Immunomodulatory and behavioral effects of CAR T regulatory cell therapy for Alzheimer's Disease”.

CAR T 调节细胞疗法对阿尔茨海默病的免疫调节和行为影响。

• 批准号: 10633721
• 负责人: Charles L. Sentman
• 金额: $ 24.6万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633721
• 关键词: Acceleration; Affect; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid beta-Protein; Anti-Inflammatory Agents; Area; Autologous; Behavior; Behavioral; Binding; Brain; CAR T cell therapy; Cell Therapy; Central Nervous System; Clinic; Clinical Management; Cognitive; Cognitive deficits; Data; Dementia; Deposition; Development; Disease; Engineering; Evaluation; Excision; FOXP3 gene; Fiber; Foundations; Gliosis; Goals; Hippocampus; Immune; Immune response; Immune system; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory; Laboratories; Macrophage; Mediating; Memory impairment; Microglia; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neuronal Dysfunction; Neurons; Patients; Peripheral; Production; Property; Proteins; Reaction; Regulatory T-Lymphocyte; Role; Sampling; Senile Plaques; Site; Specificity; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Toxicity Tests; abeta accumulation; abeta oligomer; cancer therapy; cellular engineering; chimeric antigen receptor; clinical candidate; cognitive function; effector T cell; engineered T cells; extracellular; family management; first-in-human; frontal lobe; genetically modified cells; immune modulating agents; immunoregulation; improved; in vivo; innovation; manufacture; mouse model; neoplastic cell; neuroinflammation; neuron loss; neuroprotection; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; protein aggregation; scale up; tau Proteins; trafficking

Project Summary/Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is one of the primary reasons for memory dysfunction and dementia after 60 years of age. Neuronal dysfunction and death in the frontal cortex and hippocampus, along with glia-mediated neuroinflammation and formation of aberrant protein aggregates and fibrils are hallmarks of AD. Sporadic and familial forms of AD have an overproduction and/or decreased clearance of extracellular amyloid-beta (Aβ) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near Aβ plaques there is a greater neurodegeneration. Furthermore, peripheral immune activity and inflammation can affect inflammation in the CNS. T regulatory cells (Tregs) are a subset of T cells that have inherent anti-inflammatory and immunomodulatory properties. Tregs are found in the CNS under steady state conditions and increase trafficking to regions of CNS inflammation. Less active or decreased numbers of Tregs has been found in AD patients and depletion of Tregs can accelerate cognitive defects in murine AD models. We hypothesize that Tregs expressing chimeric antigen receptors (CARs) with specificity to amyloid-beta (Aβ) will have immunomodulatory activity and improve cognitive function of the 5xFAD B6 mice, a murine AD model. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against amyloid-beta will demonstrate immunomodulatory effects in the CNS and in the peripheral tissues resulting in improved cognitive behavior. The data generated will provide key proof-of-concept data to develop this novel therapeutic idea forward.

项目摘要/摘要： 阿尔茨海默病（AD）是一种进行性神经退行性疾病，是导致阿尔茨海默病的主要原因之一。 60 岁后记忆功能障碍和痴呆。额叶皮质神经元功能障碍和死亡。 和海马体，以及神经胶质介导的神经炎症和异常蛋白质聚集体的形成 和原纤维是 AD 的标志，散发性和家族性 AD 的产生过多和/或减少。 细胞外淀粉样β (Aβ) 肽和神经元内扭曲 tau 蛋白纤维缠结的清除。 众所周知，AD 中会发生神经炎症，并且当与 Aβ 斑块附近相关时，会产生更大的神经炎症。 此外，外周免疫活动和炎症也会影响神经系统的炎症。 CNS 调节性 T 细胞 (Treg) 是 T 细胞的一个子集，具有固有的抗炎和抗炎作用。 在稳态条件下，中枢神经系统中存在免疫调节特性，并增加运输量。 在 AD 患者和中枢神经系统炎症区域中发现 Tregs 活性较低或数量减少。 我们发现 Tregs 的表达会加速小鼠 AD 模型中的认知缺陷。 对淀粉样蛋白-β (Aβ) 具有特异性的嵌合抗原受体 (CAR) 将具有免疫调节活性 改善 5xFAD B6 小鼠（一种小鼠​​ AD 模型）的认知功能 本提案的目的是测试 Tregs 设计用于表达针对淀粉样蛋白 β 的 CAR 的创新概念将得到展示 中枢神经系统和周围组织的免疫调节作用，从而改善认知行为。 生成的数据将提供关键的概念验证数据，以进一步发展这种新颖的治疗理念。