Proteomics

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The Glycosylation Design Space for Recombinant Lysosomal Replacement Enzymes Produced in CHO Cells

ABSTRACT: Lysosomal storage diseases are rare life-threatening disorders caused by deficiency of a lysosomal enzyme, and delivery of a recombinant replacement enzyme is the primary therapy for several of these diseases. The structures of N-glycans on recombinant replacement enzymes are important for their therapeutic efficacy, biodistribution and circulation time. Here we use alpha-galactosidase A (GLA) and beta-glucoscerebrosidase (GBA) as representative replacement enzymes, and present a panel of genetically engineered CHO cells that enable production of lysosomal replacement enzymes with different N-glycan features. We also tested several GLA variants with distinct glycoforms in a Fabry mouse model and present evidence that GLA glycoforms capped with alpha 2-3 linked sialic acids may represent a new strategy to overcome the most critical problems of rapid clearance in liver and poor biodistribution found with current ERTs.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human) Cricetulus Griseus (chinese Hamster) (cricetulus Barabensis Griseus)

TISSUE(S): Epithelial Cell

DISEASE(S): Disease Free

SUBMITTER: Sergey Vakhrushev  

LAB HEAD: Henrik Clausen

PROVIDER: PXD013140 | Pride | 2019-05-31

REPOSITORIES: Pride

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Publications

Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here w  ...[more]

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