Glycosylation-independent lysosomal targeting of acid α-glucosidase enhances muscle glycogen clearance in pompe mice. J Biol Chem 2013 Jan 18;288(3):1428-38
Date
11/29/2012Pubmed ID
23188827Pubmed Central ID
PMC3548456DOI
10.1074/jbc.M112.438663Scopus ID
2-s2.0-84872707665 (requires institutional sign-in at Scopus site) 91 CitationsAbstract
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.
Author List
Maga JA, Zhou J, Kambampati R, Peng S, Wang X, Bohnsack RN, Thomm A, Golata S, Tom P, Dahms NM, Byrne BJ, LeBowitz JHAuthor
Nancy M. Dahms PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBiological Transport
Disease Models, Animal
Drug Delivery Systems
Enzyme Replacement Therapy
Glucan 1,4-alpha-Glucosidase
Glycogen
Glycogen Storage Disease Type II
Glycosylation
HEK293 Cells
Half-Life
Humans
Insulin-Like Growth Factor II
Kinetics
Lysosomes
Mice
Muscle, Skeletal
Mutant Chimeric Proteins
Myoblasts
Plasmids
Receptor, IGF Type 2
Transfection
