Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG 
trinucleotide repeat expansion in the huntingtin (HTT) gene. Disease 
pathogenesis derives, at least in part, from the long polyglutamine tract 
encoded by mutant HTT. Therefore, considerable effort has been dedicated to the 
development of therapeutic strategies that significantly reduce the expression 
of the mutant HTT protein. Antisense oligonucleotides (ASOs) targeted to the CAG 
repeat region of HTT transcripts have been of particular interest due to their 
potential capacity to discriminate between normal and mutant HTT transcripts. 
Here, we focus on phosphorodiamidate morpholino oligomers (PMOs), ASOs that are 
especially stable, highly soluble and non-toxic. We designed three PMOs to 
selectively target expanded CAG repeat tracts (CTG22, CTG25 and CTG28), and two 
PMOs to selectively target sequences flanking the HTT CAG repeat (HTTex1a and 
HTTex1b). In HD patient-derived fibroblasts with expanded alleles containing 44, 
77 or 109 CAG repeats, HTTex1a and HTTex1b were effective in suppressing the 
expression of mutant and non-mutant transcripts. CTGn PMOs also suppressed HTT 
expression, with the extent of suppression and the specificity for mutant 
transcripts dependent on the length of the targeted CAG repeat and on the CTG 
repeat length and concentration of the PMO. PMO CTG25 reduced HTT-induced 
cytotoxicity in vitro and suppressed mutant HTT expression in vivo in the 
N171-82Q transgenic mouse model. Finally, CTG28 reduced mutant HTT expression 
and improved the phenotype of Hdh(Q7/Q150) knock-in HD mice. These data 
demonstrate the potential of PMOs as an approach to suppressing the expression 
of mutant HTT.