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Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2005 Jan; Vol. 11 (1), pp. 48-56. - Publication Year :
- 2005
-
Abstract
- Pompe disease (type II glycogen storage disease) is an autosomal recessive disorder caused by a deficiency of lysosomal acid alpha-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.
- Subjects :
- Animals
Autophagy
Cell Line
Cricetinae
Endocytosis
Genetic Therapy
Glucan 1,4-alpha-Glucosidase deficiency
Glucan 1,4-alpha-Glucosidase genetics
Glycogen analysis
Glycogen metabolism
Glycogen Storage Disease Type II therapy
Humans
Liver metabolism
Lysosomes metabolism
Mice
Microscopy, Electron
Muscle Fibers, Fast-Twitch cytology
Muscle, Skeletal metabolism
Myocardium metabolism
Recombinant Proteins genetics
Recombinant Proteins metabolism
alpha-Glucosidases
Glucan 1,4-alpha-Glucosidase metabolism
Glucan 1,4-alpha-Glucosidase pharmacology
Glycogen Storage Disease Type II enzymology
Glycogen Storage Disease Type II genetics
Muscle Fibers, Fast-Twitch drug effects
Muscle Fibers, Fast-Twitch metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0016
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 15585405
- Full Text :
- https://doi.org/10.1016/j.ymthe.2004.09.017