A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III

• Published in: The Journal of clinical investigation Vol. 134; no. 2; pp. 1 - 14
• Main Authors: Gardin, Antoine, Rouillon, Jérémy, Montaivo-Romera, Valle, Rossiaud, Lucille, Vidal, Patrice, Launay, Romain, Vie, Mallaury, Benchekroun, Youssef Krimi, Cosette, Jérémie, Bertin, Bérangére, La Bella, Tiziana, Dubreuil, Guillaume, Nozi, Justine, Jauze, Louisa, Fragnoud, Romain, Daniele, Nathalie, Van Wittenberghe, Laetitia, Esque, Jérémy, André, Isabelle, Nissan, Xavier, Hoch, Lucile, Ronzitti, Giuseppe
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 01.01.2024
• Subjects: Cardiac muscle; Clinical trials; Cytomegalovirus; Disease; Enzymes; Gene therapy; Genotype & phenotype; Glycogen; Heart; Hypoglycemia; Inborn errors of metabolism; Liver cirrhosis; Metabolism; Molecular modelling; Muscle strength; Musculoskeletal system; Mutation; Phenotypes; Proteins; Skeletal muscle; Storage diseases; Transgenes; Vectors (Biology)
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI172018.

Glycogen storage disease type III (CSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGŁ gene encoding for the glycogen debranching enzyme (CDE). No curative treatment exists for CSDIII. The 4.6 kb CDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus-derived (rAAV-derived) vector gene therapy strategy. Using information on CDE structure and molecular modeling, we generated multiple truncated CDEs. Among them, an N-terminal-truncated mutant, ANter2-CDE, had a similar efficacy in vivo compared with the full-size enzyme. A rAAV vector expressing ANter2-CDE allowed significant glycogen reduction in heart and muscle of Agi"1" mice 3 months after i.v. injection, as well as normalization of histology features and restoration of muscle strength. Similarly, glycogen accumulation and histological features were corrected in a recently generated Agi1' rat model. Finally, transduction with rAAV vectors encoding ANter2-CDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of CSDIII. In conclusion, our results demonstrated the ability of a single rAAV vector expressing a functional mini-GDE transgene to correct the muscle and heart phenotype in multiple models of CSDIII, supporting its clinical translation to patients with CSDIII.