AAV-mediated muscle-directed gene transfer for Alzheimer's disease

AAV 介导的肌肉定向基因转移治疗阿尔茨海默病

• 批准号: 7237742
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 16.47万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237742
• 关键词: AN-1792; APP gene; Adverse effects; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Amyloid deposition; Antibodies; Appendix; Attenuated; Behavioral; Biochemical; Blood Circulation; Blood Vessels; Brain; Cerebrum; Clinical Trials; Cognitive deficits; Dementia; Deposition; Elderly; Encephalitis; Epitopes; Etiology; Fc Receptor; Goals; Human; Immune; Immune response; Immunization; Immunotherapy; Inflammatory Response; Injection of therapeutic agent; Knock-out; Learning; Mediating; Memory; Memory impairment; Modality; Monitor; Mus; Muscle; Mutation; Needles; Neurodegenerative Disorders; Neurofibrillary Tangles; Passive Immunization; Pathogenesis; Pathology; Patients; Peptides; Peripheral; Play; Prevention; Production; Protein Overexpression; Recombinant adeno-associated virus (rAAV); Reporting; Role; Safety; Screening procedure; Senile Plaques; Serum; Skeletal Muscle; T-Lymphocyte; Therapeutic Effect; Thigh structure; Topical application; Toxic effect; Transgenic Mice; amyloid peptide; base; cell mediated immune response; familial Alzheimer disease; gene therapy; immunoreactivity; improved; mouse model; mutant; neuron loss; novel; peptide A; presenilin-1; prevent; prophylactic; vector

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is the most common cause of dementia after the age of 60. The pathological hallmarks of Alzheimer's disease 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 Alzheimer's disease. Immunization of mouse models of Alzheimer's disease 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 also involved in the clearance. We have demonstrated that human single chain antibody (scFv) against A¿ was also effective in reducing brain A¿ load in an AD mouse model. Although these passive immunization modalities may be effective in treating AD patients without inducing side effects such as inflammatory responses, such modalities suffer from repeated administrations of antibodies, leading to a large financial and physical burden to AD patients. We hypothesize that scFvs against A¿ are effective and safe in treating AD patients as well as AD mouse models. We propose to use novel immune gene therapy for Alzheimer's disease, whereby recombinant adeno-associated virus (rAVV) vectors encoding anti-A¿ scFvs are directed to skeletal muscles in order to deliver the scFvs into the circulation and, probably, into the brain. This study will serve as a proof of principle to demonstrate if this gene therapy modality can deliver anti-A¿ scFvs into the circulation enough to reduce brain A¿ load and improve learning and memory deficits in an AD mouse model. In Specific Aim 1, we will evaluate prophylactic effects of muscle directed gene therapy modality by an rAAV vector encoding anti-A¿ scFv on prevention of A¿ deposits and behavioral deficits in an AD mouse model. In Aim 2, we will evaluate therapeutic effects of muscle-directed gene therapy modality by an rAAV vector encoding anti-A¿ scFv on clearance of A¿ deposits as well as improvement of behavioral deficits in an AD mouse model. We utilize neuropathological, biochemical, immunological, and behavioral analyses to determine the prophylactic and therapeutic effects and safety of the modality. The long-term goal is to establish the logical basis for developing safe and effective gene therapy modalities for AD utilizing rAAV and scFv.

描述（由申请人提供）：阿尔茨海默病（AD）是 60 岁以后痴呆的最常见原因。阿尔茨海默病的病理特征包括淀粉样蛋白沉积 ¿神经炎斑块和脑血管、神经原纤维缠结和神经元损失中的β-肽(A¿) 越来越多的证据支持A¿及其前体在阿尔茨海默病的发病机制中发挥重要作用 用合成的 A¿ 免疫阿尔茨海默病小鼠模型。 A 减少然而，最近的临床试验因脑部炎症而停止，这可能是由 T 细胞介导和/或 Fc 介导的外周注射抗 A 抗体引起的。还诱导 AD 小鼠模型中预先存在的淀粉样蛋白斑块的清除，表明无需局部应用 F(ab')2，而无需抗 A¿ 抗体。导致 AD 小鼠模型中淀粉样沉积物的清除，表明非 Fc 介导的机制也参与清除，我们已经证明针对 A¿ 的人单链抗体 (scFv)。也能有效减少脑A?尽管这些被动免疫方式可能有效治疗 AD 患者，且不会引起炎症反应等副作用，但这种方式会导致抗体的重复施用，给 AD 患者带来巨大的经济和身体负担。保持 scFv 对抗 A¿我们建议使用新型免疫基因疗法治疗阿尔茨海默氏病，从而编码抗-A¿的重组腺相关病毒（rAVV）载体。 scFv 被定向到骨骼肌，以便将 scFv 输送到循环系统中，并可能输送到大脑中。这项研究将作为原理证明，证明这种基因治疗方式是否可以输送抗 A 抗体。 scFv 进入循环足以减少脑 A¿在特定目标 1 中，我们将评估编码抗 A 的 rAAV 载体的肌肉定向基因治疗方式的预防效果。 scFv 预防 A¿在目标 2 中，我们将评估编码抗 A¿ 的 rAAV 载体的肌肉定向基因治疗方式的治疗效果。 scFv 对 A¿ 的清除我们利用神经病理学、生化、免疫学和行为分析来确定该方法的预防和治疗效果以及安全性。利用 rAAV 和 scFv 开发安全有效的 AD 基因治疗方式。