title: Chemical chaperone therapy: clinical effect in murine G(M1)-gangliosidosis.
abstract: Certain low-molecular-weight substrate analogs act both as in vitro competitive inhibitors of lysosomal hydrolases and as intracellular enhancers (chemical chaperones) by stabilization of mutant proteins. In this study, we performed oral administration of a chaperone compound N-octyl-4-epi-beta-valienamine to G(M1)-gangliosidosis model mice expressing R201C mutant human beta-galactosidase. A newly developed neurological scoring system was used for clinical assessment. N-Octyl-4-epi-beta-valienamine was delivered rapidly to the brain, increased beta-galactosidase activity, decreased ganglioside G(M1), and prevented neurological deterioration within a few months. No adverse effect was observed during this experiment. N-Octyl-4-epi-beta-valienamine will be useful for chemical chaperone therapy of human G(M1)-gangliosidosis.
authors.affiliation: Graduate School, International University of Health and Welfare, Otawara, Japan. suzukiy@iuhw.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichinomiya
authors.forename: Mieko
authors.initials: M
authors.lastname: Kurosawa
authors.forename: Masato
authors.initials: M
authors.lastname: Ohkubo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takimoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Miho
authors.initials: M
authors.lastname: Tabe
authors.forename: Masami
authors.initials: M
authors.lastname: Iida
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kubo
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ogawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D016537:Gangliosidosis, GM1 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D006595:Hexosamines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009154:Mutation; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D009994:Osmolar Concentration; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D006595:Hexosamines; D018832:Molecular Chaperones; C116532:N-octyl-beta-valienamine; D001616:beta-Galactosidase