Innate Immunity Stimulation via CpG ODN in a Non-Human Primate Model of Sporadic Cerebral Amyloid Angiopathy

摘要 一些报告概述了通过治疗靶向单个核细胞来减少 阿尔茨海默病(AD)相关病理学。先天免疫细胞可以表现出功能失调/衰老的特征 随着阿尔茨海默病的进展，以迁移和吞噬功能受损为特征。因此，调制 巨噬细胞/小胶质细胞图谱代表了减少AD病理的潜在治疗途径。我们有 专注于调和与年龄相关的免疫细胞功能缺陷，并通过Toll样受体9应对AD (TLR9)。我们在多个AD小鼠模型上的发现表明，通过TLR9刺激先天免疫 有了CpG，ODN可以安全地改善所有以AD为特征的病理损害，没有任何毒性。一个 目前免疫治疗方法的缺点是对脑淀粉样蛋白的疗效有限。 血管病变(CAA)和过度的神经炎症。目前的证据表明，CAA在 导致淀粉样蛋白相关成像异常(ARIA)的病理生理学。解决问题 CAA正成为确保免疫治疗成功的首要任务。我们最新的数据来自一种生物 散发性CAA的非人类灵长类动物模型--松鼠猴(Saimiri玻利viens)--表明 在没有不良反应的情况下，使用CpG ODN治疗可以改善认知和减少CAA 事件。在这里，我们建议使用TLR9配体，B类CpG ODN 1018 ISS，它已显示出良好的安全性 目前正在进行各种适应症的临床试验。目前的研究 将第一个评估1018 ISS对老年松鼠猴子的治疗效果和长期安全性 已确定的病理学，并将为IND的应用和随后的应用提供基本的临床前证据 1018例阿尔茨海默病患者ISS的Ib期检测1018ISS对CAA水平的疗效，以及低水平的 这个模型中存在的实质性淀粉样蛋白沉积将与行为评估、生物标记物 评估和核磁共振检查。我们的新磁共振成像方法，使用双功能超小超顺磁性氧化铁 将聚乙二醇和40偶联的纳米粒子将允许1018ISS的治疗效果 关于淀粉样蛋白负荷的纵向跟踪。因此，我们计划的研究也将证明 USPIO-PEG-Aβ在未来临床试验中的适用性。此外，对ARIA的监控将进一步增加 1018国际空间站疗效和安全性评估的复杂性。这里介绍的项目旨在 鉴定参与CpG ODN介导的信号转导和信号转导的基因表达和蛋白表达谱 吞噬细胞途径。我们计划评估1018个ISS的免疫刺激效应，负责激活 巨噬细胞/小胶质细胞倾向于有益的表型，这可能有助于清除CAA的病理。 我们相信，拟议的全面评估将有助于建立一组新的生物标志物和 为未来1018项ISS临床试验确定适当的结果衡量标准。总体而言，我们认为 建议的研究对于使CpG ODN 1018 ISS更适合人类应用是至关重要的。

ABSTRACT Several reports have outlined the potential benefit of therapeutically targeting mononuclear cells to reduce Alzheimer's disease (AD) related pathology. Innate immune cells can exhibit dysfunctional/senescent profiles characterized by impaired migration and phagocytosis as AD progresses. Therefore, modulating macrophage/microglia profiles represents a potential therapeutic avenue to reduce AD pathology. We have focused on reconciling the age related defects in immune cell function and tackling AD via Toll-like receptor 9 (TLR9). Our findings from multiple AD mouse models demonstrate that stimulation of innate immunity via TLR9 with CpG ODN can safely ameliorate all the pathological lesions that characterize AD without any toxicity. A drawback of present immunotherapeutic approaches is a limited effectiveness against cerebral amyloid angiopathy (CAA) and excessive neuroinflamation. Current evidence points to a key role for CAA in the pathophysiology leading to development of amyloid-related imaging abnormalities (ARIA). Solving the problem of CAA is becoming the priority for ensuring the success of immunotherapy. Our recent data from a biologically advantageous non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis), indicate that treatment with CpG ODN results in cognitive improvements and a reduction of CAA in the absence of adverse events. Here we propose using a TLR9 ligand, class B CpG ODN 1018 ISS, which has shown good safety profiles in humans and is currently being tested in clinical trials for a variety of indications. The present study will be the first to evaluate the 1018 ISS treatment effects and long term safety in aged squirrel monkeys with established pathology, and will provide essential preclinical evidence for an IND application and subsequent phase Ib testing of 1018 ISS in AD patients. 1018 ISS efficacy on CAA levels, as well as the low levels of parenchymal amyloid deposits present in this model, will be correlated with behavioral assessments, biomarker evaluation and MRI. Our novel MRI methodology, using bi-functional ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles coupled to polyethylene glycol (PEG) and A40, will allow 1018 ISS treatment effects on amyloid burden to be followed longitudinally. Hence, our planned studies will also demonstrate the suitability of USPIO-PEG-Aβ for future clinical trials. Furthermore, monitoring for ARIA will add further complexity to evaluation of 1018 ISS efficacy and safety. The project described here is designed to characterize gene expression and protein expression profiles involved in CpG ODN-mediated signaling and phagocytic pathways. We plan to assess 1018 ISS immunostimulatory effects responsible for activating macrophages/microglia towards beneficial phenotypes, which may contribute to clearance of CAA pathology. We believe the proposed comprehensive assessments will help establish a panel of novel biomarkers and determine appropriate outcome measures for future 1018 ISS clinical trials. Overall, we believe that the proposed studies are essential to make use of CpG ODN 1018 ISS more feasible for human application.