Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia

Gene Ther. 2006 Sep;13(17):1281-9. doi: 10.1038/sj.gt.3302774. Epub 2006 May 4.


The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to 2-week-old GSD-Ia mice (n = 9). Median survival was prolonged to 7 months following vector administration, in contrast to untreated GSD-Ia mice that survived for only 2 weeks. Although GSD-Ia mice were initially growth-retarded, treated mice increased fourfold in weight to normal size. Blood glucose was partially corrected by 2 weeks following treatment, whereas blood cholesterol normalized. Glucose-6-phosphatase activity was partially corrected to 25% of the normal level at 7 months of age in treated mice, and blood glucose during fasting remained lower in treated, affected mice than in normal mice. Glycogen storage was partially corrected in the liver by 2 weeks following treatment, but reaccumulated to pre-treatment levels by 7 months old (m.o.). Vector genome DNA decreased between 3 days and 3 weeks in the liver following vector administration, mainly through the loss of single-stranded genomes; however, double-stranded vector genomes were more stable. Although CD8+ lymphocytic infiltrates were present in the liver, partial biochemical correction was sustained at 7 m.o. The development of efficacious AAV vector-mediated gene therapy could significantly reduce the impact of long-term complications in GSD-Ia, including hypoglycemia, hyperlipidemia and growth failure.

Publication types

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

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Dependovirus / genetics*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage*
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology
  • Glucose-6-Phosphatase / analysis
  • Glucose-6-Phosphatase / genetics*
  • Glucose-6-Phosphatase / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
  • Glycogen / analysis
  • Glycogen Storage Disease Type I / enzymology
  • Glycogen Storage Disease Type I / immunology
  • Glycogen Storage Disease Type I / therapy*
  • Immunohistochemistry
  • Injections, Intravenous
  • Kidney / chemistry
  • Kidney / enzymology
  • Kidney / immunology
  • Liver / chemistry
  • Liver / enzymology
  • Liver / immunology
  • Mice
  • Mice, Knockout
  • Models, Animal
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transduction, Genetic / methods


  • RNA, Messenger
  • Glycogen
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Glucose-6-Phosphatase