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：ADRD中脑淀粉样血管病病理学的治疗性降低 脑血管淀粉样血管病或CAA是一种常见的脑小血管疾病，很普遍 在较旧的时候，阿尔茨海默氏病（AD）患者的突出合并症以及 血管认知障碍和痴呆（VCID）统称为ADRD（AD及相关） 尽管人们对CAA对AD和VCID中痴呆症的贡献的认识日益认识到，但 目前，对于这种情况，目前存在有效的治疗干预措施。 CAA独特地有助于认知 VCID的下降和广告以几种方式进行。例如，为了响应CAA中沉积的纤维aßeta， 认知障碍因慢性周围神经炎症而恶化，其特征是 反应性星形胶质细胞和活化的小胶质细胞，产生促炎性细胞因子，趋化因子，反应性 氧和氮种。同样，CAA会增加血管周围表达和某些的激活 有助于微吸收性的蛋白水解酶，容器壁完整性和大脑的破坏 出血，都是疾病的高度缺失的表现。那是血管周 神经炎症和有害的血管事件，例如出血和/或血管阻塞 与脑血管淀粉样蛋白相关，代表了治疗CAA/VCID/ADRD的潜在治疗靶标。 我们报道了载脂蛋白-E的模拟辣椒表现出强大的抗炎和 中风和颅内出血模型（ICH）中的神经保护活性，它们共享许多 具有CAA/VCID/ADRD的特征。为了改善这种apoe-Mimetic的方法，我们将COG1410修改为 生成RGN728，这是一种新的APOE模仿，在大鼠和 非人类的中风模型。现在，我们提出了一项协作努力，以测试新型大鼠CAA是否 范诺斯特兰德（Van Nostrand）及其同事创建的模型将在使用我们的抗炎和治疗时会有所改善 由Li和Vitek创建的神经保护性RGN728。行为，病理和生化结果将是 测量以确定RGN728治疗的统计学上是否有显着改善。 成功改善结果将为高级临床前效率和安全测试奠定基础 为了实现新型神经保护和抗炎药的人类临床试验，RGN728在 CAA/VCID。