Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors

Mol Ther. 2002 May;5(5 Pt 1):571-8. doi: 10.1006/mthe.2002.0580.


Pompe disease is a lysosomal storage disease caused by the absence of acid alpha-1,4 glucosidase (GAA). The pathophysiology of Pompe disease includes generalized myopathy of both cardiac and skeletal muscle. We sought to use recombinant adeno-associated virus (rAAV) vectors to deliver functional GAA genes in vitro and in vivo. Myotubes and fibroblasts from Pompe patients were transduced in vitro with rAAV2-GAA. At 14 days postinfection, GAA activities were at least fourfold higher than in their respective untransduced controls, with a 10-fold increase observed in GAA-deficient myotubes. BALB/c and Gaa(-/-) mice were also treated with rAAV vectors. Persistent expression of vector-derived human GAA was observed in BALB/c mice up to 6 months after treatment. In Gaa(-/-) mice, intramuscular and intramyocardial delivery of rAAV2-Gaa (carrying the mouse Gaa cDNA) resulted in near-normal enzyme activities. Skeletal muscle contractility was partially restored in the soleus muscles of treated Gaa(-/-) mice, indicating the potential for vector-mediated restoration of both enzymatic activity and muscle function. Furthermore, intramuscular treatment with a recombinant AAV serotype 1 vector (rAAV1-Gaa) led to nearly eight times normal enzymatic activity in Gaa(-/-) mice, with concomitant glycogen clearance as assessed in vitro and by proton magnetic resonance spectroscopy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / therapy
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Genetic Therapy / methods*
  • Genetic Vectors*
  • Glycogen / metabolism
  • Glycogen Storage Disease Type II / enzymology
  • Glycogen Storage Disease Type II / genetics
  • Glycogen Storage Disease Type II / therapy*
  • Homozygote
  • Humans
  • Immunoenzyme Techniques
  • Infant
  • Lysosomal Storage Diseases / metabolism
  • Lysosomal Storage Diseases / therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Muscle, Skeletal / physiopathology*
  • Myocardium / metabolism
  • Transduction, Genetic
  • alpha-Glucosidases / genetics*
  • alpha-Glucosidases / metabolism


  • Glycogen
  • alpha-Glucosidases