Natural History of Friedreich ataxia in children

儿童弗里德赖希共济失调的自然史

• 批准号: 9770557
• 负责人: DAVID ROBINSON LYNCH
• 金额: $ 39.91万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770557
• 关键词: Natural; History; Friedreich; ataxia; children

Abstract Friedreich’s ataxia (FRDA) is the most common form of hereditary ataxia, affecting approximately 1 in every 50,000 people in the United States and Europe. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. The pathophysiology of FRDA reflects the deficiency of the protein frataxin. Reduced frataxin levels impair the function of mitochondrial iron-sulfur-cluster-containing enzymes and ability to produce ATP. Recently, amelioration of frataxin deficiency by gene therapy in mouse models of FRDA has produced impressive benefit in reversing the phenotype, providing an evidenced-based approach for treatment of FRDA patients. Mitigation of mitochondrial dysfunction also represents a valid therapeutic approach. However, if attempts at these therapies were made today, they would be limited by the inability to assess the human biology of FRDA in detail, as well as the inability to target therapies to the most biologically responsive individuals, children. To achieve this goal, we will study the natural history of FRDA in children, to understand the course of disease activity in this age group. In the first aim, we will assess potential measures of disease progression in the youngest subjects with FRDA (n=100 at 3 sites) These will include specific revisions and modifications of timed walks (in order to identify a test more suitable for use in young individuals, and an automated measure of upper extremity coordination (the CCFS) that is useful in older FRDA subjects. In aim 2 we will assess biochemical measures of frataxin deficiency and downstream metabolic function, and understand their utility in serial monitoring.in children with FRDA. Peripheral samples (blood, buccal cells, isolated platelets) will be obtained from a large heterogeneous cohort of subjects with FRDA (n=100 at 3 sites). We will then assay the primary biomarker of disease severity, frataxin level, in the samples with a newly devised mass spectrometry-based assay to understand how such levels reflect disease status. In parallel, we will examine mitochondrial-derived alterations in metabolic pathways in platelets to examine events downstream from frataxin deficiency. Finally we will examine physiological tests (motor evoked potentials, Cr-CEST of muscle) that can link clinical parameters with biochemical measurements. Cumulatively these aims will define the utility of such approaches in clinical measurement of FRDA in children, and validate such approaches as the definitive measures needed for design of informative trials in children with FRDA.

抽象的 弗里德里希（Friedreich）的共济失调（FRDA）是遗传性共济失调的最​​常见形式，每一个影响约1 美国和欧洲有50,000人。症状通常在5至15岁之间开始 随着时间的流逝，更糟的是。 FRDA的病理生理反映了蛋白质Frataxin的缺乏。减少 Frataxin水平损害线粒体铁硫簇簇的功能，并产生产生的能力 ATP。最近，在FRDA小鼠模型中通过基因治疗改善Frataxin缺乏症已产生 在逆转表型方面令人印象深刻的好处，为FRDA的治疗提供了一种有证据的方法 患者。线粒体功能障碍的缓解也代表了一种有效的治疗方法。但是，如果 这些疗法的尝试是今天进行的，它们将受到无法评估人类生物学的限制 FRDA的详细信息，以及无法将疗法靶向最有反应敏感的个体， 孩子们。为了实现这一目标，我们将研究儿童FRDA的自然历史，以了解 该年龄段的疾病活动。 在第一个目标中，我们将评估FRDA最年轻受试者的疾病进展的潜在度量 （n = 3个站点的100）将包括特定的修订和定时步行的修改（以识别测试 更适合在年轻人中使用，并自动测量上肢协调（ CCFS）在较旧的FRDA受试者中有用。在AIM 2中，我们将评估Frataxin缺乏症的生化测量 以及下游代谢功能，并了解其在frda儿童中的串行监控方面的效用。 将从较大的异质队列中获得外围样品（血液，颊细胞，孤立的血小板） 有FRDA的受试者（3个地点n = 100）。然后，我们将主张疾病严重程度Frataxin的主要生物标志物 级别，在具有新设计的基于质谱法的样品中，以了解这种水平如何反映 疾病状况。同时，我们将检查血小板中代谢途径的线粒体衍生改变 检查Frataxin缺乏症下游的事件。最后，我们将检查生理测试（运动 诱发的电位，肌肉的cret）可以将临床参数与生化测量联系起来。 累计这些目标将定义此类方法在儿童FRDA临床测量中的实用性， 并验证此类方法，例如设计具有 FRDA。