Mannose Receptor-mediated Delivery of Moss-made α-galactosidase A Efficiently Corrects Enzyme Deficiency in Fabry Mice

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2015 Aug 28

PMID 26310963

Citations 53

Authors

Jin-Song Shen

Andreas Busch

Taniqua S Day

Xing-Li Meng

Chun I Yu

Paulina Dabrowska-Schlepp

Benjamin Fode

Holger Niederkruger

Sabrina Forni

Shuyuan Chen

Raphael Schiffmann

Thomas Frischmuth

Andreas Schaaf

Affiliations

Soon will be listed here.

Abstract

Enzyme replacement therapy (ERT) is an effective treatment for several lysosomal storage disorders (LSDs). Intravenously infused enzymes are taken up by tissues through either the mannose 6-phosphate receptor (M6PR) or the mannose receptor (MR). It is generally believed that M6PR-mediated endocytosis is a key mechanism for ERT in treating LSDs that affect the non-macrophage cells of visceral organs. However, the therapeutic efficacy of MR-mediated delivery of mannose-terminated enzymes in these diseases has not been fully evaluated. We tested the effectiveness of a non-phosphorylated α-galactosidase A produced from moss (referred to as moss-aGal) in vitro and in a mouse model of Fabry disease. Endocytosis of moss-aGal was MR-dependent. Compared to agalsidase alfa, a phosphorylated form of α-galactosidase A, moss-aGal was more preferentially targeted to the kidney. Cellular localization of moss-aGal and agalsidase alfa in the heart and kidney was essentially identical. A single injection of moss-aGal led to clearance of accumulated substrate in the heart and kidney to an extent comparable to that achieved by agalsidase alfa. This study suggested that mannose-terminated enzymes may be sufficiently effective for some LSDs in which non-macrophage cells are affected, and that M6P residues may not always be a prerequisite for ERT as previously considered.

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