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

Autor: Eggers M; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA., Vannoy CH; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA., Huang J; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA., Purushothaman P; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA., Brassard J; Jacqueline Brassard Toxicologic Pathology Consulting, Tustin, CA, USA., Fonck C; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA., Meng H; Department of Pathology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA., Prom MJ; Department of Pathology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA., Lawlor MW; Department of Pathology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA., Cunningham J; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA., Sadhu C; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA., Mavilio F; Nonclinical, Pharmacology/Toxicology, Audentes Therapeutics, San Francisco, CA, USA.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2022 Jan 11; Vol. 14 (1), pp. e13968. Date of Electronic Publication: 2021 Dec 01.
DOI: 10.15252/emmm.202113968
Abstrakt: 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.
(© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE