Immunotherapy against tauopathy in a transgenic mouse model

转基因小鼠模型中针对 tau 蛋白病的免疫疗法

基本信息

批准号：
8263382
负责人：
David Morgan
金额：
$ 34.61万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8263382
关键词：
Acute Address Adverse event Age Alzheimer&apos s Disease Amyloid Antibodies Antibody Formation Avastin Axonal Transport Behavioral Binding Binding Sites Brain Brain Diseases Brain region Categories Cause of Death Cessation of life Clinic Clinical Trials Cognitive Data Dementia Deposition Disease Dose Doxycycline Drug Industry Epitopes Etanercept FDA approved Genes Histologic Human Humira IgG1 Immunotherapeutic agent Immunotherapy Individual Injection of therapeutic agent Lead Lobe Measures Mediating Memory impairment Methods Modeling Modification Monoclonal Antibodies Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organism Pathology Patients Peptides Peripheral Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Phosphorylation Pick Disease of the Brain Prevention strategy Prosencephalon Protein Isoforms Proteins Regulation Research Research Design Route Safety Silver Staining Structure Tauopathies Temporal Lobe Testing Therapeutic Therapeutic antibodies Time Transgenic Mice Transgenic Model Vaccination Vaccines age related aged amyloid pathology base behavior measurement cost effective experience middle age mouse model neurochemistry neuron loss nitration pre-clinical prevent public health relevance research study response tau Proteins tau aggregation transgene expression

项目摘要

DESCRIPTION (provided by applicant): Tau pathology is implicated as a pathogenic factor in a number of neurodegenerative disorders. Mutations in the tau gene cause some familial cases of frontotemporal lobe dementia, which occurs without concomitant amyloid pathology. The Tg4510 mouse is a transgenic model based on one of these mutations in tau. It is an aggressive model of tauopathy and results in age-dependent tau deposition, behavioral disturbance and neurodegeneration in multiple forebrain structures. Immunotherapy is rapidly advancing with almost 30 FDA approved medications. Immunotherapy is also one of the most advanced anti-amyloid approaches. Multiple clinical trials are testing anti-A¿ immunotherapy as a treatment for dementia. Our group supplied the bulk of the preclinical mouse data supporting the use of one of these agents being pursued in the clinic by Pfizer. Although less extensively examined, presently there are only a few therapeutic strategies targeting tau as a treatment for dementia. Given the broader involvement of tau in neurodegenerative disorders than amyloid, approaches targeting this peptide may have even greater impact than anti-amyloid strategies. This application will investigate the use of anti-tau antibodies as an approach to removing tau deposits in the Tg4510 mouse model. Preliminary data shows that a single intracranial injection of an antibody directed against all forms of tau (tau-5, mid domain epitope IgG1, not phosphorylation specific) can reduce histologically identified tau and reduce silver stained deposits identified by Gallyas. We wish to pursue this initial observation to address 4 specific aims. The first aim will examine the efficacy of 9 different antibodies from 3 different categories using intracranial injections. The first category is antibodies binding all isoforms of tau, like the tau-5 antibody which was successful in the preliminary data. The second category is antibodies targeting specific phosphorylated residues on tau. In a different tau model, Sigurdsson's group has shown vaccines targeting phospho-forms of tau can reduce tau deposition (ref in application). The third category of antibodies targets specific modifications of tau, including conformational changes, nitration and truncation. These latter antibodies might have a greater safety profile, if effective, as they should not target tau isoforms involved with regulation of axonal transport. The second aim will test whether some of these antibodies can prevent further tau deposition using young mice and systemic administration. Aim 3 will test if the systemic route of administration can remove pre-existing tau deposits using systemic administration in older mice. Aim 4 will test the hypothesis that combining intracranial injections to clear pre-existing deposits and following up with systemic administration to prevent formation of new deposits is a superior strategy than either alone. PUBLIC HEALTH RELEVANCE: A protein called tau accumulates in the brain of many humans who develop age-associated brain diseases. The deposited tau causes death of neurons and impairs normal brain function. Diseases include Pick's disease, frontotemporal lobe dementia and Alzheimer's disease. These experiments will use antibodies that bind to the tau protein in an attempt to eliminate it from the brain. This may lead to use of similar antibodies or possible vaccines to treat patients with these diseases.

描述（由申请人提供）：tau 病理学是许多神经退行性疾病的致病因素。tau 基因突变会导致一些家族性额颞叶痴呆病例，而这种情况的发生并不伴有淀粉样蛋白病理学。Tg4510 小鼠是转基因模型。基于 tau 蛋白的这些突变之一，它是一种侵袭性的 tau 蛋白病模型，会导致年龄依赖性 tau 蛋白沉积、行为障碍。多种前脑结构的神经退行性疾病正在迅速发展，近 30 种 FDA 批准的药物也是最先进的抗淀粉样蛋白方法之一。我们的小组提供了大量临床前小鼠数据，支持辉瑞公司在临床上使用其中一种药物，尽管研究较少，但目前只有少数针对 tau 蛋白的治疗策略。鉴于 tau 蛋白比淀粉样蛋白更广泛地参与神经退行性疾病，因此针对该肽的方法可能比抗淀粉样蛋白策略具有更大的影响，本申请将研究使用抗 tau 抗体作为去除 tau 蛋白的方法。 Tg4510 小鼠模型中的沉积物初步数据表明，单次颅内注射针对所有形式 tau 的抗体（tau-5，中域表位 IgG1，非磷酸化特异性）可以减少组织学鉴定的 tau 并减少通过银染色鉴定的沉积物。 Gallyas。我们希望通过这一初步观察来解决 4 个具体目标，第一个目标是使用 3 个不同类别的 9 种不同抗体来检验其功效。第一类是结合 tau 的所有同种型的抗体，例如在抗体的初步数据中取得成功的 tau-5 抗体。研究表明，针对 tau 磷酸化形式的疫苗可以减少 tau 沉积（参考申请）。第三类抗体针对 tau 的特定修饰，包括构象变化、硝化。如果有效的话，后一种抗体可能具有更高的安全性，因为它们不应该针对参与轴突运输调节的 tau 异构体。目标 3 将测试全身给药途径是否可以在老年小鼠中使用全身给药来清除预先存在的 tau 沉积物，目标 4 将测试结合颅内注射以清除预先存在的沉积物的假设。通过系统管理来防止新存款的形成是比单独采取任何一种策略更好的策略。公共健康相关性：许多患有与年龄相关的脑部疾病的人的大脑中会积聚一种名为 tau 的蛋白质，这种蛋白质会导致神经元死亡并损害正常的大脑功能，这些疾病包括皮克氏病、额颞叶痴呆和阿尔茨海默病。将使用与 tau 蛋白结合的抗体，试图将其从大脑中消除，这可能会导致使用类似的抗体或可能的疫苗来治疗患有这些疾病的患者。