Gene therapy reduces liver disease in mouse model of ARC syndrome
UCL and Great Ormond Street Hospital researchers say a liver-targeted gene therapy improved outcomes in mice without causing tumors in tests so far.
By Tom Brennan · Health & Medicine Correspondent
3 min read
Researchers at University College London and Great Ormond Street Hospital have reported early evidence that gene therapy could treat ARC syndrome, a rare inherited liver disease that is often fatal in infancy. The finding matters because children diagnosed with the disorder have few treatment options and, according to the research team, rarely survive past their first year.
The study, published in Nature Communications, tested a therapy designed to replace the faulty or missing VPS33B gene that commonly causes arthrogryposis, renal dysfunction and cholestasis syndrome. UCL said researchers injected a working version of the gene into mice engineered to model the disease.
ARC syndrome disrupts bile flow from the liver, according to UCL. When bile cannot move normally, substances including bilirubin and bile acids can accumulate in the liver and enter the bloodstream, a process that can lead to sepsis and death.
Mouse study found longer survival
The UCL-GOSH team used mice whose VPS33B gene did not function properly. Some had no working copy of the gene in the liver and were used as disease models, while others had one working copy and were used in safety testing, UCL said.
Researchers found the treatment improved liver function in the mice. According to UCL, about 80% of treated mice survived, compared with about 33% of mice that did not receive the therapy, and treated animals had less liver scarring.
The team also found that a version delivered throughout the body produced stronger disease effects than a version aimed only at the liver. But UCL said the broader approach carried a safety problem: in early versions of the therapy, genes were abnormally activated, and about 30% of those mice developed liver tumors.
The final version was designed to target liver cells specifically. UCL said none of the mice treated with that version developed tumors, though the researchers said more testing is needed before any trial in people.
Safety design was central
Dr. Claudiu Cozmescu of the UCL Great Ormond Street Institute of Child Health, the study’s lead author, said the work provides proof of concept that gene therapy could become a treatment for ARC syndrome and possibly other inherited liver diseases with limited options. He also said the study showed that gene therapy design matters, with liver targeting improving safety while preserving benefit.
Cozmescu said long-term toxicology and safety studies would be required before human testing. UCL said as many as six pregnancies a year in the UK may be affected by ARC syndrome.
Professor Paul Gissen, a co-author at the 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 treatment has appeared safe so far. He said the earlier version helped the team understand how to make gene therapies safer, including by keeping gene levels close to those seen in healthy cells.
George Orphanides, chief scientific officer at LifeArc, said ARC syndrome is an ultra-rare condition with very limited treatment options. He said the findings are an early step toward determining whether gene therapy could one day offer another approach for affected children and families.
The paper is titled “Safety and efficacy analysis of in vivo lentiviral gene therapy in pre-clinical ARC syndrome models.” It was published in Nature Communications.
This story draws on original reporting from Medical Xpress.