Gene therapy shows promise against deadly childhood liver disease

A new gene therapy has been used to successfully treat a deadly childhood liver disease using mice that model this disease by researchers at UCL and Great Ormond Street Hospital.

Lead author Dr Claudiu Cozmescu (UCL Great Ormond Street Institute of Child Health) said: "Our findings are important because it provides proof-of-concept that gene therapy could become a realistic treatment for ARC syndrome and potentially other inherited liver diseases that currently have few or no effective options.

"It also highlights that how a gene therapy is designed is critical: targeting treatment specifically to the liver improved safety while maintaining benefit.

"The findings should be of interest to patients and families affected by rare liver diseases, clinicians, gene therapy researchers, biotech developers, regulators, and charities supporting rare disease research.

"Before human trials, further long-term toxicology and safety studies will be needed."

ARC syndrome is a medical condition where the flow of bile from your liver is reduced or completely blocked. Bile is a digestive fluid produced by the liver to break down fats. When its flow is stalled, bile components (like bilirubin and bile acids) build up in the liver and leak into the bloodstream, leading to sepsis which is usually fatal.

For the trial the scientists used special mice that had been genetically engineered so that the VPS33B gene did not work properly.

Some mice had no working copy of the gene in their liver (the "disease" mice) while others had only one working copy (which were used for safety testing).

Because of this missing or faulty gene, the mice developed liver problems similar to those seen in children with ARC syndrome.

The researchers found that the treatment helped the mice's livers start working properly again: the mice lived longer (about 80% survived compared with about 33% which did not have the treatment), and their livers had less scarring (fibrosis).

The treatment was more effective when given throughout the body rather than just targeting the liver.

However, in the initial attempts to cure the disease around 30% of those mice developed liver tumours - the risk of cancer developing as a side effect of gene therapy has been raised in previous trials.

But none of the mice treated with the final, liver-targeted version developed tumours, suggesting gene therapy can be safe if done correctly.

Co-author Professor Paul Gissen, Clinical Professor of Paediatric Metabolic Medicine at UCL Great Ormond Street Institute of Child Health and Director Designate of the National Institute for Health and Care Research GOSH Biomedical Research Centre, said: "The final version of the treatment is shown to be safe so far. The earlier version gave us a new window into the understanding of how to make gene therapies safer for the patients. One of these insights is to keep the levels of genes as close to those found in healthy cells as possible."

George Orphanides, Chief Scientific Officer at LifeArc, said: "ARC syndrome is a serious, ultra-rare condition with very limited treatment options. These early findings are an important step towards understanding whether gene therapy could one day offer a new approach for affected children and their families.

"For many rare diseases, promising science can struggle to progress beyond the lab. LifeArc's rare disease work supports research into diseases with clear patient need and strong scientific potential move closer to the point where it could make a difference, while ensuring safety is considered from the outset."

All research at GOSH is supported by the NIHR GOSH Biomedical Research Centre but the NIHR did not directly fund the animal research.

Source:

University College London

Journal reference:

Cozmescu, C. A., Nazari, M., Touramanidou, L., Gurung, S., Perocheau, D., Sebire, N., Hu, Y.-T., Goldsworthy, S., Burden, J. J., Khalil, Y., Doykov, I., Counsell, J. R., Karda, R., Castellano, S., Mills, P., Clayton, P., Heywood, W., Moulding, D., Waddington, S. N., & Baruteau, J. (2026). Safety and efficacy analysis of in vivo lentiviral gene therapy in pre-clinical ARC syndrome models. Nature Communications. https://doi.org/10.1038/s41467-026-73631-x