Enzyme replacement therapy in the mouse model of Pompe disease

N. Raben, M. Danon, A. L. Gilbert, S. Dwivedi, B. Collins, B. L. Thurberg, R. J. Mattaliano, K. Nagaraju, P. H. Plotz

Research output: Contribution to journalArticlepeer-review

161 Scopus citations


Deficiency of acid alpha-glucosidase (GAA) results in widespread cellular deposition of lysosomal glycogen manifesting as myopathy and cardiomyopathy. When GAA-/- mice were treated with rhGAA (20mg/kg/week for up to 5 months), skeletal muscle cells took up little enzyme compared to liver and heart. Glycogen reduction was less than 50%, and some fibers showed little or no glycogen clearance. A dose of 100mg/kg/week resulted in ∼75% glycogen clearance in skeletal muscle. The enzyme reduced cardiac glycogen to undetectable levels at either dose. Skeletal muscle fibers with residual glycogen showed immunoreactivity for LAMP-1/LAMP-2, indicating that undigested glycogen remained in proliferating lysosomes. Glycogen clearance was more pronounced in type 1 fibers, and histochemical analysis suggested an increased mannose-6-phosphate receptor immunoreactivity in these fibers. Differential transport of enzyme into lysosomes may explain the strikingly uneven pattern of glycogen removal. Autophagic vacuoles, a feature of both the mouse model and the human disease, persisted despite glycogen clearance. In some groups a modest glycogen reduction was accompanied by improved muscle strength. These studies suggest that enzyme replacement therapy, although at much higher doses than in other lysosomal diseases, has the potential to reverse cardiac pathology and to reduce the glycogen level in skeletal muscle.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalMolecular Genetics and Metabolism
Issue number1-2
StatePublished - Sep 2003
Externally publishedYes


  • Acid alpha-glucosidase
  • Enzyme replacement therapy
  • Glycogen accumulation
  • Lysosomal storage
  • Pompe disease

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism


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