1. Glycosylation-independent lysosomal targeting of acid α-glucosidase enhances muscle glycogen clearance in pompe mice.
- Author
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Maga JA, Zhou J, Kambampati R, Peng S, Wang X, Bohnsack RN, Thomm A, Golata S, Tom P, Dahms NM, Byrne BJ, and LeBowitz JH
- Subjects
- Animals, Biological Transport drug effects, Disease Models, Animal, Drug Delivery Systems methods, Glucan 1,4-alpha-Glucosidase genetics, Glycogen Storage Disease Type II genetics, Glycosylation, HEK293 Cells, Half-Life, Humans, Insulin-Like Growth Factor II genetics, Insulin-Like Growth Factor II metabolism, Kinetics, Lysosomes enzymology, Mice, Muscle, Skeletal drug effects, Muscle, Skeletal enzymology, Muscle, Skeletal pathology, Mutant Chimeric Proteins genetics, Mutant Chimeric Proteins metabolism, Myoblasts drug effects, Myoblasts enzymology, Myoblasts pathology, Plasmids, Receptor, IGF Type 2 agonists, Receptor, IGF Type 2 metabolism, Transfection, Enzyme Replacement Therapy methods, Glucan 1,4-alpha-Glucosidase metabolism, Glycogen metabolism, Glycogen Storage Disease Type II drug therapy, Glycogen Storage Disease Type II enzymology, Lysosomes drug effects
- Abstract
We have used a peptide-based targeting system to improve lysosomal delivery of acid α-glucosidase (GAA), the enzyme deficient in patients with Pompe disease. Human GAA was fused to the glycosylation-independent lysosomal targeting (GILT) tag, which contains a portion of insulin-like growth factor II, to create an active, chimeric enzyme with high affinity for the cation-independent mannose 6-phosphate receptor. GILT-tagged GAA was taken up by L6 myoblasts about 25-fold more efficiently than was recombinant human GAA (rhGAA). Once delivered to the lysosome, the mature form of GILT-tagged GAA was indistinguishable from rhGAA and persisted with a half-life indistinguishable from rhGAA. GILT-tagged GAA was significantly more effective than rhGAA in clearing glycogen from numerous skeletal muscle tissues in the Pompe mouse model. The GILT-tagged GAA enzyme may provide an improved enzyme replacement therapy for Pompe disease patients.
- Published
- 2013
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