摘要： 亨廷顿病是一种以运动、认知和精神障碍为主要表现的遗传性中枢神经系统变性疾病，其致病基因IT-15 突变可引起胞嘧啶-腺嘌呤-鸟嘌呤（CAG）三核苷酸重复序列异常扩增，导致所编码的亨廷顿蛋白构象变化并产生神经毒性作用。亨廷顿病的基因治疗目前尚处于临床前阶段，主要包括基因沉默、诱导突变亨廷顿蛋白清除、导入神经营养因子基因，以及纠正突变型亨廷顿蛋白的毒性作用所致的基因转录、信号转导和线粒体代谢紊乱等。本文尝试对亨廷顿病的基因治疗研究进展简要叙述。

关键词: 杭廷顿病, 基因疗法, RNA 干扰, 综述

Abstract: Huntington's disease (HD) is a kind of inherited neurodegenerative disorder characterized by movement problems, cognitive decline and psychiatry disturbance. HD is caused by mutation in gene IT -15 involving the expansion of a trinucleotide (CAG) repeat encoding glutamine, which leads to abnormal conformation of huntingtin (Htt) protein and finally emerge cytotoxic functions. Currently, HD remains a fatal untreatable disease. Gene therapy for HD discussed in this review is under preclinical studies. Silencing of mutant IT-15 via RNA interference (RNAi) or antisense oligonucleotide (ASO) has shown some effectiveness in mouse model studies. Increasing the clearance of mutant Htt protein could be achieved by viral-mediated delivery of anti-Htt intrabodies (iAbs) or induction of autophagy, and beneficial results have been observed. Ectopic expression of neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), mediated either by viral vectors or transplantation of genetically modified cells, has also been proved to be effective. Other gene-modifying methods aiming at correction of transcriptional dysregulation by histone modification, activation of endogenous neural stem cells, and normalization of calcium signaling and mitochondrial function, are also under intensive research. Gene therapy for Huntington's disease is promising, yet a long way remains from preclinical studies to clinical trials.

Key words: Huntington disease, Gene therapy, RNA interference, Review