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The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.

Publication ,  Journal Article
Lee, YM; Pan, C-J; Koeberl, DD; Mansfield, BC; Chou, JY
Published in: Mol Genet Metab
November 2013

Glycogen storage disease type-Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-α (G6Pase-α or G6PC) manifest impaired glucose homeostasis characterized by fasting hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. Two efficacious recombinant adeno-associated virus pseudotype 2/8 (rAAV8) vectors expressing human G6Pase-α have been independently developed. One is a single-stranded vector containing a 2864-bp of the G6PC promoter/enhancer (rAAV8-GPE) and the other is a double-stranded vector containing a shorter 382-bp minimal G6PC promoter/enhancer (rAAV8-miGPE). To identify the best construct, a direct comparison of the rAAV8-GPE and the rAAV8-miGPE vectors was initiated to determine the best vector to take forward into clinical trials. We show that the rAAV8-GPE vector directed significantly higher levels of hepatic G6Pase-α expression, achieved greater reduction in hepatic glycogen accumulation, and led to a better toleration of fasting in GSD-Ia mice than the rAAV8-miGPE vector. Our results indicated that additional control elements in the rAAV8-GPE vector outweigh the gains from the double-stranded rAAV8-miGPE transduction efficiency, and that the rAAV8-GPE vector is the current choice for clinical translation in human GSD-Ia.

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Published In

Mol Genet Metab

DOI

EISSN

1096-7206

Publication Date

November 2013

Volume

110

Issue

3

Start / End Page

275 / 280

Location

United States

Related Subject Headings

  • Transgenes
  • Transduction, Genetic
  • Promoter Regions, Genetic
  • Organ Specificity
  • Mice, Knockout
  • Mice
  • Metabolome
  • Liver
  • Humans
  • Glycogen Storage Disease Type I
 

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Lee, Y. M., Pan, C.-J., Koeberl, D. D., Mansfield, B. C., & Chou, J. Y. (2013). The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia. Mol Genet Metab, 110(3), 275–280. https://doi.org/10.1016/j.ymgme.2013.06.014
Lee, Young Mok, Chi-Jiunn Pan, Dwight D. Koeberl, Brian C. Mansfield, and Janice Y. Chou. “The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.Mol Genet Metab 110, no. 3 (November 2013): 275–80. https://doi.org/10.1016/j.ymgme.2013.06.014.
Lee YM, Pan C-J, Koeberl DD, Mansfield BC, Chou JY. The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia. Mol Genet Metab. 2013 Nov;110(3):275–80.
Lee, Young Mok, et al. “The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.Mol Genet Metab, vol. 110, no. 3, Nov. 2013, pp. 275–80. Pubmed, doi:10.1016/j.ymgme.2013.06.014.
Lee YM, Pan C-J, Koeberl DD, Mansfield BC, Chou JY. The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia. Mol Genet Metab. 2013 Nov;110(3):275–280.
Journal cover image

Published In

Mol Genet Metab

DOI

EISSN

1096-7206

Publication Date

November 2013

Volume

110

Issue

3

Start / End Page

275 / 280

Location

United States

Related Subject Headings

  • Transgenes
  • Transduction, Genetic
  • Promoter Regions, Genetic
  • Organ Specificity
  • Mice, Knockout
  • Mice
  • Metabolome
  • Liver
  • Humans
  • Glycogen Storage Disease Type I