Receptor-Mediated Uptake of Acid α-Glucosidase Corrects Lysosomal Glycogen Storage in Cultured Skeletal Muscle

Abstract

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...

Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model

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Targeted Disruption of the Acid α-Glucosidase Gene in Mice Causes an Illness with Critical Features of Both Infantile and Adult Human Glycogen Storage Disease Type II

“…There is currently no effective therapy, but several candidate therapies, based on the discovery that acid ␣-glucosidase, like many other lysosomal enzymes, is secreted and can be taken up through cell surface mannose-6-phosphate receptors on other cells (3)(4)(5), are already under development (6 -12). These studies stimulated efforts to create a mouse model suitable for testing enzyme replacement and gene therapies.…”

Complete correction of acid α-glucosidase deficiency in Pompe disease fibroblasts in vitro, and lysosomally targeted expression in neonatal rat cardiac and skeletal muscle

“…7,8 Recognizing that mannose 6-phosphate receptors are present on the cell surface where they facilitate endocytosis and lysosomal targeting of endocytosed enzyme, attempts have been made to treat lysosomal storage disorders by exogenous administration of purified enzyme. The phosphomannosyl-bearing enzyme isolated from bovine testes proved effective in augmenting acid ␣-glucosidase activity in deficient cells in culture, [9][10][11][12] in perfused heart models 13 and in vivo. 14 Furthermore, recombinant human acid ␣-glucosidase has recently been produced in CHO cells, 15,16 and i.v.…”