The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain

PLoS One. 2017 Feb 9;12(2):e0171127. doi: 10.1371/journal.pone.0171127. eCollection 2017.


The aim of these studies was to demonstrate the therapeutic capacity of an antisense oligonucleotide with the sequence (CUG)7 targeting the expanded CAG repeat in huntingtin (HTT) mRNA in vivo in the R6/2 N-terminal fragment and Q175 knock-in Huntington's disease (HD) mouse models. In a first study, R6/2 mice received six weekly intracerebroventricular infusions with a low and high dose of (CUG)7 and were sacrificed 2 weeks later. A 15-60% reduction of both soluble and aggregated mutant HTT protein was observed in striatum, hippocampus and cortex of (CUG)7-treated mice. This correction at the molecular level resulted in an improvement of performance in multiple motor tasks, increased whole brain and cortical volume, reduced levels of the gliosis marker myo-inositol, increased levels of the neuronal integrity marker N-aceyl aspartate and increased mRNA levels of the striatal marker Darpp-32. These neuroanatomical and neurochemical changes, together with the improved motor performance, suggest that treatment with (CUG)7 ameliorates basal ganglia dysfunction. The HTT-lowering was confirmed by an independent study in Q175 mice using a similar (CUG)7 AON dosing regimen, further demonstrating a lasting reduction of mutant HTT protein in striatum, hippocampus and cortex for up to 18 weeks post last infusion along with an increase in motor activity. Based on these encouraging results, (CUG)7 may thus offer an interesting alternative HTT-lowering strategy for HD.

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Female
  • Genetic Therapy*
  • Gliosis
  • Huntingtin Protein / genetics*
  • Huntington Disease / genetics
  • Huntington Disease / therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity
  • RNA, Antisense / genetics*
  • Trinucleotide Repeat Expansion*


  • Htt protein, mouse
  • Huntingtin Protein
  • RNA, Antisense

Grant support

Funding was provided by BioMarin Nederland BV, Leiden, The Netherlands. The funder provided support in the form of salaries, equipment and facilities for all authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.