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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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）：阿尔茨海默氏病（AD）是60岁以后的最常见痴呆症原因。AD的病理标志包括淀粉样蛋白的沉积？ - 肽（A？）在神经斑块和脑血管，神经纤维纤维纤维缠结和神经元和神经元的损失中。越来越多的证据支持了一个观念？它的前体在AD的发病机理中起重要作用。与合成A的AD小鼠模型免疫？减少A？沉积并减轻他们的记忆和学习缺陷。然而，最近由于脑部炎症而停止了最近的临床试验，这可能是由T细胞介导的和/或FC介导的免疫反应引起的。对A的抗体外周施用？还诱导了AD小鼠模型中淀粉样蛋白斑块的清除，这表明无需使用主动T细胞介导的免疫反应。 f（ab'）2的局部应用，没有针对A的抗体FC？导致在AD小鼠模型中清除淀粉样蛋白沉积物，表明非FC介导的机制参与了清除率。尽管这些被动免疫方式可能有效地治疗AD患者而无需诱发炎症反应，但这种方式患有大脑出血和反复施用抗体，从而给AD患者带来了巨大的财务和身体负担。我们假设单链抗体（SCFV）针对A？在治疗AD鼠标模型方面有效且安全。我们进一步假设一个？ - 水解免疫球蛋白可变结构域（IGV）优于可逆的a？ - 清除功效和安全性。我们建议通过RAAV介导的基因递送在AD模型小鼠的大脑中产生催化和非催化Ig，并比较其在减少脑A的功效和安全性吗？负载和改善行为缺陷。这项研究将作为原理证明，以证明大脑中催化和非催化IG的表达是否可以安全地清除A？沉积并改善AD鼠标模型中的学习和记忆缺陷。这项研究的具体目的是（目标1）在年轻的AD小鼠模型中表达催化和非催化Ig，并比较其预防性疗效和安全性以及（AIM 2）在老年AD小鼠模型中表达催化和非催化Ig，并比较其治疗效率和安全性。我们利用神经病理学，生化，免疫和行为分析来确定模态的预防和治疗功效和安全性。长期目标是建立为AD开发安全有效的免疫疗法的逻辑基础。公共卫生相关性：阿尔茨海默氏病（AD）是老年痴呆症的最常见原因。但是，迄今为止，AD尚无令人满意的治疗方法。这项研究将作为原理证明，以证明我们的新型免疫基因治疗方式是否？ - 催化和非催化抗体递送在治疗AD动物模型方面有效且安全。