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Crigler-Najjar: gene therapy shows its effectiveness

Published at
« Immunologie et Thérapie Génique des Maladies du Foie » de Généthon, dirigée par le Dr Giuseppe Ronzitti

Results published in The New England Journal of Medicine demonstrate the safety and tolerance for gene therapy in Crigler-Najjar syndrome as well as its efficacy at the highest dose. This rare liver disease is characterized by a toxic build-up of bilirubin in the body, which can cause significant neurological damage and become fatal. 

Spending 12 hours a day under phototherapy to keep bilirubin levels below the toxicity threshold and avoid major neurological damage: this, along with liver transplants when it’s possible, is the only treatment available for people suffering from Crigler-Najjar syndrome. 

However, the European gene therapy clinical trial promoted by Généthon, the interim results of which were published on august 17 in The New England Journal of Medicine, opens up promising prospects. It demonstrates the good tolerance of the treatment and the possibility of restoring the expression of a liver protein by gene therapy, thus enabling 3 patients treated at the highest dose to see their bilirubin levels fall sufficiently to be able to stop phototherapy for at least 18 months. No major side effects have been observed. This is the first proof of the efficacy of a gene therapy in a metabolic disease of the liver.

The "pivotal phase" of the trial, which began last January, will need to confirm the dose-effect in a larger number of patients, including children aged 10 and over, the age at which the liver matures.

"If the results of the pivotal part confirm the efficacy of our gene therapy for Crigler-Najjar syndrome, we will be able to move on to product license application and making the treatment available to patients, providing them with significantly improved quality of life. From basic research to clinical development, Généthon has developed unique expertise with gene therapy for various families of rare diseases. We are very pleased with this new phase which highlights the excellence of the research carried out at Généthon" add Frédéric Revah, CEO of Généthon.

A candidate drug medicine designed at Généthon

The candidate drug medicine evaluated in this trial was designed by Genethon's "Immunology and Gene Therapy of Liver Diseases" team, led by Dr Giuseppe Ronzitti. It combines an AAV8 vector and a copy of the UGT1A1 gene, enabling the elimination of bilirubin.  

The trial is being conducted in collaboration with the European CureCN consortium in 4 investigating centers in France, Italy and the Netherlands. 
This gene therapy product GNT-003 received significant support from the European Medicines Agency (EMA) with a PRIME designation (PRIority MEdicines). This designation is granted only to drug candidates with major therapeutic potential, following the conclusive results of the first phases of the trial. 

Crigler-Najjar syndrome, a rare and dangerous disease

Crigler-Najjar syndrome, a rare genetic liver disease, is characterized by hyperbilirubinemia. This excess of bilirubin is due to the malfunctioning of an enzyme responsible for transforming bilirubin into a substance that can be eliminated by the body. If not treated quickly, this accumulation can lead to significant neurological damage and even death.