1. Glycoengineered acid alpha-glucosidase with improved efficacy at correcting the metabolic aberrations and motor function deficits in a mouse model of Pompe disease.
- Author
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Zhu Y, Jiang JL, Gumlaw NK, Zhang J, Bercury SD, Ziegler RJ, Lee K, Kudo M, Canfield WM, Edmunds T, Jiang C, Mattaliano RJ, and Cheng SH
- Subjects
- Animals, Disease Models, Animal, Glycogen metabolism, Glycogen Storage Disease Type II metabolism, Humans, Mice, Mice, Inbred C57BL, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Protein Binding, Receptor, IGF Type 2 metabolism, alpha-Glucosidases chemistry, alpha-Glucosidases genetics, alpha-Glucosidases pharmacology, Glycogen Storage Disease Type II drug therapy, Mannosephosphates chemistry, Oligosaccharides chemistry, Protein Engineering methods, alpha-Glucosidases metabolism, alpha-Glucosidases therapeutic use
- Abstract
Improving the delivery of therapeutics to disease-affected tissues can increase their efficacy and safety. Here, we show that chemical conjugation of a synthetic oligosaccharide harboring mannose 6-phosphate (M6P) residues onto recombinant human acid alpha-glucosidase (rhGAA) via oxime chemistry significantly improved its affinity for the cation-independent mannose 6-phosphate receptor (CI-MPR) and subsequent uptake by muscle cells. Administration of the carbohydrate-remodeled enzyme (oxime-neo-rhGAA) into Pompe mice resulted in an approximately fivefold higher clearance of lysosomal glycogen in muscles when compared to the unmodified counterpart. Importantly, treatment of immunotolerized Pompe mice with oxime-neo-rhGAA translated to greater improvements in muscle function and strength. Treating older, symptomatic Pompe mice also reduced tissue glycogen levels but provided only modest improvements in motor function. Examination of the muscle pathology suggested that the poor response in the older animals might have been due to a reduced regenerative capacity of the skeletal muscles. These findings lend support to early therapeutic intervention with a targeted enzyme as important considerations in the management of Pompe disease.
- Published
- 2009
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