Chemical chaperone therapy for brain pathology in GM1-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 (G(M1)-gangliosidosis and Morquio 8 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 NOW to a model mouse of juvenile G(M1)-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 G(M1), and G(A1) 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-gal-actosidosis and potentially other lysosomal storage diseases with central nervous system involvement.