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 Aducanamab，Donanemab和Lecanemab等抗AB免疫疗法已获得批准或正在等待 批准治疗阿尔茨海默氏病（AD）。尽管这些代理商对未来的未来充满希望 痴呆症治疗，广泛接受和使用受到对安全性的重大关注所阻碍。几乎 二十年前，我们的小组和其他人首先描述了转基因小鼠的大脑 由抗AB免疫疗法引起。从那以后，大量的抗AB临床试验受试者是 也受血管水肿的影响。重新定义为淀粉样蛋白相关的成像异常（ARIA） （ARIA-E）或出血性（ARIA-H）类型，ARIA事件发生在三分之一的Aducanamab试验参与者中，并且 围绕使用抗AB免疫疗法的主要关注点。我们将测试一个新的假设 抗AB免疫疗法通过炎症后遗症触发芳香，涉及基质激活 金属蛋白酶MMP9，降解管脉系统的紧密连接/地下机制诱导芳香。 二十年前配备了我们无法使用的新技术（即7T MRI，插入式两光孔 成像和单细胞转录组学），我们被毒死以揭示机械因果关系 使用新型的人源性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评估细胞，分子和功能 使用抗体3D6导致免疫疗法产生的变化；带有表位的鼠单克隆抗体 像阿杜卡纳纳姆。我们提出了三个特定的目的以检验假设： 特定目的1：定义人性化AB中AB免疫疗法的神经血管和神经免疫性反应 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。 特定目标3：评估MMP9抑制的潜力消除ARIA。