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

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 pro... Full description

Journal Title: Nature medicine 2019, Vol.25 (7), p.1131-1142
Main Author: Zeitler, Bryan
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
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Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
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title: Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease
format: Article
creator:
  • 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
  • Analysis
  • Animal models
  • Animals
  • Brain
  • Care and treatment
  • Cells, Cultured
  • Disease Models, Animal
  • DNA binding proteins
  • Female
  • Fibroblasts
  • Gene expression
  • Gene silencing
  • Genetic aspects
  • Genetic transcription
  • Health aspects
  • High-definition television
  • 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
  • Models
  • Molecular modelling
  • Mutation
  • Nervous system diseases
  • 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
ispartof: Nature medicine, 2019, 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
  • 1546-170X
url: Link


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titleAllele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease
creatorZeitler, 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
creatorcontribZeitler, 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
descriptionHuntington'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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1ISSN: 1546-170X
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4PMID: 31263285
languageeng
publisherUnited States: Nature Publishing Group
subjectAlleles ; Analysis ; Animal models ; Animals ; Brain ; Care and treatment ; Cells, Cultured ; Disease Models, Animal ; DNA binding proteins ; Female ; Fibroblasts ; Gene expression ; Gene silencing ; Genetic aspects ; Genetic transcription ; Health aspects ; High-definition television ; 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 ; Models ; Molecular modelling ; Mutation ; Nervous system diseases ; 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
ispartofNature medicine, 2019, Vol.25 (7), p.1131-1142
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1Froelich, Steven
2Marlen, Kimberly
3Shivak, David A
4Yu, Qi
5Li, Davis
6Pearl, Jocelynn R
7Miller, Jeffrey C
8Zhang, Lei
9Paschon, David E
10Hinkley, Sarah J
11Ankoudinova, Irina
12Lam, Stephen
13Guschin, Dmitry
14Kopan, Lexi
15Cherone, Jennifer M
16Nguyen, Hoang-Oanh B
17Qiao, Guijuan
18Ataei, Yasaman
19Mendel, Matthew C
20Amora, Rainier
21Surosky, Richard
22Laganiere, Josee
23Vu, B Joseph
24Narayanan, Anand
25Sedaghat, Yalda
26Tillack, Karsten
27Thiede, Christina
28Gärtner, Annette
29Kwak, Seung
30Bard, Jonathan
31Mrzljak, Ladislav
32Park, Larry
33Heikkinen, Taneli
34Lehtimäki, Kimmo K
35Svedberg, Marie M
36Häggkvist, Jenny
37Tari, Lenke
38Tóth, Miklós
39Varrone, Andrea
40Halldin, Christer
41Kudwa, Andrea E
42Ramboz, Sylvie
43Day, Michelle
44Kondapalli, Jyothisri
45Surmeier, D James
46Urnov, Fyodor D
47Gregory, Philip D
48Rebar, Edward J
49Muñoz-Sanjuán, Ignacio
50Zhang, H Steve
title
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descriptionHuntington'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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12Gene silencing
13Genetic aspects
14Genetic transcription
15Health aspects
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17Humans
18Huntingtin
19Huntingtin Protein - genetics
20Huntington Disease - genetics
21Huntington Disease - therapy
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40Rats as laboratory animals
41Risk factors
42Transcription factors
43Transcription, Genetic
44Trinucleotide repeat diseases
45Trinucleotide Repeats
46Zinc
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10Hinkley, Sarah J
11Ankoudinova, Irina
12Lam, Stephen
13Guschin, Dmitry
14Kopan, Lexi
