Publications

Eggers, M; Vannoy, CH; Huang, JY; Purushothaman, P; Brassard, J; Fonck, C; Meng, H; Prom, MJ; Lawlor, MW; Cunningham, J; Sadhu, C; Mavilio, F (). Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. EMBO MOLECULAR MEDICINE, e13968.

Abstract
Pompe disease is a severe disorder caused by loss of acid alpha-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.

DOI:
10.15252/emmm.202113968

ISSN:
1757-4676