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: 10700138
• 负责人: Michael S Rafii
• 金额: $ 228.73万
• 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/10700138
• 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; 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; brain volume; clinical trial readiness; cohort; data management; dementia risk; double-blind placebo controlled trial; electronic data capture system; experience; improved; lifetime risk; mRNA Expression; neuropathology; 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.

项目概要/摘要 发现患有 21 三体症或唐氏综合症 (DS) 的个体患有神经病理学 与散发性阿尔茨海默病 (AD) 患者相同的特征在 21 号染色体上支持淀粉样蛋白的淀粉样蛋白前体蛋白基因的鉴定 级联假设。 DS 患者终生患痴呆症的风险超过 75% 包括世界上最大的由基因决定的 AD 人群。就像学习DS一样 有助于确定淀粉样蛋白前体蛋白突变在 AD 发病机制中的作用， 可能会告诉我们操纵淀粉样蛋白途径对治疗的潜在益处 AD 的结果。对于 DS 人群和 AD 治疗领域来说至关重要 在 DS 患者中进行临床试验，特别是针对淀粉样蛋白积累的临床试验。 通过此应用程序，我们建议利用现有专业知识的深度和广度 NIA 资助的阿尔茨海默病临床试验联盟 (ACTC) 将在成人中开展 AD 临床试验 在 DS 领域拥有 DS 专业知识，包括阿尔茨海默病生物标志物 唐氏综合症联盟 (ABC-DS)。作为去年获得的 NIH 奖项的一部分，我们 建立了 ACTC-DS 网络，其中包括由来自以下国家领导人组成的工作组： ACTC、ABC-DS 和欧洲 Horizo​​n21 DS 网络开展合作， 在 DS 中进行 AD 临床试验所需的基础设施和计划。 在本项目拟议的 R61“试验准备阶段”期间，在目标 1 中，我们将招募 将 15 个地点的 120 名 DS 成人（年龄 35-55 岁）纳入试验准备队列 (TRC) 中以收集 结果测量和生物标志物与正在进行的 ABC- 中收集的结果一致 DS 研究（n = ~400）。在目标 2 中，我们将确定认知测量之间的关系 AD 生物标志物，以确定最能反映疾病进展的临床试验终点。 在 R33“临床试验”阶段，针对目标 3，我们建议实施第二阶段 随机、双盲、安慰剂对照试验，评估药物的安全性和耐受性 TRC 是一种有希望在个体中进行抗淀粉样蛋白治疗的方法。在目标 4 中，我们将确定 该药物对疾病改变的生物标志物证据的影响。 从根本上说，该项目将通过利用 AD 疗法为 DS 人群带来 ACTC 的基础设施并结合了 ABC-DS 的经验和专业知识以及 Horizo​​n21 网络。除了拟议的试验之外，这还将建立手段和方法 在这一人群中进行未来的治疗试验。这种方法的潜在影响 改善 DS 成人以及一般人群的生活，这一点怎么强调也不为过。