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

来那度胺作为阿尔茨海默病多效疗法的临床前测试

• 批准号: 9233889
• 负责人: Boris Decourt
• 金额: $ 10.68万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233889
• 关键词: Abeta synthesis; Adverse event; Affect; Alzheimer disease prevention; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Autopsy; Award; Behavioral; Biological; Blocking Antibodies; Brain; Brain Diseases; Brain Pathology; Brain region; Cell Culture Techniques; Cell Line; Chronic; Clinical Research; Clinical Trials; Cognition; Cognitive; Culture Media; Data; Deposition; Development; Disease; Disease model; Dose; Encephalitis; Environment; FDA approved; Frequencies; Future; Gliosis; Goals; Human; Impaired cognition; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; International; K-Series Research Career Programs; Lead; Malignant Neoplasms; Measurement; Mediating; Mentors; Methods; Mission; Molecular; Mus; Neuroblastoma; Neurofibrillary Tangles; Neurons; Pathology; Patients; Pharmaceutical Preparations; Phosphotransferases; Pilot Projects; Preventive; Property; Proteins; Publications; Recombinant Proteins; Regimen; Regulation; Research; Scientist; Short-Term Memory; Signal Transduction; Societies; Synapses; TNF gene; Techniques; Testing; Thalidomide; Therapeutic; Training; Transgenic Mice; Translations; Work; aged; amyloidogenesis; analog; base; beta secretase; beta-site APP cleaving enzyme 1; career; clinical Diagnosis; clinical investigation; cognitive performance; cognitive testing; cost; curative treatments; cytokine; density; design; disorder prevention; drug development; drug discovery; drug testing; experience; experimental study; hyperphosphorylated tau; immunoregulation; improved; in vivo; inflammatory marker; inflammatory milieu; lenalidomide; macrophage; meetings; middle age; mouse model; neuroblastoma cell; neuroinflammation; neuropathology; oncology; pre-clinical; prevent; public health relevance; receptor; research clinical testing; spatial memory; success; tau Proteins

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 (TNF� Preliminary data obtained after administration of high doses of the TNF�ntagonist thalidomide to APP23 transgenic mice showed decreased brain TNF�evels, 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 A�eposits; 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.

描述（由适用提供）：阿尔茨海默氏病（AD）影响了估计每年耗资超过1600亿美元的社会的540万美国人，预计到本世纪中叶将三倍。这强调了对有效疗法的迫切需要，以治疗，延迟进展或预防AD。 AD脑中水平升高的主要促炎分子是TNFα（TNF）初步数据，在将高剂量的TNF tagonist thalidomide施用到APP23转基因小鼠中后，获得的初步数据显示了晚期脑TNF脑TNF脑TNF tnf ephemerals，Plaque数量，斑块和淀粉样蛋白beta载荷。这些数据是在我们的临床研究中心使用沙利度胺进行NIA赞助的人类广告试验研究的基础。但是，高剂量沙利度胺的患者经历了明显的不良事件。这导致我们为长期给药以进行AD治疗寻找更安全，更毒性的替代方法，我们确定了FDA批准的抗癌药物为莱纳莱顿胺是非常有希望的候选者。我们假设来那度胺可以通过调节慢性感染和BACE1水平来显着降低AD样神经病理学。总体而言，我们的项目旨在识别最有效的方案，以减少慢性脑感染和淀粉样蛋白伯恩。 2评估列纳莱度胺独立治疗tau病理的效力； 3驱散lenalidomide介导的AD样病理学降低的主要分子机制。为了实现这些目标，我们将结合AD转基因小鼠模型和广泛的细胞培养工作。如果成功，我们的项目将提供有关列纳替米德治疗广告潜力的关键信息。由于Lenalidomide已被FDA批准用于人类恶性治疗，因此重新利用该药物将有助于提供临床前的基础，以转化为临床试验，旨在使用可接受的患者治疗方案。我们坚信，PI，导师，顾问和环境的结合非常适合该职业发展奖项目。 PI是一位年轻的神经科学家，具有很好的出版记录，并受到该项目的极大动机，该项目将继续发展在诸如linica前开发方面的非常有前途的职业。相关的神经元疾病。此外，该项目将为他提供通往独立的道路。他的导师是阿尔茨海默氏症小鼠模型（ODDO博士）的专家，以及神经元疾病和临床试验的临床诊断（Sabbagh博士和Reiman博士）。和博士一起。 Coleman，Lahiri和Chen将向PI传授新技术和工作方法。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。横幅研究完全支持此应用程序。总的来说，所有因素都是为了获得该项目的成功而组装的，这对NIA的使命至关重要，以及将PI作为独立科学家的发展，他们将在整个职业生涯中首次将与该奖项相关的所有培训应用于他的职业生涯。