A genetic peculiarity that is sometimes found in biochemistry is ‘covalently closed circular DNA‘ (cccDNA), where the DNA molecule, instead of being a long, ribbon-like strand, becomes a closed loop. Since many medical treatments involve attacking unwanted DNA at its vulnerable open end-points, cccDNA, which has no such open end-points, is much harder to target.
Unfortunately, the hepatitis B virus (HBV) exists as rings of cccDNA in the human body, which is one reason it has been so hard develop an effective cure for the disease. Medications can suppress HBV activity but cannot eliminate this stubborn form of viral DNA, which hides inside infected liver cells and fuels relapse when treatment stops.
Now a new research project in South Africa, at the University of the Witwatersrand, Johannesburg, has made use of a new technology to try to overcome this problem. In South Africa, there are an estimated 2.5 million people living with hepatitis B, out of 54 million: this is almost 5% of the population.
This research, which is yet to be tested on humans, is showing that the genetic blueprint of the hepatitis B virus (HBV) could be permanently inactivated with newly engineered molecular “scissors” called TALENs. These ‘transcription activator-like effector nucleases‘ are enzymes that can be engineered to cut very specific sequences of DNA, which can be used to attack the ring structure of the cccDNA.
Dr Tiffany Smith, a postdoctoral research fellow at the university’s Antiviral Gene Therapy Research Unit, developed this idea. She used the TALENs because, unlike some other genetic editing techniques, they are highly effective even in complex or tightly packed DNA regions, like cccDNA rings. Smith and her team specialise in delivering mRNA in lipid nanoparticles, a platform that has already dramatically advanced vaccine development. By combining this delivery system with the precision of TALEN-based molecular scissors, they have taken an important step towards a functional cure for HBV.
“The ability to target the virus’s genetic blueprint directly paves the way for reduced healthcare costs and dramatically improved outcomes,” Dr Smith explained.
Laboratory tests on cultured human liver cells showed that the treatment reduced hepatitis B markers by 80%. In HBV-infected mice, a single dose resulted in a massive 99% reduction in circulating viral DNA. Importantly, the therapy was well tolerated, causing only mild inflammation that quickly resolved with no significant toxicity.
“These results are highly promising,” said Professor Patrick Arbuthnot, who leads the Antiviral Gene Therapy Research Unit team. “This work underscores the enormous potential of gene-editing technologies to confront persistent viral infections with precision and safety.”
The researchers now need to demonstrate that these TALENs can accurately target viral DNA while causing few or no changes to the host’s DNA. However, the ability to directly cut and disable HBV’s hidden genetic blueprint, especially its stubborn cccDNA, represents a milestone in the global effort to eliminate hepatitis B.
The study is published in the journal Viruses.
You may also be interested in this piece on how Hepatitis B DNA splicing may serve as an early marker for liver cancer.
Last updated 12 September 2025
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