Discovery of novel compounds regulating traffic to lysosomes and application for development of therapeutics

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We studied on intracellular traffic abnormality in lysosomal beta-hexosaminidase (Hex) deficiencies including Tay-Sachs disease (TSD) and Sandhoff diseases (SD) to develop novel enzyme replacement therapy based on techniques to promote delivery of recombinant Hex to lysosomes when extracellularly administrated. We developed modified Hex with high content of mannose 6-phospahte (M6P) residues, which were efficiently incorporated by disease-model cultured cells via cell surface M6P receptors. In addition, we established an iPS cell line derived from a TSD patient, and examined conditions under which neural cells including neural stem cells (NSC) and neural progenitor cells (NPC) could be induced from the TSD iPS cells. Furthermore, we developed novel fluorescent probes including Rhodol beta-GlcNAc as an artificial substrate for intracellular Hex activity and acidic pH-activatable fluorescent Rh-PM for in vivo imaging to detect lysosomal distribution of recombinant Hex.