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

批准号：
9367918
负责人：
Henrieta Scholtzova
金额：
$ 68.01万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9367918
关键词：
Acute Address Advanced Development Adverse effects Adverse event Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Behavior assessment Behavioral Biochemical Biological Biological Markers Blood Blood Vessels Brain Brain hemorrhage Cell physiology Cells Cerebral Amyloid Angiopathy Chronic Clinical Clinical Trials Cognitive Complication Coupled Cytosine DNA Data Defect Deposition Development Dose Effectiveness Elderly Ensure Environment Evaluation Evaluation Studies Exhibits Failure Functional disorder Future Gene Expression Gene Proteins Goals Guanine Histologic Human Image Immune Immune response Immune system Immunization Immunologics Immunotherapeutic agent Immunotherapy Impaired cognition Impairment Incidence Individual Innate Immune System Laboratories Lesion Ligands Longitudinal Studies Magnetic Resonance Imaging Measures Mediating Methodology Microglia Modeling Molecular Profiling Monitor Monkeys Mononuclear Natural Immunity Outcome Measure Pathologic Pathology Pathway interactions Patients Peripheral Phagocytes Phagocytosis Phase Phenotype Physical Examination Plasma Play Polyethylene Glycols Preparation Primates Problem Solving Reporting Route Safety Saimiri Sampling Senile Plaques Signal Transduction Sporadic Cerebral Amyloid Angiopathy TLR9 gene Testing Therapeutic Toxic effect Transgenic Mice Translating Vaccination Validation Vertebral column Work age related aged amyloid pathology biomarker evaluation clinical translation design efficacy testing ferumoxtran immunogenicity immunoregulation macrophage migration mouse model nano-string nanoparticle nonhuman primate novel novel marker novel strategies phosphorothioate pre-clinical protein expression response senescence subcutaneous success tau Proteins therapeutic target transcriptome sequencing treatment effect virtual

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.

抽象的几份报告概述了热靶向单核细胞的潜在益处阿尔茨海默氏病（AD）相关病理。先天的免疫电池可能会暴露功能失调/感觉型轮廓随着AD的进展，其特征是迁移和吞噬作用受损。因此，调节巨噬细胞/小胶质细胞特征代表了减少AD病理学的潜在治疗途径。我们有专注于核对免疫细胞功能中与年龄相关的缺陷，并通过Toll样受体9 （TLR9）。我们来自多个AD鼠标模型的发现表明，通过TLR9刺激先天免疫力使用CPG ODN可以安全地改善所有表征AD的病理病变，而无需任何毒性。一个当前免疫治疗方法的缺点是针对脑淀粉样蛋白的有限效力血管病（CAA）和过多的神经发作。当前的证据表明CAA在病理生理学导致与淀粉样蛋白相关成像异常的发展（ARIA）。解决问题 CAA成为确保免疫疗法成功的优先事项。我们从生物学上的最新数据有利的非人类私人私人模型，散发性CAA，松鼠猴（Saimiri boliviensis），表明用CpG ODN治疗导致认知改善和在没有逆境的情况下减少CAA 事件。在这里，我们建议使用TLR9配体B级CPG ODN 1018 ISS，它显示出很好的安全性人类中的概况，目前正在临床试验中对各种适应症进行测试。本研究将是第一个评估1018 ISS治疗效果和长期安全性的人已建立的病理学，并将为IND应用提供基本的临床前证据，随后 AD患者中1018 ISS的IB期测试。 1018 ISS的CAA水平以及低水平的ISS效率本模型中存在的实质淀粉样蛋白沉积物将与行为评估，生物标志物相关评估和MRI。我们的新型MRI方法论，使用双功能超级超级磁铁氧化铁（USPIO）与聚乙二醇（PEG）和A40耦合的纳米颗粒将允许1018 ISS治疗效果在淀粉样蛋白伯恩上进行纵向遵循。因此，我们计划的研究也将证明 USPIO-PEG-Aβ对于将来的临床试验的适用性。此外，对咏叹调的监视将进一步增加评估1018 ISS效率和安全性的复杂性。此处描述的项目旨在表征与CpG ODN介导的信号传导和吞噬途径。我们计划评估1018 ISS免疫刺激效应，负责激活巨噬细胞/小胶质细胞针对有益表型，这可能有助于清除CAA病理学。我们认为，拟议的全面评估将有助于建立一个新颖的生物标志物和确定未来1018 ISS临床试验的适当结果指标。总体而言，我们相信拟议的研究对于使用CPG ODN 1018 ISS对人类应用更可行至关重要。