The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.
dc.contributor.author | Lee, Young Mok | |
dc.contributor.author | Pan, Chi-Jiunn | |
dc.contributor.author | Koeberl, Dwight D | |
dc.contributor.author | Mansfield, Brian C | |
dc.contributor.author | Chou, Janice Y | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2015-10-30T14:33:18Z | |
dc.date.issued | 2013-11 | |
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.identifier | ||
dc.identifier | S1096-7192(13)00216-3 | |
dc.identifier.eissn | 1096-7206 | |
dc.identifier.uri | ||
dc.language | eng | |
dc.publisher | Elsevier BV | |
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 | ||
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 |
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