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）：据估计，阿尔茨海默病 (AD) 影响着 540 万美国人，每年给社会造成的损失超过 1600 亿美元，预计到本世纪中叶，这一数字将增加两倍，这强调了对有效治疗方法的迫切需要。 AD 脑中水平升高的主要促炎分子是 TNF α (TNFα)，这是在给予高剂量的 TNF α 后获得的初步数据。 APP23 转基因小鼠的 TNFα 拮抗剂沙利度胺显示出脑部 TNFα 水平、斑块数量和淀粉样蛋白负荷降低。这些数据是我们临床研究中心开展一项由 NIA 赞助的沙利度胺人类 AD 试点研究的基础。的沙利度胺经历了明显的不良事件，这促使我们寻找更安全、毒性更小的替代品来长期服用 AD 治疗，我们确定 FDA 批准的抗癌药物来那度胺是一种非常有效的药物。我们认为来那度胺可以通过调节慢性炎症和 BACE1 水平来显着减少 AD 样神经病理学，我们的项目旨在 1- 确定减少慢性脑炎症和淀粉样蛋白负担的最有效方案 2- 评估其效力。 3- 分析来那度胺介导的 AD 样病理减少的主要分子机制，以实现这些目标。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 潜力的重要信息，因为来那度胺已获得 FDA 批准用于人类恶性肿瘤治疗，因此重新利用该药物将有助于提供更多信息。我们坚信，PI、导师、顾问和环境的结合非常适合获得这一职业发展奖。项目负责人是一位年轻的神经科学家，拥有非常好的发表记录，并且对该项目非常有动力，将继续在药物临床前开发相关的神经系统疾病领域发展非常有前途的职业生涯。此外，该项目将为他提供一条道路。他的导师是阿尔茨海默氏症小鼠模型（Oddo 博士）以及神经元疾病临床诊断和临床试验（Sabbagh 博士和 Reiman 博士）以及 Coleman 博士、Lahiri 博士和Chen 表示，他们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向 PI 教授新技术和工作方法。这些因素的汇集是为了该项目的成功，这对于 NIA 的使命非常重要，并且为了将 PI 发展为一名独立科学家，他将在其整个职业生涯中直接应用与该奖项相关的所有培训。