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-vali...

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Bibliographic Details
Published in:Annals of neurology 2007-12, Vol.62 (6), p.671-675
Main Authors: Suzuki, Yoshiyuki, Ichinomiya, Satoshi, Kurosawa, Mieko, Ohkubo, Masato, Watanabe, Hiroshi, Iwasaki, Hiroyuki, Matsuda, Junichiro, Noguchi, Yoko, Takimoto, Kazuhiro, Itoh, Masayuki, Tabe, Miho, Iida, Masami, Kubo, Takatoshi, Ogawa, Seiichiro, Nanba, Eiji, Higaki, Katsumi, Ohno, Kousaku, Brady, Roscoe O
Format: Article
Language:English
Subjects:
Animals
beta-Galactosidase - deficiency
beta-Galactosidase - genetics
beta-Galactosidase - metabolism
Brain - metabolism
Gangliosidosis, GM1 - drug therapy
Gangliosidosis, GM1 - metabolism
Gangliosidosis, GM1 - physiopathology
Hexosamines - pharmacokinetics
Hexosamines - therapeutic use
Humans
Immunohistochemistry
Kidney - metabolism
Liver - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Molecular Chaperones - pharmacokinetics
Molecular Chaperones - therapeutic use
Mutation
Nervous System - drug effects
Nervous System - metabolism
Nervous System - physiopathology
Osmolar Concentration
Tissue Distribution
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Summary: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.
ISSN:1531-8249
DOI:10.1002/ana.21284