Identification and characterization of chaperone compounds for human beta-galactosidase deficiency

GM1-gangliosidosis i s a n a utosomal r ecessive l ysosomal s torage disease, caused by deficiency of lysosomal β-galactosidase (β-gal), encoded by the GLB1 gene. To date, more than 160 human GLB1 gene mutations has been identified i n patients w ith t his disease, an d ab out 7 0% o f t hem ar e m issense mutations. C hemical ( or p harmacological) ch aperone t herapy h as b een developed a s a ne w t herapeutic a pproach f or t he bran pathology of GM1gangliosidosis. This therapy employs small molecular compounds analogous to the substrate that can bind to and stabilize the mutant enzyme in affected cells. We ha ve i dentified t wo pot ential c haperone c ompounds, N-octyl-4-epi-βvalienamine ( NOEV) an d 5 N,6S-(N’-butyliminomethylidene)-6-thio-1deoxygalactonojirimycin ( 6S-NBI-DGJ), bot h of w hich i nhibit human β-gal. Both compounds could stabilize human β-gal in vitro and up-regulated residual activities of several beta-gal mutants in affected cells. Intriguingly, the profile of chaperone effects of 6S-NBI-DGJ on various mutants was different from that of NOEV, suggesting their effectiveness on di fferent ranges of β-gal mutants. When a dministrated or ally t o t he model mice, bot h c ompounds r eached t he brain by crossing the blood-brain barrier and attenuated brain pathology. These data i ndicate t hat bot h N OEV a nd 6S -NBI-DGJ ar e p otential ch aperone compounds w ith t herapeutic v alues for t he br ain pa thology o f GM1gangliosidosis.