| First Author | Gardin A | Year | 2024 |
| Journal | J Clin Invest | Volume | 134 |
| Issue | 2 | PubMed ID | 38015640 |
| Mgi Jnum | J:344227 | Mgi Id | MGI:7572665 |
| Doi | 10.1172/JCI172018 | Citation | Gardin A, et al. (2023) A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III. J Clin Invest :e172018 |
| abstractText | 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 (rAAV)-derived vector gene therapy strategy. Using information on GDE structure and molecular modeling, we generated multiple truncated GDEs retaining activity. Among them, an N-terminal-truncated mutant Nter2-GDE had a similar efficacy in vivo compared to the full-size enzyme. A rAAV vector expressing Nter2-GDE allowed significant glycogen reduction in heart and muscle of Agl-/- mice three months after intravenous 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 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 GSDIII patients. |
