Huntington's disease (HD) is a fatal, neurodegenerative disorder in which 
patients suffer from mobility, psychological and cognitive impairments. Existing 
therapeutics are only symptomatic and do not significantly alter the disease 
progression or increase life expectancy. HD is caused by expansion of the CAG 
trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to 
the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of 
muHTT protein is a major cause of the disease. In addition, it has been 
suggested that the muHTT transcript contributes to the toxicity. Thus, reduction 
of both muHTT mRNA and protein levels would ideally be the most useful 
therapeutic option. We herein present a novel strategy for HD treatment using 
oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A 
partial, but significant and potentially long-term, HTT knock-down of both mRNA 
and protein was successfully achieved. Diminished phosphorylation of HTT 
gene-associated RNA-polymerase II is demonstrated, suggestive of reduced 
transcription downstream the ON-targeted repeat. Different backbone chemistries 
were found to have a strong impact on the ON efficiency. We also successfully 
use different delivery vehicles as well as naked uptake of the ONs, 
demonstrating versatility and possibly providing insights for in vivo 
applications.