Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis.
We synthesized a galactose derivative, N-octyl-4-epi-beta-valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, beta-galactosidosis (GM1-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal beta-galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile GM1-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of GM1 and GA1 in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass biochemical analysis did not show the substrate reduction observed histochemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical chaperone therapy may be useful for certain patients with beta-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
Matsuda
Junichiro
J
Department of Veterinary Science, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
Suzuki
Osamu
O
Oshima
Akihiro
A
Yamamoto
Yoshie
Y
Noguchi
Akira
A
Takimoto
Kazuhiro
K
Itoh
Masayuki
M
Matsuzaki
Yuji
Y
Yasuda
Yosuke
Y
Ogawa
Seiichiro
S
Sakata
Yuko
Y
Nanba
Eiji
E
Higaki
Katsumi
K
Ogawa
Yoshimi
Y
Tominaga
Lika
L
Ohno
Kousaku
K
Iwasaki
Hiroyuki
H
Watanabe
Hiroshi
H
Brady
Roscoe O
RO
Suzuki
Yoshiyuki
Y
D000818:Animals; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D053138:Cyclohexenes; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D016537:Gangliosidosis, GM1 / Q000188:drug therapy* / Q000473:pathology*; D065089:Glycoside Hydrolase Inhibitors; D006595:Hexosamines / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D000520:alpha-Glucosidases / Q000172:deficiency / Q000235:genetics; D001616:beta-Galactosidase / Q000172:deficiency* / Q000235:genetics*
D053138:Cyclohexenes; D017931:DNA Primers; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D006595:Hexosamines; C030791:valienamine; D000520:alpha-Glucosidases; D001616:beta-Galactosidase