1. Glycosylation-independent Lysosomal Targeting of Acid α-Glucosidase Enhances Muscle Glycogen Clearance in Pompe Mice.
- Author
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Maga, John A., Jianghong Zhou, Kambampati, Ravi, Susan Peng, Xu Wang, Bohnsack, Richard N., Thomm, Angela, Golata, Sarah, Tom, Peggy, Dahms, Nancy M., Byrne, Barry J., and LeBowitz, Jonathan H.
- Subjects
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ALPHA-glucosidases , *GLYCOGEN storage disease type II , *RECOMBINANT human insulin , *GLYCOSYLATION , *CHIMERIC enzymes - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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