Adenovirus vectored vaccines for Alzheimer's disease

描述(申请人提供)：阿尔茨海默病(AD)是老年人最常见的神经退行性疾病。到目前为止，对于AD还没有令人满意的治疗方法。阿尔茨海默病的病理特征之一是神经性斑块和脑血管中淀粉样蛋白的沉积。越来越多的证据支持A？及其前体(APP)在AD的病因学中起致病作用的观点。在转基因小鼠中过度表达APP的突变形式导致了类似AD的病理，包括大脑中的淀粉样斑块。用人工合成的A预防或减少A的沉积并改善其记忆和学习缺陷。然而，由于T细胞介导的自身免疫反应可能引起的脑部炎症，人类Aé免疫的临床试验被叫停了。最近的临床试验报告表明，A‘免疫在清除A’沉积和改善AD患者的认知障碍方面是有效的。因此，寻找安全有效的免疫治疗方法至关重要。在AD小鼠模型中，外周注射抗A？抗体也能清除先前存在的淀粉样斑块。因此，成功的AD治疗性疫苗的开发被认为依赖于免疫策略的确定，这种免疫策略可以诱导强大的A？特异性Th2免疫反应，而不会引起不良反应。我们生产了一种腺病毒载体疫苗，它编码A的B细胞表位。腺病毒疫苗主要诱导Th2免疫反应，并对AD模型小鼠的AD样改变具有预防作用。瓦辛公司开发了专有的AdHigh系统，用于快速生产无复制能力的腺病毒(RCA)腺病毒载体。基于我们的实验结果，我们将在第一阶段项目中进一步评估无RCA的腺病毒载体治疗AD模型小鼠的安全性和有效性。其具体目的是(1)构建不含RCA的腺病毒载体，(2)检测无RCA的腺病毒载体经鼻给药在AD小鼠模型中诱导的免疫应答，(3)在AD小鼠模型中评价无RCA的腺病毒载体经鼻给药的有效性和安全性。因此，这一应用对于我们的腺病毒载体疫苗的临床试验是必要的一步。Primer病(AD)的特征是记忆力和认知功能的进行性丧失。到目前为止，对于AD还没有令人满意的治疗方法。我们建议使用AD的动物模型来测试无RCA的腺病毒载体疫苗的有效性和安全性，以治疗和预防AD。

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common neurodegenerative disease in the elderly. To date, no satisfactory treatment is available for AD. One of the pathological hallmarks of AD is deposits of amyloid protein (A¿) in neuritic plaques and cerebral vessels. Increasing lines of evidence support the notion that A¿ and its precursor (APP) play pathogenetic roles in the etiology of AD. Overexpression of the mutant forms of APP in transgenic mice led to AD-like pathologies including amyloid plaques in the brain. Parenteral immunization of these AD mouse models with synthetic A¿ prevented or reduced A¿ deposits and improved their memory and learning deficits. Human clinical trials of A¿ immunization, however, were halted due to brain inflammation presumably induced by T cell-mediated autoimmune responses. Recent reports of the clinical trials indicate that A¿ immunization is effective in clearing A¿ deposits and improving cognitive deficits in AD patients. Thus, it is crucial to find safe and effective immune therapy. Peripheral administration of antibodies against A¿ also induced clearance of preexisting amyloid plaques in AD mouse models. Therefore, the development of successful therapeutic vaccines against AD is thought to depend on identification of immunization strategies that can induce potent A¿-specific Th2 immune responses without eliciting adverse effects. We produced an adenovirus-vectored vaccine which encodes a B-cell epitope of A¿. The adenovirus vaccine induced predominantly Th2 immune responses and had prophylactic effects on AD-like changes in AD model mice. Vaxin Inc. developed the proprietary AdHigh system for rapid production of replication-competent adenovirus (RCA)-free adenovirus vectors. Based upon our experimental results, we will further assess the safety and efficacy of the RCA-free adenovirus vector in treating AD model mice in the Phase I project. The Specific Aims are (1) Construction of the RCA-free adenovirus vector, (2) Determination of immune responses induced by nasal administration of the RCA-free adenovirus vector in an AD mouse model, and (3) Evaluation of the efficacy and the safety of the nasal administration of the RCA-free adenovirus vector in an AD mouse model. Therefore, this application is a necessary step toward a clinical trial of our adenovirus vectored vaccine. Primer's disease (AD) is characterized by the progressive loss of memory and cognitive functions. To date, no satisfactory treatments are available for AD. We propose to test the efficacy and safety of a RCA-free adenovirus vectored vaccine using animal models of AD in order to treat and prevent AD.