Conditional tissue-specific expression of the acid alpha-glucosidase (GAA)gene in the GAA knockout mice: implications for therapy

Both enzyme replacement and gene therapy of lysosomal storage disorders rel y on the receptor-mediated uptake of lysosomal enzymes secreted by cells, a nd for each lysosomal disorder it is necessary to select the correct cell t ype for recombinant enzyme production or for targeting gene therapy. For ex ample, for the therapy of Pompe disease, a severe metabolic myopathy and ca rdiomyopathy caused by deficiency of acid alpha -glucosidase (GAA), skeleta l muscle seems an obvious choice as a depot organ for local therapy and for the delivery of the recombinant enzyme into the systemic circulation. Usin g knockout mice with this disease and transgenes containing cDNA for the hu man enzyme under muscle or liver specific promoters controlled by tetracycl ine, we have demonstrated that the liver provided enzyme far more efficient ly. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising <5% of body w eight, secreted 100-fold more enzyme, all of which was in the active 110 kD a precursor form. Furthermore, using tetracycline regulation, we somaticall y induced human GAA in the knockout mice, and demonstrated that the skeleta l and cardiac muscle pathology was completely reversible if the treatment w as begun early.