title: Hepatorenal correction in murine glycogen storage disease type I with a double-stranded adeno-associated virus vector.
abstract: Glycogen storage disease type Ia (GSD-Ia) is caused by the deficiency of glucose-6-phosphatase (G6Pase). Long-term complications of GSD-Ia include life-threatening hypoglycemia and proteinuria progressing to renal failure. A double-stranded (ds) adeno-associated virus serotype 2 (AAV2) vector encoding human G6Pase was pseudotyped with four serotypes, AAV2, AAV7, AAV8, and AAV9, and we evaluated efficacy in 12-day-old G6pase (-/-) mice. Hypoglycemia during fasting (plasma glucose <100 mg/dl) was prevented for >6 months by the dsAAV2/7, dsAAV2/8, and dsAAV2/9 vectors. Prolonged fasting for 8 hours revealed normalization of blood glucose following dsAAV2/9 vector administration at the higher dose. The glycogen content of kidney was reduced by >65% with both the dsAAV2/7 and dsAAV2/9 vectors, and renal glycogen content was stably reduced between 7 and 12 months of age for the dsAAV2/9 vector-treated mice. Every vector-treated group had significantly reduced glycogen content in the liver, in comparison with untreated G6pase (-/-) mice. G6Pase was expressed in many renal epithelial cells of with the dsAAV2/9 vector for up to 12 months. Albuminuria and renal fibrosis were reduced by the dsAAV2/9 vector. Hepatorenal correction in G6pase (-/-) mice demonstrates the potential of AAV vectors for the correction of inherited diseases of metabolism.
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors: Xiaoyan
authors: X
authors: Luo
authors: Gentzon
authors: G
authors: Hall
authors: Songtao
authors: S
authors: Li
authors: Andrew
authors: A
authors: Bird
authors: Peter J
authors: PJ
authors: Lavin
authors: Michelle P
authors: MP
authors: Winn
authors: Alex R
authors: AR
authors: Kemper
authors: Talmage T
authors: TT
authors: Brown
authors: Dwight D
authors: DD
authors: Koeberl
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D005953:Glycogen Storage Disease Type I / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000628:therapy; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D005952:Glucose-6-Phosphatase