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

First Author  Zeitler B Year  2019
Journal  Nat Med Volume  25
Issue  7 Pages  1131-1142
PubMed ID  31263285 Mgi Jnum  J:340189
Mgi Id  MGI:6710322 Doi  10.1038/s41591-019-0478-3
Citation  Zeitler B, et al. (2019) Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington's disease. Nat Med 25(7):1131-1142
abstractText  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.
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