Why Therapeutic Trials Fail in Primary Tauopathies.
Why Therapeutic Trials Fail in Primary Tauopathies.
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为什么原发性 Tau蛋白病的治疗试验失败。
DOI：
10.1002/mds.29322
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Litvan,Irene
中科院分区：
文献类型：
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作者：
Olfati,Nahid;Ghodsi,Hamidreza;Bayram,Ece;Litvan,Irene
原发性tau蛋白病是神经退行性疾病，其中tau蛋白聚集体构成主要的潜在神经病理过程。Tau蛋白是一组六种异构体，其结合并稳定微管，并在轴突运输中发挥作用。进行性核上性麻痹（PSP）和皮质基底节变性（CBD）被认为是基于聚集体中主要tau异构体的4-重复（4 R）tau蛋白病1，目前没有有效的药物治疗这些疾病。旨在减缓或停止疾病进展的实验性治疗试验大多针对PSP进行，而CBD的频率较低。虽然几种有前途的疾病修饰药物的不同目标和动物模型上的有效性已在精心设计的人体临床试验中实施（图），但都未能减缓或阻止疾病进展。鉴于基础研究与临床转化之间的巨大差距，本文综述了相关的实验性治疗试验步骤，包括受试者选择、治疗靶点和实验平台。提供了将未来治疗方法转化为成功的疾病修饰剂的关键考虑因素（表）。
Primary tauopathies are neurodegenerative diseases in which tau protein aggregates constitute the main underlying neuropathologic process. Tau proteins are a group of six isomers that bind to and stabilize microtubules and play a role in axonal transport. Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are considered 4-repeat (4R) tauopathies based on the predominant tau isomer in the aggregates1 and there are currently no effective pharmacological treatments for these disorders. Experimental therapeutic trials designed to slow or halt disease progression have mostly been conducted for PSP and less frequently for CBD. Although several promising disease-modifying drugs of different targets and proven efficacy on animal models have been implemented in well-designed human clinical trials (Figure), all have failed to slow or halt disease progression. In the view of the wide gap between basic research and its translation into clinic, here we reviewed relevant experimental therapeutic trial steps, including participant selection, therapeutic targets, and experimental platforms. Key considerations for advancing the translation of future therapeutic approaches into successful disease modifying agents are provided (Table).