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.

抽象的 抗抗体免疫疗法，例如 aducanamab、donanemab 和 Lecanemab 已获批准或正在等待 批准用于治疗阿尔茨海默病（AD）。虽然这些代理商对未来充满希望 痴呆症的治疗、其广泛接受和使用因对安全性的重大担忧而受到阻碍。几乎 二十年前，我们的小组和其他人首次描述了转基因小鼠大脑中的微出血 由抗抗体免疫治疗引起。此后，大量抗抗体临床试验受试者被 还受血管源性水肿的影响。重新定义为淀粉样蛋白相关的水肿成像异常（ARIA） （ARIA-E）或出血性（ARIA-H）类型，三分之一的阿杜卡纳马试验参与者发生了 ARIA 事件，并且 仍然是抗抗体免疫疗法使用的一个主要问题。我们将测试这个新假设 抗抗体免疫疗法通过涉及基质激活的炎症后遗症触发 ARIA 金属蛋白酶 MMP9，降解血管系统的紧密连接/基底膜，诱导 ARIA。 配备了二十年前我们所不具备的新技术（即7T 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 hAβSAA 小鼠）。我们建议使用这些新型小鼠模型来评估细胞、分子和功能 使用抗体 3D6 进行免疫治疗引起的变化；具有表位的鼠单克隆抗体 就像阿杜卡纳单抗那样。我们提出三个具体目标来检验假设： 具体目标 1：定义人源化抗体中抗体免疫治疗的神经血管和神经免疫反应 鼠标模型。 具体目标 2：确定 MMP9 在 Ab 免疫疗法引起的 ARIA 发育中的作用。 具体目标 3：评估 MMP9 抑制消除 ARIA 的潜力。