title: Intravenous administration of phosphorylated acid alpha-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice.
abstract: The lysosomal storage disorder glycogenosis type II is caused by acid alpha-glucosidase deficiency. In this study we have investigated the possible applicability of mannose 6-phosphate receptor-mediated enzyme replacement therapy to correct the enzyme deficiency in the most affected tissues. Bovine testes acid alpha-glucosidase containing phosphorylated mannose residues was intravenously administered to mice and found to be taken up by heart (70% increase of activity) and skeletal muscle (43% increase); the major target organs. The uptake of nonphosphorylated human placenta acid alpha-glucosidase by heart and skeletal muscle appeared to be significantly less efficient, whereas uptake of dephosphorylated bovine testes enzyme was not detectable. The phosphorylated bovine testes acid alpha-glucosidase remained present in mouse skeletal muscle up to 9-15 d after administration, with a half-life of 2-4 d. Besides being measured in skeletal muscle and heart, uptake of phosphorylated bovine testes and nonphosphorylated human placenta acid alpha-glucosidase was measured in several other organs, but not in brain. The increase of acid alpha-glucosidase activity was highest in liver and spleen. We concluded that application of mannose 6-phosphate receptor-mediated enzyme replacement therapy may offer new perspectives for treatment of glycogenesis type II.
authors.affiliation: Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
authors.forename: A T
authors.initials: AT
authors.lastname: Van der Ploeg
authors.forename: M A
authors.initials: MA
authors.lastname: Kroos
authors.forename: R
authors.initials: R
authors.lastname: Willemsen
authors.forename: N H
authors.initials: NH
authors.lastname: Brons
authors.forename: A J
authors.initials: AJ
authors.lastname: Reuser
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D006009:Glycogen Storage Disease Type II / Q000378:metabolism*; D008297:Male; D008360:Mannosephosphates / Q000378:metabolism; D051379:Mice; D009132:Muscles / Q000201:enzymology / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D013737:Testis / Q000201:enzymology; D014018:Tissue Distribution; D000520:alpha-Glucosidases / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D008360:Mannosephosphates; D000520:alpha-Glucosidases