Gene therapy using a novel G6PC-S298C variant enhances the long-term efficacy for treating glycogen storage disease type Ia

Biochem Biophys Res Commun. 2020 Jun 30;527(3):824-830. doi: 10.1016/j.bbrc.2020.04.124. Epub 2020 May 16.


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-α (G6Pase-α 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-α activity in G6pc-/- mice prevents hepatocellular adenoma/carcinoma (HCA/HCC) development and that mice harboring <3% of normal hepatic G6Pase-α activity are at risk of tumor development. We have also shown that G6Pase-α 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-α activity do not develop hepatic tumors or autophagy impairment but mice expressing <3% of normal hepatic G6Pase-α 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.

Keywords: Autophagy impairment; Clinical translation; Glucose-6-phosphatase-α variant; Recombinant adeno-associated virus vector.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Therapy*
  • Genetic Vectors / genetics
  • Genetic Vectors / therapeutic use*
  • Glucose-6-Phosphatase / genetics*
  • Glycogen Storage Disease Type I / genetics
  • Glycogen Storage Disease Type I / pathology
  • Glycogen Storage Disease Type I / therapy*
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Point Mutation*


  • Glucose-6-Phosphatase

Supplementary concepts

  • Hepatorenal form of glycogen storage disease

Associated data