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的治疗减少 脑血管淀粉样血管病或CAA是一种常见的脑小血管疾病， 在老年人中，阿尔茨海默病（AD）患者的一个突出的合并症，也是阿尔茨海默病（AD）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和相关疾病）， 痴呆）。尽管越来越多的人认识到CAA对AD和VCID痴呆的作用，但没有 目前存在针对这种病症的有效治疗干预。CAA独特地有助于认知 以多种方式降低VCID和AD。例如，响应于CAA中沉积的纤维状A β， 认知障碍因血管周围神经炎症的慢性状态而恶化， 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 氧和氮物种。此外，CAA增加了血管周围的表达和某些 导致微梗塞、血管壁完整性破坏和脑梗塞的蛋白水解酶 出血，这些都是疾病的高度有害表现。因此，血管周围 神经炎症和有害的血管事件，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是治疗CAA/VCID/ADRD的潜在治疗靶点。 我们报道了载脂蛋白-E模拟肽显示出强有力的抗炎作用， 在中风和颅内出血（ICH）模型中， 具有CAA/VCID/ADRD特性。为了改进这种apoE模拟方法，我们修改了COG1410， 产生RGN 728，一种在大鼠中具有改善的抗炎和神经保护活性的新的apoE模拟物， 非人类灵长类中风模型。我们现在提出一个合作的努力，以测试是否新的大鼠CAA 由货车Nostrand及其同事创建的模型在接受我们的抗炎和抗病毒药物治疗后会有所改善。 神经保护性RGN 728由Li和Vitek创建。行为，病理和生化结果将是 测量以确定在RGN 728治疗后是否存在统计学上显著的改善。 成功改善结局将为先进的临床前疗效和安全性试验奠定基础 为了使新型神经保护和抗炎剂RGN 728的人体临床试验能够在 CAA/VCID。