Establishing the role of MMP9 in amyloid-immunotherapy-induced ARIA

确定 MMP9 在淀粉样蛋白免疫疗法诱导的 ARIA 中的作用

• 批准号: 10607620
• 负责人: Donna M Wilcock
• 金额: $ 36.06万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607620
• 关键词: Adverse event; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animals; Antibodies; Arctic Regions; Basement membrane; Biochemical; Blood Vessels; Brain; Cells; Cerebral Amyloid Angiopathy; Clinical Trials; Cognitive; Data; Dementia; Development; Edema; Epitopes; Event; Future; Gelatinase A; Hemorrhage; Histologic; Human; Image; Immunotherapy; Incidence; Inflammation; Inflammatory; Inflammatory Response; Laboratories; MMP2 gene; MMP9 gene; Magnetic Resonance Imaging; Marimastat; Matrix Metalloproteinases; Mediating; Microglia; Modeling; Molecular; Mus; Mutation; Neuroimmune; Participant; Pathologic; Play; Point Mutation; Role; Safety; Testing; Tight Junctions; Time; Transgenic Mice; Transgenic Model; cerebrovascular; cytokine; digital; in vivo imaging; inhibitor; mouse model; murine monoclonal antibody; neurovascular; neurovascular unit; new technology; novel; prevent; response; sex; tool; transcriptomics; two-photon; vascular cognitive impairment and dementia; vasogenic edema

ABSTRACT Anti-Ab immunotherapies such as aducanamab, donanemab, and lecanemab are either approved or awaiting approval for the treatment of Alzheimer’s disease (AD). While these agents hold great promise for the future of dementia treatment, their broad acceptance and use is hindered by significant concerns regarding safety. Almost two decades ago, our group and others first described microhemorrhages in the brains of transgenic mice resulting from anti-Ab immunotherapy. Since then, a substantial number of anti-Ab clinical trial subjects were also affected by vasogenic edema. Re-defined as amyloid-related imaging abnormalities (ARIA) of the edema- (ARIA-E) or hemorrhagic- (ARIA-H) types, ARIA events occurred in a third of aducanamab trial participants and remain a major concern surrounding the use of anti-Ab immunotherapy. We will test the novel hypothesis that anti-Ab immunotherapy triggers ARIA through inflammatory sequelae involving activation of the matrix metalloproteinase MMP9, degrading tight junction/basement membranes of vasculature inducing ARIA. Equipped with new technologies not available to us two decades ago (i.e. 7T MRI, intravital two-photon imaging, and single cell transcriptomics), we are poised to reveal mechanistic cause-and-effect relationships between Aβ-immunotherapy, MMP9, and ARIA-H using novel humanized Aβ mouse models (i.e. hAβ and hAβSAA mice). We propose using these novel mouse models to evaluate cellular, molecular, and functional changes resulting from immunotherapy using the antibody 3D6; a murine monoclonal antibody with an epitope like that of aducanamab. We propose three specific aims to test out hypothesis: Specific Aim 1: Define neurovascular and neuroimmune responses to Ab immunotherapy in the humanized-Ab mouse model. Specific Aim 2: Determine the role of MMP9 in ARIA development resulting from Ab immunotherapy. Specific Aim 3: Evaluate the potential of MMP9 inhibition to eliminate ARIA.

摘要 aducanamab、donanemab和lecanemab等抗Ab免疫疗法要么获得批准，要么正在等待批准。 批准用于治疗阿尔茨海默病（AD）。虽然这些代理人对未来的前景充满希望， 在痴呆症治疗中，它们的广泛接受和使用受到关于安全性的重大担忧的阻碍。几乎 20年前，我们的研究小组和其他研究人员首次描述了转基因小鼠大脑中的微囊化， 由抗Ab免疫疗法引起。从那时起，大量的抗Ab临床试验受试者 也受到血管源性水肿的影响。重新定义为水肿的淀粉样蛋白相关成像异常（ARIA）- 在ARIA-E或出血性（ARIA-H）型中，三分之一的aducanamab试验参与者发生ARIA事件， 仍然是使用抗Ab免疫疗法的主要问题。我们将检验一个新的假设， 抗Ab免疫治疗通过涉及基质激活的炎症后遗症触发ARIA 金属蛋白酶MMP 9降解血管紧密连接/基底膜诱导ARIA。 配备了20年前我们无法使用的新技术（即7 T MRI，活体双光子 成像和单细胞转录组学），我们准备揭示机械因果关系 使用新型人源化Aβ小鼠模型（即hAβ和ARIA-H）， hAβSAA小鼠）。我们建议使用这些新的小鼠模型来评估细胞，分子和功能 使用抗体3D 6免疫治疗导致的变化;一种具有表位的鼠单克隆抗体 就像aducanamab一样。我们提出了三个具体目标来检验假设： 具体目标1：定义人源化Ab中对Ab免疫疗法的神经血管和神经免疫应答 小鼠模型 具体目标2：确定MMP 9在Ab免疫治疗引起的ARIA发展中的作用。 具体目标3：评价MMP 9抑制消除ARIA的潜力。