Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington's disease

被引：142

作者：

Zeitler, Bryan ^{[1
]}

Froelich, Steven ^{[1
]}

Marlen, Kimberly ^{[1
]}

Shivak, David A. ^{[1
]}

Yu, Qi ^{[1
]}

Li, Davis ^{[1
]}

Pearl, Jocelynn R. ^{[1
]}

Miller, Jeffrey C. ^{[1
]}

Zhang, Lei ^{[1
]}

Paschon, David E. ^{[1
]}

Hinkley, Sarah J. ^{[1
]}

Ankoudinova, Irina ^{[1
]}

Lam, Stephen ^{[1
]}

Guschin, Dmitry ^{[1
,9
]}

Kopan, Lexi ^{[1
]}

Cherone, Jennifer M. ^{[1
]}

Nguyen, Hoang-Oanh B. ^{[1
]}

Qiao, Guijuan ^{[1
]}

Ataei, Yasaman ^{[1
]}

Mendel, Matthew C. ^{[1
]}

Amora, Rainier ^{[1
]}

Surosky, Richard ^{[1
]}

Laganiere, Josee ^{[1
,10
]}

Vu, B. Joseph ^{[1
]}

Narayanan, Anand ^{[1
]}

Sedaghat, Yalda ^{[2
]}

Tillack, Karsten ^{[2
]}

Thiede, Christina ^{[2
]}

Gaertner, Annette ^{[2
]}

Kwak, Seung ^{[3
]}

Bard, Jonathan ^{[3
]}

Mrzljak, Ladislav ^{[3
]}

Park, Larry ^{[3
]}

Heikkinen, Taneli ^{[4
]}

Lehtimaki, Kimmo K. ^{[4
]}

Svedberg, Marie M. ^{[5
,6
]}

Haggkvist, Jenny ^{[5
,6
]}

Tari, Lenke ^{[5
,6
]}

Toth, Miklos ^{[5
,6
]}

Varrone, Andrea ^{[5
,6
]}

Halldin, Christer ^{[5
,6
]}

Kudwa, Andrea E. ^{[7
]}

Ramboz, Sylvie ^{[7
]}

Day, Michelle ^{[8
]}

Kondapalli, Jyothisri ^{[8
]}

Surmeier, D. James ^{[8
]}

Urnov, Fyodor D. ^{[1
,11
]}

Gregory, Philip D. ^{[1
]}

Rebar, Edward J. ^{[1
]}

Munoz-Sanjuan, Ignacio ^{[3
]}

机构：

[1] Sangamo Therapeut Inc, Richmond, CA 94804 USA

[2] Evotec AG, Hamburg, Germany

[3] CHDI Fdn, CHDI Management, Los Angeles, CA 90045 USA

[4] Charles River Discovery Serv, Kuopio, Finland

[5] Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden

[6] Stockholm Cty Council, Stockholm, Sweden

[7] Psychogenics Inc, Paramus, NJ USA

[8] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA

[9] Moscow Inst Phys & Technol, Lab Intracellular Signalling, Dolgoprudnyi, Russia

[10] Hema Quebec, Med Affairs & Innovat, Quebec City, PQ, Canada

[11] Innovat Genom Inst, Berkeley, CA USA

[12] Appl StemCell Inc, Milpitas, CA USA

来源：

NATURE MEDICINE | 2019年 / 25卷 / 07期

关键词：

ZINC-FINGER PROTEINS; MOUSE MODEL; PERFORMANCE EVALUATION; HD GENE; EXPRESSION; SUPPRESSION; BRAIN; DNA; INACTIVATION; DYNAMICS;

D O I：

10.1038/s41591-019-0478-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Huntington's 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 100 days 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.

引用

页码：1131 / +

页数：33

共 75 条

[1] Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice [J].