Adenovirus vectored vaccines for Alzheimer's disease

用于阿尔茨海默病的腺病毒载体疫苗

• 批准号: 7221753
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 10万
• 依托单位: VAXIN INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221753
• 关键词: AN-1792; APP gene; Adenovirus Vector; Adenoviruses; Adverse effects; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Amyloid Proteins; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Autoimmune Responses; B-Lymphocyte Epitopes; Behavioral; Biochemical; Brain; Cells; Cerebrum; Characteristics; Clinical Trials; Cognitive deficits; DNA Sequence; Deposition; Development; Disease; Elderly; Encephalitis; Etiology; Facility Construction Funding Category; Goals; Human; Immune; Immune response; Immunization; Immunologic Monitoring; Immunotherapy; Injection of therapeutic agent; Learning; Mediating; Memory; Memory Loss; Mus; Mutation; Needles; Neurodegenerative Disorders; Neurofibrillary Tangles; Nose; Pathogenesis; Pathology; Patients; Peptides; Peripheral; Phase; Play; Production; Protein Overexpression; Pseudomonas aeruginosa toxA protein; Reporting; Role; Safety; Senile Plaques; System; T-Lymphocyte; Tandem Repeat Sequences; Testing; Therapeutic Effect; Thinking; Toxic effect; Transgenic Mice; Vaccination; Vaccines; amyloid peptide; base; cell mediated immune response; cognitive function; efficacy evaluation; familial Alzheimer disease; improved; mouse model; mutant; neuron loss; peptide A; presenilin-1; prevent; prophylactic; receptor binding; therapeutic vaccine; vector

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.

描述（由申请人提供）： 阿尔茨海默病（AD）是老年人中最常见的神经退行性疾病，迄今为止，AD 的病理特征之一是淀粉样蛋白（A¿）的沉积。越来越多的证据支持 A¿其前体 (APP) 在 AD 的病因学中发挥致病作用，转基因小鼠中 APP 突变体的过度表达导致了 AD 样病变，包括用合成的 A¿预防或减少 A¿存款并改善他们的记忆和学习缺陷。然而，由于 T 细胞介导的自身免疫反应引起的脑部炎症，免疫接种被停止。最近的临床试验报告表明，A¿免疫接种可有效清除A¿因此，寻找安全有效的抗 A¿ 抗体的外周给药治疗至关重要。还诱导 AD 小鼠模型中预先存在的淀粉样斑块的清除，因此，成功的 AD 治疗疫苗的开发被认为取决于能够诱导有效 A 的免疫策略的确定。 - 特异性 Th2 免疫反应，且不会引起不良反应。我们生产了一种腺病毒载体疫苗，它编码 A¿ 的 B 细胞表位。 Vaxin Inc. 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。根据实验结果，我们将进一步评估无RCA腺病毒载体治疗AD模型小鼠的安全性和有效性，一期项目的具体目标是（1）无RCA腺病毒的构建。 (2)在 AD 小鼠模型中测定鼻腔施用无 RCA 的腺病毒载体诱导的免疫应答，以及 (3) 评估在 AD 小鼠模型中鼻腔施用无 RCA 的腺病毒载体的功效和安全性。 AD 小鼠模型。因此，该应用是我们的腺病毒载体疫苗临床试验的必要步骤。AD 的特点是逐渐丧失记忆和认知功能。迄今为止，尚无令人满意的治疗方法。我们建议测试使用 AD 动物模型来治疗和预防 AD 的无 RCA 腺病毒载体疫苗的有效性和安全性。