Nicotinamide in Friedreich's ataxia: useful or not?
Nicotinamide in Friedreich's ataxia: useful or not?
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烟酰胺治疗弗里德赖希共济失调：有用还是没用？
DOI：
10.1016/s0140-6736(14)60573-0
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Fischbeck,KennethH
中科院分区：
文献类型：
--
作者：
Lynch,DavidR;Fischbeck,KennethH
弗里德赖希共济失调症是一种常染色体隐性神经退行性疾病，由frataxin基因（FXN）突变引起，可导致进行性共济失调、心肌病、脊柱侧凸和其他各种临床特征。1大多数患者在FXN的内含子1中存在GAA重复扩增，导致fraataxin蛋白浓度降低和下游线粒体功能障碍。GAA重复序列通过异染色质形成导致基因沉默，并减少FXN mRNA的转录。mRNA的编码区和蛋白质的氨基酸序列正常，但产生的蛋白质数量减少；因此，逆转表观遗传变化（如组蛋白去乙酰化）代表了弗里德赖希共济失调的潜在治疗策略。据报道，组蛋白去乙酰化酶（HDAC）抑制剂在细胞培养和弗里德赖希共济失调动物模型中可增加卵黄蛋白浓度。2,3在《柳叶刀》上发表的一项开放标签、剂量增加的研究中，Vincenzo Libri和他的同事注意到，服用烟酰胺（一种高浓度给予具有HDAC抑制剂活性的药物）的患者外周血单核细胞中FXN mRNA表达和frataxin蛋白浓度增加。来自英国的10名成年弗里德赖希共济失调患者给予单剂量（第一阶段）和重复每日剂量2 - 8 g口服烟酰胺，持续5天（第二阶段）和8周（第三阶段）。在第一阶段，单次剂量高达8g（约为烟酰胺作为维生素的典型推荐每日允用量的200倍[B3] 5）导致外周血单个核细胞中卵黄蛋白浓度增加，并且这种效应随着剂量的增加而增加（p= 0.0004）。在第2阶段和第3阶段，每天重复给药3·5-6 g导致frataxin表达持续且显著（p< 0.0001）上调，这与染色质结构的变化有关（组蛋白H3尾部氨基酸位置9的甲基化显著降低，FXN位点H3乙酰化不显著增加）。研究者没有报告在神经测量方面有任何显著的改善，通过评估和评定共济失调量表和脊髓小脑共济失调功能指数来评估。这些结果令人感兴趣的原因有几个。首先，虽然烟酰胺有几个潜在的作用
Friedreich’s ataxia is an autosomal recessive neurodegenerative disorder caused by mutations in the frataxin gene (FXN), leading to progressive ataxia, cardiomyopathy, scoliosis, and various other clinical features. 1 Most patients have GAA repeat expansions in intron 1 of FXN, leading to decreased concentrations of frataxin protein and downstream mitochondrial dysfunction. The GAA repeats lead to gene silencing through heterochromatin formation, and decreased transcription of FXN mRNA. The coding region of the mRNA and the aminoacid sequence of the protein are normal, but the amount of protein produced is reduced; as a result, reversal of the epigenetic changes (such as histone deacetylation) represents a potential therapeutic strategy in Friedreich’s ataxia. Inhibitors of histone deacetylase (HDAC) have been reported to increase frataxin concentrations in cell culture and in animal models of Friedreich’s ataxia. 2, 3 In an open-label, dose-escalation study reported in The Lancet, Vincenzo Libri and colleagues4 note an increase in FXN mRNA expression and frataxin protein concentration in peripheral blood mononuclear cells in patients given nicotinamide, a drug that has HDAC inhibitor activity when given at high concentrations. Ten adult patients with Friedreich’s ataxia from the UK were given single doses (phase 1) and repeated daily doses of 2–8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). In phase 1, a single dose of up to 8 g (about 200 times higher than the typical recommended daily allowance for nicotinamide as a vitamin [B3] 5) led to an increase in frataxin concentration in peripheral blood mononuclear cells, and this effect increased with increasing dose (p= 0· 0004). In phases 2 and 3, repeated daily dosing at 3· 5–6 g resulted in a sustained and significant (p< 0· 0001) upregulation of frataxin expression, which was associated with changes in chromatin structure (a significant reduction methylation at aminoacid position 9 of the histone H3 tail and a non-significant increase in H3 acetylation at the FXN locus). The investigators did not report any significant improvements in neurological measures, as assessed by the scale for the assessment and rating of ataxia and the spinocerebellar ataxia functional index. These results are of interest for several reasons. First, although nicotinamide has several potential