Memory and Aging Center, Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA.
Casma Therapeutics, Cambridge, MA, USA.
Neurosci Lett. 2020 Jul 13;731:134919. doi: 10.1016/j.neulet.2020.134919. Epub 2020 May 4.
Tauopathies are a group of over 20 clinicopathological neurodegenerative diseases including Alzheimer's disease (AD), the most common type of dementia, progressive supranuclear palsy, Pick's disease, corticobasal degeneration, among others. Tauopathies are defined by neurodegeneration and the presence of tau aggregates in affected brains regions. Interestingly, regional tau aggregation burden correlates with clinical phenotype and predicts cognitive status. Autosomal dominant mutations in the MAPT gene lead to tau deposition and clinical FTD syndromes with cognitive, behavioral, and motor impairment. Polymorphisms in or around the MAPT gene have also been strongly linked to other proteinopathies including synucleinopathies. Taken together these findings suggests that tau plays a critical role in neurodegeneration and proteinopathies, supporting the idea that tau targeted approaches can be disease-modifying and lead to clinically meaningful benefits in slowing or reversing disease progression. Increasingly, human clinical trials are testing this hypothesis. This article reviews tau-targeted therapies tested in clinical trials as well as agents currently in active development based on publicly disclosed information. We describe the therapeutic approaches of these trials based on the potential pathogenic mechanism they target.
tau 病是一组超过 20 种临床病理神经退行性疾病，包括阿尔茨海默病（AD），这是最常见的痴呆症类型，进行性核上性麻痹，匹克氏病，皮质基底节变性等。tau 病的定义是神经退行性变和受影响大脑区域中 tau 聚集物的存在。有趣的是，区域 tau 聚集物负担与临床表型相关，并预测认知状态。MAPT 基因的常染色体显性突变导致 tau 沉积和临床 FTD 综合征，伴有认知、行为和运动障碍。MAPT 基因内或周围的多态性也与其他蛋白病（包括突触核蛋白病）密切相关。这些发现表明 tau 在神经退行性变和蛋白病中发挥着关键作用，支持 tau 靶向方法可以改变疾病，并在减缓或逆转疾病进展方面带来有临床意义的益处的观点。越来越多的人类临床试验正在检验这一假设。本文综述了临床试验中测试的 tau 靶向治疗方法，以及基于公开披露信息目前正在积极开发的药物。我们根据它们针对的潜在致病机制描述了这些试验的治疗方法。
