Anti-medin immunotherapy for vascular aging and related dementias

针对血管老化和相关痴呆的抗 Medin 免疫疗法

• 批准号: 10724869
• 负责人: Raymond Quezon Migrino
• 金额: $ 38.01万
• 依托单位: ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724869
• 关键词: Acceleration; Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amino Acids; Amyloidosis; Antigens; Aortic Aneurysm; Attenuated; Autoimmunity; Biochemistry; Blood Vessels; Brain Pathology; C-terminal; C57BL/6 Mouse; Cerebrovascular Disorders; Clinical Data; Data; Dementia; Development; Disease; Dose; EGF gene; Endothelial Cells; Endothelium; Epidemiology; Epitopes; Functional disorder; Gene Proteins; Goals; Human; Immunization; Immunology; Immunotherapy; Impaired cognition; Impairment; In Vitro; Inbred BALB C Mice; Inflammatory; Keyhole Limpet Hemocyanin; Knock-out; L Forms; Late Onset Alzheimer Disease; Length; Monoclonal Antibodies; Mus; Pathology; Peptides; Proteins; Regimen; Research; Risk Factors; Stress; Tertiary Protein Structure; Testing; Toxic effect; Vaccination; Vaccine Design; Vaccines; Vascular Dementia; Vascular Diseases; aged; amyloid formation; antibody immunotherapy; cerebrovascular; cerebrovascular biology; cognitive function; cytotoxicity; design; effective therapy; efficacy evaluation; efficacy testing; endothelial dysfunction; feasibility testing; immunogenicity; in vivo; in vivo evaluation; innovation; medin; member; milk fat globule; mouse model; multidisciplinary; neuroinflammation; neuropathology; neurovascular; novel; novel therapeutic intervention; pilot test; polyclonal antibody; pre-clinical; preservation; prevent; response; senescence; sialogangliosides; vaccine development; vascular inflammation

ABSTRACT Age is the most important risk factor for cardio-cerebrovascular diseases (CVD) and dementia disorders. Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with dementia disorders, including Alzheimer's disease (AD) and AD-related dementias (ADRD) such as vascular dementia (VaD). Indeed, unbiased data-driven analyses showed that vascular dysfunction is the earliest and strongest brain pathology associated with late onset AD. There is growing evidence that medin, a 50-amino acid peptide that forms one of the most common yet least studied human amyloidoses, is an important driver of vascular aging pathologies. We and others showed that vascular medin burden was associated with VaD, AD and aortic aneurysms. Medin, a cleavage product of milk fat globule-EGF factor 8 protein (MFGE8), accumulates in vessels with aging, causes endothelial dysfunction through oxidative and nitrative stress and induces endothelial pro- inflammatory activation that could initiate neuroinflammation. Knockout of MFGE8 domain containing medin prevented cerebrovascular medin amyloid formation and restored cerebrovascular function. We designed and produced an immunogen modified from the aggregation-prone C terminus of medin to be used as anti-medin vaccine and 3 monoclonal antibodies (mAbs) that have high medin affinity. Our overall goal is to evaluate anti- medin immunotherapy using medin vaccination (Aim 1) and anti-medin mAbs (Aim 2) to attenuate or prevent medin-induced vascular dysfunction and neurovascular pathology in aging C57BL/6 mice and in senescence accelerated mouse-prone 8 (SAMP8) mice. Aim 1 is to develop and test the benefit of anti-medin vaccination in preventing cerebrovascular and cognitive dysfunction and neurovascular pathology in C57BL/6 aged and SAMP8 mice. We will first determine an optimal vaccination regimen and then test the efficacy of that regimen. Aim 2 is to develop and pilot test anti-medin mAb immunotherapy to attenuate medin-induced cerebrovascular and cognitive dysfunction and neurovascular pathology in C57BL/6 aged and SAMP8 mice. First, we will determine which mAb (19H1, 6F2 and 13B7) will have the best effect in reversing medin-induced endothelial cytotoxicity. Next, we will do pilot feasibility in vivo testing of the ideal dosing of anti-medin mAbs to reduce cerebrovascular medin and preserve cerebrovascular and cognitive function. The proposal is innovative and paradigm-changing in potentially establishing medin as a new target for vascular disease and dementia, and anti-medin immunotherapy as a potential new treatment approach for vascular aging and resulting pathologies.

摘要 年龄是心脑血管疾病（CVD）和痴呆症最重要的危险因素。 流行病学、临床前和临床数据表明，血管疾病与痴呆密切相关 疾病，包括阿尔茨海默病（AD）和AD相关性痴呆（ADRD）如血管性痴呆 （VaD）。事实上，无偏见的数据驱动分析表明，血管功能障碍是最早和最强烈的 与迟发性AD相关的脑病理学。越来越多的证据表明，一种由50个氨基酸组成的肽 形成最常见但研究最少的人类淀粉样变性之一，是血管生成的重要驱动因素， 衰老病理学我们和其他研究表明，血管介质负荷与VaD、AD和主动脉粥样硬化相关。 动脉瘤Medin是乳脂球-EGF因子8蛋白（MFGE 8）的裂解产物，在血管中积累 随着年龄的增长，通过氧化和硝化应激引起内皮功能障碍，并诱导内皮细胞增殖， 可能引发神经炎症的炎症激活。含MFGE 8结构域的介导蛋白的敲除 阻止脑血管淀粉样蛋白形成，恢复脑血管功能。我们设计并 从medin的易于聚集的C末端制备了修饰的免疫原，用作抗medin 疫苗和3种具有高Medin亲和力的单克隆抗体（mAb）。我们的总体目标是评估抗- 使用medin疫苗接种（Aim 1）和抗medin mAb（Aim 2）的medin免疫疗法， C57 BL/6小鼠衰老和衰老过程中药物诱导的血管功能障碍和神经血管病理学 加速的小鼠倾向8（SAMP 8）小鼠。目的1是开发和测试抗Medin疫苗接种的益处， 预防C57 BL/6老年人的脑血管和认知功能障碍以及神经血管病变， SAMP 8小鼠。我们将首先确定最佳的疫苗接种方案，然后测试该方案的有效性。 目的二是研制抗Medin单克隆抗体免疫治疗药物，并进行初步试验 以及C57 BL/6老年小鼠和SAMP 8小鼠的认知功能障碍和神经血管病理学。一是 确定哪种mAb（19 H1、6 F2和13 B7）在逆转药物诱导的内皮细胞凋亡方面具有最佳效果， 细胞毒接下来，我们将进行抗Medin mAb的理想剂量的体内试验可行性测试，以减少 保护脑血管和认知功能。该提案具有创新性， 改变范式，可能将medin确立为血管疾病和痴呆症的新靶点， 抗medin免疫疗法作为血管老化和由此产生的病理的潜在新治疗方法。