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: 8081811
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 19.24万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081811
• 关键词: AN-1792; APP gene; Adverse effects; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Amyloid deposition; 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; Immune; Immune response; Immunization; Immunoglobulin G; Immunoglobulin Genes; 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; Peptide antibodies; 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; 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（由申请人提供）：阿尔茨海默病（AD）是60岁后痴呆症的最常见原因。AD的病理学特征包括淀粉样蛋白沉积？肽（A？）神经炎斑块和脑血管、神经纤维缠结和神经元丢失。越来越多的证据支持的概念，A？及其前体在AD的发病中起重要作用。用合成的A？减少A？沉积并减弱他们的记忆和学习缺陷。然而，最近的临床试验由于脑炎症而停止，推测是由T细胞介导和/或Fc介导的免疫应答诱导的。外周给药抗A？还诱导清除AD小鼠模型中预先存在的淀粉样蛋白斑块，表明不需要主动T细胞介导的免疫应答。局部应用的F（ab '）2没有Fc的抗体抗A？导致AD小鼠模型中淀粉样蛋白沉积物的清除，表明非Fc介导的机制参与清除。虽然这些被动免疫方式可以有效地治疗AD患者而不诱导炎症反应，但这些方式遭受脑损伤和抗体的重复施用，导致AD患者的巨大经济和身体负担。我们假设，单链抗体（scFv）对A？治疗AD小鼠模型有效、安全。我们进一步假设，A？- 水解免疫球蛋白可变结构域（IgV）是上级可逆结合免疫球蛋白方面，他们的A？- 清除效果和安全性。我们提出通过rAAV介导的基因递送在AD模型小鼠脑中产生催化和非催化IG，并比较它们在降低脑A？负荷和改善行为缺陷。这项研究将作为一个原则的证明，以证明如果在大脑中的催化和非催化免疫球蛋白的表达安全地清除A？沉积并改善AD小鼠模型中的学习和记忆缺陷。本研究的具体目的是（目的1）在年轻AD小鼠模型中表达催化和非催化Ig，并比较其预防有效性和安全性;（目的2）在老年AD小鼠模型中表达催化和非催化Ig，并比较其治疗有效性和安全性。我们利用神经病理学、生化、免疫学和行为分析来确定这些方法的预防和治疗功效和安全性。长期目标是为开发安全有效的AD免疫疗法奠定逻辑基础。 公共卫生相关性：阿尔茨海默病（AD）是老年痴呆症最常见的原因。然而，迄今为止，没有令人满意的治疗AD。这项研究将作为一个原则的证明，以证明如果我们的新的免疫基因治疗模式为A？- 催化和非催化抗体递送在治疗AD动物模型中是有效且安全的。