Gene Therapy for Rare Liver Disease Shows Promise

Rare Daily Staff

A European gene therapy clinical trial demonstrates the possibility of restoring expression of a needed liver enzyme by using gene therapy in cases of the rare liver disease Crigler-Najjar syndrome.

Results of the study, sponsored by the nonprofit lab Généthon and involving clinicians from France, Italy, and the Netherlands, were published in The New England Journal of Medicine.

Crigler-Najjar syndrome is characterized by hyperbilirubinemia. If it is not treated quickly, the build-up of bilirubin, due to a deficiency in the enzyme UGT1A1 that is responsible for metabolizing it into a substance that can be eliminated by the body, can cause significant neurological damage and become fatal. At the current time, the only treatment is phototherapy of up to 12 hours per day or a liver transplant.

The phase 1/2 trial, carried out in conjunction with the European consortium CureCN, evaluated the tolerance and efficacy of the experimental gene therapy GNT 0003, which combines an AAV8 vector with a copy of gene UGT1A1.

The results confirm the safety and tolerance for the treatment in all patients and sustained efficacy in the three patients treated with the highest dose. The experimental therapy, designed by Genethon, lowered bilirubin levels below the toxic threshold with a single intravenous injection to such an extent that the three patients treated with the highest dose have been able to stop using phototherapy for the last 18 months or more. The clinical trial is currently in the pivotal phase.

No major side effects have been observed. The only symptoms were changes in hepatic enzymes and headaches, which were resolved. This is the first proof of the efficacy of a gene therapy in a metabolic disease of the liver.

“If the results of the pivotal part confirm the efficacy of our gene therapy for Crigler-Najjar syndrome,” said Frédéric Revah, CEO of Généthon, “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.”