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

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. MendelRainier Amora, Richard Surosky, Josee Laganiere, B. Joseph Vu, Anand Narayanan, Yalda Sedaghat, Karsten Tillack, Christina Thiede, Annette Gärtner, Seung Kwak, Jonathan Bard, Ladislav Mrzljak, Larry Park, Taneli Heikkinen, Kimmo K. Lehtimäki, Marie M. Svedberg, Jenny Häggkvist, Lenke Tari, Miklós Tóth, 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 Muñoz-Sanjuán, H. Steve Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1131-1142
Number of pages12
JournalNature Medicine
Issue number7
StatePublished - Jul 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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