Leonard Wolfson Experimental Neurology Centre, University College London, London, UK; National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK.
Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
Lancet. 2014 Aug 9;384(9942):504-13. doi: 10.1016/S0140-6736(14)60382-2. Epub 2014 Apr 30.
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.
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.
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.
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.
Ataxia UK, Ataxia Ireland, Association Suisse de l'Ataxie de Friedreich, Associazione Italiana per le Sindromi Atassiche, UK National Institute for Health Research, European Friedreich's Ataxia Consortium for Translational Studies, and Imperial Biomedical Research Centre.
弗里德里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 中的扩展 GAA 重复导致其异染色质化和转录沉默。临床前研究表明，组蛋白去乙酰化酶抑制剂烟酰胺（维生素 B3）可以重塑病理性异染色质并上调 FXN 的表达。我们旨在评估高剂量烟酰胺在弗里德里希共济失调患者中的表观遗传和神经学效应及安全性。
在英国进行的这项探索性、开放标签、剂量递增的研究中，18 岁或以上的男性和女性弗里德里希共济失调患者接受单次剂量（第 1 阶段）和重复每日剂量 2-8 g 口服烟酰胺 5 天（第 2 阶段）和 8 周（第 3 阶段）。在第 1 阶段和第 2 阶段期间逐渐增加剂量，第 3 阶段使用个体最大耐受剂量。主要终点是 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法研究 FXN 基因座染色质结构的变化，并评估了烟酰胺治疗对共济失调临床量表的影响。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01589809。
烟酰胺总体上耐受性良好；主要不良事件是恶心，大多数情况下为轻度、剂量相关，且自发缓解或经减少剂量、使用止吐药或两者联合后缓解。第 1 阶段显示，frataxin 蛋白浓度从基线到 8 小时的变化与剂量呈剂量反应关系，随剂量增加而增加（p=0·0004）。贝叶斯分析预测 3·8 g 会导致 frataxin 蛋白浓度增加 1.5 倍，7.5 g 会导致其增加两倍。第 2 阶段和第 3 阶段显示，每天 3.5-6 g 剂量可使 frataxin 表达持续显著上调（p<0·0001），同时 FXN 基因座的异染色质修饰减少。临床指标无显著变化。
在 8 周的每日给药过程中，烟酰胺与 frataxin 浓度的持续改善相关，使其接近无症状携带者的水平。需要进一步研究烟酰胺的长期临床获益及其在弗里德里希共济失调中改善 frataxin 缺乏的能力。
英国共济失调协会、爱尔兰共济失调协会、瑞士弗里德里希共济失调协会、意大利共济失调协会、英国国家卫生研究院、欧洲弗里德里希共济失调转化研究联盟和帝国生物医学研究中心。
