title: Mannose receptor-mediated delivery of moss-made α-galactosidase A efficiently corrects enzyme deficiency in Fabry mice.
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.
authors: Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA. Jinsong.Shen@baylorhealth.edu.
authors: Jin-Song
authors: JS
authors: Shen
authors: Greenovation Biotech GmbH, Freiburg, Germany.
authors: Andreas
authors: A
authors: Busch
authors: Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA.
authors: Taniqua S
authors: TS
authors: Day
authors: Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA.
authors: Xing-Li
authors: XL
authors: Meng
authors: Baylor Institute for Immunology Research, Dallas, TX, 75204, USA.
authors: Chun I
authors: CI
authors: Yu
authors: Greenovation Biotech GmbH, Freiburg, Germany.
authors: Paulina
authors: P
authors: Dabrowska-Schlepp
authors: Greenovation Biotech GmbH, Freiburg, Germany.
authors: Benjamin
authors: B
authors: Fode
authors: Greenovation Biotech GmbH, Freiburg, Germany.
authors: Holger
authors: H
authors: Niederkrüger
authors: Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA.
authors: Sabrina
authors: S
authors: Forni
authors: Baylor Research Institute, Dallas, TX, 75226, USA.
authors: Shuyuan
authors: S
authors: Chen
authors: Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA.
authors: Raphael
authors: R
authors: Schiffmann
authors: Greenovation Biotech GmbH, Freiburg, Germany.
authors: Thomas
authors: T
authors: Frischmuth
authors: Greenovation Biotech GmbH, Freiburg, Germany.
authors: Andreas
authors: A
authors: Schaaf
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy / Q000379:methods; D000795:Fabry Disease / Q000201:enzymology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008360:Mannosephosphates / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins; D000519:alpha-Galactosidase / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C000627036:agalsidase alfa; C027693:mannose-6-phosphate; D000519:alpha-Galactosidase