Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study
Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study
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DOI：
10.1016/s0140-6736(14)60382-2
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发表时间：
2014-08-09
期刊：
影响因子：
168.9
通讯作者：
Festenstein, Richard
中科院分区：
文献类型：
--
作者：
Libri, Vincenzo;Yandim, Cihangir;Festenstein, Richard
背景弗里德赖希共济失调是一种由 frataxin 蛋白缺乏引起的进行性退行性疾病。 frataxin (FXN) 基因内含子 1 内扩展的 GAA 重复导致其异染色质化和转录沉默。临床前研究表明，组蛋白脱乙酰酶抑制剂烟酰胺（维生素B3）可以重塑病理性异染色质并上调FXN的表达。我们的目的是评估高剂量烟酰胺对弗里德赖希共济失调患者的表观遗传和神经学影响以及安全性。 方法 在这项在英国进行的探索性、开放标签、剂量递增研究中，患有弗里德赖希共济失调的男性和女性患者（18 岁或以上）接受单剂量（第 1 阶段）和每日重复剂量 2-8 g 口服烟酰胺，持续 5 天（第 2 阶段）和 8 周（第 3 阶段）。在第 1 阶段和第 2 阶段，剂量逐渐增加，第 3 阶段使用个体最大耐受剂量。主要结果是 frataxin 表达的上调。我们还评估了烟酰胺的安全性和耐受性，使用染色质免疫沉淀研究 FXN 基因位点染色质结构的变化，并评估了烟酰胺治疗对共济失调临床规模的影响。这项研究已在 ClinicalTrials.gov 注册，编号为 NCT01589809。 结果 烟酰胺总体耐受性良好；主要不良事件是恶心，在大多数情况下，恶心是轻微的，与剂量相关，并且可以自行缓解或在减少剂量、使用抗恶心药物或两者兼而有之后缓解。第一阶段显示了 frataxin 蛋白浓度从基线到给药后 8 小时的比例变化的剂量反应关系，该变化随着剂量的增加而增加 (p = 0.0004)。贝叶斯分析预测，3.8 g 将导致 frataxin 蛋白质浓度增加 1 5 倍，7.5 g 将导致 frataxin 蛋白质浓度增加一倍。第 2 期和第 3 期显示，每日给药 3·5-6 g 会导致 frataxin 表达持续显着上调 (p < 0.0001)，同时 FXN 基因座异染色质修饰减少。临床测量结果未显示显着变化。 解释 烟酰胺与 frataxin 浓度持续改善有关，在 8 周的每日给药期间，无症状携带者的浓度持续改善。有必要进一步研究烟酰胺的长期临床益处及其改善弗里德赖希共济失调中 frataxin 缺乏的能力。
Background Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia.Methods In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia 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). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809.Findings Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p = 0.0004). Bayesian analysis predicted that 3.8 g would result in a 1 5-times increase and 7.5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3 5-6 g resulted in a sustained and significant (p < 0.0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes.Interpretation Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted.