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

Antoine Gardin (1, 2) , Jérémy Rouillon (1, 2) , Valle Montalvo-Romeral (1, 2) , Lucille Rossiaud (1, 2, 3) , Patrice Vidal (1, 2) , Romain Launay (4) , Mallaury Vie (1, 2) , Youssef Krimi Benchekroun (1, 2) , Jérémie Cosette (4, 1) , Bérangère Bertin (1, 2) , Tiziana La Bella (1, 2) , Guillaume Dubreuil (1) , Justine Nozi (1, 2) , Louisa Jauze (1, 2) , Romain Fragnoud (1) , Nathalie Daniele (1) , Laetitia van Wittenberghe (1) , Jérémy Esque (4) , Isabelle André (4) , Xavier Nissan (5, 3) , Lucile Hoch (5, 3) , Giuseppe Ronzitti (1, 2)

1 Généthon
2 INTEGRARE - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
3 I-STEM - Institut des cellules souches pour le traitement et l'étude des maladies monogéniques
4 TBI - Toulouse Biotechnology Institute
5 CECS - Centre d'Etude des Cellules Souches

Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE 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 GDE structure and molecular modeling, we generated multiple truncated GDEs. Among them, an N-terminal-truncated mutant, Delta Nter2-GDE, had a similar efficacy in vivo compared with the full-size enzyme. A rAAV vector expressing Delta Nter2-GDE allowed significant glycogen reduction in heart and muscle of Agl-/- 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 Agl-/- rat model. Finally, transduction with rAAV vectors encoding Delta Nter2-GDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of GSDIII. 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 GSDIII, supporting its clinical translation to patients with GSDIII.

Domaines: Biotechnologies; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Endocrinologie et métabolisme

Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, et al.. A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III. The Journal of clinical investigation, 2023, 134 (2), pp.e172018. ⟨10.1172/JCI172018⟩. ⟨hal-04387513⟩