ENGINEERED HUMAN MICROGLIA AS A CELL-BASED THERAPY FOR A-BETA PLAQUE REMOVAL

项目总结 AD是老年性痴呆最常见的原因，其特点是进行性损害 认知功能。病理上，AD患者表现为广泛的β斑块和神经原纤维缠结 神经元和突触丢失。不幸的是，仍然没有有效的治疗方法来治疗这种毁灭性的疾病。 失败可能是由于淀粉样蛋白在症状出现前10-20年内积聚，以及有限的血脑屏障造成的 (Bbb)许多候选疗法的外显性。早期诊断加上有效和持续的 因此，脑内疗法的来源可能为改善AD的病理提供一种有效的方法。在此，我们 探索一种变革性的方法，将治疗有效载荷输送到大脑中，以治疗β斑块负载。 我们将测试工程人类小胶质细胞是否可以被设计成安全有效地将疗法输送到小鼠体内 AD的模型。第一个具体目标是通过确定变化来证明该方法的可行性 在β负荷下进行工程化小胶质细胞移植。第二个目标将确定是否减少了Aβ斑块负荷 结果挽救了长期增强缺陷。总体而言，这款R21准备测试新颖和 安全有效地提供治疗以对抗AD上β斑块积聚的变革性方法。 这一方法的成功示范可能会对治疗学的交付产生深远的影响 进入大脑。

PROJECT SUMMARY AD is the most common cause of age-related dementia, and is characterized by a progressive impairment in cognitive function. Pathologically, AD patients exhibit Aβ plaques and neurofibrillary tangles with extensive neuronal and synaptic loss. Unfortunately, there is still no effective treatment for this devastating disease. Failures likely arise from amyloid accumulation 10-20 years prior to symptoms and the limited blood brain barrier (BBB) penetrance of many candidate therapies. Earlier diagnoses coupled with an effective and continuous source of in-brain therapy may therefore provide a powerful approach to ameliorate AD pathology. Herein we explore a transformative approach toward delivering therapeutic payloads into the brain to treat Aβ plaque load. We will test if engineered human microglia can be designed to safely and effectively deliver therapies into mouse models of AD. The first specific aim is to demonstrate the feasibility of the approach by determining the change in Aβ load with engineered microglia transplantation. The second aim will determine if reduced Aβ plaque load results in rescue of long-term potentiation defects. Overall, this R21 is poised to test the feasibility of novel and transformative approaches for safe and effective delivery of therapies to combat Aβ plaque buildup on AD. Successful demonstration of this approach could have far-reaching implications for the delivery of therapeutics into the brain.