Therapeutic Reduction of Cerebral Amyloid Angiopathy Pathologies in ADRD

ADRD 中脑淀粉样血管病病理学的治疗性减少

• 批准号: 10546175
• 负责人: Michael P. Vitek
• 金额: $ 49.99万
• 依托单位: REGENNOVA, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546175
• 关键词: Age-Months; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amides; Amyloid; Amyloid beta-Protein; Animals; Anti-Inflammatory Agents; Apolipoprotein E; Astrocytes; Behavioral; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Brain Ischemia; Brain Pathology; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Characteristics; Chronic; Clinical; Clinical Trials; Complement; Data; Dementia; Deposition; Disease; Dose; E protein; Elderly; Encephalitis; Event; Foundations; Hemorrhage; Human; Impaired cognition; Inflammation; Inflammatory; Intracranial Hemorrhages; Matrix Metalloproteinases; Measurement; Measures; Microglia; Middle Cerebral Artery Occlusion; Modeling; Mus; Neuroprotective Agents; Nitrogen; Outcome; Outcome Measure; Oxygen; Pathologic; Pathology; Patients; Peptide Hydrolases; Peptides; Performance; Property; Proteins; Rattus; Recovery; Reperfusion Injury; Reporting; Stroke; Subarachnoid Hemorrhage; Testing; Therapeutic; Therapeutic Intervention; Transgenic Model; Transgenic Organisms; Vascular Diseases; Work; abeta accumulation; behavior measurement; behavioral outcome; cerebrovascular; cerebrovascular amyloid; chemokine; clinical candidate; comorbidity; cytokine; efficacy testing; improved; improved outcome; mimetics; neurobehavioral; neuroinflammation; neuron loss; nonhuman primate; novel; peptide analog; peptidomimetics; preclinical efficacy; response; safety testing; stroke model; therapeutic target; therapeutically effective; thrombotic; vascular cognitive impairment and dementia

ABSTRACT: Therapeutic Reduction of Cerebral Amyloid Angiopathy Pathologies in ADRD Cerebrovascular Amyloid Angiopathy or CAA is a common cerebral small vessel disease that is prevalent in the elderly, a prominent comorbidity of patients with Alzheimer's disease (AD), and an important driver of vascular cognitive impairment and dementia (VCID) that are collectively known as ADRDs (AD and Related Dementias). Despite the growing recognition of the contribution of CAA to dementia in AD and in VCID, no effective therapeutic interventions currently exist for this condition. CAA uniquely contributes to cognitive decline in VCID and AD in several manners. For example, in response to deposited fibrillar Aßeta in CAA, cognitive impairment is worsened by a chronic state of perivascular neuro-inflammation that is characterized by reactive astrocytes and activated microglia that produce pro-inflammatory cytokines, chemokines, reactive oxygen and nitrogen species. Also, CAA increases perivascular expression and activation of certain proteolytic enzymes that contribute to microinfarcts, disruption of vessel wall integrity and cerebral hemorrhage, which are all highly deleterious manifestations of the disease. Thus, perivascular neuroinflammation and harmful vascular events such as hemorrhage and/or vessel occlusions that are associated with cerebral vascular amyloid represent potential therapeutic targets to treat CAA/VCID/ADRD. We reported that mimetic peptides of apolipoprotein-E displayed robust anti-inflammatory and neuroprotective activities in models of stroke and intracranial hemorrhage (ICH), which share many characteristics with CAA/VCID/ADRD. To improve this apoE-mimetic approach, we modified COG1410 to generate RGN728, a new apoE-mimetic with improved anti-inflammatory and neuroprotective activity in rat and non-human primate models of stroke. We now propose a collaborative effort to test whether the novel rat CAA model created by Van Nostrand and colleagues will improve when treated with our anti-inflammatory and neuroprotective RGN728 created by Li and Vitek. Behavioral, pathological and biochemical outcomes will be measured to determine whether there is a statistically significant improvement upon RGN728 treatment. Successful improvement of outcomes will lay the foundation for advanced preclinical efficacy and safety tests to enable human clinical trials of the novel neuroprotective and anti-inflammatory agent, RGN728 in CAA/VCID.

摘要：治疗性减少 ADRD 中的脑淀粉样血管病病理 脑血管淀粉样血管病（CAA）是一种常见的脑小血管疾病 在老年人中，这是阿尔茨海默病 (AD) 患者的一个突出的合并症，也是阿尔茨海默氏病 (AD) 患者的一个重要驱动因素 血管性认知障碍和痴呆 (VCID) 统称为 ADRD（AD 和相关 尽管人们越来越认识到 CAA 对 AD 和 VCID 痴呆的影响，但没有 目前针对这种情况存在有效的治疗干预措施，CAA 对认知能力有独特的贡献。 VCID 和 AD 以多种方式下降，例如，响应 CAA 中沉积的纤维状 Aßeta， 血管周围神经炎症的慢性状态会加剧认知障碍，其特征是 反应性星形胶质细胞和活化的小胶质细胞产生促炎细胞因子、趋化因子、反应性 此外，CAA 还会增加血管周围的表达和某些物质的激活。 导致微梗死、血管壁完整性破坏和脑损伤的蛋白水解酶 出血，这些都是该疾病的高度有害的表现。 神经炎症和有害血管事件，例如出血和/或血管闭塞 与脑血管淀粉样蛋白相关的蛋白质代表了治疗 CAA/VCID/ADRD 的潜在治疗靶点。 我们报道了载脂蛋白-E 的模拟肽表现出强大的抗炎和 中风和颅内出血（ICH）模型中的神经保护活性，它们有许多共同点 为了改进这种 apoE 模拟方法，我们将 COG1410 修改为 产生 RGN728，一种新的 apoE 模拟物，在大鼠和小鼠体内具有改善的抗炎和神经保护活性 我们现在提议合作测试新型大鼠 CAA 是否有效。 Van Nostrand 及其同事创建的模型在接受我们的抗炎和 Li 和 Vitek 开发的神经保护 RGN728 将产生行为、病理和生化结果。 测量以确定 RGN728 治疗是否有统计上显着的改善。 结果的成功改善将为先进的临床前疗效和安全性测试奠定基础 使新型神经保护和抗炎剂 RGN728 能够在人体中进行临床试验 CAA/VCID。