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Liu L, Lee WS, Doray B, et al. Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy. Mol Ther Methods Clin Dev. 2017;5:59-65doi: 10.1016/j.omtm.2017.03.006.
Liu, L., Lee, W. S., Doray, B., & Kornfeld, S. (2017). Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy. Molecular therapy. Methods & clinical development, 559-65. https://doi.org/10.1016/j.omtm.2017.03.006
Liu, Lin, et al. "Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy." Molecular therapy. Methods & clinical development vol. 5 (2017): 59-65. doi: https://doi.org/10.1016/j.omtm.2017.03.006
Liu L, Lee WS, Doray B, Kornfeld S. Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy. Mol Ther Methods Clin Dev. 2017 Mar 29;5:59-65. doi: 10.1016/j.omtm.2017.03.006. eCollection 2017 Jun 16. PMID: 28480305; PMCID: PMC5415318.
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Mol Ther Methods Clin Dev. 2017 Mar 29;5:59-65. doi: 10.1016/j.omtm.2017.03.006. eCollection 2017 Jun 16.

Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy.

Molecular therapy. Methods & clinical development

Lin Liu, Wang-Sik Lee, Balraj Doray, Stuart Kornfeld

Affiliations

  1. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

PMID: 28480305 PMCID: PMC5415318 DOI: 10.1016/j.omtm.2017.03.006

Abstract

Several lysosomal enzymes currently used for enzyme replacement therapy in patients with lysosomal storage diseases contain very low levels of mannose 6-phosphate, limiting their uptake via mannose 6-phosphate receptors on the surface of the deficient cells. These enzymes are produced at high levels by mammalian cells and depend on endogenous GlcNAc-1-phosphotransferase α/β precursor to phosphorylate the mannose residues on their glycan chains. We show that co-expression of an engineered truncated GlcNAc-1-phosphotransferase α/β precursor and the lysosomal enzyme of interest in the producing cells resulted in markedly increased phosphorylation and cellular uptake of the secreted lysosomal enzyme. This method also results in the production of highly phosphorylated acid β-glucocerebrosidase, a lysosomal enzyme that normally has just trace amounts of this modification.

Keywords: GlcNAc-1-phosphotransferase; enzyme replacement therapy; lysosomal enzyme; lysosomal storage disorders; mannose 6-phosphate

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