Molecular biology and gene therapy for glycogen storage disease type Ib
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Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose-6-phosphate (G6P) transporter (G6PT or SLC37A4). The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the endoplasmic reticulum (ER). Inside the ER, G6P is hydrolyzed to glucose and phosphate by either the liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α) or the ubiquitously expressed G6Pase-β. A deficiency in G6Pase-α causes GSD type Ia (GSD-Ia) and a deficiency in G6Pase-β causes GSD-I-related syndrome (GSD-Irs). In gluconeogenic organs, functional coupling of G6PT and G6Pase-α is required to maintain interprandial blood glucose homeostasis. In myeloid tissues, functional coupling of G6PT and G6Pase-β is required to maintain neutrophil homeostasis. Accordingly, GSD-Ib is a metabolic and immune disorder, manifesting impaired glucose homeostasis, neutropenia, and neutrophil dysfunction. A G6pt knockout mouse model is being exploited to delineate the pathophysiology of GSD-Ib and develop new clinical treatment options, including gene therapy. The safety and efficacy of several G6PT-expressing recombinant adeno-associated virus pseudotype 2/8 vectors have been examined in murine GSD-Ib. The results demonstrate that the liver-directed gene transfer and expression safely corrects metabolic abnormalities and prevents hepatocellular adenoma (HCA) development. However, a second vector system may be required to correct myeloid and renal dysfunction in GSD-Ib. These findings are paving the way to a safe and efficacious gene therapy for entering clinical trials.
This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
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Conflict of interest
J. Y. Chou, J.-H. Cho, G.-Y. Kim, and B. C. Mansfield declare that they have no conflicts of interest.
This article does not contain any studies with human subjects performed by any of the authors.
All institutional and national guidelines for the care and use of laboratory animals were followed.
- Donadieu J, Leblanc T, Bader Meunier B et al (2005) Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group. Haematologica 90:45–53Google Scholar
- Liang CL, Liu L, Sheng HY et al (2013) Gene mutations and clinical manifestations in children with glycogen storage disease type Ib. Zhongguo Dang Dai Er Ke Za Zhi 15:661–665Google Scholar
- Qiu ZQ, Lu CX, Wang W, Qiu JJ, Wei M (2011) Mutation in the SLC37A4 gene of glycogen storage disease type Ib in 15 families of the mainland of China. Zhonghua Er Ke Za Zhi 49:203–208Google Scholar
- Schroeder T, Hildebrandt B, Mayatepek E, Germing U, Haas R (2008) A patient with glycogen storage disease type Ib presenting with acute myeloid leukemia (AML) bearing monosomy 7 and translocation t(3;8)(q26;q24) after 14 years of treatment with granulocyte colony-stimulating factor (G-CSF): a case report. J Med Case Rep 2:319CrossRefGoogle Scholar