Gene therapy restores liver function in Crigler-Najjar patients
A gene therapy trial for the ultra-rare Crigler-Najjar syndrome shows durable benefits after four years, with patients maintaining safe bilirubin levels and two stopping lifelong phototherapy.
Gene therapy GNT0003 has successfully restored liver function in three patients with Crigler-Najjar syndrome, eliminating the need for phototherapy in two cases. The four-year follow-up data from an Italian hospital trial confirms the treatment's sustained efficacy and safety for this genetic disorder, which affects approximately 500 people in Europe.
Crigler-Najjar syndrome is caused by a deficiency of the UGT1A1 enzyme, which is required for bilirubin metabolism. Without it, toxic levels of bilirubin can build up, posing a serious risk of neurotoxicity. Patients have historically relied on daily blue-light phototherapy to control these levels. The only definitive curative option has been liver transplantation, a procedure that carries significant risks and complications.
The experimental therapy, GNT0003, aims to correct this by using an adeno-associated virus (AAV8) vector to deliver a functional copy of the UGT1A1 gene directly to liver cells. Three patients received the therapeutic dose at Papa Giovanni XXIII Hospital in Bergamo, Italy. The results have been major. Two of those patients have completely discontinued phototherapy. The third maintains a partial response, requiring only reduced exposure.
Crucially, bilirubin levels in all three patients have remained significantly below the threshold associated with neurotoxicity risk for the entire four-year period. Also, sustained normalization of alanine aminotransferase (ALT) levels was observed, indicating healthy liver function without signs of damage.
Safety and long-term benefits confirmed
The study confirms the long-term safety and sustained efficacy of this gene therapy approach for Crigler-Najjar syndrome. Giuseppe Ronzitti, from Généthon’s Immunology and Gene Therapy for Liver Diseases team, stated that the four-year follow-up results confirm the safety and sustained efficacy of GNT0003. No neurotoxicity or major complications related to the treatment have been observed in the patients over this extended period.
Broader impact on treatment pathways
This breakthrough opens a new path toward correcting genetic liver diseases that affect both children and adults and would otherwise be incurable, according to Lorenzo D’Antiga, Director of the Paediatrics Department at the hospital in Bergamo. The therapy offers a potential definitive alternative to high-risk liver transplantation for patients with this ultra-rare condition.
The impact on quality of life and long-term health prospects is significant. In a landmark outcome, one patient completed a pregnancy without complications following the gene therapy and gave birth to a healthy baby. This event shows the treatment's potential to support normal life stages.
The key part of the trial began in January 2023 and aims to confirm the effect in a larger patient population, including children aged 10 years and older. The international CureCN consortium, sponsored by Généthon, is conducting this work. The four-year data provides a strong foundation for this next phase, confirming the durable benefit of the intervention.
