Grüninger F
Pharmaceutical Research and Early Development, NORD Disease & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, CH-4070, Basel, Switzerland.
Neuropathol Appl Neurobiol. 2015 Feb;41(1):81-96. doi: 10.1111/nan.12192.
Many different approaches to treating tauopathies are currently being explored, with a few compounds already in clinical development (including small molecules such as anti-aggregation compound LMTX and active vaccines AADvac1 and ACI-35). This review aims to summarize the status of the clinical candidates and to highlight the emerging areas of research that hold promise for drug development. Tau is post-translationally modified in several different ways (phosphorylated, acetylated, glycosylated and truncated). The extent of these modifications can be manipulated to influence tau aggregation state and pathogenesis and the enzymes involved provide tractable targets for drug intervention. In addition, modulation of tau expression levels is an attractive therapeutic approach. Finally, the recently described prion-like spreading of tau between cells opens up novel avenues from the tau drug development perspective. The review compares the merits of small-molecule and antibody-based therapies and emphasizes the need for amenable clinical biomarkers for drug development, particularly PET imaging.
目前正在探索多种治疗tau蛋白病的不同方法，已有一些化合物进入临床开发阶段（包括抗聚集化合物LMTX等小分子以及活性疫苗AADvac1和ACI-35）。本综述旨在总结临床候选药物的现状，并突出那些有望用于药物开发的新兴研究领域。Tau蛋白会通过几种不同方式进行翻译后修饰（磷酸化、乙酰化、糖基化和截短）。这些修饰的程度可被调控，以影响tau蛋白的聚集状态和发病机制，且所涉及的酶为药物干预提供了易于处理的靶点。此外，调节tau蛋白的表达水平是一种有吸引力的治疗方法。最后，最近所描述的tau蛋白在细胞间的朊病毒样传播，从tau蛋白药物开发的角度开辟了新途径。本综述比较了小分子疗法和基于抗体疗法的优点，并强调了药物开发中需要合适的临床生物标志物，尤其是PET成像。
