Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine–adenine–guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full‐time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches—hypothesis‐based candidate molecule testing and hypothesis‐free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.

中文翻译：

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聚谷氨酰胺疾病的治疗方法的发现：最近的工作总结

聚谷氨酰胺（PolyQ）疾病是由特定基因编码区中胞嘧啶-腺嘌呤-鸟嘌呤（CAG）三核苷酸重复序列的扩增引起的一组神经退行性疾病。这导致了含有严重扩展的谷氨酰胺片段的致病蛋白的产生。尽管polyQ疾病很少见，但是这9种疾病在10到30年间不可逆转地发展，严重损害并最终致死这一事实，通常牵涉到长期护理人员的全职患者支持，这对其经济和社会影响产生了影响。相当重要。这已导致全球数名研究人员研究了polyQ疾病的致病机制和治疗策略。尽管最近几十年来该领域的研究显着增长，我们仍然没有有效的治疗方法来为患者提供治疗，而决定将哪些化合物翻译到临床上的决定可能非常具有挑战性。在这篇综述中，我们对polyQ疾病领域的最新药物发现工作进行了全面而严格的概述，包括从两种不同类型的方法中得出的最相关的发现：基于假设的候选分子测试和无假设的无偏见药物放映。我们在此总结并反思迄今为止的临床前研究以及所有临床试验，旨在为日益成功的未来药物发现和开发工作提供有用的框架。我们对polyQ疾病领域的最新药物发现工作进行了全面而严格的概述，包括从两种不同类型的方法中得出的最相关的发现：基于假设的候选分子测试和无假设的无偏见药物筛选。我们在此总结并反思迄今为止的临床前研究以及所有临床试验，旨在为日益成功的未来药物发现和开发工作提供有用的框架。我们对polyQ疾病领域的最新药物发现工作进行了全面而严格的概述，包括从两种不同类型的方法中得出的最相关的发现：基于假设的候选分子测试和无假设的无偏见药物筛选。我们在此总结并反思迄今为止的临床前研究以及所有临床试验，旨在为日益成功的未来药物发现和开发工作提供有用的框架。