Pre-clinical testing of lenalidomide as pleiotropic therapeutics of Alzheimer's disease

描述(申请人提供)：阿尔茨海默病(AD)影响着大约540万美国人，每年给社会造成超过1600亿美元的损失，预计到本世纪中叶这个数字将增加两倍。这强调迫切需要有效的治疗方法来治疗、延缓进展或预防阿尔茨海默病。阿尔茨海默病患者脑组织中一种主要的促炎分子是肿瘤坏死因子α(α)。在给APP23转基因小鼠注射高剂量的肿瘤坏死因子α拮抗剂沙利度胺后获得的初步数据显示，脑肿瘤坏死因子α水平、斑块数量和淀粉样β蛋白负荷降低。这些数据是在我们的临床研究中心用沙利度胺进行NIA赞助的人类AD先导研究的基础。然而，服用大剂量沙利度胺的患者出现了明显的不良反应。这促使我们寻找更安全、毒性更低的替代药物用于AD的慢性给药，我们确定FDA批准的抗癌药物来那度胺是一个非常有前途的候选药物。我们假设来那度胺可以通过调节慢性炎症和BACE1水平来显著降低AD样神经病理。总体而言，我们的项目旨在1-确定减少慢性脑部炎症和淀粉样蛋白负担的最有效方案；2-评估来那度胺在存在A？沉积物的情况下独立治疗tau病变的效力；以及3-剖析来那度胺介导的AD样病理减少的主要分子机制。为了达到这些目标，我们将使用AD转基因小鼠模型和广泛的细胞培养工作相结合。如果成功，我们的项目将提供有关来那度胺治疗AD的潜力的关键信息。由于来那度胺是FDA批准用于治疗人类恶性肿瘤的药物，重新调整该药物的用途将有助于为转化为临床试验提供临床前基础，旨在使用患者可以接受的方案。我们坚信，PI、导师、顾问和环境的组合非常适合这个职业发展奖项目。PI是一位年轻的神经科学家，有着非常好的发表记录，并对这个项目非常感兴趣，该项目将继续在药物临床前开发相关神经元障碍方面发展非常有前途的职业生涯。此外，该项目将为他提供一条独立的道路。他的导师是阿尔茨海默病小鼠模型方面的专家(奥多博士)，以及神经元疾病的临床诊断和临床试验方面的专家(萨巴格博士和雷曼博士)。他们将与科尔曼、拉希里和陈博士一起，向PI传授新的技术和工作方法。内部培训将通过参加药物发现和开发的国际培训以及科学会议来完成。Banner Research全力支持这一应用程序。总而言之，所有的因素都是为了该项目的成功，这对NIA的使命非常重要，以及对于PI作为一名独立科学家的发展，他将在他的职业生涯中直接应用与该奖项相关的所有培训。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) affects an estimated 5.4 million Americans costing the society more than $160 billion annually, and this figure is expected to triple by the middle of the century. This emphasizes the urgent need for efficacious therapies for the treatment, delay of progression, or prevention of AD. A major proinflammatory molecule which levels are increased in the AD brain is TNF alpha (TNFα). Preliminary data obtained after administration of high doses of the TNFα antagonist thalidomide to APP23 transgenic mice showed decreased brain TNFα levels, plaque number, and amyloid beta loads. These data were the basis to conduct an NIA-sponsored human AD pilot study with thalidomide at our clinical research center. However, patients on high doses of thalidomide experience pronounced adverse events. This led us to search for safer and less toxic alternatives for chronic administration for AD treatment, and we identified the FDA-approved anti-cancer drug lenalidomide as a very promising candidate. We hypothesize that lenalidomide can significantly decrease AD-like neuropathology by modulating chronic inflammation and BACE1 levels. Overall, our project is designed to 1- identify the most efficient regimen to reduce chronic brain inflammation and amyloid burden; 2- assess the potency of lenalidomide to treat tau pathology independently and in presence of Aß deposits; and 3- dissect the main molecular mechanisms underlying lenalidomide-mediated reduction in AD-like pathology. To reach these goals, we will use a combination of AD transgenic mouse models and extensive cell culture work. If successful, our project will provide critical information regarding the potential of lenalidomide t treat AD. Since lenalidomide is FDA-approved for human malignancies treatment, repurposing this drug would help provide the pre-clinical underpinnings for translation into clinical trials aiming at using patient-acceptable regimens. We strongly believe that the combination of the PI, mentors, consultants, and the environment are perfectly fitted for this career development award project. The PI is a young neuroscientist with a very good publication record and is extremely motivated by this project that will continue to develop a very promising career in drug pre-clinica development related neuronal disorders. In addition, the project will provide him a path towards independence. His mentors are experts in Alzheimer's mouse models (Dr. Oddo), and in clinical diagnosis of neuronal disorders and clinical trials (Dr. Sabbagh and Dr. Reiman). Along with Drs. Coleman, Lahiri, and Chen, they will teach new techniques and working methods to the PI. The in-house training will be completed by attending international trainings in drug discovery and development, as well as scientific meetings. Banner Research is fully supportive of this application. Collectively, all the factors are assembled for the success of the project which is highly significant to the NIA's mission, and for the development of the PI as an independent scientist who will apply first hand all the training associated with this award throughout his career.