Send to

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

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

Author information

BioMarin Nederland BV, Leiden, The Netherlands.
Charles River Discovery Research Services, Kuopio, Finland.


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.

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

NAD, AG-B, EK, RW, JvdG, SM and JCTvD are (former) employees of BioMarin Nederland BV (formerly Prosensa Therapeutics BV) that sponsored this study. SM is inventor on related patent WO2013/162363. OK, TH and KL are employees of Charles River Research Discovery Services in Finland and have no financial conflict of interest related to the submitted manuscript. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center