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

Thomas J. Fraites, Mary R. Schleissing, R. Andrew Shanely, Glenn A. Walter, Denise A. Cloutier, Irene Zolotukhin, Daniel F. Pauly, Nina Raben, Paul H. Plotz, Scott K. Powers, Paul D. Kessler, Barry J. Byrne

Research output: Contribution to journalArticlepeer-review

100 Scopus citations


Pompe disease is a lysosomal storage disease caused by the absence of acid α-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.

Original languageEnglish (US)
Pages (from-to)571-578
Number of pages8
JournalMolecular Therapy
Issue number5 I
StatePublished - 2002
Externally publishedYes


  • Cardiovascular diseases
  • Gene therapy
  • Glycogen storage disease type II
  • Lysosomal storage diseases
  • Musculoskeletal diseases

ASJC Scopus subject areas

  • Molecular Biology


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