Progress in Treating Patients Immunised Against AAV Vectors Used in Gene Therapy
A patient with Crigler–Najjar syndrome, immunised against the AAV vector used in gene therapy, was able to receive treatment as part of a Genethon-led trial, thanks to the prior administration of imlifidase, an enzyme developed by Hansa Biopharma.
Gene therapy involves injecting a gene-based medicine into the body using a vector – a "transport vehicle" most often derived from a virus, such as adeno-associated viruses (AAV), which are commonly used in gene therapy for neuromuscular, liver and vision-related diseases. A prior exposure to the natural virus can cause the body to develop specific antibodies that neutralise the AAVs: immunoglobulin G (IgG).
Frédéric Revah, Chief Executive Officer of Genethon, explains: “30% to 50% of patients who could benefit from an approved gene therapy or participate in a clinical trial are unable to do so because they are seropositive for the AAV virus used in many gene therapy products. Overcoming this barrier is therefore a major challenge that Genethon is committed to addressing.”
To overcome this obstacle, Genethon’s researchers tested imlifidase, an enzyme developed by Hansa Biopharma, as a pre-treatment. By inhibiting IgG, the enzyme reduces the level of anti-AAV antibodies, thereby enabling the administration of a candidate gene therapy product.
A Clinical Application for Crigler–Najjar Syndrome
The results of using imlifidase as a pre-treatment ahead of the gene therapy developed by Genethon (GNT 0003) in a patient with a severe form of Crigler–Najjar syndrome and naturally immunised against the AAV8 vector were presented at the 2025 annual congress of the European Society of Gene & Cell Therapy (ESGCT).
Conducted as part of the clinical trial led by Genethon (GNT-018-IDES), in collaboration with Hansa Biopharma, this first administration in an immunised patient demonstrated both the feasibility and safety of the approach: imlifidase, given prior to GNT0003 gene therapy, neutralised the patient’s antibodies and made the treatment possible, with no serious adverse events reported.
Initial efficacy data were also observed: the candidate product led to a significant reduction in bilirubin levels, allowing the patient to stop daily phototherapy – previously essential for her survival – sixteen weeks after the injection, as specified in the protocol.
Additional data will be required to confirm the long-term efficacy of the approach.
A New Perspective for Patients Immunised Against AAVs
This first administration of gene therapy in a patient with Crigler–Najjar syndrome, despite the presence of neutralising antibodies against AAV8, opens up new possibilities.
While the results must be confirmed in the next stages of the trial, this approach offers new hope for patients who are currently ineligible for clinical trials or approved gene therapy products.
An advance highlighted by Frédéric Revah: “The results presented today at ESGCT represent a significant step forward in enabling a greater number of patients to benefit from these innovative treatments, which have the potential to change lives. This first scientific and clinical demonstration once again reflects the excellence of the research carried out at Genethon, and I am particularly proud that our laboratory is leading the way.”