期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：26
页码：15912-15917
DOI：10.1073/pnas.2536657100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
