title: Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers.
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.
authors.affiliation: Arthritis and Rheumatism Branch, NIAMS, National Institutes of Health, 9000 Rockville Pike, Building 10/9N244, Bethesda, MD 20892, USA. rabenn@arb.niams.nih.gov
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Tokiko
authors.initials: T
authors.lastname: Fukuda
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Gilbert
authors.forename: Deborah
authors.initials: D
authors.lastname: de Jong
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mattaliano
authors.forename: Peter
authors.initials: P
authors.lastname: Meikle
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Paul H
authors.initials: PH
authors.lastname: Plotz
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D006224:Cricetinae; D004705:Endocytosis; D015316:Genetic Therapy; D005087:Glucan 1,4-alpha-Glucosidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006003:Glycogen / Q000032:analysis / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D006801:Humans; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008854:Microscopy, Electron; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000520:alpha-Glucosidases
chemical_list: D011994:Recombinant Proteins; D006003:Glycogen; D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase