Muscle‐directed gene therapy corrects Pompe disease and uncovers species‐specific GAA immunogenicity

Pompe disease is a severe disorder caused by loss of acid α‐glucosidase (GAA), leading to glycogen accumulation in tissues and neuromuscular and cardiac dysfunction. Enzyme replacement therapy is the only available treatment. AT845 is an adeno‐associated viral vector designed to express human GAA specifically in skeletal muscle and heart. Systemic administration of AT845 in Gaa (−/−) mice led to a dose‐dependent increase in GAA activity, glycogen clearance in muscles and heart, and functional improvement. AT845 was tolerated in cynomolgus macaques at low doses, while high doses caused anti‐GAA immune response, inflammation, and cardiac abnormalities resulting in unscheduled euthanasia of two animals. Conversely, a vector expressing the macaque GAA caused no detectable pathology, indicating that the toxicity observed with AT845 was an anti‐GAA xenogeneic immune response. Western blot analysis showed abnormal processing of human GAA in cynomolgus muscle, adding to the species‐specific effects of enzyme expression. Overall, these studies show that AAV‐mediated GAA delivery to muscle is efficacious in Gaa (−/−) mice and highlight limitations in predicting the toxicity of AAV vectors encoding human proteins in non‐human species.