To provide an innovative drugs for treating rare disease patients.

Lysosomal acid-glycosidases are retaining exo-glucosidase responsible for the cleavage of the glycosidic bond of glycolipids to release ceramide and corresponding mono-sugars. Lysosomal disease is caused by mutations in the gene encoding lysosomal glycosidases and these mutations result in reduced cellular enzyme activity and the progressive accumulation of glycolipids in the macrophages, leading to various clinical manifestations that include hepatosplenomegaly, secondary hypersplenism, anemia, skeletal abnormality, neurologic dysfunctions. Many mutations in the gene have been reported which cause defects in transcription, translation, monomer folding and/or dimerization of lysosomal acid glycosidases. Enzyme replacement therapy (ERT) is the principal treatment for most of these diseases. However, these therapies are often complicated by immune responses to the enzymes. We focused that these mutant enzymes keep their kinetic properties, while their thermostabilities are obviously lower than wild-type enzyme at neutral PH condition. Based on these findings our teams group based around Prof. Fan, Ishii, and Asano advocated the theory of “pharmacological chaperone”. Pharmacological chaperones, such as substrate-like reversible competitive inhibitors, appear to be able to act as a template that stabilizes the native folding state in the ER by occupying the active site of the mutant enzyme, thus allowing its maturation and trafficking to the lysosome. The aim of our research was to provide general guidelines for the effective design of iminosugar-based pharmacological chaperone and to show their applicability to human disease treatment.