Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia

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

“…Consistent with the hypothesis that episomal vector genomes might be lost following vector administration to neonatal animals with GSDIa, an AAV2/8 vector decreased from 42 copies per liver cell at 3 weeks of age to 0.3 copies per liver cell at 26 weeks of age following administration to 2-week-old G6pase (À/À) mice. 26 Despite the loss of vector genomes, the current data for an HDAd vector that persisted at 40.1 copies per nuclear genome for 6 to 22 months following vector administration to dogs with GSD-Ia are comparable to the former data for an AAV2/8 vector in G6pase (À/À) mice. Chou and colleagues 21 also highlighted the transience of AAV vector-mediated expression by measuring a 12-fold decline in G6Pase expression in mice from age 2-6 weeks.…”

“…The structure of the polysaccharide was inferred by using phosphorylase free of debranching enzyme to measure the yield of glucose-1-phosphate. Real-time PCR was performed by standard methods with Syber Green as described 26 to quantify vector genomes using the following primers: HDAd vector detection (cG6P51F: 5¢-GCTGTGCAGCTGAACGTC-3¢; cG6P6R: 5¢-GGCTTTTTCCAGTGTCCA-3¢), and canine b-actin control detection (cb-actinF: 5¢-AGCGGGAAATCGTGCGT GAC-3¢; cb-actinR: 5¢-CAATAGTGATGACCTGCCCGT-3¢). The limit of detection for real-time PCR as performed was 0.001 vector genome/nuclear genome.…”

Potential of AAV vectors in the treatment of metabolic disease

“…Excluding GSD II, which is discussed as an LSD, GDS Ia is the only disease in the class to have received attention as a possible target for AAV-mediated gene therapy. [83][84][85] While dietary therapy has improved growth and survival, improved therapies are required to address problematic long-term complications, including liver tumors, osteoporosis and renal failure. The possibility of ERT, as described for GSD II, is precluded by the fact that the deficient enzyme, glucose-6-phosphatase-a, is a hydrophobic endoplasmic reticulum-associated transmembrane protein that cannot be expressed in a soluble active form.…”

“…86 Murine and canine models of GSD Ia exist, and both have been used to explore AAV-mediated phenotype correction. [83][84][85] In mice, substantial biochemical correction, including abnormal glycogen storage, has been achieved with vectors bearing serotype 1 or 8 capsids., 84,85 In dogs, consistent reduction in liver glycogen has been achieved with normalization of fasting glucose, cholesterol, triglycerides and lactic acid reported in one animal. Whether longer term complications mentioned earlier can be ameliorated remains unknown, and truly effective therapy is likely to require highly efficient gene delivery to both liver and kidney.…”

Adeno-associated virus gene therapy prevents hepatocellular adenoma in murine model of glycogen storage disease type Ia

“…Using AAV8 or AAV1 vectors prolonged survival, and partial biochemical correction was demonstrated in G6pc À/À mice. 10,11 However, both studies required high vector doses in excess of 2 Â 10 14 vector genome/kg while still failing to fully correct biochemical parameters and restore G6Pase deficiency. Further improvements in efficacy were achieved by using a scAAV8 vector expressing human G6Pase-a from a minimal human G6Pase promoter.…”