International Crigler-Najjar Day: A Treatment in Trial

Crigler-Najjar syndrome is a rare genetic liver disorder caused by a deficiency in a specific enzyme. This deficiency leads to an accumulation of bilirubin in the blood (chronic jaundice), which can become toxic to the brain. Only phototherapy can reduce bilirubin levels, forcing patients to remain under blue UV lamps for up to 12 hours a day.
Fanny Collaud, a researcher in the “Immunology and Gene Therapy of Liver Diseases” team at Généthon, explains Crigler-Najjar syndrome (in french)  : 

Developed by Généthon, the AFM-Téléthon’s laboratory, within the “Immunology and Liver Diseases” team led by Dr. Giuseppe Ronzitti, the ongoing gene therapy trial aims to correct the genetic anomaly responsible for Crigler-Najjar syndrome. It involves delivering a functional copy of the defective gene directly into liver cells in order to restore their ability to eliminate bilirubin, a toxic pigment that accumulates in the blood of affected patients.

Since 2017, an international clinical trial, sponsored by Généthon, has been underway in France (Béclère Hospital in Clamart), in Italy (two centers), and in the Netherlands. A few patients have been treated and the initial results of this investigational drug are promising: the treatment has proven to be safe, well tolerated, and some patients have been able to discontinue phototherapy. The trial of this innovative treatment is continuing with the inclusion of new patients and the long-term follow-up of those already treated, to assess the durability of the therapeutic effect.

Elena, 14, joined the pivotal phase of the gene therapy trial in 2023. Diagnosed shortly after birth, she spent nearly 13 years under phototherapy lamps at night. But since July 2023, her life—and her family’s—has changed dramatically. She received the treatment developed by Généthon, and four months after the injection, Elena was able to stop phototherapy. Today, the teenager is enjoying a new life :

Elena’s story illustrates the tangible benefits of this therapeutic breakthrough. But it also highlights that, to this day, not all patients can benefit from it. Such is the case of Kelly, 17, who still undergoes phototherapy for 10 to 12 hours a day.The reason: the presence of anti-AAV antibodies, developed when the immune system has already been exposed to the virus used as a vector to deliver the therapeutic gene. These antibodies prevent the viral vector from effectively reaching the liver, rendering the treatment ineffective.

To overcome this immune barrier, Généthon is currently conducting the IDES trial. This trial evaluates the potential of pre-treatment with imlifidase, an enzyme capable of temporarily eliminating anti-AAV antibodies before administering the viral vector. This innovative protocol could enable previously excluded patients to access gene therapy and pave the way for new applications in other rare diseases facing similar immune challenges.

The advances made by Généthon in Crigler-Najjar syndrome highlight gene therapy’s potential to transform patients’ lives. But they also underscore the need to continue research to address all clinical situations, including those of patients currently excluded from treatment.

Through its laboratory Généthon and all of its initiatives, AFM-Téléthon pursues a clear objective: to bring forth innovative therapies for rare diseases, 95% of which still have no therapeutic solution. Today, the association supports 40 clinical trials across 33 diseases affecting the muscles, skin, blood, brain, or vision.