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治疗靶向单核细胞的潜在益处，以减少阿尔茨海默病 (AD) 相关病理学可能表现出功能障碍/衰老特征。随着 AD 的进展，其特征是迁移和吞噬作用受损，因此需要进行调节。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。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 解决 AD (TLR9)。我们对多个 AD 小鼠模型的研究结果表明，通过 TLR9 刺激先天免疫。含有 CpG ODN 的药物可以安全地改善 AD 的所有病理损伤，且无任何毒性。目前的免疫治疗方法的缺点是针对脑淀粉样蛋白的效果有限目前的证据表明 CAA 在血管病 (CAA) 和过度的神经炎症中发挥着关键作用。导致淀粉样蛋白相关成像异常（ARIA）发生的病理生理学问题。 CAA 的研究正在成为确保免疫疗法成功的首要任务。散发性 CAA 的有利非人类灵长类动物模型松鼠猴 (Saimiri Boliviensis) 表明在没有不良反应的情况下，CpG ODN 治疗可改善认知能力并减少 CAA 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。人体概况，目前正在针对各种适应症进行临床试验。将是第一个评估 1018 ISS 在老年松鼠猴中的治疗效果和长期安全性的项目建立病理学，并将为 IND 申请和随后的临床前证据提供必要的临床前证据 1018 ISS 对 AD 患者的 Ib 期测试对 CAA 水平以及低水平的 1018 ISS 的疗效。该模型中存在的实质淀粉样沉积物将与行为评估、生物标志物相关我们的新型 MRI 方法，使用双功能超小型超顺磁性氧化铁。 (USPIO) 纳米颗粒与聚乙二醇 (PEG) 和 A40 偶联，将实现 1018 ISS 治疗效果因此，我们计划的研究也将证明淀粉样蛋白负担。 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。评估 1018 ISS 功效和安全性的复杂性此处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质表达谱，我们计划评估负责激活的 ISS 免疫刺激作用。巨噬细胞/小胶质细胞向有益的表型发展，这可能有助于清除 CAA 病理。我们相信，拟议的综合评估将有助于建立一组新型生物标志物和为未来 1018 ISS 临床试验确定适当的结果衡量标准总体而言，我们认为拟议的研究对于使 CpG ODN 1018 ISS 更适合人类应用至关重要。