Combining AD Epitope Vaccine with Innate Immunity

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因。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。该疾病的神经病理学特征包括淀粉样蛋白（A）沉积、神经元缠结（tau）和受影响脑区域的神经元丢失。目前，主要的病因学理论是淀粉样蛋白级联假说。根据这一假设，各种形式的可溶性和/或不溶性A β的积累在AD的发作和进展中起着核心作用，并导致神经元性tau缠结的形成。然而，最近使用生物标志物的临床研究表明，A β异常先于tau病理和认知能力下降10年或更长时间，而病理性tau的积累与临床症状的发作相关。因此，本领域的共识是，基于tau的免疫调节剂可以有效地作为极早期AD（前驱期）和/或处于AD风险的无症状受试者的预防措施，而基于tau的免疫调节剂可以用作轻度-中度AD患者的治疗措施。因此，我们的团队开发了三种基于重组蛋白的表位疫苗，它们同时靶向病理性A β（AV-1959R）、tau（AV-1980R）或A β/tau（AV-1953R），并在野生型小鼠中测试了这些疫苗的免疫原性。值得注意的是，所有这些疫苗都是在专有的通用MultiTEP平台（已提交美国专利）上构建的，该平台在小鼠、兔和猴中具有高度免疫原性。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一和双重疫苗在具有A β和tau病理的3xTg-AD小鼠中的有效性和安全性。将追求以下3个目标以实现这些目标：在目标1中，我们将测试在AD样病理学发作之前在年轻的3xTg-AD小鼠中开始的预防性疫苗接种的功效。更具体地说，我们将研究靶向A β（AV-1959R）或tau（AV-1980R）或A β/tau同时（AV-1953R）的表位疫苗的功效。此外，我们将在这些实验中优化疫苗接种方案。在目标2中，我们计划研究治疗性/预防性疫苗接种方案在具有确定的A β病理学但在tau病理学发作之前的3xTg-AD小鼠中的功效。这些研究的完成将使我们能够评估AV-1959 R的治疗功效、AV-1980 R的预防功效和AV-1953 R疫苗的治疗/预防功效。同样，在这个目标中，我们将优化治疗性/预防性疫苗接种方案。最后，在目的3中，我们将研究治疗性疫苗接种方案在疫苗接种开始时具有确定的AD样病理学的3xTg-AD小鼠中的功效。我们相信，我们的多学科团队（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策略并将其转化为临床。

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.