University College London (UCL), Huntington's Disease Centre.
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL.
Curr Opin Neurol. 2020 Aug;33(4):508-518. doi: 10.1097/WCO.0000000000000835.
Huntington's disease is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HTT gene, and current therapies focus on symptomatic treatment. This review explores therapeutic approaches that directly target the pathogenic mutation, disrupt HTT mRNA or its translation.
Zinc-finger transcription repressors and CRISPR-Cas9 therapies target HTT DNA, thereby preventing all downstream pathogenic mechanisms. These therapies, together with RNA interference (RNAi), require intraparenchymal delivery to the brain in viral vectors, with only a single delivery potentially required, though they may carry the risk of irreversible side-effects.Along with RNAi, antisense oligonucleotides (ASOs) target mRNA, but are delivered periodically and intrathecally. ASOs have safely decreased mutant huntingtin protein (mHTT) levels in the central nervous system of patients, and a phase 3 clinical trial is currently underway.Finally, orally available small molecules, acting on splicing or posttranslational modification, have recently been shown to decrease mHTT in animal models.
Huntingtin-lowering approaches act upstream of pathogenic mechanisms and therefore have a high a priori likelihood of modifying disease course. ASOs are already in late-stage clinical development, whereas other strategies are progressing rapidly toward human studies.
目的综述：亨廷顿病是一种致命的常染色体显性神经退行性疾病，由 HTT 基因中的三核苷酸扩展引起，目前的治疗方法侧重于症状治疗。本综述探讨了直接针对致病突变、破坏 HTT mRNA 或其翻译的治疗方法。
最新发现：锌指转录抑制剂和 CRISPR-Cas9 疗法靶向 HTT DNA，从而阻止所有下游致病机制。这些疗法与 RNA 干扰 (RNAi) 一起，需要通过病毒载体向大脑内的脑实质递送，尽管只需进行一次递送，但可能存在不可逆转的副作用风险。与 RNAi 一起，反义寡核苷酸 (ASO) 靶向 mRNA，但需要定期鞘内给药。ASO 已安全降低了患者中枢神经系统中的突变型亨廷顿蛋白 (mHTT) 水平，目前正在进行一项 3 期临床试验。最后，最近已经证明，可口服的小分子药物通过剪接或翻译后修饰来降低 mHTT 在动物模型中的水平。
总结：降低亨廷顿蛋白的方法作用于致病机制的上游，因此具有改变疾病进程的高度先验可能性。ASO 已经处于临床开发的后期阶段，而其他策略也在迅速推进到人体研究。
