Scientists revive decades-old approach to target cancer-linked genes using synthetic DNA

• The research focuses on how to target specific sections of DNA inside cells 

• Researchers targeted MYC, a gene linked to cancer growth 

• Modified DNA molecules reduced MYC activity by 50 - 80% in laboratory tests 

Researchers have developed a promising new approach that uses synthetic DNA molecules to target cancer-linked genes directly, opening new possibilities for future treatments, diagnostics and biological research. 

The study focuses on a long-standing challenge in genetic medicine: how to accurately target specific sections of DNA inside cells. While many modern genetic medicines work by targeting RNA, the molecule that carries genetic instructions from DNA, directly targeting DNA itself has proven much more difficult. 

Dr David Rusling, Associate Professor in Bioengineering, from the University’s School of Medicine, Pharmacy and Biological Sciences, is lead author of the paper and has worked in the field for more than 20 years. He said the new approach could provide a more precise way of controlling 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 team used specially designed pieces of synthetic DNA known as triplex-forming oligonucleotides, or TFOs. These molecules are designed to recognise and attach to specific DNA sequences, allowing researchers to target individual genes while leaving the rest of the genome untouched. 

A major obstacle has been that naturally occurring DNA bases do not bind strongly enough to double-stranded DNA to be effective inside cells. To overcome this, the researchers incorporated a commercially available synthetic DNA base known as Z. 

The modification allowed the synthetic DNA molecules to bind more strongly and selectively to difficult-to-target regions of DNA that contain high levels of the genetic building blocks guanine (G) and cytosine (C). These GC-rich regions play important roles in controlling gene activity but have historically been challenging to access. 

The researchers tested the approach on MYC, a gene that is known to drive the growth of many cancers when it becomes overactive. The modified DNA molecules successfully attached to the target DNA and reduced MYC gene activity by between 50 and 80 per cent in laboratory experiments. 

Importantly, the new molecules outperformed both unmodified DNA and several previously developed approaches that attempt to target the same DNA regions. 

Dr Rusling added: “Triplex-forming oligonucleotides were a beautiful idea, but in many ways biology defeated the original concept. They could recognise 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.”  

The work also addresses a practical problem that has slowed progress in DNA-targeting therapies. Previously, many specialised DNA modifications had to be custom-made by expert chemists, making them difficult for other researchers to access. The modified bases used in this study are commercially available, making the technology much easier for laboratories around the world to adopt. 

“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 its potential role in treating disease, the technology could become a valuable research tool. Scientists could use it to temporarily switch off individual genes and study how cells respond, helping improve understanding of everything from cancer biology to genetic disorders. 

Because the system relies on DNA sequence recognition, researchers believe it may eventually be adapted to target many different genes simply by altering the sequence of the synthetic DNA molecule. 

While further research will be needed before the technology could be used in patients, the study demonstrates a powerful new method for precisely targeting genes and regulating their activity. 

The paper is published today in Nucleic Acids Research. It has been given ‘breakthrough’ status, which means it represents the top one to two per cent of papers published in the journal. 

Dr Rusling is a member of the University of Portsmouth's Institute of Life Sciences and Healthcare, an integrated, inclusive and supportive research environment for Research and Innovation (R&I) activities spanning the life sciences and healthcare space.