Journal Article

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

N. Raben, N. Lu, K. Nagaraju, Y. Rivera, A. Lee, B. Yan, B. Byrne, P.J. Meikle, K. Umapathysivam, J.J. Hopwood and P.H. Plotz

in Human Molecular Genetics

Volume 10, issue 19, pages 2039-2047
Published in print September 2001 | ISSN: 0964-6906
Published online September 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.19.2039
Conditional tissue-specific expression of the acid α-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy

Show Summary Details

Preview

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 α-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.

Journal Article.  6184 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.