Genethon and Hansa Biopharma report GNT-018-IDES trial data showing imlifidase enables gene therapy for Crigler–Najjar patients.

The trial demonstrates that this approach allows delivery of Genethon’s GNT0003 gene therapy even in patients with pre-existing antibodies, potentially expanding access to treatment for those previously ineligible for AAV-based therapies.

Crigler–Najjar syndrome is a rare liver disease in which patients require daily phototherapy to manage bilirubin levels. Gene therapy for the condition involves delivering the GNT0003 gene candidate via an AAV vector. However, prior exposure to natural AAVs can trigger the production of immunoglobulin G (IgG) antibodies that neutralise the vector, preventing effective treatment.

It is estimated that approximately one in three people is naturally immune to AAVs, which has excluded a substantial proportion of patients from gene therapy clinical trials.

To address this challenge, researchers at Genethon tested imlifidase, an IgG-cleaving enzyme developed by Hansa Biopharma, as a pre-treatment. The enzyme rapidly reduces anti-AAV antibody levels, enabling subsequent administration of GNT0003.

In the first patient treated, the study demonstrated the feasibility and safety of this approach. Imlifidase successfully inactivated the patient’s antibodies, allowing delivery of GNT0003 without severe adverse effects. Early efficacy data showed a significant reduction in bilirubin levels, enabling the patient to discontinue daily phototherapy sixteen weeks after the gene therapy injection, as outlined in the trial protocol.

Giuseppe Ronzitti, head of the immunology and liver disease laboratory and director of scientific forecasting at Genethon, said: “It’s a project that involved a significant portion of Genethon working toward a common goal. The preliminary data we’ve obtained indicate that we still have a lot to learn about the immune response to AAV vectors, but the solution is potentially there.”

This is the first reported instance of gene therapy being successfully administered to a patient with Crigler–Najjar syndrome who had pre-existing antibodies against AAV8. If these results are confirmed in later stages of the trial, the approach could provide a new treatment option for patients previously ineligible for AAV-based gene therapies.

The GNT-018-IDES trial results were presented at the 2025 European Society of Gene & Cell Therapy (ESGCT) congress, highlighting the potential for combining immunomodulatory enzymes with gene therapy to expand patient access.