近日，美国桑加莫治疗公司Bryan Zeitler等研究人员，锌指蛋白转录因子（ZFP-TFs）以靶向致病性CAG重复，并选择性地降低突变的亨廷顿蛋白（mHTT），同时保留正常的HTT等位基因的表达，该研究表明锌指蛋白转录因子（ZFP-TFs）具有等位基因选择性，能够有效且持续性治疗亨廷顿症。2019年7月，国际知名学术期刊《自然—医学》发表了这一成果。

由于正常的HTT被认为对大脑功能有重要影响，研究人员设计了锌指蛋白转录因子(ZFP-TFs)靶向致病性CAG重复，选择性降低mHTT作为治疗策略。利用患者来源的成纤维细胞和神经元，证明了ZFP-TFs在大剂量范围内选择性地抑制了>99%的导致突变的等位基因，同时保留了>86%正常等位基因的表达。其他含CAG的基因受影响最小，病毒传递的ZFP-TFs在培养超过100天的HD神经元中活跃且耐受良好，在小鼠大脑中至少持续9个月。使用三种HD小鼠模型，我们证明了在分子、组织病理学、电生理和功能端点的一系列改进。该研究结果支持继续开发用于HD治疗的等位基因选择性ZFP-TF。

据悉，亨廷顿舞蹈病(HD)是一种显性遗传性神经退行性疾病，由亨廷顿基因(HTT) CAG三核苷酸异常扩增引起，该基因编码病理突变的HTT (mHTT)蛋白。

附：英文原文

Title: Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease

Author: Bryan Zeitler, Steven Froelich, Kimberly Marlen, David A Shivak, Qi Yu, Davis Li, Jocelynn R Pearl, Jeffrey C Miller, Lei Zhang, David E Paschon, Sarah J Hinkley, Irina Ankoudinova, Stephen Lam, Dmitry Guschin, Lexi Kopan, Jennifer M Cherone, Hoang-Oanh B Nguyen, Guijuan Qiao, Yasaman Ataei, Matthew C Mendel, Rainier Amora, Richard Surosky, Josee Laganiere, B Joseph Vu, Anand Narayanan, Yalda Sedaghat, Karsten Tillack, Christina Thiede, Annette Grtner, Seung Kwak, Jonathan Bard, Ladislav Mrzljak, Larry Park, Taneli Heikkinen, Kimmo K Lehtimki, Marie M Svedberg, Jenny Hggkvist, Lenke Tari, Mikls Tth, Andrea Varrone, Christer Halldin, Andrea E Kudwa, Sylvie Ramboz, Michelle Day, Jyothisri Kondapalli, D James Surmeier, Fyodor D Urnov, Philip D Gregory, Edward J Rebar, Ignacio Muoz-Sanjun, H Steve Zhang

Issue&Volume: Volume 25 Issue 7, July 2019

Abstract: Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress>99% of HD-causing alleles over a wide dose range while preserving expression of>86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100days in culture and for at least nine months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.

DOI: 10.1038/s41591-019-0478-3

Source:https://www.nature.com/articles/s41591-019-0478-3