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

描述（由申请人提供）：阿尔茨海默病（AD）影响估计540万美国人，每年花费社会超过1600亿美元，预计到世纪中期，这一数字将增加两倍。这强调迫切需要有效的治疗、延缓进展或预防AD的疗法。AD脑中水平升高的主要促炎分子是TNF α（TNFα）。对APP 23转基因小鼠给予高剂量TNFα拮抗剂沙利度胺后获得的初步数据显示脑TNFα水平、斑块数量和淀粉样蛋白β负荷降低。这些数据是在我们的临床研究中心进行NIH申办的沙利度胺人类AD初步研究的基础。然而，高剂量沙利度胺的患者会出现明显的不良事件。这促使我们寻找更安全，毒性更低的替代品用于AD治疗的长期给药，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BACE 1水平来显著降低AD样神经病理学。总体而言，我们的项目旨在1-确定减少慢性脑炎症和淀粉样蛋白负荷的最有效方案; 2-评估来那度胺独立治疗tau病理和存在Aβ沉积的效力; 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的组合。如果成功，我们的项目将提供关于来那度胺治疗AD潜力的关键信息。由于来那度胺是FDA批准用于人类恶性肿瘤治疗的药物，因此重新利用这种药物将有助于为转化为旨在使用患者可接受方案的临床试验提供临床前基础。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励项目。PI是一位年轻的神经科学家，具有非常好的出版记录，并受到该项目的极大激励，该项目将继续在药物临床前开发相关神经元疾病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走向独立的道路。他的导师是阿尔茨海默氏症小鼠模型（Oddo博士）和神经元疾病临床诊断和临床试验（Sabbagh博士和Reiman博士）的专家。沿着科尔曼、拉希里和陈博士，他们将向PI教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方面的国际培训以及科学会议来完成。Banner Research完全支持这项申请。总的来说，所有的因素都是为了项目的成功而聚集的，这对NIA的使命非常重要，也是为了PI作为一名独立科学家的发展，他将在整个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 Aβ 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.