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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（TNF。在施用高剂量的 TNF 后获得的初步数据）。 TNF 拮抗剂沙利度胺对 APP23 转基因小鼠的大脑 TNF 水平、斑块数量和淀粉样蛋白载量有所降低。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。高剂量的沙利度胺会出现明显的不良事件，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，我们确定了 FDA 批准的抗癌药物来那度胺。作为一种非常有前途的候选药物，我们努力发现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，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担的最有效方案；评估来那度胺独立治疗 tau 病理的效力；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。为了实现这些目标，我们将结合使用 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 AD 潜力的关键信息，因为来那度胺已获得 FDA 批准用于人类恶性肿瘤治疗，并重新利用它。药物将有助于为转化为旨在使用患者可接受的方案的临床试验提供临床前基础，我们坚信 PI、导师、顾问和环境的结合非常适合。该项目的负责人是一位年轻的神经科学家，拥有非常好的发表记录，并且受到该项目的极大激励，将继续在药物临床前开发相关的神经元疾病领域发展非常有前途的职业生涯。他的导师是阿尔茨海默病小鼠模型（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）方面的专家。 Lahiri 和 Chen，他们将向 PI 教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方面的国际培训以及科学会议来完成。总的来说，所有因素都是为了该项目的成功，这对于 NIA 的使命以及 PI 作为独立科学家的发展非常重要，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。