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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.

dc.contributor.author Chou, JY
dc.contributor.author Koeberl, Dwight D
dc.contributor.author Lee, YM
dc.contributor.author Mansfield, BC
dc.contributor.author Pan, CJ
dc.coverage.spatial United States
dc.date.accessioned 2015-10-30T14:33:18Z
dc.date.issued 2013-11
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/23856420
dc.identifier S1096-7192(13)00216-3
dc.identifier.uri http://hdl.handle.net/10161/10803
dc.description.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.
dc.language eng
dc.relation.ispartof Mol Genet Metab
dc.relation.isversionof 10.1016/j.ymgme.2013.06.014
dc.subject AAV
dc.subject Adeno-associated virus
dc.subject G6P
dc.subject G6PC promoter/enhancer
dc.subject G6Pase
dc.subject GPE
dc.subject GSD-Ia
dc.subject Gene therapy
dc.subject Glucose-6-phosphatase
dc.subject Glycogen storage disease type I
dc.subject HCA
dc.subject adeno-associated virus
dc.subject glucose-6-phosphatase
dc.subject glucose-6-phosphate
dc.subject glycogen storage disease type Ia
dc.subject hepatocellular adenoma
dc.subject Animals
dc.subject Dependovirus
dc.subject Disease Models, Animal
dc.subject Enhancer Elements, Genetic
dc.subject Gene Expression
dc.subject Gene Expression Regulation
dc.subject Genetic Therapy
dc.subject Genetic Vectors
dc.subject Glucose
dc.subject Glucose-6-Phosphatase
dc.subject Glycogen Storage Disease Type I
dc.subject Humans
dc.subject Liver
dc.subject Metabolome
dc.subject Mice
dc.subject Mice, Knockout
dc.subject Organ Specificity
dc.subject Promoter Regions, Genetic
dc.subject Transduction, Genetic
dc.subject Transgenes
dc.title The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/23856420
pubs.begin-page 275
pubs.end-page 280
pubs.issue 3
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pediatrics
pubs.organisational-group Pediatrics, Medical Genetics
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 110
dc.identifier.eissn 1096-7206


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