15Cherone, Jennifer M
16Nguyen, Hoang-Oanh B
17Qiao, Guijuan
18Ataei, Yasaman
19Mendel, Matthew C
20Amora, Rainier
21Surosky, Richard
22Laganiere, Josee
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24Narayanan, Anand
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titleAllele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease
authorZeitler, 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
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1Analysis
2Animal models
3Animals
4Brain
5Care and treatment
6Cells, Cultured
7Disease Models, Animal
8DNA binding proteins
9Female
10Fibroblasts
11Gene expression
12Gene silencing
13Genetic aspects
14Genetic transcription
15Health aspects
16High-definition television
17Humans
18Huntingtin
19Huntingtin Protein - genetics
20Huntington Disease - genetics
21Huntington Disease - therapy
22Huntington's chorea
23Huntington's disease
24Huntingtons disease
25Male
26Medical treatment
27Medicin och hälsovetenskap
28Mice
29Mice, Inbred C57BL
30Mice, Inbred CBA
31Models
32Molecular modelling
33Mutation
34Nervous system diseases
35Neurodegenerative diseases
36Neurons
37Neuroprotection
38Polyglutamine
39Proteins
40Rats as laboratory animals
41Risk factors
42Transcription factors
43Transcription, Genetic
44Trinucleotide repeat diseases
45Trinucleotide Repeats
46Zinc
47Zinc finger proteins
48Zinc Fingers
toplevelpeer_reviewed
creatorcontrib
0Zeitler, Bryan
1Froelich, Steven
2Marlen, Kimberly
3Shivak, David A
4Yu, Qi
5Li, Davis
6Pearl, Jocelynn R
7Miller, Jeffrey C
8Zhang, Lei
9Paschon, David E
10Hinkley, Sarah J
11Ankoudinova, Irina
12Lam, Stephen
13Guschin, Dmitry
14Kopan, Lexi
15Cherone, Jennifer M
16Nguyen, Hoang-Oanh B
17Qiao, Guijuan
18Ataei, Yasaman
19Mendel, Matthew C
20Amora, Rainier
21Surosky, Richard
22Laganiere, Josee
23Vu, B Joseph
24Narayanan, Anand
25Sedaghat, Yalda
26Tillack, Karsten
27Thiede, Christina
28Gärtner, Annette
29Kwak, Seung
30Bard, Jonathan
31Mrzljak, Ladislav
32Park, Larry
33Heikkinen, Taneli
34Lehtimäki, Kimmo K
35Svedberg, Marie M
36Häggkvist, Jenny
37Tari, Lenke
38Tóth, Miklós
39Varrone, Andrea
40Halldin, Christer
41Kudwa, Andrea E
42Ramboz, Sylvie
43Day, Michelle
44Kondapalli, Jyothisri
45Surmeier, D James
46Urnov, Fyodor D
47Gregory, Philip D
48Rebar, Edward J
49Muñoz-Sanjuán, Ignacio
50Zhang, H Steve
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jtitleNature medicine
delivery
delcategoryRemote Search Resource
fulltextno_fulltext
addata
au
0Zeitler, Bryan
1Froelich, Steven
2Marlen, Kimberly
3Shivak, David A
4Yu, Qi
5Li, Davis
6Pearl, Jocelynn R
7Miller, Jeffrey C
8Zhang, Lei
9Paschon, David E
10Hinkley, Sarah J
11Ankoudinova, Irina
12Lam, Stephen
13Guschin, Dmitry
14Kopan, Lexi
15Cherone, Jennifer M
16Nguyen, Hoang-Oanh B
17Qiao, Guijuan
18Ataei, Yasaman
19Mendel, Matthew C
20Amora, Rainier
21Surosky, Richard
22Laganiere, Josee
23Vu, B Joseph
24Narayanan, Anand
25Sedaghat, Yalda
26Tillack, Karsten
27Thiede, Christina
28Gärtner, Annette
29Kwak, Seung
30Bard, Jonathan
31Mrzljak, Ladislav
32Park, Larry
33Heikkinen, Taneli
34Lehtimäki, Kimmo K
35Svedberg, Marie M
36Häggkvist, Jenny
37Tari, Lenke
38Tóth, Miklós
39Varrone, Andrea
40Halldin, Christer
41Kudwa, Andrea E
42Ramboz, Sylvie
43Day, Michelle
44Kondapalli, Jyothisri
45Surmeier, D James
46Urnov, Fyodor D
47Gregory, Philip D
48Rebar, Edward J
49Muñoz-Sanjuán, Ignacio
50Zhang, H Steve
formatjournal
genrearticle
ristypeJOUR
atitleAllele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease
jtitleNature medicine
addtitleNat Med
date2019-07
risdate2019
volume25
issue7
spage1131
epage1142
pages1131-1142
issn
01078-8956
11546-170X
eissn1546-170X
abstractHuntington'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.
copUnited States
pubNature Publishing Group
pmid31263285
doi10.1038/s41591-019-0478-3
tpages2
orcidid
0https://orcid.org/0000-0003-0353-3577
1https://orcid.org/0000-0002-4709-9699
2https://orcid.org/0000-0002-4184-0001
3https://orcid.org/0000-0002-4439-0085
4https://orcid.org/0000-0002-2559-4998