Combining AD Epitope Vaccine with Innate Immunity

AD表位疫苗与先天免疫相结合

• 批准号: 9439835
• 负责人: Michael G Agadjanyan
• 金额: $ 1.02万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-28 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9439835
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animals; Antibodies; B-Lymphocyte Epitopes; B-Lymphocytes; Behavioral; Biological Markers; Brain; Brain region; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Cognitive; Combined Vaccines; Consensus; Cyclic GMP; Cytoskeletal Proteins; DNA; DNA Recombinant Proteins; DNA Vaccines; Data; Data Reporting; Dementia; Development; Diagnosis; Disease; Disease Progression; Elderly; Epitopes; Etiology; Europe; Goals; Histocompatibility Antigens Class II; Human; Immunization; Immunologist; Immunotherapeutic agent; Impaired cognition; Incidence; Lead; Measures; Molecular; Monkeys; Mus; Natural Immunity; Neurofibrillary Tangles; Oryctolagus cuniculus; Pathologic; Pathology; Patients; Peptides; Pharmacologic Substance; Prevention; Preventive vaccine; Publishing; Recombinant Proteins; Regimen; Reporting; Research Personnel; Role; Safety; Scientist; Series; Symptoms; Testing; Tg2576; Therapeutic; Translating; Treatment Efficacy; Vaccinated; Vaccination; Vaccines; Wild Type Mouse; aged; amyloid pathology; autoreactivity; base; behavior test; cognitive function; efficacy study; efficacy testing; experimental study; extracellular; glial activation; immunogenic; immunogenicity; improved; inhibiting antibody; meetings; multidisciplinary; neuron loss; phase I trial; prevent; prophylactic; public health relevance; recombinant peptide; tau Proteins; tau aggregation; theories; therapeutic evaluation; therapeutic vaccine

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly. It is characterized clinically by progressive cognitive decline, eventually resulting in death, usually within 10 years of diagnosis. The neuropathological features of the disease include depositions of amyloid-� (A�), neurofibrillary tangles (tau), and neuronal loss in affected brain regions. Currently, the predominant theory of the etiology is delineated in the amyloid cascade hypothesis. According to this hypothesis, the accumulations of various forms of soluble and/or insoluble A� have a central role in the onset and progression of AD and lead to the formation of neurofibrillary tau tangles. However, recent clinical studies using biomarkers demonstrated that A� abnormalities precede the tau pathology and cognitive decline by 10 years or more, whereas accumulation of pathological tau correlates with the onset of clinical symptoms. Thus, there is a consensus in the field that A� - based immunotherapeutic(s) can be effective as a prophylactic measure in very early AD (prodromal) and/or in non-symptomatic subjects at risk for AD, while tau-based immunotherapeutic(s) can be used as a therapeutic measure in patients with mild-moderate AD. Accordingly, our team developed three recombinant protein- based epitope vaccines that target pathological A� (AV-1959R), tau (AV-1980R) or A� /tau (AV-1953R) simultaneously and tested the immunogenicity of these vaccines in wild-type mice. Of note, all these vaccines have been constructed on the proprietary universal MultiTEP platform (US patents submitted) that is highly immunogenic in mice, rabbits and monkeys. Based on these published results and preliminary data the goals of this competitive renewal project are to study the efficacy and safety of single and dual vaccines in 3xTg-AD mice that have both A� and tau pathologies. The following 3 aims will be pursued to achieve these goals: In Aim 1 we will test the efficacy of prophylactic vaccination initiated in young 3xTg-AD mice before the onset of AD-like pathology. More specifically, we will study the efficacy of epitope vaccines targeting either A� (AV- 1959R) or tau (AV-1980R) or A� /tau simultaneously (AV-1953R). In addition, we will optimize the vaccination regimen in these experiments. In Aim 2 we are planning to study the efficacy of a therapeutic/prophylactic vaccination regimen in 3xTg-AD mice with established A� -pathology but before the onset of tau pathology. The completion of these studies will allow us to evaluate the therapeutic efficacy of AV-1959R, the prophylactic efficacy of AV-1980R, and therapeutic/prophylactic efficacies of AV-1953R vaccines. Again, in this aim we will optimize the therapeutic/prophylactic vaccination regimen. Finally, in Aim 3 we will study the efficacy of the therapeutic vaccination regimen in 3xTg-AD mice with established AD-like pathology at the start of vaccination. We believe that the completion of all three Aims by our stellar multidisciplinary team including immunologists, vaccine researchers, neuroscientists/cognitive scientists, and molecular biologists can help us to identify the best immunotherapeutic strategy and translate it to the clinic.

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆的最常见原因，其临床特征是进行性认知能力下降，最终导致死亡，通常在诊断后 10 年内发生。包括淀粉样蛋白 (A�) 沉积、神经原纤维缠结 (tau) 和受影响大脑区域的神经元丢失。目前，主要的病因学理论在淀粉样蛋白级联假说。根据这一假说，各种形式的可溶性和/或不溶性 A� 的积累在 AD 的发病和进展中发挥着核心作用，并导致神经原纤维 tau 缠结的形成。然而，最近使用生物标志物的临床研究。 A� 异常的表现先于 tau 蛋白病理学和认知能力下降 10 年或更长时间，而病理性 tau 蛋白的积累与临床症状的出现相关。因此，该领域达成了共识。基于 A� 的免疫治疗可作为非常早期 AD（前驱期）和/或有 AD 风险的无症状受试者的有效预防措施，而基于 tau 的免疫治疗可用作治疗措施因此，我们的团队开发了三种针对病理性 A� (AV-1959R)、tau 的重组蛋白表位疫苗。 (AV-1980R) 或 A�/tau (AV-1953R) 同时测试这些疫苗在野生型小鼠中的免疫原性。值得注意的是，所有这些疫苗都是在专有的通用 MultiTEP 平台上构建的（已提交美国专利）。基于这些已发表的结果和初步数据，该竞争性更新项目的目标是研究单疫苗和双疫苗在同时具有 A 的 3xTg-AD 小鼠中的功效和安全性。为了实现这些目标，我们将追求以下 3 个目标： 在目标 1 中，我们将测试在 AD 样病理发作之前对年轻 3xTg-AD 小鼠进行预防性疫苗接种的效果。同时针对 A� (AV-1959R) 或 tau (AV-1980R) 或 A�/tau (AV-1953R) 的表位疫苗的功效。在目标 2 中，我们计划研究在 tau 病理发生之前的 3xTg-AD 小鼠中治疗/预防疫苗接种方案的效果。让我们能够评估 AV-1959R 的治疗功效、AV-1980R 的预防功效以及 AV-1953R 疫苗的治疗/预防功效。同样，在这个目标中，我们将优化治疗/预防性疫苗接种方案最后，在目标 3 中，我们将研究在疫苗接种开始时已确定的 AD 样病理的 3xTg-AD 小鼠的治疗性疫苗接种方案的功效。我们一流的多学科团队（包括免疫学家、疫苗研究人员、神经科学家/认知科学家和分子生物学家）完成所有三个目标可以帮助我们确定最佳的免疫治疗策略并将其转化为临床。