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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.
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 articleSubject
AAVAdeno-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
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https://hdl.handle.net/10161/10803Published Version (Please cite this version)
10.1016/j.ymgme.2013.06.014Publication Info
Lee, 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.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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Show full item recordScholars@Duke
Dwight D. Koeberl
Professor of Pediatrics
As a physician-scientist practicing clinical and biochemical genetics, I am highly
motivated to seek improved therapy for my patients with inherited disorders of metabolism.
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

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