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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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.
Glycogen storage disease type I
glycogen storage disease type Ia
Disease Models, Animal
Enhancer Elements, Genetic
Gene Expression Regulation
Glycogen Storage Disease Type I
Promoter Regions, Genetic
Published Version (Please cite this version)10.1016/j.ymgme.2013.06.014
Publication InfoLee, Young Mok; Pan, Chi-Jiunn; Koeberl, Dwight D; Mansfield, Brian C; & Chou, Janice 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). pp. 275-280. 10.1016/j.ymgme.2013.06.014. Retrieved from https://hdl.handle.net/10161/10803.
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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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