Translating in vivo drug screens to Alzheimer's patients with a pharmaco-epidemiological approach

利用药物流行病学方法将体内药物筛选应用于阿尔茨海默病患者

• 批准号: 10727993
• 负责人: Rachel Litke
• 金额: $ 9.46万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727993
• 关键词: Address; Aging; Agreement; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-Protein; Arthritis; Automobile Driving; Award; Biological Assay; Biology of Aging; Caenorhabditis elegans; Case/Control Studies; Categories; Cell Culture Techniques; Chronic; Clinical Trials; Crohn' s disease; Data; Data Set; Databases; Development; Disease; Drug Screening; Drug Targeting; Drug usage; Elderly; Epidemiologist; Epidemiology; Event; FDA approved; Feasibility Studies; Functional disorder; Funding; Future; Geriatrics; Goals; Human; Impaired cognition; Inflammation; Inflammatory; Interleukin-6; Investments; Knowledge; Libraries; Longevity; Medicare; Mentors; Methods; Microglia; Modeling; Mus; Muscle; Myelogenous; Neurodegenerative Disorders; Outcome Measure; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacologic Substance; Phenothiazines; Phenotype; Pilot Projects; Pioglitazone; Population; Probability; Process; Protective Agents; Proteins; Protocols documentation; Psoriasis; Recording of previous events; Research; Research Personnel; Risk; Risk Reduction; Safety; Sampling; Source; Specialist; TNF gene; Technology; Testing; Therapeutic; Time; Toxic effect; Transgenic Organisms; Translating; Translations; United States Centers for Medicare and Medicaid Services; abeta toxicity; adalimumab; age related; beneficiary; career; clinically significant; cytokine; demographics; design; disease diagnosis; drug candidate; drug repurposing; experience; genome wide association study; hazard; health record; high-throughput drug screening; improved; in vivo; innovation; interest; medical schools; model organism; monocyte; novel; pharmacologic; population health; protective effect; proteotoxicity; safety assessment; screening; symptom treatment; tau Proteins

Project Summary/Abstract (30 lines) We hypothesize that drug trials, in Alzheimer's disease (AD) have failed in humans because AD entails both proteotoxicity (involving at least Aß and tau) AND microglial activity (clearly demonstrated by GWAS studies), probably with hypersecretion of inflammatory cytokines. Successful treatments will probably require drugs that ameliorate proteotoxicity AND microglial hypersecretion of cytokines, rather than targeting levels of a single protein or peptide. We propose that a phenotype-based screening approach is more likely to lead to overall successful therapies for AD and aging related diseases in general. Although 5 drugs are approved to treat AD, they only treat symptoms, not causes of AD, and it is widely agreed that the clinical significance of these drugs is modest at best. An increasing number of pharmaceutical companies have abandoned the search for treatments for AD. We therefore developed an innovative high-throughput drug screening platform and conducted two unparalleled high-throughput drug-repurposing screens for their ability to protect against Aß toxicity in Caenorhabditis elegans as a model for the more general process of proteotoxicity in vivo. In subsequent studies, the most protective drugs in C. elegans were then rescreened in microglia for their ability to reduce cytokine release (primarily TNF-alpha and IL-6). These screens led us to prioritize approximately 50 FDA- approved drugs that were protective in these phenotypic assays. The objective of the presently proposed studies is to evaluate if treatment with these FDA-approved drugs (or drugs in similar categories) reduce the risk of AD. We propose to use population-level administrative claims data collected from the Centers for Medicare and Medicaid Services (CMS) to assess if FDA-approved drugs that are protective in a C. elegans model of AD also lower the risk for AD and related dementia in humans. The proposed project is an observational retrospective pharmaco-epidemiological case-control study. The team will use a cox proportional hazard regression to obtain hazard ratios of AD associated with each prioritized FDA-approved drug. Data will be acquired from CMS to cover 5 consecutive years and all models will be fitted and adjusted to the covariates. The end goal of the study is to identify drugs to be repurposed to treat AD and related dementia and to accumulate strong epidemiological evidence in addition to the existing evidence from the model organism C. elegans and cell culture studies. This transdisciplinary research between aging biologists, geriatricians, and epidemiologists will yield data and experience essential to launch the applicant’s subsequent research and independent research career. The results of the proposed study will be further compared with data from other population health records and incorporated into the design of a future clinical trial. The research will take place at the Icahn School of Medicine at Mount Sinai, which has a leading Geriatrics Department and world experts in pharmaco- epidemiology.

项目摘要/摘要(30行) 我们假设，治疗阿尔茨海默病(AD)的药物试验在人类身上失败了，因为AD既需要 蛋白毒性(至少涉及Aü和tau)和小胶质细胞活性(Gwas研究清楚地证明)， 可能与炎性细胞因子的过度分泌有关。成功的治疗可能需要以下药物 改善蛋白毒性和小胶质细胞高分泌细胞因子，而不是靶向水平的单一 蛋白质或多肽。我们认为，基于表型的筛查方法更有可能导致总体 治疗阿尔茨海默病和衰老相关疾病的成功案例。尽管有5种药物被批准用于治疗AD， 它们只治疗阿尔茨海默病的症状，而不是病因，人们普遍认为，这些药物的临床意义 充其量也就是谦虚。越来越多的制药公司已经放弃了对 治疗阿尔茨海默病。因此，我们开发了创新的高通量药物筛选平台，并 进行了两个无与伦比的高通量药物再利用筛查，以了解它们抵御A？的能力 秀丽隐杆线虫的毒性作为体内更一般的蛋白毒性过程的模型。在……里面 随后的研究中，线虫中最具保护性的药物在小胶质细胞中进行了重新筛选，以确定它们是否具有 减少细胞因子(主要是肿瘤坏死因子-α和白介素6)的释放。这些筛选使我们确定了大约50个FDA的优先顺序- 批准的药物在这些表型分析中具有保护性。目前拟议研究的目标 是评估这些FDA批准的药物(或类似类别的药物)治疗是否降低AD的风险。 我们建议使用从医疗保险和医疗保险中心收集的人口级别的行政索赔数据 医疗补助服务(CMS)评估FDA批准的对线虫模型AD具有保护作用的药物是否也 降低人类患阿尔茨海默病和相关痴呆的风险。建议的项目是一次观察性回顾。 药物流行病学病例对照研究。该团队将使用考克斯比例风险回归来获得 与FDA批准的每种优先药物相关的AD风险比。数据将从CMS获取到 覆盖连续5年，所有模型都将根据协变量进行拟合和调整。这项研究的最终目标 是确定用于治疗阿尔茨海默病和相关痴呆的药物，并积累强大的流行病学 证据除了现有的来自模式生物线虫和细胞培养研究的证据外。 老年生物学家、老年病学家和流行病学家之间的这项跨学科研究将产生数据和 开展后续研究和独立研究事业所必需的经验。这个 建议的研究结果将进一步与其他人口健康记录和 纳入到未来临床试验的设计中。这项研究将在伊坎医学院进行 在西奈山，那里有领先的老年病学系和世界药物流行病学专家。