School of Medicine, Jinan University, Guangzhou, China.
Guangdong Key Laboratory of Non-Human Primate Models, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
Clin Pharmacol Ther. 2024 Dec;116(6):1452-1471. doi: 10.1002/cpt.3341. Epub 2024 Jun 11.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a triad of motor, cognitive, and psychiatric problems. Caused by CAG repeat expansion in the huntingtin gene (HTT), the disease involves a complex network of pathogenic mechanisms, including synaptic dysfunction, impaired autophagy, neuroinflammation, oxidative damage, mitochondrial dysfunction, and extrasynaptic excitotoxicity. Although current therapies targeting the pathogenesis of HD primarily aim to reduce mHTT levels by targeting HTT DNA, RNA, or proteins, these treatments only ameliorate downstream pathogenic effects. While gene therapies, such as antisense oligonucleotides, small interfering RNAs and gene editing, have emerged in the field of HD treatment, their safety and efficacy are still under debate. Therefore, pharmacological therapy remains the most promising breakthrough, especially multi-target/functional drugs, which have diverse pharmacological effects. This review summarizes the latest progress in HD drug development based on clinicaltrials.gov search results (Search strategy: key word "Huntington's disease" in HD clinical investigational drugs registered as of December 31, 2023), and highlights the key role of multi-target/functional drugs in HD treatment strategies.
亨廷顿病（HD）是一种显性遗传的神经退行性疾病，其特征是运动、认知和精神问题的三联征。该疾病由亨廷顿基因（HTT）中的 CAG 重复扩展引起，涉及包括突触功能障碍、自噬受损、神经炎症、氧化损伤、线粒体功能障碍和突触外兴奋性毒性在内的复杂致病机制网络。尽管目前针对 HD 发病机制的治疗方法主要旨在通过靶向 HTT DNA、RNA 或蛋白质来降低 mHTT 水平，但这些治疗方法仅能改善下游的致病效应。尽管基因疗法，如反义寡核苷酸、小干扰 RNA 和基因编辑，已经在 HD 治疗领域崭露头角，但它们的安全性和疗效仍存在争议。因此，药物疗法仍然是最有前途的突破，特别是多靶点/多功能药物，它们具有多种药理学作用。本综述总结了基于 clinicaltrials.gov 搜索结果（搜索策略：截至 2023 年 12 月 31 日，在注册的用于治疗亨廷顿病的药物中输入关键字“亨廷顿病”）的 HD 药物开发的最新进展，并强调了多靶点/多功能药物在 HD 治疗策略中的关键作用。
