scFv-based Abeta Oligomer Targeting in 3xTg-AD Mice

基于 scFv 的 Abeta 寡聚体靶向 3xTg-AD 小鼠

• 批准号: 7777857
• 负责人: WILLIAM J. BOWERS
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777857
• 关键词: Age-Months; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Antibodies; Appearance; Area; Arts; Bacteriophages; Behavior; Behavioral; Brain; Capsid; Cell Line; Common Epitope; Convection; Data; Development; Disease; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Event; Foundations; Functional disorder; Gene Transfer; Genes; Goals; Harvest; Hippocampus (Brain); His-His-His-His-His-His; Histology; Human; Immune; Immunotherapy; Inflammatory Response; Infusion procedures; Injection of therapeutic agent; Intervention; Laboratories; Lead; Learning; Libraries; Ligands; Measures; Mediator of activation protein; Memory; Memory impairment; Mus; Neurodegenerative Disorders; Neurons; Passive Immunization; Pathogenesis; Pathologic; Pathology; Peptides; Phage Display; Process; Production; Proteins; RNA; Recombinant adeno-associated virus (rAAV); Recombinants; Research; Reverse Transcriptase Polymerase Chain Reaction; Senile Plaques; Serotyping; Signal Transduction; Site; Staging; Symptoms; Synapses; Testing; Therapeutic; Tissues; Transgenic Organisms; Viral; Viral Vector; Virus; Western Blotting; Work; abeta oligomer; adeno-associated viral vector; antibody engineering; base; brain tissue; c-myc Genes; cell type; cellular transduction; cognitive function; cohort; design; economic impact; extracellular; in vivo; insight; interest; memory retention; morris water maze; mouse model; neurofibrillary tangle formation; neurotoxicity; novel therapeutics; prevent; programs; prophylactic; public health relevance; secretase; synaptic function; tau Proteins; tau function; vector; vector control

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressively dementing disorder characterized by the accumulation in the brain of pathogenic peptides largely comprised of amyloid-beta peptide (Ab), a derivative of the amyloid precursor protein (APP). Ab1-42, the predominant extracellular form, arises from cleavage of APP by two endoproteases, the 2- and 3- secretases, and undergoes assembly into oligomeric forms some of which are postulated to compromise synaptic function. Our laboratory is interested in understanding the early mechanisms that initiate or perpetuate this temporal and spatial progression of AD pathogenesis, and in exploiting an understanding of these mechanisms to derive novel therapeutics. One strategy to treat AD is to deplete the Ab within the parenchymal space and preclude formation of the putative damaging oligomeric forms. Several groups have been successful by introducing antibodies through either active or passive means, although many have incurred untoward immunological events. Among the approaches pursued we seek to deliver to the AD brain recombinant viral vectors that will express a human single chain fragment variable (scFv) antibody directed against Ab oligomeric forms with the goal of facilitating its clearance and preventing synaptic dysfunction and neuronal toxicity. We hypothesize that gene-based passive immunization using single-chain antibodies directed against oligomeric forms of Ab will prevent Ab-engendered synaptotoxicity and will diminish the downstream pathological events that include amyloid plaques, neurofibrillary tangle formation, and associated effects on neuronal viability. Recombinant adeno-associated virus (rAAV) vectors expressing the engineered antibodies will be administered to 3xTg-AD mice, a mouse model of AD that develops both amyloid and tau pathology, prior to the initial appearance of intraneuronal Ab (2 months of age). This work will provide mechanistic insight into the involvement of oligomeric Ab in the temporal and spatial progression of early AD pathogenic events and will potentially lead to the development of new anti-Ab therapeutics designed for early-stage intervention. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is an insidious neurodegenerative disorder that wields significant societal and economic impact. The development of more refined therapeutics directed at disease targets presently believed to be early mediators of the disease and their detailed assessment in state-of-the-art animal models will usher in a new class of therapeutics with the potential to be more than symptom-ameliorating, but truly disease course-modifying.

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性痴呆病症，其特征在于主要由淀粉样蛋白-β肽（Ab）组成的致病肽在脑中积聚，所述淀粉样蛋白-β肽是淀粉样蛋白前体蛋白（APP）的衍生物。Ab 1 -42是主要的细胞外形式，由两种内切蛋白酶（2-和3-分泌酶）切割APP产生，并经历组装成寡聚体形式，其中一些寡聚体形式被假定为损害突触功能。我们的实验室有兴趣了解早期机制，启动或延续这种时空进展的AD发病机制，并利用这些机制的理解，以获得新的治疗方法。治疗AD的一种策略是耗尽实质空间内的Ab并排除推定的损伤性寡聚体形式的形成。几个小组已经成功地通过主动或被动方式引入抗体，尽管许多人已经发生了不利的免疫事件。在所追求的方法中，我们寻求向AD脑递送重组病毒载体，其将表达针对Ab寡聚体形式的人单链片段可变（scFv）抗体，目的是促进其清除并预防突触功能障碍和神经元毒性。我们假设，基于基因的被动免疫，使用单链抗体针对寡聚体形式的抗体将防止抗体产生的突触毒性，并将减少下游的病理事件，包括淀粉样蛋白斑块，神经元缠结的形成，和相关的影响神经元的活力。表达工程化抗体的重组腺相关病毒（rAAV）载体将在神经元内Ab的初始出现（2月龄）之前施用于3xTg-AD小鼠，3xTg-AD小鼠是发展淀粉样蛋白和tau病理的AD小鼠模型。这项工作将提供机制的洞察寡聚抗体参与的时间和空间进展的早期AD致病事件，并可能导致开发新的抗抗体治疗设计的早期干预。公共卫生相关性：阿尔茨海默病（AD）是一种潜在的神经退行性疾病，具有重大的社会和经济影响。针对目前被认为是疾病早期介质的疾病靶点的更精细治疗剂的开发及其在最先进的动物模型中的详细评估将带来一类新的治疗剂，其具有改善疾病的潜力，但真正改变疾病进程。