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Chimeric antigen receptor T regulatory cells as therapy for Alzheimer's Disease

嵌合抗原受体 T 调节细胞治疗阿尔茨海默病

基本信息

批准号：
10025408
负责人：
Charles L. Sentman
金额：
$ 45.1万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025408
关键词：
Affect Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid beta-Protein Anti-Inflammatory Agents Antigens Area Autologous Binding Brain Brain region CAR T cell therapy Cell Therapy Clinic Clinical Management Cognitive deficits Data Dementia Deposition Development Engineering Evaluation Excision FOXP3 gene Fiber Foundations Genetic Engineering Goals Hippocampus (Brain)Human Human Activities Immune Immune response Immunomodulators Impaired cognition Inflammation Inflammation Mediators Inflammatory Laboratories Localized Disease Mediating Memory impairment Microglia Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Patients Peptides Property Proteins Receptor Signaling Regulatory T-Lymphocyte Role Sampling Senile Plaques Signal Transduction Site Specificity T-Lymphocyte Subsets Testing Therapeutic Toxicity Tests Transgenic Mice abeta accumulation base cancer therapy chimeric antigen receptor cognitive function design effector T cell engineered T cells extracellular family management first-in-human frontal lobe immunoregulation in vivo innovation macrophage mouse model neoplastic cell neuroinflammation neuron loss neuroprotection neurotoxicity new technology novel novel therapeutics pre-clinical progressive neurodegeneration protein aggregation response scale up tau Proteins trafficking

项目摘要

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 microglia-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. Data suggest that inflammatory microglia, the resident macrophages of the central nervous system, have a role in neurodegeneration and cognitive decline. 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) would have therapeutic immunomodulatory and localized disease-modifying activity at brain regions of Aβ accumulation and progressive neurodegeneration. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against Aβ will demonstrate immunoregulatory and neuroprotective activities in mouse models of Alzheimer's disease. We will test murine and human Tregs for activity in AD models when Aβ is present. The data generated will provide key proof-of-concept data to move this novel therapeutic idea forward

项目总结/文摘: