Gene Therapy for Type I Glycogen Storage Diseases

Abstract

The type I glycogen storage diseases (GSD-I) are a group of related diseases caused by a deficiency in the glucose-6-phosphatase-α (G6Pase-α) system, a key enzyme complex that is essential for the maintenance of blood glucose homeostasis between meals. The complex consists of a glucose-6-phosphate transporter (G6PT) that translocates glucose-6-phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, and a G6Pase-α catalytic unit that hydrolyses the glucose-6-phosphate into glucose and phosphate. A deficiency in G6Pase-α causes GSD type Ia (GSD-Ia) and a deficiency in G6PT causes GSD type Ib (GSD-Ib). Both GSD-Ia and GSD-Ib patients manifest a disturbed glucose homeostasis, while GSD-Ib patients also suffer symptoms of neutropenia and myeloid dysfunctions. G6Pase-α and G6PT are both hydrophobic endoplasmic reticulum-associated transmembrane proteins that can not expressed in soluble active forms. Therefore protein replacement therapy of GSD-I is not an option. Animal models of GSD-Ia and GSD-Ib that mimic the human disorders are available. Both adenovirus-and adeno-associated virus (AAV)-mediated gene therapies have been evaluated for GSD-Ia in these model systems. While adenoviral therapy produces only short term corrections and only impacts liver expression of the gene, AAV-mediated therapy delivers the transgene to both the liver and kidney, achieving longer term correction of the GSD-Ia disorder, although there are substantial differences in efficacy depending on the AAV serotype used. Gene therapy for GSD-Ib in the animal model is still in its infancy, although an adenoviral construct has improved the metabolic profile and myeloid function. Taken together further refinements in gene therapy may hold long term benefits for the treatment of type I GSD disorders.

Glucose-6-phosphatase Catalytic Subunit Gene Family

“…With respect to G6PC, studies are ongoing to determine whether gene therapy will provide a cure for GSD type 1a (52). Another challenge will be understanding how the actions of the multiple factors that individually regulate G6PC transcription are integrated at the G6PC promoter.…”

Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas

“…Identification of the G6pc gene in 1993 has enabled a G6pc-knockout mouse model to be developed [16,17], as well as the evaluation of gene therapy approaches to correct G6pc deficiency ( [18,19], see [20] for review). However, long-term complications cannot be evaluated because even with continuous glucose therapy, the total G6pc knock-out mice rarely live to be over 3 months of age [16].…”

Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia

“…1 Dietary therapy fails to prevent long-term complications including short stature, renal dysfunction and hepatic adenomas in many affected patients. 6 New therapies, including gene therapy, are under development for GSD-Ia. Effective gene therapy should maintain stable, long-term transgene expression in the involved tissues, especially the liver and kidney.…”