Development of a new molecular therapeutic drug for brain pathology in lysosomal storage diseases

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We synthesized a novel galactose derivative, N-octyl-4-epi-β-valienamine(NOEV), for a new molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, β-galactosidosis (G_<M1>-gangliosidosis and Morquio B disease). It has a molecular structure analogous to galactose ; molecular weight is 287.40. It is stable at room temperature, and has limited solubility in water (up to 5 mM), but freely soluble in methanol or dimethylsulfoxide. It is a potent competitive inhibitor of lysosomal (β-galactosidase in vitro. IC50 is 0.2 μM. 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. We collected 50 fibroblast strains from β-galactosidase deficiency disorders from all over the world, for testing the NOEV effect in the culture system. More than 3-fold increase was observed in 35% of them. The effect was most prominent in mutations causing juvenile G_<M1>-gangliosidosis, and less effective to those causing infantile or adult G_<M1>-gangliosidosis. So far Morquio B cells did not respond significantly in this assay system. We have established a method of NOEV determination in tissues and blood, and started mouse experiments by oral administration of this compound. Chemical chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.