Synthetic DNA Approach Targets Cancer-Linked Genes Directly

Accurately targeting specific sections of DNA inside cells has long been a challenge for genetic medicine. Many modern genetic medicines act on RNA because going after DNA directly has proven much harder. A new study published in Nucleic Acids Research describes an approach that uses synthetic DNA molecules to target cancer-linked genes directly, with possible applications in treatment, diagnostics, and biological research.

The paper’s lead author is David Rusling from the Univeristy of Portsmouth who has worked in the field for more than 20 years. He said the approach could offer a more precise way to control gene activity. “Most drugs target proteins, which are the end product of a long biological process. If you target DNA directly, you’re working at the very start of that process. Each cell only contains two copies of a gene, so in theory it offers a highly efficient way to influence how genes behave.” 

The researchers worked with triplex-forming oligonucleotides (TFOs), specially designed pieces of synthetic DNA that recognize and attach to specific DNA sequences. This lets researchers target individual genes without affecting the rest of the genome. A major obstacle, however, has been that naturally occurring DNA bases don’t bind strongly enough to double-stranded DNA to work inside cells. 

To get around this, the team added a commercially available synthetic DNA base called Z. The modification helped the molecules bind more strongly and selectively to DNA regions rich in guanine (G) and cytosine (C). These GC-rich regions are important for controlling gene activity but have historically been difficult to reach.

The researchers tested the approach on MYC, a gene that drives the growth of many cancers when it becomes overactive. In laboratory experiments, the modified molecules attached to the target DNA and reduced MYC gene activity by 50 to 80 percent. They also performed better than unmodified DNA and several earlier approaches aimed at the same DNA regions.

“Triplex-forming oligonucleotides were a beautiful idea, but in many ways biology defeated the original concept. They could recognize DNA very precisely in a test tube, but the chemistry of natural DNA meant that many important sequences could not be targeted effectively under the conditions found inside cells. What we are doing is changing that chemistry rather than abandoning the idea,” Dr. Rusling said.

The work also tackles a practical barrier that has slowed DNA-targeting therapies. Many specialized DNA modifications previously had to be custom-made by expert chemists, which limited who could use them. The modified bases in this study can be bought commercially, so laboratories around the world can adopt the technology more easily. 

“What I really like about this chemistry is that if we can obtain these molecules, other researchers can too,” said Dr. Rusling. “That accessibility means the whole field can move forward much more quickly.”

Beyond possible uses in treating disease, the technology could serve as a research tool. Scientists could use it to temporarily switch off individual genes and watch how cells respond, improving understanding of areas ranging from cancer biology to genetic disorders. Because the system works through DNA sequence recognition, the researchers think it may eventually be adapted to target many different genes simply by changing the sequence of the synthetic DNA molecule. Further research will be needed before the technology could be used in patients.