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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• 作者：Young Mok Lee ; Chi-Jiunn Pan ; Dwight D. Koeberl ; Brian C. Mansfield ; Janice Y. Chou
• 关键词：GSD-Ia ; glycogen storage disease type Ia ; G6Pase ; glucose-6-phosphatase ; G6P ; glucose-6-phosphate ; HCA ; hepatocellular adenoma ; AAV ; adeno-associated virus ; GPE ; G6PC promoter/enhancer
• 刊名：Molecular Genetics and Metabolism
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：110
• 期：3
• 页码：275-280
• 全文大小：540 K

文摘

Glycogen storage disease type-Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-¦Á (G6Pase-¦Á 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-¦Á 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-¦Á 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.