Repositioning of Clinically Approved Drugs toward the Prevention and Risk Evaluation of Early Cataract Progression

重新定位临床批准药物以预防早期白内障进展并进行风险评估

• 批准号: 10164795
• 负责人: VINCENT M MONNIER
• 金额: $ 65.86万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164795
• 关键词: Affect; Age; American; Animal Model; Arthritis; Asthma; Biological; Biological Models; Cataract; Clinical; Communities; Computational algorithm; Crystallins; Data; Development; Disease; Elderly; Evaluation; FDA approved; Genetic; Genomics; Goals; Human; In Vitro; Individual; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Libraries; Mediating; Medical; Metabolic; Mus; Nuclear; Output; Oxidative Stress; Parkinson Disease; Patients; Pharmaceutical Preparations; Phase; Phenotype; Prevention; Production; Property; Proteins; Reactive Oxygen Species; Risk; Risk Assessment; Risk Factors; Stress; Testing; Therapeutic; age related; drug candidate; drug testing; high throughput screening; in silico; in vitro Model; innovation; irradiation; knowledge base; lens; mouse model; mutant; novel; oxidation; phenomics; prevent; programs; protein aggregation; screening; small molecule; ultraviolet irradiation; web app

ABSTRACT Age-related cataract is a universal, slowly progressive, insidious blinding disease that affects 20 million Americans above the age of 65 years. Yet, it is unclear why cataract progresses faster in some vs other individuals who are seemingly protected and cataract free at an advanced age. The existence of differential progression rates of lens opacification among individuals implies the existence of protective as well as deleterious factors that are as yet poorly understood. We hypothesize that there are, among today’s clinically approved drugs, candidate drugs that have anti-cataract properties, and therefore could be developed as such, while others may have cataract promoting properties unbeknownst to patients and the medical community. To test this hypothesis, we propose to combine two innovative and complementary approaches, i.e. a computational approach to simultaneously identify, among clinically approved drugs, potentially anti- and pro-cataractogenic compounds, with an experimental approach geared at simultaneously identifying drugs that prevent or worsen in vitro generated oxidative stress and lens crystallin destabilization. Candidate drugs emerging from this dual approach will be tested in mouse models of age-related cataract. Using a multi-PI strategy consisting of a team of experts in computational drug repositioning, and a team of experts in high throughput screening of small molecules, animal models of age-related cataract, in oxidative stress and protein aggregation, we propose four focused and achievable goals over a four year period: Aim 1: Development of novel data-driven computational algorithms to identify repositioned anti-cataract drugs and cataract risk promoting drugs from all FDA-approved drugs. Aim 2: Testing of 2650 FDA approved clinical drugs from the Microsource Spectrum library for their efficacy or deleterious properties on protein aggregation/denaturation in three in vitro stress model systems, i.e. oxidative metabolic damage to gamma and beta crystallins, UV irradiation and whole lens in vitro incubation stress. Aim 3: Test the top candidate drugs emerging from the above in silico and experimental search for their potential therapeutic or deleterious activity on cataract progression in two mouse models of cataract, i.e. the LEGSKO/Gclm (Double knockout) DKO mouse and the alphaB crystallin R120G mutant knock-in mouse. Aim 4: Develop a comprehensive knowledge base and make all the data publicly available via interactive web application. The successful execution of this innovative program is expected to have a transformative impact in the cataract field by potentially repositioning known drugs toward both early cataract prevention as well cataract progression risk assessment.

摘要 白内障是一种普遍的、缓慢进展的、隐匿性致盲疾病， 65岁以上的美国人。然而，目前还不清楚为什么白内障在老年人中进展得更快。 有些人与其他人谁似乎是保护和白内障免费在一个先进的年龄。 个体间透镜混浊进展速度的差异意味着 保护性因素和有害因素的存在至今仍知之甚少。我们 假设在当今临床批准的药物中， 具有抗白内障的特性，因此可以这样开发，而其他的可以 具有患者和医学界不知道的白内障促进特性。 为了验证这一假设，我们建议将联合收割机两种创新和互补的方法结合起来， 即一种计算方法，在临床批准的药物中， 潜在的抗白内障和促白内障化合物， 同时鉴定预防或恶化体外产生的氧化应激的药物， 透镜晶状体蛋白不稳定。从这种双重方法中产生的候选药物将在 年龄相关性白内障的小鼠模型。 使用由计算药物专家团队组成的多PI策略 重新定位，以及高通量筛选小分子，动物 模型的年龄相关性白内障，在氧化应激和蛋白质聚集，我们提出了四个 目标1：开发新的数据驱动的 识别重新定位的抗白内障药物和白内障风险促进的计算算法 所有FDA批准的药物。目标2：检测2650种FDA批准的临床药物， 微源光谱库对蛋白质的功效或有害特性 三种体外应激模型系统中的聚集/变性，即氧化代谢损伤 γ和β晶体蛋白、紫外线照射和整个透镜体外孵育应力。目标三： 通过计算机模拟测试上述药物中出现的最佳候选药物，并进行实验性搜索， 在两种小鼠模型中对白内障进展的潜在治疗或有害活性 白内障，即LEGSKO/Gclm（双敲除）DKO小鼠和α B晶体蛋白R120 G 突变基因敲入小鼠。目标4：建立一个全面的知识库，使所有数据 通过交互式网络应用程序公开提供。这一创新的成功实施 该计划预计将在白内障领域产生变革性的影响， 将已知药物重新定位于早期白内障预防和白内障进展风险 考核