CAR-based approaches for the treatment of Alzheimer's Disease

基于 CAR 的阿尔茨海默病治疗方法

• 批准号: 10481511
• 负责人: Gary E. Grajales-Reyes
• 金额: $ 39.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481511
• 关键词: Accounting; Aducanumab; Affect; Age; Alzheimer' s Disease; American; Amyloid beta-Protein; Antibodies; Astrocytes; Back; Binding; Bone Marrow; Bone Marrow Cells; Brain; CD8B1 gene; Cause of Death; Cell Line; Cell Therapy; Cells; Central Nervous System Diseases; Cessation of life; Chimeric Proteins; Clinical; Clinical Trials; Confocal Microscopy; Data; Dementia; Deposition; Disease; Disease Progression; Economic Burden; Economics; FDA approved; Flow Cytometry; Frequencies; Funding; Genetic; Genomic medicine; Gliosis; Goals; Hippocampus (Brain); Human; Immunology; Incidence; Infection; Intervention; Knowledge; Label; Laboratories; Leadership; Light; Membrane; Mentors; Microglia; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurosciences; Outcome; Pathologic; Pathology; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phase; Phosphorylation; Physiology; Prevention; Primary Prevention; Recombinants; Research; Research Personnel; Research Project Grants; Risk Factors; Scientist; Symptoms; Technology; Testing; Time; Training; United States; United States Food and Drug Administration; Vision; Work; abeta deposition; aged; base; career; catalyst; chimeric antigen receptor; cost; cost effective; cost estimate; design; effective therapy; experience; in vivo; live cell imaging; neuroimmunology; neuron loss; novel; novel strategies; prevent; professor; programs; protein aggregation; receptor binding; stem cells; tau Proteins; tertiary prevention; therapy development; treatment duration; treatment strategy

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by beta-amyloid (AP) deposition, neurofibrillary tangles, neuronal loss, and gliosis. AD is the 6th leading cause of death in the United States and more than 6.2 million Americans suffer from this disease. This year the estimated cost of AD and other dementias is projected to reach $355 billion and can rise to $1 .1 trillion by 2050. The cause of AD remains elusive, and it is likely multifactorial. The greatest risk factors are known to be age, genetics, and inheritance. Despite monumental efforts and vast funding for research, only one therapy has been approved since 2003 and no medication can prevent acquisition of the disease or halt progression. In the last decade more than 200 research projects have not been completed or have failed. More than 15 clinical trials have attempted to promote AP clearance but only one has received controversial approval from the Food and Drug Administration. Most of these studies have treated patients with mild-moderate symptomatic AD, phases by which irreversible damage have already occurred. Therefore, it has been hypothesized that intervention preceding permanent pathological changes could provide better outcomes. However, it is estimated that pathological changes start 15-20 years before the onset of clinical symptoms. Given the extraordinary cost of antibody-based AP, and prolonged treatment periods both primary prevention and tertiary prevention become cost-prohibitive and unsustainable. To develop novel and cost-effective approaches, we have developed phagocytic chimeric antigen receptors (CARs) that can promote stable AP clearance with minimal treatment frequency. Our initial CAR designs promote remarkable induction of potent phagocytosis of oligomeric AP in human microglial cell lines. Using this technology, we propose to design CAR-based cellular therapies to stably promote clearance of AP plaques and prevent further AP deposition. The approach described in this proposal has the potential to be transformative in the treatment of AD and can likely be developed into successful treatments of other protein aggregation diseases of the central nervous system.

阿尔茨海默病（AD）是一种以β-淀粉样蛋白（AP）沉积为特征的神经退行性疾病， 神经元缠结、神经元损失和神经胶质增生。AD是美国第六大死亡原因， 超过620万美国人患有这种疾病。今年，AD和其他痴呆症的估计成本 预计将达到3550亿美元，到2050年可能上升到1.1万亿美元。AD的原因仍然难以捉摸，它是 可能是多因素的已知最大的风险因素是年龄，遗传和遗传。尽管 巨大的努力和大量的研究资金，自2003年以来，只有一种治疗方法被批准， 药物治疗可以防止疾病的获得或停止进展。在过去的十年里，200多项研究 项目没有完成或失败。超过15项临床试验试图促进AP 但只有一种获得了食品和药物管理局有争议的批准。大部分 这些研究已经治疗了患有轻中度症状性AD的患者， 已经发生了。因此，有人假设，在永久性病理性疾病之前进行干预， 改变可以带来更好的结果。然而，据估计，病理变化开始15-20年 在临床症状出现之前。考虑到基于抗体的AP的高昂成本， 治疗期间，初级预防和三级预防都变得费用高昂，难以为继。 为了开发新的和具有成本效益的方法，我们开发了吞噬嵌合抗原受体 （汽车），其可以以最小的治疗频率促进稳定的AP清除。我们最初的CAR设计促进了 显著诱导人小胶质细胞系中寡聚AP的有效吞噬作用。使用此 技术，我们建议设计基于CAR的细胞疗法，以稳定地促进AP斑块的清除， 防止AP进一步沉积。本提案中所述的方法有可能在以下方面产生变革性影响： 治疗AD，并可能发展为其他蛋白质聚集疾病的成功治疗 中枢神经系统。