Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/17413
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Type: Journal article
Title: Replacing acid ∝-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers
Other Titles: Replacing acid is proportional to-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers
Author: Raben, N.
Fukuda, T.
Gilbert, A.
de Jong, D.
Thurberg, B.
Mattaliano, R.
Meikle, P.
Hopwood, J.
Nagashima, K.
Nagaraju, K.
Plotz, P.
Citation: Molecular Therapy, 2005; 11(1):48-56
Publisher: Academic Press Inc Elsevier Science
Issue Date: 2005
ISSN: 1525-0016
1525-0024
Statement of
Responsibility: 
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 and Paul H. Plotz
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.
Keywords: Muscle Fibers, Fast-Twitch; Muscle, Skeletal; Myocardium; Liver; Cell Line; Lysosomes; Animals; Humans; Mice; Glycogen Storage Disease Type II; Glycogen; alpha-Glucosidases; Glucan 1,4-alpha-Glucosidase; Recombinant Proteins; Microscopy, Electron; Endocytosis; Autophagy; Cricetinae; Genetic Therapy
RMID: 0020052061
DOI: 10.1016/j.ymthe.2004.09.017
Appears in Collections:Paediatrics publications

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