Statins for Alzheimer's disease immunotherapy

他汀类药物用于阿尔茨海默病免疫治疗

• 批准号: 7579780
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579780
• 关键词: AN-1792; APP gene; Actins; Adenoviruses; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Amyloid deposition; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Affinity; Behavioral; Biochemical; Blood Vessels; Brain; Cerebral hemisphere hemorrhage; Cerebrum; Clinical Trials; Cognitive deficits; Combined Modality Therapy; Cytomegalovirus; DNA; Dementia; Deposition; Elderly; Encephalitis; Enhancers; Etiology; Goals; Hemorrhage; Human; Immune response; Immunization; Immunotherapy; Learning; Mediating; Memory; Meningoencephalitis; Modality; Mouse Strains; Mus; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Passive Immunization; Pathogenesis; Patients; Peptide antibodies; Peptides; Peripheral; Phase II Clinical Trials; Phenotype; Play; Production; Pseudomonas aeruginosa toxA protein; Reporting; Research Project Grants; Resources; Role; Safety; Senile Plaques; Serological; Serum; Simvastatin; T-Lymphocyte; Tandem Repeat Sequences; Testing; Therapeutic Effect; Transgenic Mice; Treatment Protocols; Vaccines; Virus; amyloid peptide; base; familial Alzheimer disease; improved; mouse model; mutant; neuron loss; neurotoxic; overexpression; peptide A; plasmid DNA; presenilin-1; prevent; promoter; prophylactic; public health relevance; receptor binding; response; vector

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia after the age of 60. The pathological hallmarks of AD include deposition of amyloid b-peptide (Ab) in neuritic plaques and cerebral blood vessels, neurofibrillary tangles and loss of neurons. Increasing evidence supports the notion that Ab and its precursor play important roles in the pathogenesis of AD. Immunization of AD mouse models with synthetic Ab prevented or reduced Ab deposits and improved their memory and learning deficits. Human clinical trials of Ab immunization (AN1792) were halted due to brain inflammation. In addition, the clinical trials and passive immunization induced cerebral hemorrhages in one AD patient and some AD mouse models, respectively. Recent reports of the clinical trials indicate that Ab immunization is effective in clearing Ab deposits and improving cognitive deficits in AD patients Thus, it is crucial to find a safe and effective immune therapy. Because peripheral administration of antibodies against Ab also induced clearance of preexisting amyloid plaques in AD mouse models and because meningoencephalitis associated with the AN1792 trial is thought to be T-cell-mediated auto-immune responses, immunization modalities that elicit predominantly T helper (Th) type 2 immune responses are considered to be safer for AD prevention and treatment. Another obstacle for AD immunotherapy is the difficulty to induce an appropriate anti-Ab titer in AD patients. In the phase II clinical trial, 19.7% of AD patients developed a positive Ab titer. In attempting to develop such safe, effective vaccines, we demonstrated that adenovirus-vectored vaccines encoding Ab can induce Th2-polarized anti-inflammatory immune responses in several strains of mice. We found that a DNA prime-adenovirus boost regimen increased the number of mice positive for anti-Ab antibody, the value of the antibody titer and the affinity of the antibody to amyloid plaques compared with only adenovirus immunization. Thus, the heterologous DNA prime-adenovirus boost regimen is superior to its homologous counterpart. We hypothesize that a heterologous DNA prime-adenovirus boost regimen is effective in reducing Ab deposits and in improving behavioral deficits in AD mouse models and that statins enhance Th2-type responses induced by a DNA prime-adenovirus boost regimen and protect animals against brain inflammation and hemorrhages. In Aim 1, we will evaluate the efficacy and safety of DNA prime-adenovirus boost immunization in AD model mice. In Aim2, We will evaluate the efficacy and safety of combined treatment of DNA prime-adenovirus boost immunization with simvastatin in AD model mice. We will perform immunological, histopathological, immunohistochemical, biochemical and behavioral analyses on the animals to determine the efficacy and safety of the modalities. The efficacy and safety of the immunization with simvastatin will be compared with those without statins The goal of this project is to establish the logical basis for developing safe, effective modalities for AD by testing combination therapy of DNA prime-adenovirus boost regimens with statins. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. This study will serve as a proof of principle to demonstrate if DNA prime-virus boost immunization with statins can induce potentially safer and more efficacious immune responses to treat AD than that without statins.

描述（申请人提供）：阿尔茨海默氏病（AD）是60岁以后痴呆的最常见原因。AD的病理特征包括淀粉样蛋白b-肽（Ab）在神经炎斑块和脑血管中沉积、神经原纤维缠结和神经元的损失。越来越多的证据支持 Ab 及其前体在 AD 发病机制中发挥重要作用的观点。用合成抗体对 AD 小鼠模型进行免疫可以防止或减少抗体沉积，并改善其记忆和学习缺陷。由于脑部炎症，抗体免疫（AN1792）的人体临床试验被停止。此外，临床试验和被动免疫分别在一名 AD 患者和一些 AD 小鼠模型中诱发脑出血。最近的临床试验报告表明，抗体免疫可有效清除AD患者的抗体沉积并改善认知缺陷，因此，找到安全有效的免疫疗法至关重要。由于针对 Ab 的抗体的外周给药也诱导了 AD 小鼠模型中预先存在的淀粉样斑块的清除，并且由于与 AN1792 试验相关的脑膜脑炎被认为是 T 细胞介导的自身免疫反应，因此主要引发 T 辅助细胞 (Th) 的免疫方式2 型免疫反应被认为对于 AD 预防和治疗更安全。 AD 免疫治疗的另一个障碍是难以在 AD 患者中诱导适当的抗抗体滴度。在II期临床试验中，19.7%的AD患者出现抗体滴度阳性。在尝试开发这种安全、有效的疫苗时，我们证明编码 Ab 的腺病毒载体疫苗可以在几种小鼠品系中诱导 Th2 极化抗炎免疫反应。我们发现，与仅腺病毒免疫相比，DNA初免-腺病毒加强方案增加了抗Ab抗体阳性的小鼠数量、抗体滴度值以及抗体对淀粉样斑块的亲和力。因此，异源DNA初免-腺病毒加强方案优于同源方案。我们假设异源 DNA 初免-腺病毒加强方案可有效减少 AD 小鼠模型中的抗体沉积和改善行为缺陷，并且他汀类药物可增强 DNA 初免-腺病毒加强方案诱导的 Th2 型反应，并保护动物免受脑部炎症和出血。在目标 1 中，我们将评估 DNA 初免-腺病毒加强免疫对 AD 模型小鼠的有效性和安全性。在Aim2中，我们将评估辛伐他汀联合DNA初免-腺病毒加强免疫治疗AD模型小鼠的有效性和安全性。我们将对动物进行免疫学、组织病理学、免疫组织化学、生化和行为分析，以确定这些方法的有效性和安全性。将使用辛伐他汀与不使用他汀类药物的免疫效果和安全性进行比较。该项目的目标是通过测试 DNA 初免-腺病毒加强方案与他汀类药物的联合治疗，为开发安全、有效的 AD 模式建立逻辑基础。公共卫生相关性：阿尔茨海默病 (AD) 是老年人痴呆症的最常见原因。然而，迄今为止，AD 尚无令人满意的治疗方法。这项研究将作为原理证明，证明使用他汀类药物增强 DNA 病毒增强免疫是否可以诱导比不使用他汀类药物更安全、更有效的免疫反应来治疗 AD。