Human Molecular Genetics, 2001, Vol. 10, No. 19 2039-2047
© 2001 Oxford University Press
Conditional tissue-specific expression of the acid 
-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy
Arthritis and Rheumatism Branch, NIAMS, 9000 Rockville Pike, Clinical Center Building 10/9N244, National Institutes of Health, Bethesda, MD 20892, USA, 1Gene Therapy Center and Departments of Medicine, Pediatrics, and Molecular Genetics, University of Florida College of Medicine, Gainesville, FL 32610, USA and 2Department of Chemical Pathology, Women’s and Children’s Hospital, North Adelaide, 5006 Australia
Both enzyme replacement and gene therapy of lysosomal storage disorders rely on the receptor-mediated uptake of lysosomal enzymes secreted by cells, and for each lysosomal disorder it is necessary to select the correct cell type for recombinant enzyme production or for targeting gene therapy. For example, for the therapy of Pompe disease, a severe metabolic myopathy and cardiomyopathy caused by deficiency of acid 
-glucosidase (GAA), skeletal muscle seems an obvious choice as a depot organ for local therapy and for the delivery of the recombinant enzyme into the systemic circulation. Using knockout mice with this disease and transgenes containing cDNA for the human enzyme under muscle or liver specific promoters controlled by tetracycline, we have demonstrated that the liver provided enzyme far more efficiently. 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 weight, secreted 100-fold more enzyme, all of which was in the active 110 kDa precursor form. Furthermore, using tetracycline regulation, we somatically induced human GAA in the knockout mice, and demonstrated that the skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.
+ To whom correspondence should be addressed. Tel: +1 301 496 1474; Fax: +1 301 402 0012; Email: rabenn@arb.niams.nih.gov
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