Risk of myocarditis identified in primates receiving gene therapy for Pompe disease

As part of animal toxicity studies prior to the launch of a gene therapy clinical trial for Pompe disease, researchers at the University of Pennsylvania have reported safety problems.

• Rhesus macaque primates were given a gene therapy product developed by the Amicus laboratory in increasing doses by the systemic route.
• The construct included the human GAA gene encoding acid maltase and a tracer gene, contained in an AAV9-like AAV« adeno-associated virus » , ou virus adéno-associé est un petit virus à ADN simple brin. Il fait partie de la famille des Parvoviridae et appartient au genre des Dependovirus. La particule virale est constituée d’un brin d’ADN de polarité positive ou négative protégé par une capside. La taille moyenne d’une particule d’AAV et de 18 à 22 nm. Les AAV sont les seuls parvovirus non autonomes. Lorsqu’on emploie « rAAV » , il s’agit du virus AAV recombinant, c’est-à-dire qu’il a été modifié pour devenir un vecteur (et n’est donc plus virulent)..
• Cardiac toxicity, probably of immune origin, was noted in 5 of the 11 monkeys injected.

These findings call for a degree of vigilance in the context of clinical development, even though this type of complication has not been reported in other gene therapy trials currently underway in Pompe disease.

Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase. Hordeaux J, Ramezani A, Tuske S et al. Front Immunol. 2023 Mar.