Exploiting the diphtheria toxin internalization receptor enhances delivery of proteins to lysosomes for enzyme replacement therapy

S. N. Sugiman-Marangos, G. L. Beilhartz, X. Zhao, D. Zhou, R. Hua, P. K. Kim, J. M. Rini, B. A. Minassian, R. A. Melnyk

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Enzyme replacement therapy, in which a functional copy of an enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases. The inefficient uptake of recombinant enzymes via the mannose-6-phosphate receptor, however, prohibits the broad utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endolysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that chimeric TPP1 binds with high affinity to target cells and is efficiently delivered into lysosomes. Further, we show superior uptake of chimeric TPP1 over TPP1 alone in brain tissue following intracerebroventricular injection in mice lacking TPP1, demonstrating the potential of this strategy for enhancing lysosomal storage disease therapy.

Original languageEnglish (US)
Article numbereabb0385
JournalScience Advances
Volume6
Issue number50
DOIs
StatePublished - Dec 11 2020

ASJC Scopus subject areas

  • General

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