Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion 
in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein 
whose abnormal function is traditionally associated with HD pathogenesis; 
however, recent evidence has also linked HD pathogenesis to RNA stable hairpins 
formed by the mutant HTT expansion. Here, we have shown that a locked nucleic 
acid-modified antisense oligonucleotide complementary to the CAG repeat 
(LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or 
protein levels. LNA-CTGs produced rapid and sustained improvement of motor 
deficits in an R6/2 mouse HD model that was paralleled by persistent binding of 
LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied 
by a pronounced recovery in the levels of several striatal neuronal markers 
severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked 
several pathogenic mechanisms caused by expanded CAG RNA, including small RNA 
toxicity and decreased Rn45s expression levels. These results suggest that 
LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG 
repeats within HTT mRNA. The present data emphasize the relevance of expanded 
CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not 
required to reverse motor deficits, and further suggest a therapeutic potential 
for LNA-CTG in polyglutamine disorders.