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 journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
JournalNature Medicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Huntington Disease
Zinc Fingers
Genes
Alleles
Zinc
Transcription Factors
Proteins
Neurons
Brain
Therapeutics
Mutant Proteins
Fibroblasts
Neurodegenerative Diseases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zeitler, B., Froelich, S., Marlen, K., Shivak, D. A., Yu, Q., Li, D., ... Zhang, H. S. (Accepted/In press). Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nature Medicine. https://doi.org/10.1038/s41591-019-0478-3
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. / Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. In: Nature Medicine. 2019.
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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.",
author = "Bryan Zeitler and Steven Froelich and Kimberly Marlen and Shivak, {David A.} and Qi Yu and Davis Li and Pearl, {Jocelynn R.} and Miller, {Jeffrey C.} and Lei Zhang and Paschon, {David E.} and Hinkley, {Sarah J.} and Irina Ankoudinova and Stephen Lam and Dmitry Guschin and Lexi Kopan and Cherone, {Jennifer M.} and Nguyen, {Hoang Oanh B.} and Guijuan Qiao and Yasaman Ataei and Mendel, {Matthew C.} and Rainier Amora and Richard Surosky and Josee Laganiere and Vu, {B. Joseph} and Anand Narayanan and Yalda Sedaghat and Karsten Tillack and Christina Thiede and Annette G{\"a}rtner and Seung Kwak and Jonathan Bard and Ladislav Mrzljak and Larry Park and Taneli Heikkinen and Lehtim{\"a}ki, {Kimmo K.} and Svedberg, {Marie M.} and Jenny H{\"a}ggkvist and Lenke Tari and Mikl{\'o}s T{\'o}th and Andrea Varrone and Christer Halldin and Kudwa, {Andrea E.} and Sylvie Ramboz and Michelle Day and Jyothisri Kondapalli and Surmeier, {D. James} and Urnov, {Fyodor D.} and Gregory, {Philip D.} and Rebar, {Edward J.} and Ignacio Mu{\~n}oz-Sanju{\'a}n and Zhang, {H. Steve}",
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Zeitler, B, Froelich, S, Marlen, K, Shivak, DA, Yu, Q, Li, D, Pearl, JR, Miller, JC, Zhang, L, Paschon, DE, Hinkley, SJ, Ankoudinova, I, Lam, S, Guschin, D, Kopan, L, Cherone, JM, Nguyen, HOB, Qiao, G, Ataei, Y, Mendel, MC, Amora, R, Surosky, R, Laganiere, J, Vu, BJ, Narayanan, A, Sedaghat, Y, Tillack, K, Thiede, C, Gärtner, A, Kwak, S, Bard, J, Mrzljak, L, Park, L, Heikkinen, T, Lehtimäki, KK, Svedberg, MM, Häggkvist, J, Tari, L, Tóth, M, Varrone, A, Halldin, C, Kudwa, AE, Ramboz, S, Day, M, Kondapalli, J, Surmeier, DJ, Urnov, FD, Gregory, PD, Rebar, EJ, Muñoz-Sanjuán, I & Zhang, HS 2019, 'Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease', Nature Medicine. https://doi.org/10.1038/s41591-019-0478-3

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

In: Nature Medicine, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease

AU - Zeitler, Bryan

AU - Froelich, Steven

AU - Marlen, Kimberly

AU - Shivak, David A.

AU - Yu, Qi

AU - Li, Davis

AU - Pearl, Jocelynn R.

AU - Miller, Jeffrey C.

AU - Zhang, Lei

AU - Paschon, David E.

AU - Hinkley, Sarah J.

AU - Ankoudinova, Irina

AU - Lam, Stephen

AU - Guschin, Dmitry

AU - Kopan, Lexi

AU - Cherone, Jennifer M.

AU - Nguyen, Hoang Oanh B.

AU - Qiao, Guijuan

AU - Ataei, Yasaman

AU - Mendel, Matthew C.

AU - Amora, Rainier

AU - Surosky, Richard

AU - Laganiere, Josee

AU - Vu, B. Joseph

AU - Narayanan, Anand

AU - Sedaghat, Yalda

AU - Tillack, Karsten

AU - Thiede, Christina

AU - Gärtner, Annette

AU - Kwak, Seung

AU - Bard, Jonathan

AU - Mrzljak, Ladislav

AU - Park, Larry

AU - Heikkinen, Taneli

AU - Lehtimäki, Kimmo K.

AU - Svedberg, Marie M.

AU - Häggkvist, Jenny

AU - Tari, Lenke

AU - Tóth, Miklós

AU - Varrone, Andrea

AU - Halldin, Christer

AU - Kudwa, Andrea E.

AU - Ramboz, Sylvie

AU - Day, Michelle

AU - Kondapalli, Jyothisri

AU - Surmeier, D. James

AU - Urnov, Fyodor D.

AU - Gregory, Philip D.

AU - Rebar, Edward J.

AU - Muñoz-Sanjuán, Ignacio

AU - Zhang, H. Steve

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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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