Abstract
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 language | English (US) |
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Pages (from-to) | 571-578 |
Number of pages | 8 |
Journal | Molecular Therapy |
Volume | 5 |
Issue number | 5 I |
DOIs | |
State | Published - 2002 |
Externally published | Yes |
Keywords
- Cardiovascular diseases
- Gene therapy
- Glycogen storage disease type II
- Lysosomal storage diseases
- Musculoskeletal diseases
ASJC Scopus subject areas
- Molecular Biology