Since the discovery of siRNA, companies like Silence Therapeutics, Sirna Therapeutics and AVI Biopharma have been racing to apply the Nobel prize-winning technology to biopharmaceutical treatments. The RNA-based antigene therapies have limitations, however, that include concerns over chronic use and the need to target thousands of mRNA molecules per cell in order to control expression of a gene product.
Another form of triplex forming oligonucleoide (TFO) technology has come into the limelight in recent years, as a possible solution to the shortcomings of siRNA and other antisense technologies. Called antigene therapy, this method goes back a level in its approach to gene control. By targeting the actual gene of interest, instead of the mRNA product, the biopharmaceutical drug would only need to make contact with 2 molecules per cell: the two copies of the gene. Once a complimentary nucleotide strand binds to DNA, forming a TFO, the DNA at that particular site is modified which leads to recruitment of DNA repair enzymes and may result in a permanent mutation, thus inactivating the gene.
Adaptations of the antigene therapy approach are in development that can increase the level of control over when and where genes are modified. One such adaptation was the subject of a review article in December 2010, in the journal Oligonucleotides. This method involves linking a photoreactive ligand to the DNA, to increase the stringency of the method in terms of where the DNA damage occurs. In addition, this method can be used to control the type of DNA modifications (i.e., cross-linkage formation versus double-stranded breaks.
Kolevzon, N. and Yavin, E. 2010. Site-specific DNA photocleavage and photomodulation by oligonucleotide conjugates. Oligonucleotides 20(6):263-275. doi:10.1089/oli.2010.0247.