A Therapeutic DNA Epitope Vaccine for Alzheimer's Disease

阿尔茨海默病（AD）是老年人中最常见的痴呆形式。据估计，目前全球有超过1800万人患有AD，预计到2025年，这一数字将增加近一倍，达到3400万。AD的巨大的、日益增加的全球医疗保健负担和有效药物的缺乏表明用于治疗AD的新的预防和/或治疗方法是必不可少的。该疾病的一个神经病理学特征是存在主要由称为B-淀粉样蛋白（A？）的肽组成的斑块。目前，AD病因学的主流理论是A？在AD的发病和进展中起着重要作用。根据这一假设，积累的A？肽，无论是通过过度生产或异常清除，结果在沉积的A？在斑块中，它促进神经元缠结和细胞死亡的形成，导致痴呆症。许多战略的发展，治疗AD的目的是降低水平的A？和/或阻断肽组装成破坏认知功能的病理形式。各种基于主动（即，疫苗）或被动（即，单克隆抗体）免疫治疗A？有能力改变A？疾病模型和早期临床试验中的斑块负荷。最先进的临床试验评估了A？肽疫苗（AN 1792）。尽管在一些免疫受试者中观察到AD相关的认知下降减少，但由于疫苗接种者亚组中发生神经炎症，试验提前停止。随后的分析牵连诱导自身反应性T细胞反应的A？肽（而不是抗体反应）在这些不良事件的发展。根据这些发现，A？设计了B细胞表位DNA疫苗ADepVac，以引起对A？同时避免自身反应性T细胞的发展。该候选药物在AD鼠疾病模型中表现出令人信服的安全性和有效性特征，并与基于电穿孔的DNA递送技术具有强协同作用。为了评价该产品作为AD干预措施的长期潜力，Ichor及其合作者提出SBIR U44 I期研究的目的是验证ADepVac在电穿孔介导的递送下可安全有效地诱导非人灵长类动物的目标免疫应答水平。如果达到安全性和性能可行性标准，将启动U44 II期研究，以完成支持启动人体I期临床试验所需的非临床安全性/毒理学研究和监管申报。基于项目合作者之间汇集的多元化、跨学科专业知识，该项目处于将ADepVac引入临床试验的有利地位。

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is estimated that there are currently more than 18 million people worldwide with AD and this number is projected to nearly double by 2025 to 34 million. The enormous, increasing worldwide healthcare burden of AD and the lack of effective drugs indicate new prophylactic and/or therapeutic approaches for treating AD are essential. One neuropathological feature of the disease is the presence of plaques composed primarily of a peptide called b- amyloid (A?). Currently, the predominant theory of the etiology of AD is that A? has a central role in the onset and progression of AD. According to this hypothesis, the accumulation of A? peptide, either by overproduction or aberrant clearance, results in the deposition of A? in plaques, which promotes the formation of neurofibrillary tangles and cell death, resulting in dementia. Many strategies for the development of therapies for AD are aimed at reducing the level of A? in the brain and/or blocking assembly of the peptide into pathological forms that disrupt cognitive function. A variety of approaches based on active (i.e., vaccines) or passive (i.e., monoclonal antibodies) immunotherapy against A? have demonstrated the capability to alter A? plaque burden in disease models and early phase clinical trials. The most advanced clinical trial evaluated an A? peptide vaccine (AN1792) developed by Elan Pharmaceuticals. Although a reduction in AD-related cognitive decline was observed in some of the immunized subjects, the trial was halted prematurely due to the occurrence of neuroinflammation in a subset of vaccine recipients. Subsequent analysis implicated the induction of autoreactive T cell responses to the A? peptide (but not antibody responses) in the development of these adverse events. Based on these findings, an A? B cell epitope DNA vaccine, ADepVac, was designed to elicit potent antibody responses to A? while avoiding the development of autoreactive T-cells. This candidate has demonstrated compelling safety and efficacy characteristics in AD murine disease models and strong synergy with electroporation-based DNA delivery technology. To evaluate the long term potential of this product as an intervention for AD, Ichor and its collaborators propose that the objective of SBIR U44 Phase I will be to verify that ADepVac can safely and effectively induce target levels of immune responses in non-human primates when delivered with electroporation-mediated delivery. If the safety and performance feasibility criteria are achieved, U44 Phase II will be initiated in order to complete the nonclinical safety/toxicological studies and regulatory filings necessary to support the initiation of a Phase I clinical trial in humans. Based on the diverse, interdisciplinary expertise assembled among the program collaborators, the project is well positioned to bring ADepVac into clinical testing.