Abstract
A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.
Highlights
Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is an inherited metabolic disorder resulting from a deficiency in the enzyme glucose 6-phosphataseα (G6Pase; EC 3.1.3.9)
The canine model of GSDIa has a similar genetic and underlying metabolic basis compared to GSDIa in humans
Clinicopathologic, pathologic, and clinical manifestations of GSDIa in this model are very similar to what is observed in humans, including lactic acidosis which is not a consistent feature of the murine model
Summary
Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is an inherited metabolic disorder resulting from a deficiency in the enzyme glucose 6-phosphataseα (G6Pase; EC 3.1.3.9). In contrast to humans, adenoma formation at equivalently young ages is uncommon While this model has proven very useful in furthering our understanding of GSDIa, an animal model with physiology and long-term consequences closer to what is observed in humans is advantageous before the experimental techniques can safely be attempted in humans. An emphasis will be placed on how the canine model is currently being used in preclinical trials for gene therapy mediated correction of GSDIa and how such research can contribute to the development of new potential therapies and cures for this and possibly other genetic and metabolic disease conditions
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