At Papa Giovanni XXIII Hospital in Bergamo, Italy, three people with a rare liver disorder still showed benefits from gene therapy four years after treatment. Two no longer needed the blue-light sessions that had helped control their illness; the third needed less time under the lights.
Crigler-Najjar syndrome affects about 500 people in Europe. It is caused by a lack of UGT1A1, an enzyme the liver needs to process bilirubin, a substance made as the body breaks down old red blood cells. If bilirubin builds up too high, it can cause lasting brain damage and, in the most severe cases, death. Until now, patients have relied on blue-light phototherapy to keep bilirubin levels down. A liver transplant can offer a cure, but it also carries risks.
The therapy, called GNT0003, uses a harmless modified virus known as AAV8 to deliver genetic instructions to liver cells. The aim is to help the liver make UGT1A1 and bring bilirubin levels under control. In a study published in The New England Journal of Medicine, Lorenzo D'Antiga, head of pediatrics at Papa Giovanni XXIII Hospital, and his co-authors followed the three patients who received the therapeutic dose there. Four years later, bilirubin levels in all three remained well below the level linked to a risk of nerve damage.
Two patients had stopped phototherapy, while the third continued with a reduced amount. Researchers also found that levels of alanine aminotransferase, or ALT, had stayed normal in all three patients treated at the highest dose. ALT is a liver enzyme used to check how well the organ is working. The study says this long-lasting change had not been achieved with phototherapy alone.
One patient also completed a pregnancy without complications after receiving the therapy and gave birth to a healthy baby. That is a meaningful detail for people living with a disease that can shape daily care and long-term health decisions, though the study involved only three patients at this dose and cannot show how the treatment will work for everyone.
The new findings build on results from the Phase I–II CureCN trial, published in the same journal in 2023. That earlier study reported that the treatment was safe and could correct the disease in patients receiving the therapeutic dose, allowing them to stop phototherapy. A larger, pivotal part of the trial began in January 2023. It is designed to test the effect in more people, including children aged 10 and older, when the liver is considered mature.
The results add to growing interest in gene therapy for inherited liver diseases. D'Antiga said the trial points to a possible path for genetic conditions that have no lasting treatment today. Giuseppe Ronzitti of Généthon, which helped develop the therapy, said the four-year follow-up supports the possibility of lasting benefit. The larger trial will help show whether that promise holds across more patients and over time.