Clinical Trial Readiness for SCA1 and SCA3

SCA1 和 SCA3 的临床试验准备情况

基本信息

批准号：
10327685
负责人：
TETSUO ASHIZAWA
金额：
$ 109.88万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327685
关键词：
Address Age Animal Model Antidepressive Agents Ataxia Biochemical Biological Markers Biomedical Engineering Blood Brain Injuries Cell model Cerebrospinal Fluid Cessation of life Citalopram Clinical Clinical Research Clinical Trials Clinical Trials Design Code Cohort Studies Collaborations Complex DNA Sequence Alteration Data Databases Development Diffusion Disease Disease Progression Europe European FDA approved Face Foundations Functional Magnetic Resonance Imaging Funding Future Gene Silencing Genes Genetic Genotype Goals Hour Image Inherited International Intervention Intervention Trial Investigation MJD1 protein Machado-Joseph Disease Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Messenger RNA Mitogen-Activated Protein Kinase Inhibitor Morphology Mutation National Institute of Neurological Disorders and Stroke Natural History Nerve Degeneration Neurodegenerative Disorders Neurons Nucleotides Onset of illness Pathogenicity Pathology Pathway interactions Patients Pharmaceutical Preparations Population Proteins Protocols documentation RPS6KA5 gene Rare Diseases Ras Inhibitor Research Rest Sampling Serotonergic System Site Spinocerebellar Ataxias Standardization Study Subject Technology Testing Treatment Efficacy Type 1 Spinocerebellar Ataxia United States National Institutes of Health Validation animal data base clinical outcome assessment clinical trial readiness cohort design disability drug candidate imaging biomarker improved inhibitor morphometry motor deficit multimodality mutant mutation carrier neurotoxicity patient population patient stratification polyglutamine pre-clinical predictive modeling prospective success targeted treatment treatment arm trial design trial readiness

项目摘要

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.

脊髓小脑共济失调 1 型 (SCA1) 和 3 型 (SCA3) 是罕见的遗传性神经退行性疾病，会不断发展至完全残疾和死亡。 SCA1 是进展最快的 SCA，而 SCA3 是美国和欧洲最常见的 SCA。在各自的基因 ATXN1 和 ATXN3 中编码聚谷氨酰胺 (polyQ) 的扩展 (CAG)n 重复序列会导致 SCA1 和 SCA3。针对复杂致病级联上游途径的疾病缓解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 SCA1 的 MSK1 抑制剂、用于 SCA3 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药物，将在五年内进行临床试验。然而，我们目前在此类疾病缓解疗法的临床试验准备中面临的挑战是，根据共济失调评估和评级量表（SARA；最稳健和经过充分验证的量表）衡量，候选药物的效应大小适中。临床结果评估措施）需要大量研究对象才能获得足够的统计功效。为了实现我们建立临床试验准备的目标，我们建议发起一项国际性、多地点的工作，重点关注早期疾病阶段的突变携带者和患者，他们可能是在不可逆的脑损伤之前对疾病缓解干预措施的反应者。基于我们由 NIH 和国家共济失调基金会 (NAF) 资助的研究，美国共济失调联盟开发了一个前所未有的机会，与欧洲共济失调研究组紧密合作，共同应对这一挑战，并为 SCA1 和 SCA3 的临床试验做好准备。为了实现我们的目标，我们提出以下具体目标：目标 1. 通过结合来自美国和欧洲的队列、临床结果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兆/早期 SCA1 和 SCA3 队列目标 2验证前期和早期 SCA1 和 SCA3 中的 MR 形态、生化和功能生物标志物目标 3. 适应统计设计的最新进展SCA 的小群体试验和分析。