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.

项目概要/摘要（30行） 我们假设，阿尔茨海默病（AD）的药物试验在人类身上失败了，因为AD需要两个 蛋白毒性（至少涉及A β和tau）和小胶质细胞活性（GWAS研究清楚地证明）， 可能伴有炎性细胞因子分泌过多成功的治疗可能需要药物， 改善蛋白质毒性和小胶质细胞分泌过多的细胞因子，而不是靶向水平的单一 蛋白质或肽。我们建议基于表型的筛选方法更有可能导致总体 AD和衰老相关疾病的成功疗法。虽然有5种药物被批准用于治疗AD， 它们只治疗症状，而不是AD的病因，并且人们普遍认为这些药物的临床意义 最多是谦虚。越来越多的制药公司放弃了寻找 治疗AD。因此，我们开发了一个创新的高通量药物筛选平台， 进行了两次无与伦比的高通量药物再利用筛选，以确定其预防Ablation的能力 在秀丽隐杆线虫中的毒性作为体内蛋白毒性的更一般过程的模型。在 随后的研究表明，C.然后在小胶质细胞中重新筛选了秀丽线虫， 减少细胞因子释放（主要是TNF-α和IL-6）。这些屏幕使我们优先考虑大约50个FDA- 在这些表型分析中具有保护作用的批准药物。目前拟议研究的目的是 评估这些FDA批准的药物（或类似类别的药物）治疗是否可以降低AD的风险。 我们建议使用从医疗保险中心收集的人口水平的行政索赔数据， 医疗补助服务（CMS），以评估FDA批准的药物是否在C。AD的elegans模型还 降低人类患AD和相关痴呆症的风险。拟议的项目是一个观察回顾 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。将从CMS获取数据， 覆盖连续5年，所有模型将根据协变量进行拟合和调整。研究的最终目标 是确定药物被重新用于治疗AD和相关痴呆症，并积累强大的流行病学 除了来自模式生物C的现有证据之外，elegans和细胞培养研究。 这种老龄生物学家、老年病学家和流行病学家之间的跨学科研究将产生数据， 对申请人随后的研究和独立研究生涯至关重要的经验。的 拟议研究的结果将进一步与其他人口健康记录的数据进行比较， 纳入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，它有一个领先的老年病部门和世界药物流行病学专家。