Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II.

Abstract

Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid alpha-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1 x 10(10) vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3 x 10(10) vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice.

• Authors: Baodong Sun, Haoyue Zhang, Daniel K Benjamin Jr, Talmage Brown, Andrew Bird, Sarah P Young, Alison McVie-Wylie, Y-T Chen, Dwight D Koeberl
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 14 Issue 6 Pg. 822-30 (Dec 2006) ISSN: 1525-0016 [Print] United States
• PMID: 16987711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Sorting Signals
• Recombinant Fusion Proteins
• Glycogen
• Glucan 1,4-alpha-Glucosidase

Topics

• Animals
• Blotting, Western
• Cell Line
• Cells, Cultured
• Dependovirus (genetics)
• Fibroblasts (metabolism)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Glucan 1,4-alpha-Glucosidase (genetics, metabolism)
• Glycogen (metabolism)
• Glycogen Storage Disease Type II (genetics, pathology, therapy)
• Humans
• Mice
• Mice, Knockout
• Protein Sorting Signals (genetics)
• Recombinant Fusion Proteins (genetics, metabolism)
• Transfection
• Treatment Outcome