Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis.

Abstract

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.

• Authors: Junichiro Matsuda, Osamu Suzuki, Akihiro Oshima, Yoshie Yamamoto, Akira Noguchi, Kazuhiro Takimoto, Masayuki Itoh, Yuji Matsuzaki, Yosuke Yasuda, Seiichiro Ogawa, Yuko Sakata, Eiji Nanba, Katsumi Higaki, Yoshimi Ogawa, Lika Tominaga, Kousaku Ohno, Hiroyuki Iwasaki, Hiroshi Watanabe, Roscoe O Brady, Yoshiyuki Suzuki
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 26 Pg. 15912-7 (Dec 23 2003) ISSN: 0027-8424 [Print] United States
• PMID: 14676316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclohexenes
• DNA Primers
• Enzyme Inhibitors
• Glycoside Hydrolase Inhibitors
• Hexosamines
• valienamine
• alpha-Glucosidases
• beta-Galactosidase

Topics

• Animals
• Brain (pathology)
• Cells, Cultured
• Cyclohexenes
• DNA Primers
• Enzyme Inhibitors (therapeutic use)
• Fibroblasts (drug effects, physiology)
• Gangliosidosis, GM1 (drug therapy, pathology)
• Glycoside Hydrolase Inhibitors
• Hexosamines (therapeutic use)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Polymerase Chain Reaction
• alpha-Glucosidases (deficiency, genetics)
• beta-Galactosidase (deficiency, genetics)