Production of α-L-iduronidase in maize for the potential treatment of a human lysosomal storage disease.

Abstract

Lysosomal storage diseases are a class of over 70 rare genetic diseases that are amenable to enzyme replacement therapy. Towards developing a plant-based enzyme replacement therapeutic for the lysosomal storage disease mucopolysaccharidosis I, here we expressed α-L-iduronidase in the endosperm of maize seeds by a previously uncharacterized mRNA-targeting-based mechanism. Immunolocalization, cellular fractionation and in situ RT-PCR demonstrate that the α-L-iduronidase protein and mRNA are targeted to endoplasmic reticulum (ER)-derived protein bodies and to protein body-ER regions, respectively, using regulatory (5'- and 3'-UTR) and signal-peptide coding sequences from the γ-zein gene. The maize α-L-iduronidase exhibits high activity, contains high-mannose N-glycans and is amenable to in vitro phosphorylation. This mRNA-based strategy is of widespread importance as plant N-glycan maturation is controlled and the therapeutic protein is generated in a native form. For our target enzyme, the N-glycan structures are appropriate for downstream processing, a prerequisite for its potential as a therapeutic protein.

• Authors: Xu He, Thomas Haselhorst, Mark von Itzstein, Daniel Kolarich, Nicolle H Packer, Tracey M Gloster, David J Vocadlo, Lorne A Clarke, Yi Qian, Allison R Kermode
• Journal: Nature communications (Nat Commun) Vol. 3 Pg. 1062 ( 2012) ISSN: 2041-1723 [Electronic] England
• PMID: 22990858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Polysaccharides
• Iduronidase

Topics

• Humans
• Iduronidase (chemistry, genetics, metabolism, therapeutic use)
• Lysosomal Storage Diseases (drug therapy)
• Polysaccharides (chemistry, metabolism)
• Zea mays (enzymology, genetics, metabolism)