title: Differences in cleavage of globotriaosylceramide and its derivatives accumulated in organs of young Fabry mice following enzyme replacement therapy.
abstract: In Fabry disease, large amounts of globotriaosylceramide (Gb3) and related glycosphingolipids accumulate in organs due to a deficiency of α-galactosidase A (GLA) activity. Enzyme replacement therapy (ERT) with recombinant GLA is now available, and it has been reported that ERT is beneficial for patients with Fabry disease, especially those who start treatment at an early stage of the disease. However, it seems that the efficacy of ERT differs with each organ, and Gb3 accumulated in the kidneys shows resistance to ERT when it is started at a late stage. In this study, we examined the differences in cleavage of Gb3 isoforms, and lyso-Gb3 and its analogues in the kidneys, liver, and heart in young Fabry mice subjected to ERT. The results revealed that recurrent administration of recombinant GLA had prominent effects in terms of degradation of Gb3 and its derivatives accumulated in the organs. However, particular Gb3 isoforms, i.e., Gb3 (C20:0) and Gb3 (C24OH), accumulated in the kidneys largely escaped from degradation. Such Gb3 isoforms may gradually accumulate in the kidneys from a young age, which results in a reduction in the efficacy of ERT for Fabry disease.
authors.affiliation: Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsukimura
authors.affiliation: Laboratory of Biomembrane, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 113-0021, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawashima
authors.affiliation: Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
authors.affiliation: Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. Electronic address: tadayasu@my-pharm.ac.jp.
authors.forename: Tadayasu
authors.initials: T
authors.lastname: Togawa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004351:Drug Resistance; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D014281:Trihexosylceramides / Q000737:chemistry*; D000519:alpha-Galactosidase / Q000627:therapeutic use*
chemical_list: D007527:Isoenzymes; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase; C459420:agalsidase beta
keywords: Enzyme replacement therapy; Fabry disease; Globotriaosylceramide; Globotriaosylsphingosine; α-Galactosidase A; α-Galactosidase A knockout mouse