This breakthrough in research was presented May 7, 2015 at the 48th Annual Meeting of the ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology and Nutrition.
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 bliver in the body.
Indeed, when the UDP-glucuronosyltransferase 1 isotype A1 (UGT1A1), thebenzyme responsible for removing bilirubin, doesn’t work, the substance accumulates, causing absevere and chronic jaundice, and becoming toxic for the brain and leading to lethality.
A single one injection is enough
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 (adenoassociated 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).
"These promising results allowed us to start thinking about clinical trial, which hopefully will start by the end of 2016 or early 2017.” says Federico Mingozzi, driver for this work. “ 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 sees this trial as the promise of a new challenge for his laboratory : “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.”