Clearance and In Vivo Detection of Tau Pathology

描述（由申请人提供）：淀粉样蛋白-β (Aβ)在阿尔茨海默病（AD）中的靶向治疗正在几个临床试验中，其中许多是免疫疗法。迄今为止的研究结果表明，清除Aβ斑块并不能减缓痴呆症的进展，这强调了寻找替代靶点的必要性，最近的III期Aβ抗体试验的失败进一步支持了这一点。显然，tau病理是AD的另一个重要靶点，也是其他tau病变的主要靶点。与Aβ沉积相比，病理性tau的存在与痴呆程度的相关性要好得多。因此，一旦认知障碍明显，清除tau可能比清除Aβ更有效，理想情况下，AD的这两种特征最终应该一起预防。在诊断方面，单链可变抗体片段（scFv's）作为成像配体用于检测AD或其他tau病变的tau病变是有吸引力的。β片结合染料衍生的a β斑块成像探针已经在临床应用，一些这样的tau结合染料正在动物和人类中进行评估。抗体衍生探针可能为检测tau病变提供更大的特异性。此外，通道追踪锰增强磁共振成像（tt-MEMRI）是一种独特的技术，用于研究tau病理如何损害活体动物的神经元运输，并用于纵向监测相关治疗的疗效。特异性目的1是在转基因牛头病小鼠中确定最有效的tau活性免疫方法。我们已经评估了各种磷酸化tau免疫原的疗效，其中最有效的一个包含P-Ser396, 404表位。假设靶向多个表位将增强疗效。如果不是，那么临床上使用单个表位进行免疫会更安全，因为这些表位不太可能导致不良的T

DESCRIPTION (provided by applicant): Amyloid-β (Aβ) in Alzheimer's disease (AD) is being targeted in several clinical trials, with many being immunotherapies. Findings to date indicate that Aβ plaque clearance does not slow progression of dementia, emphasizing the need for alternative targets, further supported by the recent failures of Phase III Aβ antibody trials. Obviously, tau pathology is another important target in AD, and the primary one in other tauopathies. Presence of pathological tau correlates much better with the degree of dementia than Aβ deposition. Hence, clearing tau may be more effective than removing Aβ once cognitive impairments are evident, and ideally both these hallmarks of AD should eventually be targeted together prophylactically. On the diagnostic front, single chain variable antibody fragments (scFv's) are attractive as imaging ligands to detect tau lesions in AD or other tauopathies. Aβ plaque imaging probes derived from β-sheet binding dyes are already in clinical use, and a few such tau-binding dyes are being evaluated in animals and humans. Antibody-derived probes are likely to provide greater specificity for detecting tau lesions. Furthermore, tract-tracing manganese-enhanced magnetic resonance imaging (tt-MEMRI) is a unique technique to study how tau pathology impairs neuronal transport in live animals, and for monitoring longitudinally the efficacy of related therapies. Specific Aim 1 is to identify the most efficacious active tau immunization approach in transgenic tauopathy mice. We have assessed the efficacy of various phospho-tau immunogens, with the most efficacious one encompassing the P-Ser396, 404 epitope. It is hypothesized that targeting multiple epitopes will enhance efficacy. If not, it woul be clinically safer to immunize with a single epitope as those are less likely to lead to adverse T cell activation. Ideally, this should be clarified prior to clinical trials. Specific Aim 2 is to asess the therapeutic and diagnostic utility of various tau antibody fragments that we have generated using phage display technology. We hypothesize that because of their smaller size, scFv's will be more efficacious than antibodies as therapy or diagnostic PET markers for tau pathology. We have already identified several tau-targeting scFv's that show promise in vitro and in vivo. Specific Aim 3 is to determine if tau immunotherapy can acutely improve neuronal transport in vivo, and/or reverse such impairments. Furthermore, it will be clarified if such improvements correlate with clearance of pathological soluble and/or insoluble tau. We have shown with tt-MEMRI that neuronal transport decreases as tau pathology advances, and that prophylactic active tau immunization improves such transport. We now seek to assess acute and long term benefits of tau antibodies with such imaging. We hypothesize that both approaches (acute, reversal) will improve neuronal transport but only the latter will correlate with clearance of insoluble tau, suggesting that soluble tau is a valid therapeutic target. Overall, these three aims may lead to novel therapies and diagnostic markers for AD and related tauopathies.