Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease

Amber L Southwell; Holly B Kordasiewicz; Douglas Langbehn; Niels H. Skotte; Matthew P Parsons; Erika B Villanueva; Nicholas S Caron; Michael E Østergaard; Lisa M Anderson; Yuanyun Xie; Louisa Dal Cengio; Hailey Findlay-Black; Crystal N Doty; Bethany Fitsimmons; Eric E Swayze; Punit P Seth; Lynn A Raymond; C Frank Bennett; Michael R Hayden

doi:10.1126/scitranslmed.aar3959

Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease

Amber L Southwell, Holly B Kordasiewicz, Douglas Langbehn, Niels H. Skotte, Matthew P Parsons, Erika B Villanueva, Nicholas S Caron, Michael E Østergaard, Lisa M Anderson, Yuanyun Xie, Louisa Dal Cengio, Hailey Findlay-Black, Crystal N Doty, Bethany Fitsimmons, Eric E Swayze, Punit P Seth, Lynn A Raymond, C Frank Bennett, Michael R Hayden

44 Citations (Scopus)

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.

Original language	English
Article number	eaar3959
Journal	Science Translational Medicine
Volume	10
Issue number	461
Pages (from-to)	1-12
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.aar3959
Publication status	Published - 2018
Externally published	Yes

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Southwell, A. L., Kordasiewicz, H. B., Langbehn, D., Skotte, N. H., Parsons, M. P., Villanueva, E. B., Caron, N. S., Østergaard, M. E., Anderson, L. M., Xie, Y., Cengio, L. D., Findlay-Black, H., Doty, C. N., Fitsimmons, B., Swayze, E. E., Seth, P. P., Raymond, L. A., Frank Bennett, C., & Hayden, M. R. (2018). Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease. Science Translational Medicine, 10(461), 1-12. [eaar3959]. https://doi.org/10.1126/scitranslmed.aar3959

Southwell, AL, Kordasiewicz, HB, Langbehn, D, Skotte, NH, Parsons, MP, Villanueva, EB, Caron, NS, Østergaard, ME, Anderson, LM, Xie, Y, Cengio, LD, Findlay-Black, H, Doty, CN, Fitsimmons, B, Swayze, EE, Seth, PP, Raymond, LA, Frank Bennett, C & Hayden, MR 2018, 'Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease', Science Translational Medicine, vol. 10, no. 461, eaar3959, pp. 1-12. https://doi.org/10.1126/scitranslmed.aar3959

@article{31428ce6c71c47ad824eaad310cac31a,

title = "Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease",

abstract = "Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.",

author = "Southwell, {Amber L} and Kordasiewicz, {Holly B} and Douglas Langbehn and Skotte, {Niels H.} and Parsons, {Matthew P} and Villanueva, {Erika B} and Caron, {Nicholas S} and {\O}stergaard, {Michael E} and Anderson, {Lisa M} and Yuanyun Xie and Cengio, {Louisa Dal} and Hailey Findlay-Black and Doty, {Crystal N} and Bethany Fitsimmons and Swayze, {Eric E} and Seth, {Punit P} and Raymond, {Lynn A} and {Frank Bennett}, C and Hayden, {Michael R}",

note = "Niels H. Skotte : Present address: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Erika B Villanueva : Present address: Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen 2200, Denmark.",

year = "2018",

doi = "10.1126/scitranslmed.aar3959",

language = "English",

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AU - Southwell, Amber L

AU - Kordasiewicz, Holly B

AU - Langbehn, Douglas

AU - Skotte, Niels H.

AU - Parsons, Matthew P

AU - Villanueva, Erika B

AU - Caron, Nicholas S

AU - Østergaard, Michael E

AU - Anderson, Lisa M

AU - Xie, Yuanyun

AU - Cengio, Louisa Dal

AU - Findlay-Black, Hailey

AU - Doty, Crystal N

AU - Fitsimmons, Bethany

AU - Swayze, Eric E

AU - Seth, Punit P

AU - Raymond, Lynn A

AU - Frank Bennett, C

AU - Hayden, Michael R

N1 - Niels H. Skotte : Present address: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Erika B Villanueva : Present address: Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen 2200, Denmark.

PY - 2018

Y1 - 2018

N2 - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.

AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.

U2 - 10.1126/scitranslmed.aar3959

DO - 10.1126/scitranslmed.aar3959

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SN - 1946-6234

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SP - 1

EP - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 461

M1 - eaar3959

ER -

Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease

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