Combining AD Epitope Vaccine with Innate Immunity

描述(申请人提供)：阿尔茨海默病(AD)是导致老年人痴呆症的最常见原因。它的临床特征是进行性认知能力下降，最终导致死亡，通常在确诊后10年内。该病的神经病理特征包括淀粉样蛋白(A�，A�)沉积、神经原纤维缠结(Tau)，以及受影响脑区的神经元丢失。目前，主要的病因学理论是淀粉样级联假说。根据这一假说，各种形式的可溶和/或不溶A-�的积聚在AD的发生和发展中起着中心作用，并导致神经纤维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�异常先于tau病理和认知功能下降10年或更长时间，而病理性tau的积累与临床症状的开始相关。因此，业内已达成共识，基于�的免疫治疗(S)可作为预防措施用于极早期AD(前驱症状)和/或无症状的AD风险人群，而基于tau的免疫治疗(S)可作为轻中度AD患者的治疗措施。因此，我们的团队开发了三种同时针对病理性A�(AV-1959R)、tau(AV-1980R)或A�/tau(AV-1953R)的重组蛋白表位疫苗，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多TEP平台(美国提交的专利)上构建的，该平台对小鼠、兔子和猴子具有高度的免疫原性。基于这些已发表的结果和初步数据，这一竞争性更新项目的目标是研究单一疫苗和双重疫苗在同时患有A�和tau病理的3xTg-AD小鼠中的有效性和安全性。为了实现这些目标，我们将追求以下三个目标：在目标1中，我们将测试在AD样病理发生之前在3xTg-AD幼鼠中开始预防性接种的效果。更具体地说，我们将研究针对A�(AV-1959R)或tau(AV-1980R)或同时针对A�/tau(AV-1953R)的表位疫苗的有效性。此外，我们还将在这些实验中优化疫苗接种方案。在目标2中，我们计划在3xTg-AD小鼠中研究治疗性/预防性疫苗接种方案的有效性，这些小鼠已确定为A-�病理，但在tau病理开始之前。这些研究的完成将使我们能够评估AV-1959R的治疗效果、AV-1980R的预防效果以及AV-1953R疫苗的治疗/预防效果。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，在目标3中，我们将研究治疗性疫苗接种方案在3xTg-AD小鼠中的疗效，这些小鼠在接种开始时已确定有AD样病理。我们相信，我们出色的多学科团队(包括免疫学家、疫苗研究人员、神经学家/认知学家和分子生物学家)完成所有这三个目标后，可以帮助我们确定最佳免疫治疗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.