Clinical trials to prevent Alzheimer's Disease in Down Syndrome

预防唐氏综合症中阿尔茨海默病的临床试验

• 批准号: 10689370
• 负责人: Michael S Rafii
• 金额: $ 229.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689370
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Award; Biological Markers; Brain; Cause of Death; Chromosome 21; Clinical; Clinical Trials; Clinical assessments; Cognitive; Collaborations; Conduct Clinical Trials; Congenital chromosomal disease; Data; Dementia; Disease; Disease Marker; Disease Progression; Double-Blind Method; Down Syndrome; Enrollment; Ethics; European; Exhibits; Funding; Future; Gene Proteins; General Population; Genes; Genetic; Hippocampus (Brain); Image; Immunotherapy; Impaired cognition; Individual; Infrastructure; Intellectual functioning disability; Link; Liquid substance; Magnetic Resonance Imaging; Measures; Methods; Modification; Monitor; Mutation; Neurofibrillary Tangles; Outcome Measure; Participant; Pathogenesis; Pathway interactions; Persons; Phase; Placebo Control; Placebos; Plasma; Play; Population; Positron-Emission Tomography; Procedures; Randomized; Role; Running; Safety; Senile Plaques; Site; Therapeutic; Therapeutic Clinical Trial; Therapeutic Trials; Treatment outcome; United States National Institutes of Health; base; brain volume; clinical biomarkers; clinical trial readiness; cohort; data management; dementia risk; double-blind placebo controlled trial; electronic data capture system; experience; improved; lifetime risk; mRNA Expression; non-demented; performance site; phase II trial; prevent; progression marker; protein expression; tau Proteins; trial readiness; working group

PROJECT SUMMARY/ABSTRACT The discovery that individuals with Trisomy 21, or Down syndrome (DS) have neuropathological features identical to those with sporadic Alzheimer's disease (AD) played a critical role in the identification of the amyloid precursor protein gene on chromosome 21 supporting the amyloid cascade hypothesis. People with DS have a lifetime risk for dementia in excess of 75% and comprise the world's largest population of genetically-determined AD. Just as studying DS helped identify the role of amyloid precursor protein mutations in AD pathogenesis, it is also likely to inform us of the potential benefit of manipulating the amyloid pathway on treatment outcomes in AD. It is critically important to the DS population and to the AD therapeutics field to conduct clinical trials, particularly those targeting amyloid accumulation, in individuals with DS. With this application, we propose to utilize the existing depth and breadth of expertise of the NIA-funded Alzheimer's Clinical Trial Consortium (ACTC) to conduct AD clinical trials in adults with DS across performance sites with expertise in DS including the Alzheimer's Biomarker Consortium for Down Syndrome (ABC-DS). As part of an NIH award received last year, we established the ACTC-DS network which includes working groups comprised of leaders from ACTC, ABC-DS and the European Horizon21 DS network to develop the collaborations, infrastructure and plans required to conduct AD clinical trials in DS. During the proposed R61 `Trial Readiness Phase' of the present project, in Aim 1, we will enroll 120 adults with DS (ages 35-55) across 15 sites into a trial ready cohort (TRC) to collect outcome measures and biomarkers harmonized with those being collected in the ongoing ABC- DS study (n = ~400). In Aim 2, we will determine the relationships between cognitive measures and AD biomarkers to identify endpoints for clinical trials that best reflect disease progression. During the R33 `Clinical Trial' phase, for Aim 3, we propose to implement a phase II randomized, double-blind, placebo-controlled trial to evaluate the safety and tolerability of a promising anti-amyloid therapeutic among individuals the TRC. In Aim 4, we will determine the impact of this agent on biomarker evidence of disease modification. Fundamentally, this project will serve to bring AD therapies to the DS population by leveraging the infrastructure of ACTC and incorporating the experience and expertise of the ABC-DS and Horizon21 networks. Beyond the proposed trial, this will establish the means and methods to conduct future therapeutic trials in this population. The potential impact of this approach on improving the lives of adults with DS as well as the general population cannot be overstated.

项目摘要/摘要 发现21或唐氏综合症（DS）患有神经病理学的人（DS）的发现 与零星阿尔茨海默氏病（AD）的特征相同 在21染色体上鉴定淀粉样蛋白蛋白基因的21支持淀粉样蛋白 级联假设。 DS患者的痴呆风险超过75％，并且 构成了世界上最大的遗传确定的广告人群。就像研究DS一样 帮助确定淀粉样蛋白前体蛋白突变在AD发病机理中的作用，也是 可能会告知我们处理治疗淀粉样蛋白途径的潜在好处 广告中的结果。它对DS人群和广告疗法领域至关重要 在患有DS的个体中，进行临床试验，尤其是针对淀粉样蛋白积累的临床试验。 通过此应用程序，我们建议利用现有的深度和广度 NIA资助的阿尔茨海默氏症临床试验联盟（ACTC）在成人中进行AD临床试验 具有跨性能网站的DS，具有DS的专业知识，包括阿尔茨海默氏症的生物标志物 唐氏综合症联盟（ABC-DS）。作为去年NIH奖的一部分，我们 建立了ACTC-DS网络，其中包括由领导者组成的工作组 ACTC，ABC-DS和欧洲Horizo​​n21 DS网络开发合作， 在DS中进行AD临床试验所需的基础设施和计划。 在本项目的拟议的R61“试验准备阶段”中，在AIM 1中，我们将注册 在15个地点，有120名DS成年人（年龄35-55岁）进入试用式准备队列（TRC），以收集 结果指标和生物标志物与正在进行的ABC中收集的结果统一 DS研究（n = 〜400）。在AIM 2中，我们将确定认知措施之间的关系 和AD生物标志物，以确定最能反映疾病进展的临床试验的终点。 在R33“临床试验”阶段，对于AIM 3，我们建议实施II期 随机，双盲，安慰剂对照试验，以评估A的安全性和耐受性 在trc中有希望的抗淀粉样蛋白治疗。在AIM 4中，我们将确定 该药物对疾病修饰的生物标志物的影响。 从根本上讲，该项目将通过利用来将广告疗法带入DS人群 ACTC的基础架构，并纳入ABC-DS的经验和专业知识和专业知识 Horizo​​n21网络。除了提议的审判之外，这还将建立手段和方法 在该人群中进行未来的治疗试验。这种方法对 改善DS和普通人群的成年人的生活不能被夸大。