Background Huntington's disease (HD) is a devastating disease for which currently no therapy is available. It is a progressive autosomal dominant neurodegenerative disorder that is caused by a CAG repeat expansion in the HD gene which results in an expansion of polyglutamines at the N terminal end of the huntingtin (htt) protein and the accumulation of cytoplasmic and nuclear aggregates in neurons. The polyglutamine expansion results in a toxic gain of function for the huntingtin protein and plays a central role in the disease. The size of this expansion has a direct link to the aggregation proneness as well as the severity of pathological and clinical features.

Aims The aim of our study is reducing mutant htt transcript and protein levels by targeting its prolonged CAG repeat in the HD gene and thereby inhibiting all downstream toxic effects.

Methods Patient derived fibroblasts and lymphoblasts were used to transfect fully modified 2'O methyl phosphorothioate antisense oligonucleotides (AONs), designed to target the expanded CAG repeat in HD. Various AON concentrations and CUG lengths were applied. Htt transcript levels were measured by RT-PCR and qRT-PCR and protein levels were measured by Western blot and time resolved FRET.

Results We show that an AON that recognises seven consecutive CAG trinucleotides reduces both mutant htt transcript and protein levels in patient derived cells. In the human genome there are numerous proteins that contain polyQ tracts and these are usually encoded by a combination of CAG and CAA triplets. Those CAG enclosing transcripts were found to be unaffected by the (CUG)₇ AON treatment.

Conclusions Here we make use of AONs targeting the CAG repeat as a therapeutic strategy to effectively reduce both htt transcript and protein levels in patient derived HD cells. Other endogenous CAG enclosing transcripts were found to be unaffected by AON treatment, making the (CUG)₇ AON a promising therapeutic tool to specifically reduce mutant htt in HD.