A peptide-linked recombinant glucocerebrosidase for targeted neuronal delivery: Design, production, and assessment

Journal of Biotechnology
Paul A GramlichP S Fishman

Abstract

Although recombinant glucocerebrosidase (GCase) is the standard therapy for the inherited lysosomal storage disease Gaucher's disease (GD), enzyme replacement is not effective when the central nervous system is affected. We created a series of recombinant genes/proteins where GCase was linked to different membrane binding peptides including the Tat peptide, the rabies glycoprotein derived peptide (RDP), the binding domain from tetanus toxin (TTC), and a tetanus like peptide (Tet1). The majority of these proteins were well-expressed in a mammalian producer cell line (HEK 293F). Purified recombinant Tat-GCase and RDP-GCase showed similar GCase protein delivery to a neuronal cell line that genetically lacks the functional enzyme, and greater delivery than control GCase, Cerezyme (Genzyme). This initial result was unexpected based on observations of superior protein delivery to neurons with RDP as a vector. A recombinant protein where a fragment of the flexible hinge region from IgA (IgAh) was introduced between RDP and GCase showed substantially enhanced GCase neuronal delivery (2.5 times over Tat-GCase), suggesting that the original construct resulted in interference with the capacity of RDP to bind neuronal membranes. Extended t...Continue Reading

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Citations

Nov 12, 2016·EBioMedicine·Francis Y M Choy, Chloe L Christensen
Feb 6, 2018·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Roberta Balestrino, Anthony H V Schapira
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Sep 22, 2017·Diseases·Tamanna Roshan Lal, Ellen Sidransky
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