Clinical Trial Readiness for SCA1 and SCA3

脊髓小脑性共济失调1型(SCA1)和3型(SCA3)是罕见的遗传性神经退行性疾病，无情地进展到完全残疾和死亡。SCA1是发展最快的SCA，而SCA3是美国和欧洲最常见的SCA。在各自的基因ATXN1和ATXN3中，编码多谷氨酸(PolyQ)的(CAG)n重复序列导致了SCA1和SCA3。针对复杂致病级联上游途径的疾病修正疗法将提供最终治疗。科学前提和临床前动物数据有力地支持MSK1抑制剂治疗SCA1，西酞普兰治疗SCA3，以及基于核苷酸的基因沉默这两种SCA作为药物将在五年内进行临床试验。然而，在我们目前此类疾病修改疗法的临床试验准备情况下，我们面临的挑战是，以共济失调评估和评级量表(SARA；最强大和最有效的临床结果评估指标)衡量的候选药物的适度效果规模需要大量研究对象来获得足够的统计能力。为了实现我们建立临床试验准备的目标，我们建议发起一项国际、多地点的努力，重点放在疾病早期的显性突变携带者和患者身上，他们可能是在不可逆转的脑损伤之前对疾病修改干预的应答者。基于我们由NIH和国家共济失调基金会(NAF)资助的研究，美国共济失调财团开发了一个前所未有的机会，与欧洲共济失调研究小组密切合作，共同应对这一挑战，并为SCA1和SCA3建立临床试验准备。为了实现我们的目标，我们提出了以下具体目标：目的1.结合队列、临床结果评估数据和来自美国和欧洲的生物液样本(血液、脑脊液)，建立世界上最大的显性前期/早期SCA1和SCA3队列；2.验证显性前期和早期SCA1和SCA3的MR形态、生化和功能标志物；3.使小群体试验的统计设计和分析方面的最新进展适用于SCA。

Spinocerebellar ataxia types 1 (SCA1) and 3 (SCA3) are rare, inherited neurodegenerative disorders that relentlessly progress to total disability and death. SCA1 is the fastest progressing SCA while SCA3 is the most common SCA in US and Europe. Expanded (CAG)n repeats encoding polyglutamines (polyQ) in the respective genes, ATXN1 and ATXN3, cause SCA1 and SCA3. Disease-modifying therapies that target the pathway upstream of the complex pathogenic cascade will offer ultimate treatment. Scientific premise and preclinical animal data strongly support MSK1 inhibitors for SCA1, citalopram for SCA3, and nucleotide-based gene silencing for both SCAs as drugs to be examined in clinical trials in five years. However, the challenge that we face in our current clinical trial readiness for such disease-modifying therapies is that the modest effect size of candidate drugs as measured by the Scale for the Assessment and Rating of Ataxia (SARA; the most robust and well-validated clinical outcome assessment measure) requires large cohorts of study subjects to achieve sufficient statistical power. To accomplish our goal of establishing clinical trial readiness, we propose to launch an international, multi-site effort focusing on premanifest mutation carriers and patients in an early disease stage, who are likely responders to the disease-modifying interventions prior to irreversible brain damage. Based on our studies funded by NIH and the National Ataxia Foundation (NAF), the US ataxia consortium has developed an unprecedented opportunity for tight collaborations with the European Ataxia Study Group to jointly address this challenge and establish clinical trial readiness for SCA1 and SCA3. To achieve our goal, we propose the following specific aims: Aim 1. Establish the world's largest cohorts of premanifest/early SCA1 and SCA3 by combining cohorts, clinical outcome assessment data and biofluid samples (blood, cerebrospinal fluid) from US and Europe Aim 2. Validate MR morphological, biochemical and functional biomarkers in premanifest and early SCA1 and SCA3 Aim 3. Adapt recent developments on statistical design and analysis of small population trials to SCAs.