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

Dwight D. Koeberl, B. D. Sun, T. V. Damodaran, T. Brown, D. S. Millington, D. K. Benjamin, A. Bird, A. Schneider, S. Hillman, M. Jackson, R. M. Beaty, Y. T. Chen

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1281-1289
Number of pages9
JournalGene Therapy
Issue number17
StatePublished - Sep 2006
Externally publishedYes


  • Adeno-associated virus
  • Glucose-6-phosphatase
  • Glycogen storage disease
  • Growth failure
  • Hypoglycemia
  • Metabolism

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics


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