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
• 负责人: Henrieta Scholtzova
• 金额: $ 82.3万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665767
• 关键词: Acceleration; Adjuvant; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Animals; Autopsy; Behavioral; Biological Assay; Biological Markers; Biological Response Modifiers; Blood; Blood Vessels; Brain; Brain Pathology; Cells; Cerebral Amyloid Angiopathy; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Complication; Data; Defect; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease Progression; Effectiveness; Elderly; Environment; Enzyme-Linked Immunosorbent Assay; Evaluation; FDA approved; Failure; Family; Formalin; Goals; Hemorrhage; Hepatitis B Vaccines; Human; Image; Immune; Immunohistochemistry; Immunotherapeutic agent; Impaired cognition; Incidence; Individual; Inflammation; Intervention; Label; Lesion; Link; Liquid substance; Macrophage Activation; Magnetic Resonance Imaging; Maps; Mass Spectrum Analysis; Measures; Methods; Microglia; Modeling; Monitor; Monkeys; Natural Immunity; Nerve Degeneration; Paraffin Embedding; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Phenotype; Play; Primates; Process; Proteins; Proteome; Proteomics; Risk Factors; Role; Safety; Saimiri; Saline; Senile Plaques; Severities; Sporadic Cerebral Amyloid Angiopathy; Stimulus; Structure of choroid plexus; System; TLR9 gene; Techniques; Testing; Therapeutic; Time; Tissue Embedding; Toll-like receptors; Transgenic Mice; Translations; Vascular Diseases; White Matter Hyperintensity; age related; aged; amyloid pathology; biomarker signature; brain tissue; cell type; clinical application; clinically relevant; cognitive benefits; cognitive task; cognitive testing; cohort; coronavirus disease; design; diagnostic biomarker; diagnostic value; imaging biomarker; immunoregulation; improved; in vivo; innovation; insight; laser capture microdissection; magnetic resonance imaging biomarker; mouse model; neuropathology; neuroprotection; new therapeutic target; nonhuman primate; pre-clinical; premature; response; screening; social group; tau Proteins; tau-1; trafficking; treatment effect; treatment response; vaccine trial; white matter; white matter change

PROJECT SUMMARY Dysregulation of innate immunity is thought to be a significant contributor to Alzheimer’s disease (AD) pathogenesis. We have focused on harnessing innate immunity via Toll-like receptor 9 (TLR9) to modulate age- related defects in immune cells to counteract AD pathology. Our findings from multiple AD pathology transgenic mouse models provide the first in vivo evidence that stimulation of innate immunity with TLR9 agonist CpG ODN can reduce behavioral deficits and ameliorate all pathological hallmarks of AD. Most current immunotherapeutic trials for AD have been associated with a major complication referred to as amyloid-related imaging abnormalities (ARIA), which is linked to the presence and extent of cerebral amyloid angiopathy (CAA). CAA is present in a majority of individuals with AD, and its severity is an independent risk factor for cognitive decline. Hence, it is critical to develop a therapy effective against CAA without inducing ARIA complications. Additionally, the premature translation of promising transgenic mice data directly to patients has been associated with a very high clinical trial failure rate. Our recent study established that squirrel monkeys (SQMs), an NHP model that develops extensive age-dependent CAA unlike other primates, represent an opportune environment for demonstrating the therapeutic benefits of our immunomodulation using CpG ODN 2006. Here we propose the use of class B CpG 1018, which is currently being tested in clinical trials for a variety of indications. The collective studies are designed to provide a comprehensive portrayal of CpG 1018 efficacy and long-term safety by integrating biofluid biomarker signatures with imaging markers, cognitive measures, in addition to neuropathology correlates. Disease progression and safety will also be monitored by a combination of MRI techniques, which will enable morphometric characterization and screening for ARIA. The utility of a multi-shell diffusion MRI model to follow CpG 1018’s treatment effects in vivo on brain microstructural integrity, especially WM integrity changes, will be validated for the first time. An additional strength of this proposal is the use of our powerful proteomic strategy to unveil the first comprehensive characterization of the CAA and choroid plexus (CP) proteomes in association with disease progression and CpG 1018 intervention. This localized proteomic approach is a preferred method as it combines unbiased mass spectrometry examination with laser capture microdissection to precisely excise defined neuropathological lesions. A further aim of this study is to map involvement of the CP-CSF system in immune cell trafficking in response to CpG 1018. Delineating the CAA and CP protein signatures will advance understanding of CpG 1018’s favorable immunomodulatory capabilities, as well as provide insights into CAA pathogenesis to improve diagnostic capability. Overall, the interventions described here will provide essential preclinical evidence that will enhance CpG 1018’s potential for clinical application.

项目概要 先天免疫失调被认为是导致阿尔茨海默病 (AD) 的一个重要因素 发病。我们专注于通过 Toll 样受体 9 (TLR9​​) 利用先天免疫来调节年龄 免疫细胞的相关缺陷可以抵消 AD 病理。我们对多种 AD 病理转基因的发现 小鼠模型提供了第一个体内证据，证明 TLR9 激动剂 CpG ODN 可以刺激先天免疫 可以减少行为缺陷并改善 AD 的所有病理特征。目前最先进的免疫治疗 AD 试验与一种称为淀粉样蛋白相关影像异常的主要并发症有关 （ARIA），与脑淀粉样血管病（CAA）的存在和程度有关。 CAA 存在于 大多数人患有AD，其严重程度是认知能力下降的独立危险因素。因此，它是 开发一种有效治疗 CAA 且不引起 ARIA 并发症的疗法至关重要。此外， 将有希望的转基因小鼠数据直接翻译给患者的过早翻译与非常高的风险相关。 临床试验失败率。我们最近的研究表明，松鼠猴 (SQM) 是一种 NHP 模型， 与其他灵长类动物不同，广泛的年龄依赖性 CAA 代表了展示 我们使用 CpG ODN 2006 进行免疫调节的治疗效果。在此，我们建议使用 B 类 CpG 1018，目前正在针对多种适应症进行临床试验。集体研究是 旨在通过整合生物流体来全面描述 CpG 1018 的功效和长期安全性 生物标志物特征与成像标志物、认知测量以及神经病理学相关。 疾病进展和安全性也将通过 MRI 技术的组合进行监测，这将使 ARIA 的形态表征和筛选。多壳扩散 MRI 模型的效用 CpG 1018 在体内对大脑微结构完整性，特别是 WM 完整性变化的治疗作用将是 首次得到验证。该提案的另一个优势是使用我们强大的蛋白质组策略 首次全面揭示 CAA 和脉络丛 (CP) 蛋白质组的关联性 随着疾病进展和 CpG 1018 干预。这种局部蛋白质组学方法是首选方法 因为它结合了无偏质谱检查和激光捕获显微切割来精确切除 明确的神经病理学病变。本研究的另一个目的是绘制 CP-CSF 系统参与的图谱 响应 CpG 1018 的免疫细胞贩运。描绘 CAA 和 CP 蛋白特征将推进 了解 CpG 1018 有利的免疫调节能力，并提供对 CAA 的见解 发病机制，提高诊断能力。总的来说，这里描述的干预措施将提供 重要的临床前证据将增强 CpG 1018 的临床应用潜力。