Huntington's disease (HD) is marked by the expansion of a tract of repeated CAG codons in the HD-gene, IT15. Once expressed, the expanded poly Q region of the huntingtin protein (Htt), which is normally soluble, becomes insoluble, leading to the formation of intracellular inclusions and ultimately to neuronal degeneration. Interruption of the pure poly Q tract at the genetic level should undermine the transition from Htt solubility to Htt insolubility. Modified single-stranded oligonucleotides were used to direct the nucleotide exchange of an A residue to a T residue in the second codon of the HD-gene, resulting in the creation of a leucine residue among the poly Q tract. Consistent with results from other groups, we provide evidence that short synthetic DNA molecules can modify the HD-gene directly, preliminarily offering a potential therapeutic approach to Huntington's disease. (C) 2003 Elsevier Inc. All rights reserved.