly isolated peripheral blood cells. We anticipate that SMN spot analysis will become the primary endpoint assay for the evaluation and monitoring of therapeutic intervention, with SMN serving as a reliable biomarker of therapeutic efficacy in SMA patients.