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: 9913182
• 负责人: Boris Decourt
• 金额: $ 10.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 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/9913182
• 关键词: 3xTg-AD mouse; Abeta synthesis; Adverse event; Affect; Alzheimer disease prevention; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; 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; Preclinical Testing; 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; amyloidogenesis; analog; anti-cancer; base; beta secretase; beta-site APP cleaving enzyme 1; career; clinical Diagnosis; clinical investigation; cognitive performance; cognitive testing; cost; curative treatments; cytokine; density; design; drug development; drug discovery; drug testing; experience; experimental study; human old age (65+); hyperphosphorylated tau; immunoregulation; improved; in vivo; inflammatory marker; inflammatory milieu; lenalidomide; macrophage; meetings; middle age; mouse model; neuroblastoma cell; neuroinflammation; neuropathology; oncology; pre-clinical; preservation; prevent; public health relevance; receptor; 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 (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.

描述（由申请人提供）：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，这一数字将增加两倍。这强调了迫切需要有效的治疗方法，延迟进展，或预防阿尔茨海默病。在ap23转基因小鼠中给予高剂量的TNFα拮抗剂沙利度胺后获得的初步数据显示，脑中TNFα水平、斑块数量和淀粉样蛋白负荷下降。这些数据是在我们的临床研究中心进行nia赞助的使用沙利度胺的人类AD初步研究的基础。然而，服用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、毒性更低的替代药物用于慢性给药治疗阿尔茨海默病，我们确定了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水平显著降低ad样神经病理。总的来说，我们的项目旨在1-确定最有效的方案来减少慢性脑炎症和淀粉样蛋白负担；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来那度胺治疗阿尔茨海默病潜力的关键信息。由于来那度胺是fda批准用于人类恶性肿瘤治疗的药物，重新利用这种药物将有助于为临床试验提供临床前基础，旨在使用患者可接受的方案。我们坚信，PI、导师、顾问和环境的结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，有着非常好的发表记录，并且非常受这个项目的激励，这个项目将继续在与神经疾病相关的药物临床前开发方面发展一个非常有前途的职业。此外，这个项目将为他提供一条通往独立的道路。他的导师是阿尔茨海默氏症小鼠模型（Oddo博士）和神经疾病临床诊断和临床试验（Sabbagh博士和Reiman博士）方面的专家。和dr。科尔曼、拉希里和陈，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。横幅研究是完全支持这个应用程序。总的来说，所有的因素都是为了项目的成功，这对NIA的使命非常重要，对于PI作为一个独立科学家的发展，他将在整个职业生涯中应用与该奖项相关的所有培训。