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

在散发性脑淀粉样血管病的非人灵长类动物模型中通过 CpG ODN 刺激先天免疫

基本信息

项目摘要

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.
摘要 一些报告已经概述了治疗靶向单核细胞以减少肿瘤的潜在益处。 阿尔茨海默病(AD)相关病理学。先天免疫细胞可表现出功能失调/衰老特征 其特征在于随着AD的进展,迁移和吞噬作用受损。因此,调制 巨噬细胞/小胶质细胞谱代表了减少AD病理的潜在治疗途径。我们有 专注于协调免疫细胞功能中与年龄相关的缺陷,并通过Toll样受体9治疗AD。 (TLR9)。我们从多种AD小鼠模型中的发现表明,通过TLR 9刺激先天免疫, CpG ODN可安全地改善AD的所有病理学病变,且无任何毒性。一 目前免疫治疗方法的缺点是对脑淀粉样蛋白的有效性有限 血管病(CAA)和过度的神经炎症。目前的证据表明,CAA在 病理生理学导致淀粉样蛋白相关成像异常(ARIA)的发展。解决问题 CAA正在成为确保免疫治疗成功的优先事项。我们最近从生物学上获得的数据 散发性CAA的有利的非人灵长类动物模型松鼠猴(Saimiri Boliviensis)表明, CpG ODN治疗导致认知改善和CAA减少, 事件在这里,我们建议使用TLR 9配体,B类CpG ODN 1018 ISS,其已显示出良好的安全性 目前正在临床试验中测试各种适应症。本研究 将是第一个评估1018 ISS治疗效果和长期安全性的老年松鼠猴, 已建立的病理学,并将为IND申请和后续的临床前研究提供必要的证据。 1018例ISS在AD患者中的Ib期试验。1018 ISS对CAA水平的疗效,以及低水平的 该模型中存在的实质淀粉样蛋白沉积将与行为评估、生物标志物 评估和MRI。我们的新MRI方法,使用双功能超小超顺磁性氧化铁 (USPIO)纳米颗粒耦合到聚乙二醇(PEG)和A β 40,将允许1018 ISS治疗效果 对淀粉样蛋白负荷的影响。因此,我们计划的研究也将证明 USPIO-PEG-Aβ对未来临床试验的适用性。此外,对ARIA的监测将进一步增加 1018 ISS疗效和安全性评价的复杂性。这里描述的项目旨在 表征参与CpG ODN介导的信号传导的基因表达和蛋白表达谱, 吞噬途径我们计划评估1018 ISS的免疫刺激作用, 这可能有助于清除CAA病理。 我们相信,拟议的全面评估将有助于建立一个新的生物标志物小组, 确定未来1018 ISS临床试验的适当结局指标。总的来说,我们认为, 所提出的研究对于使CpG ODN 1018 ISS的使用对于人类应用更可行是必要的。

项目成果

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Henrieta Scholtzova其他文献

Henrieta Scholtzova的其他文献

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{{ truncateString('Henrieta Scholtzova', 18)}}的其他基金

Characterization of Biomarkers and the Vascular Amyloid Proteome in a Non-human Primate Model of Alzheimer’s Disease
阿尔茨海默病非人灵长类动物模型中生物标志物和血管淀粉样蛋白组的表征
  • 批准号:
    10558614
  • 财政年份:
    2022
  • 资助金额:
    $ 53.88万
  • 项目类别:
Innate Immunity Stimulation Effects on Biomarkers, Cognition, and the Vascular Amyloid Proteome in a Squirrel Monkey Model of Sporadic CAA
先天免疫刺激对散发性 CAA 松鼠猴模型中生物标志物、认知和血管淀粉样蛋白组的影响
  • 批准号:
    10665767
  • 财政年份:
    2022
  • 资助金额:
    $ 53.88万
  • 项目类别:
Characterization of Biomarkers and the Vascular Amyloid Proteome in a Non-human Primate Model of Alzheimer’s Disease
阿尔茨海默病非人灵长类动物模型中生物标志物和血管淀粉样蛋白组的表征
  • 批准号:
    10433252
  • 财政年份:
    2022
  • 资助金额:
    $ 53.88万
  • 项目类别:
Innate Immunity Stimulation Effects on Biomarkers, Cognition, and the Vascular Amyloid Proteome in a Squirrel Monkey Model of Sporadic CAA
先天免疫刺激对散发性 CAA 松鼠猴模型中生物标志物、认知和血管淀粉样蛋白组的影响
  • 批准号:
    10503406
  • 财政年份:
    2022
  • 资助金额:
    $ 53.88万
  • 项目类别:
Innate Immunity Stimulation via CpG ODN in a Non-Human Primate Model of Sporadic Cerebral Amyloid Angiopathy
在散发性脑淀粉样血管病的非人灵长类动物模型中通过 CpG ODN 刺激先天免疫
  • 批准号:
    9367918
  • 财政年份:
    2017
  • 资助金额:
    $ 53.88万
  • 项目类别:
Testing of Innate Immunity Stimulation via TLR9 on CAA using Non-human Primates.
使用非人类灵长类动物测试通过 TLR9 对 CAA 进行先天免疫刺激。
  • 批准号:
    8531364
  • 财政年份:
    2012
  • 资助金额:
    $ 53.88万
  • 项目类别:
Testing of Innate Immunity Stimulation via TLR9 on CAA using Non-human Primates.
使用非人类灵长类动物测试通过 TLR9 对 CAA 进行先天免疫刺激。
  • 批准号:
    8359340
  • 财政年份:
    2012
  • 资助金额:
    $ 53.88万
  • 项目类别:

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