What question did this study set out to answer?

To determine whether remodelling the carbohydrate structures of recombinant acid α-glucosidase to increase affinity for the cation-independent mannose 6-phosphate receptor enhances enzyme delivery and glycogen clearance in Pompe disease models.

July 26, 2005Biochemical JournalOpen Access

Carbohydrate-remodelled acid α-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice

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Authors

YZYunxiang ZhuZhejiang Cancer Hospital XLXuemei LiArmy Medical University AMAlison McVie‐WylieSanofi (United States)

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Implication

Preclinical study demonstrates enhanced muscle uptake and glycogen clearance with remodelled acid alpha-glucosidase in Pompe mice, indicating improved enzyme replacement therapy.

Key Points

To determine whether remodelling the carbohydrate structures of recombinant acid α-glucosidase to increase affinity for the cation-independent mannose 6-phosphate receptor enhances enzyme delivery and glycogen clearance in Pompe disease models.
Conjugated approximately six synthetic oligosaccharide ligands bearing mannose 6-phosphate onto recombinant human acid α-glucosidase (rhGAA) using carbonyl chemistry to generate neo-rhGAA.
Assessed specific activity, receptor binding affinity, and cellular uptake kinetics in L6 myoblasts in vitro.
Administered neo-rhGAA and unmodified rhGAA to Pompe mice, including an older refractory cohort receiving 40 mg/kg, to evaluate tissue glycogen clearance across cardiac, diaphragm, and skeletal muscles.
Neo-rhGAA demonstrated significantly increased affinity for the cation-independent mannose 6-phosphate receptor and achieved approximately 20-fold more efficient internalization in L6 myoblasts than unmodified rhGAA.
In Pompe mice, neo-rhGAA produced comparable glycogen reduction at approximately 8-fold lower doses in the heart and diaphragm and approximately 4-fold lower doses in skeletal muscles compared to unmodified rhGAA.
Treatment of older refractory Pompe mice with 40 mg/kg neo-rhGAA produced near-complete glycogen clearance across all affected muscles, whereas unmodified rhGAA yielded only partial correction.

Cite This Study

Zhu et al. (2005) studied this question.

synapsesocial.com/papers/6a771d0bdf493903fd1eadce https://doi.org/10.1042/bj20050364

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Implication

Preclinical study demonstrates enhanced muscle uptake and glycogen clearance with remodelled acid alpha-glucosidase in Pompe mice, indicating improved enzyme replacement therapy.

Carbohydrate-remodelled acid α-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice

Discussion

Member takes

Implication

Key Points

Cite This Study

Carbohydrate-remodelled acid α-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice

Discussion

Member takes

Implication

Key Points

Cite This Study

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