ICGEB Team contributes to proving efficacy of gene therapy in metabolic liver disease

17 August 2023 – the results of a European gene therapy clinical trial involving clinicians from France, Italy and the Netherlands have been published in The New England Journal of Medicine and referenced in Nature Italy. The ICGEB Mouse Molecular Genetics Group set the basis for the clinical translation of the trial as one of the founders of the project.

ICGEB Group Leader, Mouse Molecular Genetics Lab, Dr. Andrés F. Muro and Research Associate, Dr. Giulia Bortolussi have taken part in the European research project CureCN, which aims to develop a curative gene therapy for the ultra-rare Crigler-Najjar syndrome (CN) – a life-threatening liver disease which affects one in a million individuals at birth.

The project commenced in 2013 and is led by Généthon, France and sponsored by the European Union’s Horizon 2020 research and innovation programme. The consortium includes 11 partners from six European countries and has involved the external collaboration of ICGEB which was pivotal in generating pre-clinical data using its Ugt1a KO mouse model, thus setting the basis for the subsequent clinical translation of the trial.

The results of the trial were published in a joint manuscript in the New England Journal of Medicine, co-authored by Dr. Bortolussi and Dr. Muro. These represent the first clinical demonstration of the efficacy of gene therapy in a metabolic disease of the liver, demonstrating the safety and tolerance for the treatment as well as its efficacy at the highest dose.

We are very proud of our contribution to the trial. The obtained in-patient results represent a fundamental step forward towards the application of gene therapy non only for Crigler-Najjar patients, but also for other liver genetic diseases. This is the first report of a long-term correction of a disease caused by a non-secreted liver protein.
Dr. Andrés F. Muro

The gene therapy strategy is based on the administration of a non-pathogenic virus that naturally infects hepatocytes, in which the viral genes were replaced by the wild type UGT1A1 gene. The trial demonstrated restored long-term expression of the missing enzyme with a large reduction in plasma bilirubin levels in the three adult patients treated with the highest viral dose.

The trial was performed in 4 European centres: France (Prof. Labrune, Hôpital Béclère; Italy (Prof. d’Antiga, Papa Giovanni XXIII hospital, Bergamo, and Prof. Brunetti-Pierri, Federico II hospital, Naples); and The Netherlands (Prof. Beuers, AMC, Amsterdam). The current phase of the study, launched in January 2023, aims to confirm the observed effect in a larger number of patients including children aged 10 years and over, the age at which the liver matures. Should the results be conclusive, this would enable a product license application at the French and European authorities.

The inherited Crigler-Najjar syndrome occurs directly after birth. It is caused by the deficiency of a liver-specific enzyme (uridine diphosphate Glucuronosyltransferase 1A1) that leads to the accumulation of toxic unconjugated bilirubin in all body tissues. Untreated, CN causes irreversible neurological damage in the brain and leads to death. At present, the only treatment is phototherapy of up to 12 hours per day – which loses efficacy as patients grow up – and sooner or later a liver transplant, implying high risks and possible complications.

Press release

Further reading in Nature Italy

Coverage in the Italian daily “Il Piccolo”: Part 1, Part 2