A randomized, double-blind, placebo-controlled, parallel-group, multi-centre study of the efficacy andsafety of nicotinamide in patients with Friedreich ataxia

弗里德赖希共济失调是最常见的早发常染色体隐性遗传性共济失调。它是由frataxin基因（FXN）的第一个内含子中的GAA重复的病理性扩增引起的，该基因存在于98%的疾病等位基因中。内含子GAA重复序列的扩增超过病理阈值会抑制frataxin的表达，导致frataxin蛋白水平降低。Frataxin是一种线粒体蛋白，参与铁稳态的控制和铁硫簇的生物发生。在典型弗里德赖希共济失调患者的外周血单个核细胞中，平均残余水平降至36%。Frataxin缺乏导致无情的进行性神经退行性疾病，经常出现在青春期左右。患者逐渐失去协调能力，变得运动困难，并经常在青少年时期被轮椅束缚。没有疾病改善治疗，许多患者过早死于心肌病。已有研究表明，gaa三联体重复序列可以触发体内相关报告基因的异常压实，从而导致典型的表观遗传基因沉默现象，即位置效应杂色（PEV） （Saveliev, 2003）。这种gaa重复沉默对编码修饰染色质的酶的PEV修饰剂的基因剂量非常敏感。随后发现，FXN基因在染色质水平上通过异染色质的形成被沉默，并且这种异染色质的形成可以被组蛋白去乙酰化酶抑制剂（HDACi）拮抗（Chan, 2013）。最近一项针对10名弗里德里希共济失调患者的概念验证临床研究表明，使用III类HDACi，烟酰胺，在患者耐受良好的剂量下，frataxin水平可以恢复到健康杂合遗传携带者的水平（Libri, 2014）。因此，将frataxin的表达恢复到这些水平可能有望阻止疾病的进展。烟酰胺很容易穿过血脑屏障，以前对正常人长期给予高剂量，没有严重的副作用（Gale, 2004; Knip, 2000）。本研究以随机双盲、安慰剂对照、平行组临床疗效研究的形式解决了这一假设。主要终点是与对照组相比，使用评估和评定共济失调量表（SARA）的神经系统状况的稳定性，这已经通过我们之前对该疾病的自然历史研究得到验证（Reetz, 2015）。进一步的测量将评估生活质量、运动功能和认知、心脏功能以及大脑改变。本研究将首次为烟酰胺治疗弗里德赖希共济失调患者的有效性和安全性提供临床证据。

Friedreich ataxia is the most frequent early-onset autosomal recessive hereditary ataxia. It is caused by a pathological expansion of a GAA repeat in the first intron of the frataxin gene (FXN), which is present in 98% of the disease alleles. The expansion of the intronic GAA repeat beyond the pathologic threshold inhibits frataxin expression, resulting in decreased levels of frataxin protein. Frataxin is a mitochondrial protein involved in the control of iron homeostasis and in the biogenesis of iron-sulphur clusters. In peripheral blood mononuclear cells, mean residual levels of frataxin are reduced to 36% in typical patients with Friedreich ataxia. Frataxin deficiency results in a relentlessly progressive neurodegenerative condition which frequently presents around puberty. Patients gradually lose coordination, become dysarthric and are frequently wheel-chair bound as adolescents. There is no disease modifying therapy and many patients die prematurely of cardiomyopathy. It has been demonstrated that GAA-triplet repeats can trigger abnormal compaction of a linked reporter gene in vivo leading to the archetypal epigenetic gene silencing phenomenon of position effect variegation (PEV) (Saveliev, 2003). This GAA-repeat silencing was exquisitely sensitive to the gene dosage of PEV modifiers which encode enzymes that modify chromatin. It was subsequently found that the FXN gene is silenced at the chromatin level by the formation of heterochromatin and that this heterochromatin formation can be antagonised by histone deacetylase inhibitors (HDACi) (Chan, 2013).A recent proof-of-concept clinical study on ten patients with Friedrich ataxia demonstrated that frataxin levels can be restored to levels of healthy heterozygous genetic carriers using the class III HDACi, nicotinamide, at a dose that is well tolerated by patients (Libri, 2014). Therefore, restoration of frataxin expression to these levels might be expected to halt disease progression. Nicotinamide readily crosses the blood brain barrier and has previously been given at high doses for long periods to normal individuals without serious adverse effects (Gale, 2004; Knip, 2000). This study addresses this hypothesis in the form of a randomised double-blind, placebo-controlled, parallel group study for clinical efficacy. The primary endpoint is the stabilisation of the neurological condition compared to the control group using the scale for assessment and rating of ataxia (SARA), which has been validated by our previous natural history study for this condition (Reetz, 2015). Further measures will assess quality of life, motor function and cognition, cardiac function as well as brain alteration. This study will be the first to provide clinical evidence for the efficacy and safety of nicotinamide in patients with Friedreich ataxia.