Repurposing drugs for Alzheimer´s disease using a reverse translational approach

使用逆翻译方法重新利用治疗阿尔茨海默病的药物

• 批准号: 10295809
• 负责人: Sara Hagg
• 金额: $ 156.24万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295809
• 关键词: Adoption; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Astrocytosis; Autophagocytosis; Baltimore; Basic Science; Biological; Biological Aging; Caenorhabditis elegans; Cell model; Cells; Clinical; Cultured Cells; Data; Dementia; Disease; Disease Progression; Drug Prescriptions; Drug Screening; Drug Targeting; Drug usage; Epidemiology; Equation; Exhibits; Follow-Up Studies; Genes; Genetic; Genomics; Genotype; Human; Impaired cognition; In Vitro; Incidence; Individual; Knock-in; Knock-in Mouse; Knockout Mice; Lead; Link; Longevity; Longitudinal Studies; Longitudinal cohort; Measurement; Memory Loss; Mendelian randomization; Methods; Microglia; Modeling; Molecular; Molecular Epidemiology; Moods; Mus; Nematoda; Nerve Degeneration; Participant; Pathology; Patients; Personality; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Preventive; Primary Prevention; Process; Progeria; Randomized; Registries; Research Personnel; Risk; Sampling; Series; Societies; Speed; Sweden; Symptoms; Synapses; Syndrome; System; Testing; Toxic effect; Twin Studies; Ursidae Family; Validation; Work; abeta accumulation; age effect; age related; aging brain; anti aging; base; beta amyloid pathology; cost effective; disease phenotype; drug candidate; drug development; drug repurposing; drug testing; epidemiologic data; ethnic diversity; follow-up; genome wide association study; human data; human old age (65+); in silico; in vitro Assay; in vivo; innovation; instrument; mouse model; neuroinflammation; novel therapeutics; prevent; preventive intervention; promoter; proteostasis; reduce symptoms; research clinical testing; safety assessment; screening; socioeconomics; statistics; targeted therapy trials; tau Proteins; tau aggregation; translational approach

PROJECT SUMMARY Age is the major risk factor for Alzheimer´s disease (AD), and as the world’s population is becoming older it is increasingly prevalent. There are many commonalities between aging and AD, both on the molecular and systems level. There is also ample evidence, in particular from work in animal models, that a broad spectrum of aging-preventive interventions that confer longevity have the ability to alleviate diverse aspects of AD pathology, such as Aβ and tau aggregation. These pathologies lead to severe neurodegeneration and occurrence of clinical symptoms such as memory loss, mood swings and changes in personality. No disease-modifying treatments exist, only medications that relieve the symptoms temporarily. To find treatments that prevent disease progression, testing drugs that have already been approved for other indications – a strategy referred to as drug repurposing – may be useful. A major benefit of drug repurposing is that it speeds up drug development and reduces the risks for patients, since these drugs have already passed safety assessment in humans. Thus, we propose a data-driven approach to search among drugs used for other age-related conditions and identify some that can be repurposed for the prevention of AD. Towards this approach, we will investigate the effect of the 20 most commonly used drug classes among 65+ year-olds in Sweden (>200 substances also approved for use in the U.S.) on biological aging and AD in a series of epidemiological analyses. We will use deeply phenotyped longitudinal cohort data to see how drug treatment changes biological aging trajectories, as well as apply Mendelian Randomizations to mimic the modulation on drug targets using large-scale genotyping data and emulated target trials in the Swedish Prescribed Drug Register linked to a quality register on dementia. Following this, the individual substances within the 2-3 most promising drug classes will be screened in vitro in human cellular models of AD and in vivo in C. elegans models of aging and of human Aβ and tau aggregation and toxicity. Top candidates will be tested in established and most relevant AD mouse models and in models of accelerated aging. Taken together, our approach to discover new drugs for AD prevention by screening already approved substances bears great benefits. The fact that much of the testing happens in silico and that the screening focuses only on drugs that are already approved for use in patients makes our approach faster and more cost- effective than conventional de novo compound screens.

项目总结 年龄是阿尔茨海默病S病(AD)的主要危险因素，随着世界人口的老龄化，年龄也越来越大 变得越来越普遍。衰老和阿尔茨海默病之间有许多共同点，无论是在分子上还是在 系统级别。也有充分的证据，特别是来自动物模型的研究，表明广泛的 延年益寿的预防衰老干预措施有能力缓解AD病理的各个方面， 例如Aβ和tau聚集体。这些病理改变会导致严重的神经变性和临床 诸如记忆力丧失、情绪波动和个性变化等症状。没有改善疾病的治疗方法 存在，只有暂时缓解症状的药物。找到预防疾病的治疗方法 进展，测试已经被批准用于其他适应症的药物-这一策略被称为药物 重新调整用途--可能是有用的。药物再利用的一个主要好处是它加快了药物开发和 降低患者的风险，因为这些药物已经通过了人体安全性评估。 因此，我们提出了一种数据驱动的方法在用于其他年龄相关疾病的药物中进行搜索，并 找出一些可以重新用于预防AD的药物。 为此，我们将调查65+中20种最常用的药物类别的效果 瑞典的一岁儿童(美国也批准使用200种物质)生物衰老与阿尔茨海默病系列研究 流行病学分析。我们将使用深入的表型纵向队列数据来观察药物治疗如何 改变生物老化轨迹，以及应用孟德尔随机化来模拟对 瑞典处方药中使用大规模基因分型数据和模拟靶点试验的药物靶标 登记册链接到痴呆症的质量登记册。紧随其后的是2-3个个体内物质最多 将在人体AD细胞模型和线虫体内模型中筛选有前景的药物类别 对衰老和人类Aβ和tau聚集和毒性的影响。顶尖的候选人将在既定的和 最相关的AD小鼠模型和加速衰老模型。 综上所述，我们通过筛选发现预防AD的新药的方法已经获得批准 物质有很大的好处。事实上，许多测试都是在硅胶中进行的，而且筛查 只关注已批准用于患者的药物使我们的方法更快、成本更高- 比传统的新式复合筛网更有效。

项目成果

Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study.

• DOI: 10.1212/wnl.0000000000200771
• 发表时间: 2022-08-16
• 期刊: Neurology
• 影响因子: 9.9

Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging.

• DOI: 10.1007/s11357-023-00784-8
• 发表时间: 2023-06
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Tang, Bowen;Li, Xia;Wang, Yunzhang;Sjolander, Arvid;Johnell, Kristina;Thambisetty, Madhav;Ferrucci, Luigi;Reynolds, Chandra A.;Finkel, Deborah;Jylhava, Juulia;Pedersen, Nancy L.;Hagg, Sara
• 通讯作者: Hagg, Sara