Huntingtin suppression restores cognitive function in a mouse model of Huntington’s disease
| Autor: | Amber L. Southwell, Hailey Findlay-Black, Yuanyun Xie, Bethany Fitsimmons, Michael E. Østergaard, C. Frank Bennett, Niels H. Skotte, Louisa Dal Cengio, Punit P. Seth, Crystal N. Doty, Michael R. Hayden, Erika B. Villanueva, Douglas R. Langbehn, Lynn A. Raymond, Lisa M. Anderson, Holly B. Kordasiewicz, Eric E. Swayze, Matthew P. Parsons, Nicholas S. Caron |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Primates 0301 basic medicine Dopamine and cAMP-Regulated Phosphoprotein 32 congenital hereditary and neonatal diseases and abnormalities Huntingtin Mutant Single-nucleotide polymorphism Disease Anxiety Biology medicine.disease_cause 03 medical and health sciences Cognition 0302 clinical medicine Limbic system Huntington's disease mental disorders Limbic System medicine Animals Humans Huntingtin Protein Mutation Behavior Animal Brain General Medicine Oligonucleotides Antisense medicine.disease nervous system diseases 3. Good health Cortex (botany) Disease Models Animal Huntington Disease 030104 developmental biology medicine.anatomical_structure nervous system Female Mutant Proteins Atrophy Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Science Translational Medicine. 10 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aar3959 |
| Popis: | Huntington 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. |
| Databáze: | OpenAIRE |
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