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Milwaukee, Wisconsin, United States

Maga J.A.,ZyStor Therapeutics | Zhou J.,ZyStor Therapeutics | Zhou J.,Oncode Med Inc. | Kambampati R.,ZyStor Therapeutics | And 11 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Acid-glucosidase, an enzyme replacement therapy for Pompe disease, is poorly targeted to lysosomes when relying on phosphomannose residues. Results: Fusing IGF-II to acid α-glucosidase resulted in more efficient uptake and glycogen clearance from muscle of Pompe mice. Conclusion: Enhanced binding to the cation-independent mannose 6-phosphate receptor (CI-MPR) enabled improved glycogen clearance in Pompe mice. Significance: BMN 701 is now being tested for Pompe disease in human clinical studies. We have used a peptide-based targeting system to improve lysosomal delivery of acid-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. GILTtagged 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-taggedGAA 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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

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