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

烟酰胺治疗 Friedreich 共济失调患者疗效和安全性的随机、双盲、安慰剂对照、平行组、多中心研究

• 批准号: 346404983
• 负责人: Professor Dr. Thomas Klopstock
• 金额: --
• 依托单位: Klinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/346404983?language=en
• 关键词: randomized; double; blind; placebo; controlled

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.

弗里德赖希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。它是由共济失调蛋白基因（FXN）第一内含子中GAA重复序列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抑制共济失调蛋白的表达，导致共济失调蛋白水平降低。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。在外周血单个核细胞中，典型的弗里德赖希共济失调患者中共济失调蛋白的平均残留水平降低至36%。 Frataxin缺乏导致无情地进行性神经退行性疾病，通常在青春期左右出现。患者逐渐失去协调性，出现构音障碍，并在青少年时期经常坐轮椅。目前还没有改善疾病的治疗方法，许多患者过早死于心肌病。已经证明，GAA-三联体重复可以在体内触发连锁报告基因的异常压缩，导致位置效应杂色（PEV）的原型表观遗传基因沉默现象（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基因通过异染色质的形成而在染色质水平沉默，并且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共济失调患者的概念验证临床研究表明，使用III类HDACi，共济失调蛋白水平可以恢复到健康杂合遗传携带者的水平，烟酰胺，患者耐受良好的剂量（Libri，2014）。因此，将共济失调蛋白表达恢复到这些水平可能会阻止疾病进展。烟酰胺易于穿过血脑屏障，之前曾长期以高剂量给予正常个体，未出现严重不良反应（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阐述了这一假设。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，神经系统疾病的稳定性，这已通过我们先前针对该疾病的自然史研究进行了验证（雷茨，2015）。进一步的措施将评估生活质量，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疗效和安全性提供临床证据。