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.

Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity / Eggers, M.; Vannoy, C. H.; Huang, J.; Purushothaman, P.; Brassard, J.; Fonck, C.; Meng, H.; Prom, M. J.; Lawlor, M. W.; Cunningham, J.; Sadhu, C.; Mavilio, F.. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 14:1(2022), pp. 1-15. [10.15252/emmm.202113968]

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

Mavilio F.
2022

Abstract

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.
2022
14
1
1
15
Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity / Eggers, M.; Vannoy, C. H.; Huang, J.; Purushothaman, P.; Brassard, J.; Fonck, C.; Meng, H.; Prom, M. J.; Lawlor, M. W.; Cunningham, J.; Sadhu, C.; Mavilio, F.. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 14:1(2022), pp. 1-15. [10.15252/emmm.202113968]
Eggers, M.; Vannoy, C. H.; Huang, J.; Purushothaman, P.; Brassard, J.; Fonck, C.; Meng, H.; Prom, M. J.; Lawlor, M. W.; Cunningham, J.; Sadhu, C.; Mav...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1280324
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