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, P. H. Plotz

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)2039-2047
Number of pages9
JournalHuman Molecular Genetics
Volume10
Issue number19
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Raben, N., Lu, N., Nagaraju, K., Rivera, Y., Lee, A., Yan, B., Byrne, B., Meikle, P. J., Umapathysivam, K., Hopwood, J. J., & Plotz, P. H. (2001). Conditional tissue-specific expression of the acid α-glucosidase (GAA) gene in the GAA knockout mice: Implications for therapy. Human Molecular Genetics, 10(19), 2039-2047.