INTRAVENOUS ADMINISTRATION OF PHOSPHORYLATED ACID ALPHA-GLUCOSIDASE LEADS TO UPTAKE OF ENZYME IN HEART AND SKELETAL-MUSCLE OF MICE

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 tests 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 glycogenosis type II.