Researchers at UCL and Great Ormond Street Hospital have successfully used a new gene therapy to treat a deadly childhood liver disease using mice that model the disease.
Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a usually fatal genetic disease caused by a deficiency of the VPS33B protein, and children diagnosed with the disease rarely live beyond the first year of life.
Now, in a study published in nature communications, The UCL-GOSH team found that they could treat the condition in mice lacking VPS33B by injecting a healthy version of the gene into their bodies.
Importantly, while the final version of the treatment, which specifically targeted liver cells, was harmless, earlier versions activated genes abnormally, causing cancer cells to grow and spread in some cases.
Although more trials need to be conducted before this treatment can be tested in humans, the researchers’ breakthrough offers hope for infants and their families with this devastating disease. In the UK, up to six pregnancies a year can be affected by ARC syndrome. Additionally, we may be able to better understand why some treatments cause cancer.
Our findings are important because they provide proof of concept that gene therapy could be a viable treatment for ARC syndrome and potentially other inherited liver diseases for which there are currently few or no effective options.
It also highlights the importance of how gene therapies are designed. Treatments that specifically target the liver improve safety while maintaining benefit.
The findings should be of interest to patients and families affected by rare liver diseases, clinicians, gene therapy researchers, biotechnology developers, regulatory authorities, and charities supporting rare disease research.
Further long-term toxicology and safety studies will be required before human clinical trials. ”
Dr Claudiu Cozmescu, UCL Great Ormond Street Institute of Child Health, first author
ARC syndrome is a medical condition in which the flow of bile from the liver is reduced or completely blocked. Bile is a digestive fluid produced by the liver to break down fats. When bile flow is blocked, bile components (such as bilirubin and bile acids) accumulate in the liver and leak into the bloodstream, causing sepsis, which is usually fatal.
In this study, scientists used special mice that had been genetically engineered to prevent the VPS33B gene from working properly.
Some mice had no working copy of the gene in their livers (the “sick” mice), while others had just one working copy (used in safety tests).
Due to the deletion or defect in this gene, the mice developed liver damage similar to that seen in children with ARC syndrome.
The researchers found that with this treatment, the mice’s livers started functioning normally again. The mice lived longer (about 80% survived compared to about 33% of mice that did not receive treatment) and had less scarring (fibrosis) in their livers.
The treatment was more effective when given systemically rather than targeting only the liver.
However, in the first attempt to cure the disease, about 30% of these mice developed liver tumors. The risk of developing cancer as a side effect of gene therapy has been raised in previous trials.
However, none of the mice treated with the final liver-targeted version developed tumors, suggesting that gene therapy is safe if done correctly.
Co-author Professor Paul Gissen, Clinical Professor of Pediatric Metabolic Medicine at the UCL Great Ormond Street Institute of Child Health and appointed Director of the GOSH Biomedical Research Center at the National Institute for Health and Care Excellence, said: “These early versions have given us a new window into our understanding of how to make gene therapy safer for patients. One of these insights is to bring the gene levels closer to those found in healthy people.” cells as much as possible. ”
This research was funded by GOSH Charity and the self-funded medical research organization LifeArc.
George Orphanides, chief scientific officer at LifeArc, said, “ARC syndrome is a serious and ultra-rare disease with very limited treatment options. These early findings are an important step toward understanding whether gene therapy may one day offer a new approach to affected children and their families.”
“For many rare diseases, promising science can struggle to advance beyond the lab. LifeArc’s rare disease research supports research into diseases with clear patient needs and strong scientific potential, bringing them closer to the point where they can make a difference, while ensuring safety is considered from the start.”
All research at GOSH is supported by the NIHR GOSH Biomedical Research Center, although the NIHR did not directly fund the animal studies.
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university college london
Reference magazines:
Cosmescu, California; Others. (2026). Analysis of safety and efficacy of in vivo lentiviral gene therapy in a preclinical ARC syndrome model. Nature Communications. DOI: 10.1038/s41467-026-73631-x. https://www.nature.com/articles/s41467-026-73631-x
