Gene targeted agents: new opportunities for rational drug development.

In addition to traditional drug development methods designed to modulate the activity of protein targets, knowledge of disease gene DNA sequences provides an opportunity for the highly rational design of therapeutic agents that act at the DNA level through sequence-specific interactions. Among the ligands capable of binding DNA in a precise, sequence-specific manner are oligonucleotides, peptide nucleic acids and polyamides. Various strategies employing these agents to either transiently or permanently alter gene expression have been investigated over the past decade. During the past two to three years, important steps have been taken to illustrate the therapeutic potential of these ligands. Triple-helix (triplex) forming oligonucleotides have been particularly effective DNA-targeting agents with a wide range of applications, including the positive and negative transcriptional regulation of target genes, as well as the controlled delivery of site-specific mutations. This review will focus upon recent advances involving the use of sequence-specific DNA-binding ligands to modify gene expression and/or structure, with particular emphasis on the use of triplex-forming oligonucleotides in these roles.