Immunotherapy against tauopathy in a transgenic mouse model

描述（由申请人提供）：Tau病理学是许多神经退行性疾病中的致病因素。tau基因的突变导致了一些家族性额颞叶痴呆，这种痴呆的发生没有伴随淀粉样病变。Tg 4510小鼠是基于tau中这些突变之一的转基因模型。它是tau蛋白病的侵袭性模型，并导致多个前脑结构中的年龄依赖性tau蛋白沉积、行为障碍和神经变性。免疫疗法正在迅速发展，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。多项临床试验正在测试抗A β免疫疗法作为痴呆症的治疗方法。我们的团队提供了大量的临床前小鼠数据，支持辉瑞公司在临床上使用这些药物之一。尽管研究较少，但目前只有少数靶向tau蛋白的治疗策略可用于治疗痴呆症。鉴于tau蛋白在神经退行性疾病中的参与比淀粉样蛋白更广泛，靶向这种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Tg 4510小鼠模型中tau沉积物的方法。初步数据显示，单次颅内注射针对所有形式的tau（tau-5，中间结构域表位IgG 1，非磷酸化特异性）的抗体可减少组织学鉴定的tau并减少Gallyas鉴定的银染色沉积物。我们希望继续这一初步意见，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种不同抗体的功效。第一类是结合所有tau亚型的抗体，如在初步数据中成功的tau-5抗体。第二类是靶向tau上特异性磷酸化残基的抗体。在不同的tau模型中，Sigurdsson的研究小组已经表明，针对tau磷酸化形式的疫苗可以减少tau沉积（参考申请中）。第三类抗体靶向tau的特异性修饰，包括构象变化、硝化和截短。如果有效的话，这些后一种抗体可能具有更大的安全性，因为它们不应该靶向参与轴突运输调节的tau亚型。第二个目标将测试这些抗体中的一些是否可以使用年轻小鼠和全身给药来防止进一步的tau沉积。目的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去除预先存在的tau沉积物。目的4将检验以下假设：联合颅内注射以清除既存沉积物，并随后全身给药以防止新沉积物形成，这是一种优于单独使用的上级策略。

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-Aβ 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.