ABSTRACT. Attempts at treatment of glycogenosis type I1 and other lysosomal storage disorders by enzyme replacement have been reported. Parenteral enzyme administration has been ineffectual. Treatment by bone marrow transplantation is currently under investigation. We have used cultured skeletal muscle cells from a patient with infantile glycogenosis type I1 to study fundamental aspects of enzyme replacement therapy. Efficient uptake of acid aglucosidase was achieved by using the mannosed-phosphate receptor on the cell surface as a target for an enzyme precursor with phosphorylated high-mannose types carbohydrate chains purified from human wine. We found that the enzyme was channeled to the lysosomes and converted to mature acid a-glucosidase. Glycogen storage was reversed. The results are discussed in relation to treatment of glycogenosis type 11. (Pediatr Res 24: 90-94, 1988) Abbreviation IGF, insulin-like growth factorPompe's disease or glycogenosis type I1 is an autosomal recessive disorder (1, 2). Deficiency of acid a-glucosidase is the primary defect, leading to lysosomal accumulation of glycogen (3). Cardiomegaly, hypotonia, and moderate hepatomegaly are characteristic of the rapidly progressive infantile form of the disease. Death occurs in the first or second year of life as a result of cardiorespiratory failure (4). In late onset forms of the disease (juvenile and adult variants) impairment of skeletal muscle function is usually the only symptom (5). Patients more than 60 yr old have been described (6).In the past, enzyme replacement has been attempted in various lysosomal storage disorders by parenteral administration of purified lysosomal enzymes (7.8). Infantile P o m~e patients received acid ;-glucosidase purified &om ~s~e r~i l l~s niger (9, 10) or human wlacenta (4). None of these attemwts was clinicallv successful. At wreseit.' this form of thera~v has been abandoned.. , and treatment of lysosomal storage disorders by bone marrow transplantation is currently under investigation (1 1-16). Some beneficial effects have been reported in the mucopolysaccharidoses. However, the few attempts at treatment of glycogenosis type I1 with bone marrow transplantation have not been successful (1 5, 16). No increase of acid a-glucosidase activity was found in muscle tissue. Elevated enzyme levels were only measured in blood cells, which in fact reflected the presence of donor cells. The lack of an efficient treatment for lysosomal storage diseases in general and glycogenosis type I1 in particular has stimulated us to investigate fundamental aspects of receptor-mediated enzyme replacement therapy.During the last decade much has been learned about the role of receptors as signal transducers, and as mediators of selective transport of macromolecular compounds. The mannose-6-phosphate receptor was recognized by its function in endocytosis of high-uptake forms of lysosomal enzymes in cultured fibroblasts (17, 18). Later it became evident that the receptor is predominantly localized intracellularly, and is mainly inv...