High affinity, chemically modified triplex-forming oligonucleotides (TFOs) and methods for use thereof are disclosed. TFOs are defined as triplex-forming oligonucleotides which bind as third strands to duplex 
DNA in a sequence specific manner. Triplex-forming oligonucleotides may be comprised of any possible combination of nucleotides and modified nucleotides. Modified nucleotides may contain chemical modifications of the heterocyclic base, 
sugar moiety or 
phosphate moiety. A high affinity 
oligonucleotide (Kd≦2×10−8) which forms a triple strand with a specific 
DNA segment of a 
target gene DNA is generated. It is preferable that the Kd for the high affinity 
oligonucleotide is below 2×10−10. The 
nucleotide binds or hybridizes to a target sequence within a 
target gene or target region of a 
chromosome, forming a triplex region. The binding of the 
oligonucleotide to the target region stimulates mutations within or adjacent to the target region using 
cellular DNA synthesis, recombination, and repair mechanisms. The 
mutation generated activates, inactivates, or alters the activity and function of the 
target gene.