Although many lysosomal disorders are corrected by a small amount of the missing 
enzyme, it has been generally accepted that 20-30% of normal acid 
alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement 
therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe 
disease. We have addressed the issue of reversibility of the disease in the 
Gaa(-/-) mouse model. We have made transgenic lines expressing human GAA in 
skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at 
different stages of disease progression by using a tetracycline-controllable 
system. We have demonstrated that levels of 20-30% of normal activity are indeed 
sufficient to clear glycogen in the heart of young Gaa(-/-) mice, but not in 
older mice with a considerably higher glycogen load. However, in skeletal 
muscle-a major organ affected in infantile and in milder, late-onset variants in 
humans-induction of GAA expression in young Gaa(-/-) mice to levels greatly 
exceeding wildtype values did not result in full phenotypic correction, and some 
muscle fibers showed little or no glycogen clearance. The results demonstrate 
that complete reversal of pathology in skeletal muscle or long-affected heart 
muscle will require much more enzyme than previously expected or a different 
approach.