title: Prevention of hepatocellular adenoma and correction of metabolic abnormalities in murine glycogen storage disease type Ia by gene therapy.
abstract: Glycogen storage disease type Ia (GSD-Ia), which is characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by deficiencies in the endoplasmic reticulum (ER)-associated glucose-6-phosphatase-α (G6Pase-α or G6PC) that hydrolyzes glucose-6-phosphate (G6P) to glucose. G6Pase-α activity depends on the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the ER lumen. The functional coupling of G6Pase-α and G6PT maintains interprandial glucose homeostasis. We have shown previously that gene therapy mediated by AAV-GPE, an adeno-associated virus (AAV) vector expressing G6Pase-α directed by the human G6PC promoter/enhancer (GPE), completely normalizes hepatic G6Pase-α deficiency in GSD-Ia (G6pc(-/-) ) mice for at least 24 weeks. However, a recent study showed that within 78 weeks of gene deletion, all mice lacking G6Pase-α in the liver develop HCA. We now show that gene therapy mediated by AAV-GPE maintains efficacy for at least 70-90 weeks for mice expressing more than 3% of wild-type hepatic G6Pase-α activity. The treated mice displayed normal hepatic fat storage, had normal blood metabolite and glucose tolerance profiles, had reduced fasting blood insulin levels, maintained normoglycemia over a 24-hour fast, and had no evidence of hepatic abnormalities. After a 24-hour fast, hepatic G6PT messenger RNA levels in G6pc(-/-) mice receiving gene therapy were markedly increased. Because G6PT transport is the rate-limiting step in microsomal G6P metabolism, this may explain why the treated G6pc(-/-) mice could sustain prolonged fasts. The low fasting blood insulin levels and lack of hepatic steatosis may explain the absence of HCA.
  
  
  CONCLUSIONS
  These results confirm that AAV-GPE-mediated gene transfer corrects hepatic G6Pase-α deficiency in murine GSD-Ia and prevents chronic HCA formation.
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Lee
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Jun
authors.forename: Chi-Jiunn
authors.initials: CJ
authors.lastname: Pan
authors.forename: Su Ru
authors.initials: SR
authors.lastname: Lin
authors.forename: Lane H
authors.initials: LH
authors.lastname: Wilson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Mansfield
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
mesh_terms: D000236:Adenoma / Q000517:prevention & control*; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose; D015992:Body Mass Index; D001835:Body Weight; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D017920:Antiporters; D001786:Blood Glucose; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C111261:glucose 6-phosphate(transporter); D005952:Glucose-6-Phosphatase