Glycosylation-independent Lysosomal Targeting of Acid α-Glucosidase Enhances Muscle Glycogen Clearance in Pompe Mice
| Autor: | Susan Peng, Nancy M. Dahms, Ravi Kambampati, Xu Wang, Jonathan H. LeBowitz, Peggy Tom, John Maga, Richard N. Bohnsack, Jianghong Zhou, Angela M. Thomm, Barry J. Byrne, Sarah Golata |
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| Rok vydání: | 2013 |
| Předmět: |
Glycosylation
Mutant Chimeric Proteins Receptor Endocytosis Mannose Biology Transfection Biochemistry Receptor IGF Type 2 Myoblasts Mice chemistry.chemical_compound Drug Delivery Systems Lysosomal Storage Disease Insulin-Like Growth Factor II Lysosome Glycogen storage disease type II medicine Lysosomal storage disease Animals Humans Glycogen storage disease Enzyme Replacement Therapy Muscular Dystrophy Muscle Skeletal IGF-II Molecular Biology Glycogen Glycogen Storage Disease Type II Skeletal muscle Biological Transport Molecular Bases of Disease Cell Biology Enzyme replacement therapy Glycogen Storage Disease medicine.disease Molecular biology Disease Models Animal Kinetics HEK293 Cells medicine.anatomical_structure Pompe chemistry CI-MPR Muscle Glucan 1 4-alpha-Glucosidase Lysosomes Half-Life Plasmids |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.438663 |
| Popis: | Background: Acid α-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 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. |
| Databáze: | OpenAIRE |
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