| First Author | Zhang L | Year | 2020 |
| Journal | Biochem Biophys Res Commun | Volume | 527 |
| Issue | 3 | Pages | 824-830 |
| PubMed ID | 32430177 | Mgi Jnum | J:306074 |
| Mgi Id | MGI:6713337 | Doi | 10.1016/j.bbrc.2020.04.124 |
| Citation | Zhang L, et al. (2020) Gene therapy using a novel G6PC-S298C variant enhances the long-term efficacy for treating glycogen storage disease type Ia. Biochem Biophys Res Commun 527(3):824-830 |
| abstractText | The current phase I/II clinical trial for human glycogen storage disease type-Ia (GSD-Ia) (NCT03517085) uses a recombinant adeno-associated virus (rAAV) vector expressing a codon-optimized human glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC). DNA sequence changes introduced by codon-optimization can negatively impact gene expression. We therefore generated a novel variant in which a single amino acid change, S298C, is introduced into the native human G6PC sequence. Short term gene transfer study in G6pc-/- mice showed that the rAAV-G6PC-S298C vector is 3-fold more efficacious than the native rAAV-G6PC vector. We have shown previously that restoring 3% of normal hepatic G6Pase-alpha activity in G6pc-/- mice prevents hepatocellular adenoma/carcinoma (HCA/HCC) development and that mice harboring <3% of normal hepatic G6Pase-alpha activity are at risk of tumor development. We have also shown that G6Pase-alpha deficiency leads to hepatic autophagy impairment that can contribute to hepatocarcinogenesis. We now undertake a long-term (66-week) preclinical characterization of the rAAV-G6PC-S298C vector in GSD-Ia gene therapy. We show that the increased efficacy of rAAV-G6PC-S298C has enabled the G6pc-/- mice treated with a lower dose of this vector to survive long-term. We further show that mice expressing >/=3% of normal hepatic G6Pase-alpha activity do not develop hepatic tumors or autophagy impairment but mice expressing <3% of normal hepatic G6Pase-alpha activity display impaired hepatic autophagy with one developing HCA/HCC nodules. Our study shows that the rAAV-G6PC-S298C vector provides equal or greater efficacy to the codon optimization approach, offering a valuable alternative vector for clinical translation in human GSD-Ia. |
