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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.

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    Date
    2013-11
    Authors
    Chou, JY
    Koeberl, Dwight D
    Lee, YM
    Mansfield, BC
    Pan, CJ
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    Abstract
    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.
    Type
    Journal article
    Subject
    AAV
    Adeno-associated virus
    G6P
    G6PC promoter/enhancer
    G6Pase
    GPE
    GSD-Ia
    Gene therapy
    Glucose-6-phosphatase
    Glycogen storage disease type I
    HCA
    adeno-associated virus
    glucose-6-phosphatase
    glucose-6-phosphate
    glycogen storage disease type Ia
    hepatocellular adenoma
    Animals
    Dependovirus
    Disease Models, Animal
    Enhancer Elements, Genetic
    Gene Expression
    Gene Expression Regulation
    Genetic Therapy
    Genetic Vectors
    Glucose
    Glucose-6-Phosphatase
    Glycogen Storage Disease Type I
    Humans
    Liver
    Metabolome
    Mice
    Mice, Knockout
    Organ Specificity
    Promoter Regions, Genetic
    Transduction, Genetic
    Transgenes
    Permalink
    https://hdl.handle.net/10161/10803
    Published Version (Please cite this version)
    10.1016/j.ymgme.2013.06.014
    Publication Info
    Chou, JY; Koeberl, Dwight D; Lee, YM; Mansfield, BC; & Pan, CJ (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). pp. 275-280. 10.1016/j.ymgme.2013.06.014. Retrieved from https://hdl.handle.net/10161/10803.
    This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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    Scholars@Duke

    Koeberl

    Dwight D. Koeberl

    Professor of Pediatrics
    The focus of our research has been the development of gene therapy with  adeno-associated virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed gene therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU). 1) GSD type Ia: Glucose-6-phosphatase (G6Pase) deficient animals provide models for developing new therapy for GSD type Ia, although early mortality complicates research with both
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    Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy

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