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

Mol Ther. 2006 Dec;14(6):822-30. doi: 10.1016/j.ymthe.2006.08.001. Epub 2006 Sep 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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