Glucose–6–phosphatase dependent substrate transport in the glycogen storage disease type–1a mouse

Lei, Ke-Jian; Chen, Hungwen; Pan, Chi-Jiunn; Ward, Jerrold M.; Mosinger, B; Lee, Eric J.; Westphal, Heiner; Mansfield, Brian C.; Chou, Janice Y.

doi:10.1038/ng0696-203

Cited by 217 publications

(330 citation statements)

References 25 publications

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“…Effective G6Pase activity in vivo is dependent upon coupling of the G6Pase-a enzyme to the membrane anchored G6PT, [11][12][13] which translocates G6P from the cytoplasm into the lumen of the ER for hydrolysis. In G6Pase-a À/À mice, the transport of G6P into the hepatic and renal microsomes is markedly reduced.…”

Section: Resultsmentioning

confidence: 99%

“…In G6Pase-a À/À mice, the transport of G6P into the hepatic and renal microsomes is markedly reduced. 13 We therefore looked at the effect of the transgene expression on microsomal G6P uptake activity in the liver and the kidney of the AAV1-G6Pase-a-2X-infused animals. Both the liver and kidney microsomes from G6Pase-a +/+ / G6Pase-a +/À mice transport G6P efficiently and there is no significant G6P uptake by the liver or kidney microsomes of the untreated G6Pase-a À/À mice (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…Microsomal proteins from Ad-G6Pase-a-infected COS-1 cells were electrophoresed through a 12% polyacrylamide-SDS gel and transferred onto a PVDF membrane. The membrane strips were individually incubated with anti-human G6Pase-a antiserum (1:3000 dilution, lane 1), serum samples (1:200 dilution) from untreated G6Pase-a À/À mice (À/À, lanes 2), serum samples (1:200 dilution) from G6Pase-a +/+ /G6Pase-a +/À (+/+) littermates at age 57 weeks (lane 3), 49 weeks (lanes 6, 9, 12), and serum samples (1:200 dilution) from AAV1-G6Pase-a-2X-infused G6Pase-a À/À mice (À/À/rAAV1) at 57 weeks (lanes, 4, 5), and 49 weeks (lanes 7,8,10,11,13,14) postinfusion. 49W-1, 49W-2, and 49W-3 denote three different infused G6Pase-a À/À mice.…”

Section: Discussionmentioning

confidence: 99%

“…13 Although AAV1-G6Pase-a-2X-infused G6Pase-a À/À mice were hypoglycermic at 2 weeks of age, their serum glucose profiles were normalized soon after, and this normoglycemia was maintained throughout their postnatal development (Figure 2b). None of the mice suffered the frequent hypoglycemic seizures typical of the untreated G6Pase-a À/À mice.…”

Section: Aav1-g6pase-a-2x Infusion Corrects Pathological Manifestatiomentioning

confidence: 99%

“…13 If left untreated, the mice rarely survive weaning and live no more than 3 months, mimicking the lethality of the untreated human disorder. Using these mice, we investigated the effects of viral-mediated G6Pase-a gene transfer in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer

Ghosh

et al. 2005

Gene Ther

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Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-a (G6Pase-a), a ninetransmembrane domain, endoplasmic reticulum-associated protein expressed primarily in the liver and kidney. Previously, we showed that infusion of an adeno-associated virus (AAV) serotype 2 vector carrying murine G6Pase-a (AAV2-G6Pase-a) into neonatal GSD-Ia mice failed to sustain their life beyond weaning. We now show that neonatal infusion of GSD-Ia mice with an AAV serotype 1-G6Pase-a (AAV1-G6Pase-a) or AAV serotype 8-G6Pase-a (AAV8-G6Pase-a) results in hepatic expression of the G6Pase-a transgene and markedly improves the survival of the mice. However, only AAV1-G6Pase-a can achieve significant renal transgene expression. A more effective strategy, in which a neonatal AAV1-G6Pase-a infusion is followed by a second infusion at age 1 week, provides sustained expression of a complete, functional, G6Pase-a system in both the liver and kidney and corrects the metabolic abnormalities in GSD-Ia mice for the 57 week length of the study. This effective use of gene therapy to correct metabolic imbalances and disease progression in GSD-Ia mice holds promise for the future of gene therapy in humans. Gene Therapy (2005) 13, 321-329.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%