A study of the new therapeutic method and the clinical application for central nervous involvement in inherited metabolic diseases.

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The chemical chaperon therapy for inherited metabolic diseases including GM1-gangliosidois have been developed in the study. GM1-gangliosidosis which caused by deficiency of β-galactosidase in lysosome, is manifested by central nervous involvement. A new therapeutic method have been developed in the study. Initially more than 27 types of murine model cells containing human β-galactosidase mutation have been created. A galactose derivative, N-octyl-4-epi-β-valienamine (NOEV), which is a potent inhibitor of lysosomal β-galactosidase in vitro, was synthesized. Addition of NOEV in the culture medium restored mutant enzyme activity in murine model cells, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile GM1gangliosidosis resulted in significant enhancement of the enzyme activity in the brain and other tissues. Chemical chaperon therapy may be useful for certain patients with GM1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement.