Huntington disease (HD) is a fatal progressive neurodegenerative disorder caused by an inherited mutation in the huntingtin (HTT) gene, which encodes mutant HTT protein. Though HD remains incurable, various preclinical studies have reported a favorable response to HTT suppression, emphasizing HTT lowering strategies as prospective disease-modifying treatments. Antisense oligonucleotides (ASOs) lower HTT by targeting transcripts and are well suited for treating neurodegenerative disorders as they distribute broadly throughout the central nervous system (CNS) and are freely taken up by neurons, glia, and ependymal cells. With the FDA approval of an ASO therapy for another disease of the CNS, spinal muscular atrophy, ASOs have become a particularly attractive therapeutic option for HD. However, two types of ASOs were recently assessed in human clinical trials for the treatment of HD, and both were halted early. In this review, we will explore the differences in chemistry, targeting, and specificity of these HTT ASOs as well as preliminary clinical findings and potential reasons for and implications of these halted trials.

中文翻译：

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反义寡核苷酸疗法：从设计到亨廷顿病诊所。

亨廷顿病 (HD) 是一种致命的进行性神经退行性疾病，由亨廷顿 (HTT) 基因的遗传突变引起，该基因编码突变的 HTT 蛋白。尽管 HD 仍然无法治愈，但各种临床前研究报告了对 HTT 抑制的良好反应，强调降低 HTT 策略作为前瞻性的疾病改善治疗。反义寡核苷酸 (ASO) 通过靶向转录物降低 HTT，并且非常适合治疗神经退行性疾病，因为它们广泛分布在整个中枢神经系统 (CNS) 中，并被神经元、神经胶质细胞和室管膜细胞自由吸收。随着 FDA 批准 ASO 治疗另一种 CNS 疾病脊髓性肌萎缩症，ASO 已成为 HD 的一种特别有吸引力的治疗选择。然而，最近在治疗 HD 的人体临床试验中对两种类型的 ASO 进行了评估，但均已提前停止。在这篇综述中，我们将探讨这些 HTT ASO 在化学、靶向和特异性方面的差异，以及初步临床发现和这些暂停试验的潜在原因和影响。