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: 10706512
• 负责人: Gary E. Grajales-Reyes
• 金额: $ 38.88万
• 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/10706512
• 关键词: Accounting; Aducanumab; Affect; Age; Alzheimer' s Disease; American; Amyloid beta-Protein; Antibodies; Astrocytes; 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; Dedications; Dementia; Deposition; Disease; Disease Progression; Economic Burden; Economics; FDA approved; Flow Cytometry; Frequencies; Funding; Genetic; Genomic medicine; Gliosis; Goals; Hippocampus; Human; Immunology; Incidence; Infection; Institution; Intervention; Knowledge; Label; Laboratories; Leadership; Light; Membrane; Mentors; Microglia; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurosciences; Outcome; Pathologic; Pathology; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phase; Phosphorylation; Physiology; Postdoctoral Fellow; 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; candidate identification; career; catalyst; chimeric antigen receptor; cost; cost effective; cost estimate; design; effective therapy; experience; hyperphosphorylated tau; in vivo; live cell imaging; neuroimmunology; neuron loss; novel; novel strategies; postnatal; 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， 神经原纤维缠结、神经元丢失和胶质细胞增多症。AD是美国第六大死因， 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。阿尔茨海默病的病因仍然难以捉摸，而且确实如此 很可能是多因素的。众所周知，最大的风险因素是年龄、遗传和遗传。尽管 巨大的努力和巨大的研究资金，自2003年以来只有一种疗法获得批准，没有 药物治疗可以预防疾病的发生或阻止病情的发展。在过去的十年里，有200多项研究 项目尚未完成或已失败。已有15项以上的临床试验试图促进AP 但只有一家获得了美国食品和药物管理局(FDA)有争议的批准。大部分 这些研究治疗了轻-中度症状性阿尔茨海默病患者，这些阶段的损害是不可逆转的。 已经发生了。因此，已经假设干预发生在永久性病理之前。 变革可以带来更好的结果。然而，据估计，病变始于15-20年。 在临床症状出现之前。鉴于基于抗体的AP的超高成本，并延长了 一级预防和三级预防的治疗期变得成本高昂且不可持续。 为了开发新的和经济有效的方法，我们开发了吞噬细胞嵌合抗原受体。 (CARS)，可以以最低的治疗频率促进稳定的AP清除。我们最初的汽车设计促进了 显著诱导低聚AP在人小胶质细胞系中的吞噬作用。使用这个 技术，我们建议设计基于汽车的细胞疗法，以稳定地促进AP斑块的清除和 防止进一步的AP沉积。本提案中描述的方法有可能在 阿尔茨海默病的治疗很可能发展为其他蛋白质聚集性疾病的成功治疗 中枢神经系统。