| First Author | Eggers M | Year | 2022 |
| Journal | EMBO Mol Med | Volume | 14 |
| Issue | 1 | Pages | e13968 |
| PubMed ID | 34850579 | Mgi Jnum | J:322135 |
| Mgi Id | MGI:6852945 | Doi | 10.15252/emmm.202113968 |
| Citation | Eggers M, et al. (2022) Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. EMBO Mol Med 14(1):e13968 |
| abstractText | 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. |
