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：
8440343
负责人：
David Morgan
金额：
$ 33.8万
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/8440343
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 Frontotemporal Dementia 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.

描述（由适用提供）：在许多神经退行性疾病中，TAU病理学被作为致病因素实现。 tau基因中的突变引起了一些额颞叶痴呆的家庭病例，这些病例是没有淀粉样蛋白病理学的情况。 TG4510小鼠是基于Tau中这些突变之一的转基因模型。它是一种a酸的侵略性模型，导致多种前脑结构中的年龄依赖性tau沉积，行为灾难和神经变性。免疫疗法正在迅速前进，近30种FDA批准的药物。免疫疗法也是最先进的抗淀粉样蛋白方法之一。多次临床试验正在测试抗A疗法作为痴呆疗法的治疗方法。我们的小组提供了大部分的临床前小鼠数据，该数据支持辉瑞在诊所中使用的其中一种。尽管对较少的检查，但目前只有少数针对tau作为痴呆症治疗的治疗策略。鉴于TAU比淀粉样蛋白更广泛地参与神经退行性疾病，针对该肽的方法可能比抗淀粉样策略具有更大的影响。应用将研究使用抗TAU抗体作为去除TG4510小鼠模型中TAU沉积物的方法。初步数据表明，针对所有形式的tau（tau-5，中域表位表位IgG1而非磷酸化）的单个颅内注射可以减少组织学鉴定的tau并减少由Gallyas鉴定的银染色。我们希望追求这一初步观察，以解决4个具体目标。第一个目的将使用颅内注射从3种不同类别中检查9种不同类别的9种不同抗体的有效性。第一类是结合tau的所有同工型的抗体，例如在初步数据中成功的tau-5抗体。第二类是针对tau上特定磷酸化残差的抗体。在不同的TAU模型中，Sigurdsson的组显示了靶向Tau的磷酸化形式的阴道可以减少Tau沉积（Ref在应用中）。第三类抗体针对TAU的特定修饰，包括会议变化，硝化和截断。这些后一种抗体可能具有更大的安全性，即使是有效的，因为它们不应靶向与轴突运输调节有关的TAU同工型。第二个目标将测试其中一些抗体是否可以防止使用年轻小鼠和全身给药进一步的TAU沉积。 AIM 3将测试全身给药途径是否可以使用较老小鼠的全身给药去除现有的TAU沉积物。 AIM 4将检验以下假设：结合颅内注射以清除现有的沉积物并跟进全身给药以防止形成新的沉积物是一项优越的策略。