Prevention of hepatocellular adenoma and correction of metabolic abnormalities in murine glycogen storage disease type Ia by gene therapy.

Abstract

UNLABELLED:

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.

CONCLUSION:

These results confirm that AAV-GPE-mediated gene transfer corrects hepatic G6Pase-α deficiency in murine GSD-Ia and prevents chronic HCA formation.

• Authors: Young Mok Lee, Hyun Sik Jun, Chi-Jiunn Pan, Su Ru Lin, Lane H Wilson, Brian C Mansfield, Janice Y Chou
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 56 Issue 5 Pg. 1719-29 (Nov 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22422504 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• Antiporters
• Blood Glucose
• Insulin
• Monosaccharide Transport Proteins
• RNA, Messenger
• glucose 6-phosphate(transporter)
• Glucose-6-Phosphatase

Topics

• Adenoma (prevention & control)
• Animals
• Antiporters (genetics, metabolism)
• Blood Glucose
• Body Mass Index
• Body Weight
• Dependovirus (genetics)
• Disease Models, Animal
• Female
• Genetic Therapy (adverse effects)
• Genetic Vectors
• Glucose Tolerance Test
• Glucose-6-Phosphatase (genetics, metabolism)
• Glycogen Storage Disease Type I (enzymology, genetics, therapy)
• Homeostasis
• Insulin (blood)
• Liver (enzymology, metabolism, pathology)
• Liver Neoplasms (prevention & control)
• Male
• Mice
• Mice, Knockout
• Monosaccharide Transport Proteins (genetics, metabolism)
• Promoter Regions, Genetic
• RNA, Messenger (metabolism)