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

Friedreich共济失调是最常见的早发性常染色体隐性遗传性共济失调。它是由Frataxin基因(FXN)第一内含子中GAA重复序列的病理性扩张引起的，FXN存在于98%的疾病等位基因中。内含子GAA重复序列的扩展超过了病理阈值，抑制了Frataxin的表达，导致Frataxin蛋白水平下降。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。在典型的Friedreich共济失调患者的外周血单核细胞中，Frataxin的平均残留水平降至36%。Frataxin缺乏会导致一种无情的进行性神经退行性疾病，通常出现在青春期前后。患者逐渐失去协调性，变得关节功能障碍，青少年时期经常坐轮椅。没有疾病修正疗法，许多患者因心肌病而过早死亡。已有研究表明，GAA-三联体重复序列可在体内引发连锁报告基因的异常紧致，导致典型的位置效应变异(PEV)表观基因沉默现象(Saveliev，2003)。这种GAA重复沉默对PEV修饰剂的基因剂量非常敏感，PEV修饰剂编码修饰染色质的酶。随后发现，由于异染色质的形成，FXN基因在染色质水平上被沉默，这种异染色质的形成可以被组蛋白脱乙酰酶抑制剂(HDACi)拮抗(Chan，2013)。最近对10名Friedrich共济失调患者进行的一项概念验证临床研究表明，使用III型HDACi烟酰胺，在患者很好地耐受的剂量下，Frataxin的水平可以恢复到健康杂合基因携带者的水平(Libri，2014)。因此，将Frataxin的表达恢复到这些水平可能会阻止疾病的进展。烟酰胺很容易通过血脑屏障，以前曾长期高剂量地给正常人服用，没有严重的不良反应(Gale，2004；Knip，2000)。这项研究以临床疗效的随机双盲、安慰剂对照、平行组研究的形式解决了这一假设。主要终点是使用共济失调评估和评级量表(SARA)与对照组相比神经状况的稳定，这已被我们之前对这种状况的自然历史研究(Reetz，2015)所验证。进一步的测量将评估生活质量、运动功能和认知、心脏功能以及大脑变化。这项研究将首次为烟酰胺治疗Friedreich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.