Genethon studies cardiotoxicity associated with high doses of AAV vectors in gene therapy
In a study published on December 24, 2025 in the Journal Molecular Therapy, scientists from Isabelle Richard’s laboratory evaluated the cardiac effects associated with the administration of high doses of AAV vectors used in gene therapy.
AAV viral vectors are at the forefront of gene therapies designed to treat rare diseases. They show encouraging results and offer hope to those awaiting treatment.
However, preclinical studies and clinical trials have revealed that at high doses, they can induce cytotoxicity, particularly in the heart.
A heart-focused analysis
The team analyzed the impact of AAV vectors expressing three transgenes associated with Duchenne muscular dystrophy, γ-sarcoglycanopathy, and FKRP protein deficiency.
The researchers found that the expression of these transgenes in the heart could trigger cardiotoxicity, linked to protein overload mechanisms.
Strategies to prevent adverse effects
The researchers demonstrated that by reducing or preventing the expression of transgenes in the heart, it is possible to avoid these adverse effects. This approach has been validated in preclinical studies, confirming its safety.
A crucial issue for gene therapy
These findings highlight the particular sensitivity of the heart to transgene expression and the importance of finely regulating this expression in any therapeutic approach.
“The data from this article shed unique light on the risks of cardiac toxicity associated with high-dose gene therapy and enabled the development of products with high safety and efficacy, products from Genethon that are currently undergoing clinical trials,” concludes Isabelle Richard, Ph.D., Head of the progressive dystrophies laboratory at Genethon.
For more information
Ariane Biquand, Evelyne Gicquel, Jérôme Poupiot, Marine Faivre, Stephany Campuzano, Tiffany Bourgeton, Pierre-Romain Lebrun, Philippe Véron, Anthony Brureau, and Isabelle Richard
“Transgene-Induced Cardiotoxicity In High-Dose AAV Gene Transfer”
