Evidence of efficacy of gene therapy in rodents affected by a rare genetic liver disease, Crigler-Najjar syndrome

Federico Mingozzi, head of the Immunology and Liver Gene Therapy team at Généthon, the laboratory created by the AFM Téléthon, presented at the 48th Annual Meeting of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN, May 6-9, Amsterdam), work done in collaboration with an Italian and Dutch teams showing long term correction of a genetic defect causing toxic buildup of bilirubin in murine and rat models of Crigler-Najjar syndrome.

Crigler-Najjar syndrome is a rare autosomal recessive disorder caused by mutations in the UGT1A1 gene, which result in the toxic accumulation of bilirubin, a substance made by the liver in the body. Indeed, when the UDP-glucuronosyltransferase 1 isotype A1 (UGT1A1), the enzyme responsible for removing bilirubin, doesn’t work, the substance accumulates, causing a severe and chronic jaundice, and becoming toxic for the brain and leading to lethality.

Gene therapy has allowed the restoration of an equivalent level of bilirubin to those found in healthy animals

Federico Mingozzi team (Généthon, Evry/France), in collaboration with the team of Andres Muro (ICGRB, Trieste/Italy) and the team of Piter Bosma (AMC, Amsterdam/Netherlands), transferred with an AAV vector (adeno-associated virus), developed by Généthon, a copy of the UGT1A1 gene (coding for the production of the UGT1A1 enzyme) in liver cells (hepatocytes) of rats and mice carriers of the anomaly. After injection, levels of bilirubin in the treated animals became equivalent to those of healthy animals. The correction was confirmed more than 6 months after gene therapy, without requiring prior immunosuppression or additional intervention.

The researchers demonstrated that a single injection of the AAV vector-UGT1A1 enabled the long-term correction of the Crigler-Najjar syndrome in the treated animals.

Towards a phase I/II clinical trial

These results open the way to the establishment of a phase I/II clinical trial by the end of 2016, of which Généthon will be the promoter. In 2015, regulatory toxicity studies and industrial transposition for the production of clinical batch processing under GMP (Good Manufacturing Practices) will take place at Généthon*. Twenty patients will be enrolled in 5 clinical centers in Europe: in France (APHP Antoine Béclère), the Netherlands (Academic Medical Center), Germany (Hannover Medical School), and Italy (Azienda Ospedale Papa Giovanni XXIII in Bergamo and Federico II Hospital in Naples).

Federico Mingozzi, driver for this work: “These promising results allowed us to start thinking about clinical trial, which hopefully will start by the end of 2016 or early 2017. I am very excited to continue this project, which finds its strength in all the participating actors – the researchers, the clinical investigators, and the patients’ associations of France, Italy, and the Netherlands. Everyone has been working very hard together with the Genethon team since 2013.”

Frédéric Revah, CEO of Généthon: “This new trial will be a new challenge for Généthon. Indeed, after undertaking the development of gene therapy treatments for immune deficiencies, for diseases of the muscle and contributing to the development of treatments for diseases of the vision and blood, Généthon will begin the development of a drug candidate targeting the liver. A new exciting project for Généthon and its unique expertise: develop and simultaneously produce gene therapy treatments for different families of orphan diseases.”