1. ¹Department of Pathology, Immunology and Laboratory Medicine and The Program for Stem Cell Biology and Regenerative Medicine, University of Florida College of Medicine, Gainesville, FL, USA
2. ²Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA
3. ³Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA

Correspondence: Bryon E Petersen, PhD, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, BOX 100275, 1600 SW Archer Rd, Gainesville, FL 32610-0275, USA. E-mail: petersen@pathology.ufl.edu

Received 18 February 2009; Revised 1 June 2009; Accepted 2 June 2009; Published online 6 July 2009.

Abstract

Glycogen storage disease type Ia (GSDIa) is caused by a genetic defect in the hepatic enzyme glucose-6-phosphatase (G6Pase-), which manifests as life-threatening hypoglycemia with related metabolic complications. A G6Pase- knockout (KO) mouse model was generated to study potential therapies for correcting this disorder. Since then, gene therapy studies have produced promising results, showing long-term improvement in liver histology and glycogen metabolism. Under existing protocols, however, untreated KO pups seldom survived weaning. Here, we present a thorough characterization of the G6Pase- KO mouse, as well as the husbandry protocol for rearing this strain to adulthood. These mice were raised with only palliative care, and characterized from birth through 6 months of age. Once KO mice have survived the very frail weaning period, their size, agility, serum lipids and glycemic control improve dramatically, reaching levels approaching their wild-type littermates. In addition, our data reveal that adult mice lacking G6Pase- are able to mate and produce viable offspring. However, liver histology and glycogen accumulation do not improve with age. Overall, the reliable production of mature KO mice could provide a critical tool for advancing the GSDIa field, as the availability of a robust enzyme-deficient adult offers a new spectrum of treatment avenues that would not be tolerated by the frail pups. Most importantly, our detailed characterization of the adult KO mouse provides a crucial baseline for accurately gauging the efficacy of experimental therapies in this important model.