Replacing acid α-glucosidase in Pompe disease: Recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers

Nina Raben, Tokiko Fukuda, Abigail L. Gilbert, Deborah de Jong, Beth L. Thurberg, Robert J. Mattaliano, Peter Meikle, John J. Hopwood, Kunio Nagashima, Kanneboyina Nagaraju, Paul H. Plotz

Research output: Contribution to journalArticlepeer-review

Abstract

Pompe disease (type II glycogen storage disease) is an autosomal recessive disorder caused by a deficiency of lysosomal acid α-glucosidase (GAA) leading to the accumulation of glycogen in the lysosomes primarily in cardiac and skeletal muscle. The recombinant human GAA (rhGAA) is currently in clinical trials for enzyme replacement therapy of Pompe disease. Both clinical data and the results of preclinical studies in our knockout model of this disease show that rhGAA is much more effective in resolving the cardiomyopathy than the skeletal muscle myopathy. By contrast, another form of human GAA - transgenic enzyme constitutively produced in liver and secreted into the bloodstream of knockout mice (Gaa-/-) - completely prevented both cardiac and skeletal muscle glycogen accumulation. In the experiments reported here, the transgenic enzyme was much less efficient when delivered to skeletal muscle after significant amounts of glycogen had already accumulated. Furthermore, the transgenic enzyme and the rhGAA have similar therapeutic effects, and both efficiently clear glycogen from cardiac muscle and type I muscle fibers, but not type II fibers. Low abundance of proteins involved in endocytosis and trafficking of lysosomal enzymes combined with increased autophagy in type II fibers may explain the resistance to therapy.

Original languageEnglish (US)
Pages (from-to)48-56
Number of pages9
JournalMolecular Therapy
Volume11
Issue number1
DOIs
StatePublished - Jan 2005
Externally publishedYes

Keywords

  • Acid α-glucosidase
  • Autophagy
  • Enzyme replacement therapy
  • Lysosomal storage disease
  • Lysosomal trafficking
  • Pompe disease
  • Tetracycline-controllable system
  • Transgenic knockout

ASJC Scopus subject areas

  • Molecular Biology

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