PNAS：一种抵御亨廷顿疾病的新型工具

亨廷顿是疾病（HD）是由于编码亨廷丁蛋白DNA序列（核苷酸CAG）的多重重复所引发的一种遗传性的遗传障碍疾病。亨廷丁蛋白在机体的多种组织中存在，其对于个体的神经元发育和存活非常重要。尽管关于HD的研究很多，但是目前针对此疾病的疗法却没有。

近日，来自巴塞罗那基因组研究中心的研究者基于特定蛋白质的修饰作用开发出了一款新型工具，这些蛋白质称为锌指蛋白质，其可以识别并结合特定的DNA序列，进而调节DNA的表达。这项研究中，研究者使用新型工具降低了突变基因的错误表达，这就会有效抑制疾病的进程，相关研究成果刊登在了国际杂志PNAS上。

研究者Mireia表示，我们设计出的特定锌指蛋白质，其可以识别并特异性地结合超过35个CAG三聚体重复片段，进而以至其表达，降低突变的亨廷丁蛋白质产生。用小鼠进行实验，研究者发现实验小鼠发生HD症状有所延迟。

下一步，研究者将优化这项工具，以使得更有效和耐用的治疗亨廷顿疾病的方法问世，这无疑是病人的一大福音，相关研究成果由欧盟委员会等机构支持。

与亨廷顿相关的拓展阅读：

• Neurology：Pridopidine治疗亨廷顿病安全性和耐受性均较好
• STM：PGC-1α和TFEB两种蛋白可治疗亨廷顿氏病
• PLoS Gene：朊病毒成分和基因剂量或可控制亨廷顿氏症
• Lancet Oncol ：亨廷顿氏症患者癌症风险较低
• 干细胞移植有望治疗亨廷顿病 更多信息请点击：有关亨廷顿更多资讯

Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (HTT) gene. Although several palliative treatments are available, there is currently no cure and patients generally die 10–15 y after diagnosis. Several promising approaches for HD therapy are currently in development, including RNAi and antisense analogs. We developed a complementary strategy to test repression of mutant HTT with zinc finger proteins (ZFPs) in an HD model. We tested a “molecular tape measure” approach, using long artificial ZFP chains, designed to bind longer CAG repeats more strongly than shorter repeats. After optimization, stable ZFP expression in a model HD cell line reduced chromosomal expression of the mutant gene at both the protein and mRNA levels (95% and 78% reduction, respectively). This was achieved chromosomally in the context of endogenous mouse HTT genes, with variable CAG-repeat lengths. Shorter wild-type alleles, other genomic CAG-repeat genes, and neighboring genes were unaffected. In vivo, striatal adeno-associated virus viral delivery in R6/2 mice was efficient and revealed dose-dependent repression of mutant HTT in the brain (up to 60%). Furthermore, zinc finger repression was tested at several levels, resulting in protein aggregate reduction, reduced decline in rotarod performance, and alleviation of clasping in R6/2 mice, establishing a proof-of-principle for synthetic transcription factor repressors in the brain.