Lee, Young MokPan, Chi-JiunnKoeberl, Dwight DMansfield, Brian CChou, Janice Y2015-10-302013-11https://hdl.handle.net/10161/10803Glycogen 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.AAVAdeno-associated virusG6PG6PC promoter/enhancerG6PaseGPEGSD-IaGene therapyGlucose-6-phosphataseGlycogen storage disease type IHCAadeno-associated virusglucose-6-phosphataseglucose-6-phosphateglycogen storage disease type Iahepatocellular adenomaAnimalsDependovirusDisease Models, AnimalEnhancer Elements, GeneticGene ExpressionGene Expression RegulationGenetic TherapyGenetic VectorsGlucoseGlucose-6-PhosphataseGlycogen Storage Disease Type IHumansLiverMetabolomeMiceMice, KnockoutOrgan SpecificityPromoter Regions, GeneticTransduction, GeneticTransgenesJournal article1096-7206