A universal GlycoDesign for lysosomal replacement enzymes to improve circulation time and biodistribution

Yen-Hsi Chen, Weihua Tian, Makiko Yasuda, Zilu Ye, Ming Song, Ulla Mandel, Claus Kristensen, Lorenzo Povolo, André R. A. Marques, Tomislav Čaval, Albert J. R. Heck, Julio Lopes Sampaio, Ludger Johannes, Takahiro Tsukimura, Robert Desnick*, Sergey Y. Vakhrushev, Zhang Yang*, Henrik Clausen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Currently available enzyme replacement therapies for lysosomal storage diseases are limited in their effectiveness due in part to short circulation times and suboptimal biodistribution of the therapeutic enzymes. We previously engineered Chinese hamster ovary (CHO) cells to produce α-galactosidase A (GLA) with various N-glycan structures and demonstrated that elimination of mannose-6-phosphate (M6P) and conversion to homogeneous sialylated N-glycans prolonged circulation time and improved biodistribution of the enzyme following a single-dose infusion into Fabry mice. Here, we confirmed these findings using repeated infusions of the glycoengineered GLA into Fabry mice and further tested whether this glycoengineering approach, Long-Acting-GlycoDesign (LAGD), could be implemented on other lysosomal enzymes. LAGD-engineered CHO cells stably expressing a panel of lysosomal enzymes [aspartylglucosamine (AGA), beta-glucuronidase (GUSB), cathepsin D (CTSD), tripeptidyl peptidase (TPP1), alpha-glucosidase (GAA) or iduronate 2-sulfatase (IDS)] successfully converted all M6P-containing N-glycans to complex sialylated N-glycans. The resulting homogenous glycodesigns enabled glycoprotein profiling by native mass spectrometry. Notably, LAGD extended the plasma half-life of all three enzymes tested (GLA, GUSB, AGA) in wildtype mice. LAGD may be widely applicable to lysosomal replacement enzymes to improve their circulatory stability and therapeutic efficacy.
Original languageEnglish
Article number1128371
JournalFrontiers in Bioengineering and Biotechnology
Volume11
Number of pages18
ISSN2296-4185
DOIs
Publication statusPublished - 2023

Keywords

  • Glycoengineering
  • Enzyme replacement therapy
  • Lysosymal storage disease
  • Glycoprotein therapeutics
  • Bioengineering

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