Chemical chaperone therapy: clinical effect in murine G(M1)-gangliosidosis.
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.
Suzuki
Yoshiyuki
Y
Graduate School, International University of Health and Welfare, Otawara, Japan. suzukiy@iuhw.ac.jp
Ichinomiya
Satoshi
S
Kurosawa
Mieko
M
Ohkubo
Masato
M
Watanabe
Hiroshi
H
Iwasaki
Hiroyuki
H
Matsuda
Junichiro
J
Noguchi
Yoko
Y
Takimoto
Kazuhiro
K
Itoh
Masayuki
M
Tabe
Miho
M
Iida
Masami
M
Kubo
Takatoshi
T
Ogawa
Seiichiro
S
Nanba
Eiji
E
Higaki
Katsumi
K
Ohno
Kousaku
K
Brady
Roscoe O
RO
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
D006595:Hexosamines; D018832:Molecular Chaperones; C116532:N-octyl-beta-valienamine; D001616:beta-Galactosidase