Research ArticleHuntington’s Disease

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

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Science Translational Medicine  03 Oct 2018:
Vol. 10, Issue 461, eaar3959
DOI: 10.1126/scitranslmed.aar3959

Rescuing cognition in Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disorder caused by mutation in the HTT gene. The encoded mutated protein, called huntingtin, acquires a toxic function causing motor, cognitive, and psychiatric impairments. Southwell and colleagues show that intracerebral injection of antisense oligonucleotides (ASOs) specifically inhibiting the expression of mutant Htt improved cognition and reduced anxiety and depressive behaviors in symptomatic HD mice. Moreover, HTT-targeting ASOs reduced huntingtin expression in nonhuman primates. The results suggest that ASO-based therapies might be effective for treating the cognitive impairments associated with HD.


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.

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