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

Nature medicine, 2019-07, Vol.25 (7), p.1131-1142 [Peer Reviewed Journal]

COPYRIGHT 2019 Nature Publishing Group ;COPYRIGHT 2019 Nature Publishing Group ;Copyright Nature Publishing Group Jul 2019 ;ISSN: 1078-8956 ;ISSN: 1546-170X ;EISSN: 1546-170X ;DOI: 10.1038/s41591-019-0478-3 ;PMID: 31263285

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Title:
Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington's disease
Author: Zeitler, Bryan ; Froelich, Steven ; Marlen, Kimberly ; Shivak, David A ; Yu, Qi ; Li, Davis ; Pearl, Jocelynn R ; Miller, Jeffrey C ; Zhang, Lei ; Paschon, David E ; Hinkley, Sarah J ; Ankoudinova, Irina ; Lam, Stephen ; Guschin, Dmitry ; Kopan, Lexi ; Cherone, Jennifer M ; Nguyen, Hoang-Oanh B ; Qiao, Guijuan ; Ataei, Yasaman ; Mendel, Matthew C ; Amora, Rainier ; Surosky, Richard ; Laganiere, Josee ; Vu, B Joseph ; Narayanan, Anand ; Sedaghat, Yalda ; Tillack, Karsten ; Thiede, Christina ; Gärtner, Annette ; Kwak, Seung ; Bard, Jonathan ; Mrzljak, Ladislav ; Park, Larry ; Heikkinen, Taneli ; Lehtimäki, Kimmo K ; Svedberg, Marie M ; Häggkvist, Jenny ; Tari, Lenke ; Tóth, Miklós ; Varrone, Andrea ; Halldin, Christer ; Kudwa, Andrea E ; Ramboz, Sylvie ; Day, Michelle ; Kondapalli, Jyothisri ; Surmeier, D James ; Urnov, Fyodor D ; Gregory, Philip D ; Rebar, Edward J ; Muñoz-Sanjuán, Ignacio ; Zhang, H Steve
Subjects: Alleles ; Animal models ; Animals ; Brain ; Care and treatment ; Cells, Cultured ; Disease Models, Animal ; Female ; Fibroblasts ; Gene expression ; Gene silencing ; Health aspects ; Humans ; Huntingtin ; Huntingtin Protein - genetics ; Huntington Disease - genetics ; Huntington Disease - therapy ; Huntington's chorea ; Huntington's disease ; Huntingtons disease ; Male ; Medical treatment ; Medicin och hälsovetenskap ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Molecular modelling ; Mutation ; Neurodegenerative diseases ; Neurons ; Neuroprotection ; Polyglutamine ; Proteins ; Rats as laboratory animals ; Risk factors ; Transcription factors ; Transcription, Genetic ; Trinucleotide repeat diseases ; Trinucleotide Repeats ; Zinc ; Zinc finger proteins ; Zinc Fingers
Is Part Of: Nature medicine, 2019-07, Vol.25 (7), p.1131-1142
Description: 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.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1078-8956
ISSN: 1546-170X
EISSN: 1546-170X
DOI: 10.1038/s41591-019-0478-3
PMID: 31263285
Source: MEDLINE
ProQuest Central

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

COPYRIGHT 2019 Nature Publishing Group ;COPYRIGHT 2019 Nature Publishing Group ;Copyright Nature Publishing Group Jul 2019 ;ISSN: 1078-8956 ;ISSN: 1546-170X ;EISSN: 1546-170X ;DOI: 10.1038/s41591-019-0478-3 ;PMID: 31263285

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