Crigler-Najjar Syndrome: Gene Therapy Maintains Its Efficacy Four Years After Treatment

On 5 November 2026, the New England Journal of Medicine published a study on the long-term efficacy of AAV8-mediated gene therapy GNT0003 in patients with Crigler-Najjar syndrome. The clinical trial is sponsored by Généthon, a non-profit organisation specialising in gene therapy research and development, founded by AFM-Téléthon.

Crigler-Najjar syndrome is an extremely rare congenital liver disorder affecting approximately 500 people in Europe. It is caused by a deficiency of UGT1A1, an enzyme required for bilirubin metabolism. The accumulation of bilirubin can lead to irreversible neurological damage and, in the most severe cases, death.

Patients rely on blue-light phototherapy to control their bilirubin levels. Liver transplantation is the only definitive curative treatment option, but carries a risk of complications. GNT0003 aims to restore UGT1A1 expression in the liver and correct bilirubin levels.
 

Lorenzo D’Antiga, Director of the Paediatrics Department at Papa Giovanni XXIII Hospital, and his co-authors documented the persistence of treatment benefits four years after administration in the three patients who received the therapeutic dose at the hospital in Bergamo, Italy.

Two patients were able to discontinue phototherapy, while the third maintained a partial response, requiring reduced exposure to phototherapy. In all three patients, bilirubin levels remained significantly below the threshold associated with the risk of neurotoxicity.

The investigators also observed sustained normalization of alanine aminotransferase (ALT) levels, a key marker of liver health and function, in the three patients treated at the highest dose. This effect had never been achieved with phototherapy alone.

One patient also completed a pregnancy without complications following gene therapy and gave birth to a healthy baby.

“These four-year follow-up results confirm the potential of GNT0003 to change the management of Crigler-Najjar syndrome in the long-term. They confirm not only the safety of our approach but, above all, its potential for sustained efficacy over time. The teams at Genethon have devoted considerable effort to this project, from initial design of the treatment to clinical trial, and we are very happy of these results, which pave the way for the treatment of other metabolic diseases. This study and those to come also reflect our long-term commitment to finding therapeutic solutions for rare and ultra-rare diseases.” says Giuseppe Ronzitti, from Généthon’s Immunology and Gene Therapy for Liver Diseases team.

This publication follows the results of the phase 1/2 CureCN trial, published in the New England Journal of Medicine in 2023. Those results demonstrated the safety of the treatment and its ability to correct the disease, enabling patients who received the therapeutic dose to discontinue phototherapy.

The pivotal part of the trial, which began in January 2023, aims to confirm the observed effect in a larger patient population, including children aged 10 years and older, as this is the age at which the liver reaches maturity.

“The results of this clinical trial open a new path toward the correction of genetic liver diseases that affect both children and adults and would otherwise be incurable. Until now, adeno-associated virus (AAV) vector gene therapy has shown clinical efficacy in patients with hemophilia A and B. There is now also a clear signal of its efficacy in Crigler–Najjar syndrome. Offering real hope of a cure to patients with severe rare diseases is the greatest reward for physicians and researchers in this field. At Papa Giovanni XXIII Hospital in Bergamo, we continue our commitment to clinical research with passion and dedication, bringing to the bedside innovative therapies that may one day be available to all patients with diseases that currently lack a definitive treatment” says Lorenzo D’Antiga

References

- D’Antiga L. et al. Durability of Gene Therapy in Patients with Crigler–Najjar Syndrome. New England Journal of Medicine. 2026;395:1870–1872.
- D’Antiga L. et al. Gene Therapy in Patients with the Crigler–Najjar Syndrome. New England Journal of Medicine. 2023;389:620–631.