Immunotherapy against tauopathy in a transgenic mouse model

描述(由申请人提供)：tau病理是许多神经退行性疾病的致病因素。Tau基因的突变会导致一些家族性的额颞叶痴呆症，这种痴呆症的发生没有伴随的淀粉样病变。Tg4510小鼠是基于tau基因突变之一的转基因模型。它是一种侵袭性的tau病模型，导致与年龄相关的tau沉积，行为障碍和多个前脑结构的神经变性。免疫疗法正在迅速发展，FDA批准了近30种药物。免疫治疗也是最先进的抗淀粉样蛋白方法之一。多项临床试验正在测试抗A免疫疗法作为治疗痴呆症的方法。我们小组提供了大量临床前小鼠数据，支持辉瑞公司正在临床上使用其中一种药物。尽管研究较少，但目前只有几种治疗策略针对tau作为痴呆症的治疗方法。鉴于tau在神经退行性疾病中的作用比淀粉样蛋白更广泛，针对这种多肽的方法可能比抗淀粉样蛋白策略产生更大的影响。这项应用将研究在Tg4510小鼠模型中使用抗tau抗体作为一种去除tau沉积的方法。初步数据显示，一次颅内注射针对所有形式的tau(tau-5，中区表位IgG1，不是磷酸化特异性的)的抗体可以减少组织学鉴定的tau，并减少Galyas鉴定的银染沉积。我们希望继续进行这一初步观察，以解决4个具体目标。第一个目标是使用颅内注射检查来自3个不同类别的9种不同抗体的有效性。第一类是结合tau所有亚型的抗体，比如在初步数据中成功的tau-5抗体。第二类是针对tau上特定磷酸化残基的抗体。在一个不同的tau模型中，Sigurdsson的团队已经证明了针对磷酸型tau的疫苗可以减少tau的沉积(应用中引用)。第三类抗体针对tau的特定修饰，包括构象变化、硝化和截断。如果有效，这些后一种抗体可能具有更大的安全性，因为它们不应该针对与轴突运输调节有关的tau亚型。第二个目标将通过幼鼠和全身给药来测试其中一些抗体是否可以防止tau进一步沉积。目标3将测试全身给药途径是否可以通过全身给药在老年小鼠身上清除先前存在的tau沉积。目的4将验证这样一种假设，即联合颅内注射以清除先前存在的沉积物，并跟踪全身给药以防止新沉积物的形成是一种比单独使用任何一种方法更好的策略。 与公共健康相关：一种名为tau的蛋白质在许多患有与年龄相关的脑部疾病的人的大脑中积累。沉积的tau会导致神经元死亡，并损害正常的大脑功能。疾病包括皮克氏病、额颞叶痴呆症和阿尔茨海默病。这些实验将使用与tau蛋白结合的抗体，试图将其从大脑中消除。这可能导致使用类似的抗体或可能的疫苗来治疗这些疾病的患者。

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.