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：
9438347
负责人：
TETSUO ASHIZAWA
金额：
$ 126.09万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9438347
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 Modality Morphology Mutation National Institute of Neurological Disorders and Stroke Natural History Nerve Degeneration Neurodegenerative Disorders Neurons Nucleotides Onset of illness Outcome Assessment Pathogenicity Pathology Pathway interactions Patients Pharmaceutical Preparations Population Proteins Protocols documentation RPS6KA5 gene Rare Diseases Ras Inhibitor Readiness 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 cohort design disability drug candidate imaging biomarker improved inhibitor/antagonist morphometry motor deficit mutant mutation carrier neurotoxicity patient population patient stratification polyglutamine pre-clinical predictive modeling prospective success targeted treatment treatment arm trial design

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 Modality Morphology Mutation National Institute of Neurological Disorders and Stroke Natural History Nerve Degeneration Neurodegenerative Disorders Neurons Nucleotides Onset of illness Outcome Assessment Pathogenicity Pathology Pathway interactions Patients Pharmaceutical Preparations Population Proteins Protocols documentation RPS6KA5 gene Rare Diseases Ras Inhibitor Readiness 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 cohort design disability drug candidate imaging biomarker improved inhibitor/antagonist morphometry motor deficit mutant mutation carrier neurotoxicity patient population patient stratification polyglutamine pre-clinical predictive modeling prospective success targeted treatment treatment arm trial design

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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.

棘脑性共济失调类型1（SCA1）和3（SCA3）是罕见的，遗传性的神经退行性疾病，无情地发展为完全残疾和死亡。 SCA1是最快的SCA，而SCA3是美国和欧洲最常见的SCA。在各个基因ATXN1和ATXN3中膨胀的（CAG）N重复序列编码多谷氨酰胺（PolyQ），导致SCA1和SCA3。针对复杂致病级联反应的途径的疾病改良疗法将提供最终的治疗方法。科学前提和临床前动物数据强烈支持SCA1的MSK1抑制剂，Citalopram用于SCA3和基于核苷酸的基因沉默，用于两种SCAS，作为在五年内在临床试验中检查的药物。但是，我们在目前对这种疾病改良疗法的临床试验准备就绪的准备就绪的挑战是，通过量表测量的候选药物的适度效应大小适中，用于共济失调的评估和评级（SARA；最强大且最稳定，最稳定的临床结果评估措施）需要大量的研究研究，以实现足够的统计能力。为了实现我们建立临床试验准备就绪的目标，我们建议在早期疾病阶段发起一项国际多站点的努力，重点介绍了前蛋白突变携带者和患者，他们很可能是对疾病改良的干预措施的反应者，然后在不可逆的脑损伤之前进行了疾病的干预措施。根据我们的NIH和国家共济失调基金会（NAF）资助的研究，美国共济失调财团与欧洲共济失调研究小组紧密合作开发了一个前所未有的机会，以共同解决这一挑战并建立SCA1和SCA3的临床试验准备就绪。为了实现我们的目标，我们提出了以下具体目的：目标1。通过结合队列，临床成果评估数据以及生物液体样本（血液，脑脊髓流体），建立世界上最大的premifest/SCA1和SCA3的同类群体和SCA3。关于SCA的小人群试验的统计设计和分析的最新发展。