The ability to selectively target genes and restore their function represents an important advance in gene therapy. A new strategy for targeted gene correction combines the ability of oligonucleotides to bind to specific DNA sequences and the ability of double-stranded DNA to undergo homologous recombination. Initial studies have shown that triplex-forming oligonucleotides (TFOs) can be used to stimulate homologous recombination. When the TFO was coupled to a short span of double-stranded DNA that was homologous to a selected gene, both gene correction and mutation could be achieved. A series of tethered-donor TFOs will be developed and tested for the ability to restore the function of three mutations of the beta-globin gene: IVS2-654, IVS2-705, and IVS2-745. These genes contain single nucleotide mutations that create 5' splice sites and activate the same cryptic 3' splice site upstream resulting in aberrant splicing. Correction of these mutations could be achieved by the disruption of the cryptic 3' splice site. Potential TFO sequences have been identified that bind within close proximity of the 3' cryptic splice site. The tethered donor will recombine with the genomic DNA, disrupt the splice site, and should result in permanent correction of splicing.