Hepatorenal correction in murine glycogen storage disease type I with a double-stranded adeno-associated virus vector.
Lavin, Peter J
Winn, Michelle P
Kemper, Alex R
Brown, Talmage T
Koeberl, Dwight D
AffiliationDepartment of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Disease Models, Animal
Gene Expression Regulation
Glycogen Storage Disease Type I
MetadataShow full item record
CitationHepatorenal correction in murine glycogen storage disease type I with a double-stranded adeno-associated virus vector. 2011, 19 (11):1961-70 Mol. Ther.
JournalMolecular therapy : the journal of the American Society of Gene Therapy
AbstractGlycogen 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.
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