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Nat Med. 2019 Jul;25(7):1131-1142. doi: 10.1038/s41591-019-0478-3. Epub 2019 Jul 1.

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

Author information

1
Sangamo Therapeutics, Inc., Richmond, CA, USA. bzeitler@sangamo.com.
2
Sangamo Therapeutics, Inc., Richmond, CA, USA.
3
Laboratory of Intracellular Signalling, Moscow Institute of Physics and Technology, Dolgoprudnyi, Russian Federation.
4
Medical Affairs and Innovation, Hema-Quebec, Quebec City, Quebec, Canada.
5
Evotec AG, Hamburg, Germany.
6
CHDI Management/CHDI Foundation, Los Angeles, CA, USA.
7
Charles River Discovery Services, Kuopio, Finland.
8
Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
9
Psychogenics, Inc., Paramus, NJ, USA.
10
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
11
Innovative Genomics Institute, Berkeley, CA, USA.
12
CHDI Management/CHDI Foundation, Los Angeles, CA, USA. ignacio.munoz@chdifoundation.org.
13
Applied StemCell, Inc., Milpitas, CA, USA.

Abstract

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.

PMID:
31263285
DOI:
10.1038/s41591-019-0478-3

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