Polyglutamine (polyQ) disorders are a group of nine neurodegenerative diseases that share a common genetic cause, which is an expansion of CAG repeats in the coding region of the causative genes that are otherwise unrelated. The trinucleotide expansion encodes for an expanded polyQ tract in the respective proteins, resulting in toxic gain-of-function and eventually in neurodegeneration. Currently, no disease-modifying therapies are available for this group of disorders. Nevertheless, given their monogenic nature, polyQ disorders are ideal candidates for therapies that target specifically the gene transcripts. Antisense oligonucleotides (ASOs) have been under intense investigation over recent years as gene silencing tools. ASOs are small synthetic single-stranded chains of nucleic acids that target specific RNA transcripts through several mechanisms. ASOs can reduce the levels of mutant proteins by breaking down the targeted transcript, inhibit mRNA translation or alter the maturation of the pre-mRNA via splicing correction. Over the years, chemical optimization of ASO molecules has allowed significant improvement of their pharmacological properties, which has in turn made this class of therapeutics a very promising strategy to treat a variety of neurodegenerative diseases. Indeed, preclinical and clinical strategies have been developed in recent years for some polyQ disorders using ASO therapeutics. The success of ASOs in several animal models, as well as encouraging results in the clinic for Huntington's disease, points towards a promising future regarding the application of ASO-based therapies for polyQ disorders in humans, offering new opportunities to address unmet medical needs for this class of disorders. This review aims to present a brief overview of key chemical modifications, mechanisms of action and routes of administration that have been described for ASO-based therapies. Moreover, it presents a review of the most recent and relevant preclinical and clinical trials that have tested ASO therapeutics in polyQ disorders.

中文翻译：

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神经退行性疾病中的反义寡核苷酸疗法：多谷氨酰胺失调的情况。

聚谷氨酰胺（polyQ）疾病是一组九种神经退行性疾病，它们具有共同的遗传原因，这是CAG重复在原本不相关的病原基因的编码区域中扩展的原因。三核苷酸的扩展编码相应蛋白质中扩展的polyQ链，导致有毒的功能获得，并最终导致神经退行性变。目前，没有针对该类疾病的可改变疾病的疗法。然而，鉴于其单基因性质，polyQ疾病是专门针对基因转录物的疗法的理想候选者。近年来，反义寡核苷酸（ASO）作为基因沉默工具已经受到了广泛的研究。ASO是小的合成核酸单链链，可通过多种机制靶向特定的RNA转录本。ASO可以通过分解目标转录物，抑制mRNA的翻译或通过剪接校正来改变pre-mRNA的成熟来降低突变蛋白的水平。多年来，ASO分子的化学优化已极大地改善了它们的药理特性，从而使这类疗法成为治疗各种神经退行性疾病的非常有前途的策略。确实，近年来已经使用ASO治疗剂为某些polyQ疾病开发了临床前和临床策略。ASO在几种动物模型中的成功，以及在亨廷顿舞蹈病临床上令人鼓舞的结果，指出针对AQ疗法在人类polyQ疾病中的应用前景广阔，为解决此类疾病的未满足医疗需求提供了新的机会。这篇综述旨在简要概述已针对基于ASO的疗法描述的关键化学修饰，作用机理和给药途径。此外，它提供了最近和相关的临床前和临床试验的综述，这些试验已经在polyQ疾病中测试了ASO疗法。