Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease
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Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease. / Southwell, Amber L; Kordasiewicz, Holly B; Langbehn, Douglas; Skotte, Niels H.; Parsons, Matthew P; Villanueva, Erika B; Caron, Nicholas S; Østergaard, Michael E; Anderson, Lisa M; Xie, Yuanyun; Cengio, Louisa Dal; Findlay-Black, Hailey; Doty, Crystal N; Fitsimmons, Bethany; Swayze, Eric E; Seth, Punit P; Raymond, Lynn A; Frank Bennett, C; Hayden, Michael R.
In: Science Translational Medicine, Vol. 10, No. 461, eaar3959, 2018, p. 1-12.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease
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
M3 - Journal article
C2 - 30282695
VL - 10
SP - 1
EP - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 461
M1 - eaar3959
ER -
ID: 209264809