Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia.
Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia.
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DOI：
10.1371/journal.pone.0153574
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Cortopassi G
中科院分区：
文献类型：
--
作者：
Hayashi G;Cortopassi G
目前还没有被批准的最终致命的神经和心脏退行性疾病Friedreich共济失调(FA)的治疗方法。寻找疾病进展和药物效应的微创分子生物标记物可以支持更小、更短的临床试验。由于我们和其他人已经注意到FA中氧化应激反应的缺陷，我们研究了84个参与氧化应激、信号和保护的基因在对照组和FA淋巴母细胞中的表达，范围从460到1122个GAA重复。一些抗氧化剂基因以剂量依赖的方式对Frataxin在mRNA和蛋白质水平上的表达做出反应，这与疾病的进展和严重程度呈负相关。我们检测了富马酸二甲酯(DMF)和1型组蛋白去乙酰酶抑制剂(HDACi)对实验性Friedreich共济失调治疗后生物标记物基因表达的影响。我们观察到，淋巴母细胞暴露于DMF和HDACi呈剂量依赖性地抑制Frataxin的表达，并将潜在的生物标记物NCF2和PDLIM1的表达恢复到对照水平。我们认为，除了Frataxin的表达外，血淋巴细胞中NCF2和PDLIM1的水平可能是未来Friedreich‘s共济失调临床试验中疾病进展和药物疗效的有用生物标志物。
There is no current approved therapy for the ultimately lethal neuro- and cardio-degenerative disease Friedreich's ataxia (FA). Finding minimally-invasive molecular biomarkers of disease progression and drug effect could support smaller, shorter clinical trials. Since we and others have noted a deficient oxidative stress response in FA, we investigated the expression of 84 genes involved in oxidative stress, signaling, and protection in control and FA lymphoblasts ranging from 460 to 1122 GAA repeats. Several antioxidant genes responded in a dose-dependent manner to frataxin expression at the mRNA and protein levels, which is inversely correlated with disease progression and severity. We tested the effect of experimental Friedreich’s ataxia therapies dimethyl fumarate (DMF) and type 1 histone deacetylase inhibitor (HDACi) on biomarker mRNA expression. We observed that exposure of lymphoblasts to DMF and HDACi dose-dependently unsilenced frataxin expression and restored the potential biomarkers NCF2 and PDLIM1 expression to control levels. We suggest that in addition to frataxin expression, blood lymphoblast levels of NCF2 and PDLIM1 could be useful biomarkers for disease progression and drug effect in future clinical trials of Friedreich’s ataxia.