Clinical Trial Readiness for SCA1 and SCA3

脊髓小脑共济失调1型（SCA 1）和3型（SCA 3）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。SCA 1是进展最快的SCA，而SCA 3是美国和欧洲最常见的SCA。在各自的基因ATXN 1和ATXN 3中编码多聚谷氨酰胺（polyQ）的扩增（CAG）n重复序列引起SCA 1和SCA 3。针对复杂致病级联反应上游通路的疾病改善疗法将提供最终治疗。科学前提和临床前动物数据强烈支持用于SCA 1的MSK 1抑制剂，用于SCA 3的西酞普兰，以及用于两种SCA的基于核苷酸的基因沉默，作为五年内临床试验的药物。然而，我们在目前的临床试验准备中面临的挑战是，通过共济失调评估和评级量表（SARA;最强大和最有效的临床结局评估措施）测量的候选药物的适度效应大小需要大量的研究受试者来实现足够的统计功效。为了实现我们建立临床试验准备的目标，我们建议开展一项国际性的多中心工作，重点关注早期疾病阶段的前显突变携带者和患者，他们可能在不可逆脑损伤之前对疾病修饰干预措施有反应。基于我们由NIH和国家共济失调基金会（NAF）资助的研究，美国共济失调联盟已经开发了一个前所未有的机会，与欧洲共济失调研究小组紧密合作，共同应对这一挑战，并为SCA 1和SCA 3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：目标1。通过结合美国和欧洲的队列、临床结局评估数据和生物流体样本（血液、脑脊液），建立世界上最大的预显症/早期SCA 1和SCA 3队列。在预显和早期SCA 1和SCA 3中的MRI形态学、生化和功能生物标志物使小群体试验的统计设计和分析的最新发展适应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.