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

Publication ,  Journal Article
Koeberl, DD; Sun, BD; Damodaran, TV; Brown, T; Millington, DS; Benjamin, DK; Bird, A; Schneider, A; Hillman, S; Jackson, M; Beaty, RM; Chen, YT
Published in: Gene Ther
September 2006

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.

Duke Scholars

Published In

Gene Ther

DOI

ISSN

0969-7128

Publication Date

September 2006

Volume

13

Issue

17

Start / End Page

1281 / 1289

Location

England

Related Subject Headings

  • Transduction, Genetic
  • Time Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Messenger
  • Models, Animal
  • Mice, Knockout
  • Mice
  • Liver
  • Kidney
  • Injections, Intravenous
 

Citation

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Chicago
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MLA
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Koeberl, D. D., Sun, B. D., Damodaran, T. V., Brown, T., Millington, D. S., Benjamin, D. K., … Chen, Y. T. (2006). Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. Gene Ther, 13(17), 1281–1289. https://doi.org/10.1038/sj.gt.3302774
Koeberl, D. D., B. D. Sun, T. V. Damodaran, T. Brown, D. S. Millington, D. K. Benjamin, A. Bird, et al. “Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia.Gene Ther 13, no. 17 (September 2006): 1281–89. https://doi.org/10.1038/sj.gt.3302774.
Koeberl DD, Sun BD, Damodaran TV, Brown T, Millington DS, Benjamin DK, et al. 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.
Koeberl, D. D., et al. “Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia.Gene Ther, vol. 13, no. 17, Sept. 2006, pp. 1281–89. Pubmed, doi:10.1038/sj.gt.3302774.
Koeberl DD, Sun BD, Damodaran TV, Brown T, Millington DS, Benjamin DK, Bird A, Schneider A, Hillman S, Jackson M, Beaty RM, Chen YT. Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. Gene Ther. 2006 Sep;13(17):1281–1289.

Published In

Gene Ther

DOI

ISSN

0969-7128

Publication Date

September 2006

Volume

13

Issue

17

Start / End Page

1281 / 1289

Location

England

Related Subject Headings

  • Transduction, Genetic
  • Time Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Messenger
  • Models, Animal
  • Mice, Knockout
  • Mice
  • Liver
  • Kidney
  • Injections, Intravenous