Correction of the Enzymatic and Functional Deficits in a Model of Pompe Disease Using Adeno-associated Virus Vectors

ASU Author/Contributor (non-ASU co-authors, if there are any, appear on document)
Andrew Shanely Ph.D, Associate Professor (Creator)
Appalachian State University (ASU )
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Abstract: Pompe disease is a lysosomal storage disease caused by the absence of acid -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 treat-ment. 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 vec-tor-mediated restoration of both enzymatic activity and muscle function. Furthermore, intra-muscular 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.

Additional Information

Thomas J. Fraites Jr, 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 and Barry J. Byrne (2002) "Correction of the Enzymatic and Functional Deficits in a Model of Pompe Disease Using Adeno-associated Virus Vectors" Molecular Therapy vol 5 #5 Version of Record Available @ (doi:10.1006/mthe.2002.0580, available online at on IDEAL)
Language: English
Date: 2002
glycogen storage disease type II, gene therapy, cardiovascular diseases, lysosomal storage diseases, musculoskeletal diseases

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