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症。据估计，目前全球有超过1800万人患有阿尔茨海默病，预计到2025年，这一数字将增加近一倍，达到3400万人。阿尔茨海默病在世界范围内日益严重的医疗负担和有效药物的缺乏表明，治疗阿尔茨海默病的新的预防和/或治疗方法至关重要。这种疾病的一个神经病理特征是斑块的存在，这种斑块主要由一种称为b-淀粉样蛋白(A？)的肽组成。目前，阿尔茨海默病的病因学理论主要是A？在阿尔茨海默病的发生和发展中起着核心作用。根据这一假说，A？多肽，无论是通过过度生产或异常清除，导致A？在斑块中，这会促进神经原纤维缠结的形成和细胞死亡，导致痴呆。开发AD治疗方法的许多策略都是为了降低A？和/或阻止多肽组装成破坏认知功能的病理形式。以主动(即疫苗)或被动(即单抗)为基础的针对A？已经证明了改变A的能力？疾病模型和早期临床试验中的斑块负担。最先进的临床试验评价为A？由伊兰制药公司开发的多肽疫苗(AN1792)。尽管在一些接种疫苗的受试者中观察到与AD相关的认知能力下降的减少，但由于疫苗接受者中的一部分发生神经炎症，试验提前停止。随后的分析表明，诱导自身反应性T细胞对A？多肽(但不是抗体反应)在这些不良事件的发生中。基于这些发现，A？B细胞表位DNA疫苗ADepVac被设计用来诱导对A？同时避免自身反应性T细胞的发展。该候选药物在AD小鼠疾病模型中表现出了令人信服的安全性和有效性特征，并与基于电穿孔的DNA传递技术具有很强的协同作用。为了评估该产品作为AD干预药物的长期潜力，Ichor及其合作者提出，SBIR U44第一阶段的目标将是验证ADepVac在以电穿孔介导的递送方式递送时，可以安全有效地在非人类灵长类动物中诱导目标水平的免疫反应。如果达到安全和性能可行性标准，将启动U44第二阶段，以完成支持启动人体第一阶段临床试验所需的非临床安全性/毒理学研究和监管文件。基于项目合作者汇集的各种跨学科专业知识，该项目处于有利地位，可以将ADepVac引入临床测试。

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.