Gene Therapy Breakthrough Offers Hope for Deadly Childhood Liver Disease

A team of researchers from UCL and Great Ormond Street Hospital (GOSH) has achieved a major milestone in the fight against one of the rarest and most devastating childhood conditions: Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome.

This lethal genetic disorder, usually caused by the absence of the VPS33B protein, leaves infants unable to process bile, a vital digestive fluid, properly. Without treatment, bile builds up in the liver and bloodstream, leading to sepsis and death. Tragically, most children diagnosed with ARC syndrome do not live beyond their first year.

In a study published in Nature Communications, the UCL‑GOSH team injected a healthy version of the VPS33B gene into specially engineered mice that mimic the disease. The therapy restored liver function, reduced scarring, and dramatically improved survival rates; about 80% of treated mice lived, compared with only 33% of untreated ones.

Crucially, the final version of the therapy, which specifically targeted liver cells, caused no harmful side effects. Earlier versions had triggered abnormal gene activation, leading to cancerous growths in some mice. By refining the design, the researchers showed that gene therapy can be both effective and safe.

Lead author Dr Claudiu Cozmescu (UCL Great Ormond Street Institute of Child Health) explained:

“Our findings are important because they provide 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.”

Co‑author Professor Paul Gissen added:

“The final version of the treatment is shown to be safe so far. The earlier version gave us a new window into how to make gene therapies safer for patients. One of these insights is to keep the levels of genes as close to those found in healthy cells as possible.”

The discovery offers hope to families affected by ARC syndrome; around six pregnancies per year in the UK may be impacted. It also provides a new lens into why some gene therapies risk causing cancer, helping researchers design safer treatments for other rare liver diseases.

George Orphanides, Chief Scientific Officer at LifeArc, which co‑funded the study, 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.”

While the results are promising, the team stresses that more long‑term safety and toxicology studies are needed before human trials can begin. Still, the breakthrough marks a turning point: proof that gene therapy could one day transform the outlook for babies born with ARC syndrome, and potentially for many other rare inherited liver diseases.