Catalytic and non-catalytic Ig gene delivery for Alzheimer's disease

阿尔茨海默病的催化和非催化 Ig 基因递送

• 批准号: 7963696
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 16.68万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963696
• 关键词: AN-1792; APP gene; Adverse effects; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Animal Model; Antibodies; Antigens; Area; Attenuated; Behavioral; Binding; Biochemical; Blood Vessels; Brain; Catalytic Antibodies; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; Clinical Trials; Cognitive deficits; Complex; Dementia; Deposition; Elderly; Encephalitis; Enzymes; Etiology; Fc Receptor; Gene Delivery; Goals; Hemorrhage; Hippocampus (Brain); Human; Hydrolysis; Immune; Immune response; Immunization; Immunoglobulin G; Immunoglobulins; Immunotherapy; Inflammation; Inflammatory Response; Injection of therapeutic agent; Knock-out; Learning; Mediating; Memory; Memory impairment; Modality; Mus; Mutation; Neprilysin; Neurodegenerative Disorders; Neurofibrillary Tangles; Passive Immunization; Pathogenesis; Patients; Peptides; Peripheral; Phenotype; Play; Production; Recombinant adeno-associated virus (rAAV); Reporting; Role; Safety; Screening procedure; Senile Plaques; Serotyping; Site; T-Lymphocyte; Topical application; Transgenic Mice; Treatment Efficacy; aged; amyloid peptide; base; cell mediated immune response; familial Alzheimer disease; gene therapy; immunoreactivity; improved; lateral ventricle; mouse model; mutant; neuron loss; neurotoxicity; novel; overexpression; peptide A; presenilin-1; prevent; prophylactic; public health relevance; research study; transgene expression

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia after the age of 60. The pathological hallmarks of AD include deposition of amyloid ?-peptide (A?) in neuritic plaques and cerebral blood vessels, neurofibrillary tangles, and loss of neurons. Increasing evidence supports the notion that A? and its precursor play important roles in the pathogenesis of AD. Immunization of mouse models of AD with synthetic A? reduces A? deposits and attenuates their memory and learning deficits. Recent clinical trials, however, were halted due to brain inflammation, presumably induced by T-cell mediated and/or Fc-mediated immune responses. Peripheral administration of antibodies against A? also induced clearance of preexisting amyloid plaques in AD mouse models, indicating that an active T-cell-mediated immune response is unnecessary. Topical application of the F(ab')2 without Fc of antibodies against A? led to clearance of amyloid deposits in an AD mouse model, indicating that non-Fc-mediated mechanisms are involved in the clearance. Although these passive immunization modalities may be effective in treating AD patients without inducing inflammatory responses, such modalities suffer from cerebral hemorrhages and repeated administrations of antibodies, leading to a large financial and physical burden to AD patients. We hypothesize that single chain antibodies (scFvs) against A? are effective and safe in treating AD mouse models. We further hypothesize that A? - hydrolyzing immunoglobulin variable domains (IgVs) are superior to reversibly biding Igs in terms of their A? - clearance efficacy and safety. We proposed to produce catalytic and non-catalytic Ig in the brains of AD model mice via rAAV-mediated gene delivery and compare their efficacy and safety in reducing cerebral A? load and improving behavioral deficits. This study will serve as a proof of principle to demonstrate if expression of catalytic and non-catalytic Igs in the brain safely clears A? deposits and improves learning and memory deficits in an AD mouse model. The Specific Aims of this study are (Aim 1) to express catalytic and non-catalytic Igs in a young AD mouse model and compare their prophylactic efficacy and safety and (Aim 2) to express catalytic and non-catalytic Igs in an aged AD mouse model and compare their therapeutic efficacy and safety. We utilize neuropathological, biochemical, immunological, and behavioral analyses to determine the prophylactic and therapeutic efficacy and safety of the modalities. The long-term goal is to establish the logical basis for developing safe and effective immunotherapy for AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. This study will serve as a proof of principle to demonstrate if our novel immune gene therapy modality for A? -catalytic and non-catalytic antibody delivery is effective and safe in treating an animal model of AD.

描述(申请人提供)：阿尔茨海默病(AD)是60岁后最常见的痴呆症原因。AD的病理特征为淀粉样多肽(A？)沉积。在神经炎斑块和脑血管中，神经原纤维缠绕，神经元丢失。越来越多的证据支持A？其前体在AD的发病机制中起重要作用。人工合成A？A免疫小鼠AD模型降低A？储存和减弱他们的记忆和学习缺陷。然而，最近的临床试验由于脑部炎症而暂停，推测是由T细胞和/或FC介导的免疫反应引起的。外周注射抗A抗体？也诱导了AD小鼠模型中先前存在的淀粉样斑块的清除，表明主动的T细胞介导的免疫反应是不必要的。外用不含抗A抗体Fc的F(ab‘)2？导致AD小鼠模型中淀粉样蛋白沉积的清除，表明非FC介导的机制参与了清除。虽然这些被动免疫方案可能在不引起炎症反应的情况下有效地治疗AD患者，但这些方案存在脑出血和反复注射抗体的问题，给AD患者带来了巨大的经济和身体负担。我们假设抗A？单链抗体？对AD小鼠模型的治疗是有效和安全的。我们进一步假设，A？-水解型免疫球蛋白可变区(IgV)在A？-清除性和安全性方面优于可逆性结合的免疫球蛋白。我们建议通过rAAV介导的基因传递在AD模型小鼠脑内产生催化和非催化免疫球蛋白，并比较它们在降低脑A？加载和改善行为缺陷。这项研究将作为一个原则证明，证明大脑中催化和非催化免疫球蛋白的表达是否安全地清除A？在AD小鼠模型中沉积并改善学习和记忆缺陷。本研究的具体目的是(1)在幼年AD小鼠模型中表达催化和非催化免疫球蛋白，并比较它们的预防效果和安全性；(2)在老年AD小鼠模型中表达催化和非催化免疫球蛋白，比较它们的治疗效果和安全性。我们利用神经病理、生化、免疫学和行为分析来确定这些方法的预防和治疗效果和安全性。长期目标是为开发安全有效的阿尔茨海默病免疫疗法奠定逻辑基础。 公共卫生相关性：阿尔茨海默病(AD)是导致老年人痴呆症的最常见原因。然而，到目前为止，还没有令人满意的治疗AD的方法。这项研究将作为一个原则的证明，以证明我们的新型免疫基因疗法在治疗阿尔茨海默病动物模型中是否有效和安全。