It has been shown that glycans are pivotal in development, homeostasis, inflammation, immunity and cancer. Given the essential roles in cell-cell and cell-matrix communications, glycans are greatly involved in not only congenital disorders but also various acquired diseases. For instance, the roles of
- Selectins in inflammation including reperfusion injury, atherosclerosis, atopic dermatitis, bronchial asthma and acute respiratory distress syndrome,
- Glycosaminoglycans in inflammation in osteoarthritis, rheumatoid arthritis, psoriasis, scleroderma and inflammatory bowel disease
- N-linked glycans in tumor growth, invasion, angiogenesis and metastasis
- O-linked glycan in diabetes, IgA nephropathy and Alzheimer’s disease
have all been reported.
Since almost all human proteins are modified by the post-translational addition of complex carbohydrate chains, they would be excellent targets for the 21st century’s drug development programs. However, in vivo modification of carbohydrate chains is not a trivial task and represents a relatively unexplored area for drug development compared with other molecules. To overcome this, Stelic Institute & Co. strategically regulates glycogene expression to achieve successful modification of carbohydrate chains in vivo.
‘Glycogene’ is term for a gene involved in glycosylation of proteins, lipids and proteoglycans. Glycogenes include the genes for 1) glycosyltransferases, 2) sulfotransferase, 3) glycolytic enzymes, 4) sugar nucleotide synthetases, 5) sugar nucleotide transporters and 6) sugar chain-recognizing molecules like lectins. Over 180 glycogenes have been cloned and their functions are now under investigations using KO mice etc. as part of the national project.
Instead of direct chemical modification of carbohydrate chains, Stelic Institute & Co. has extensively investigated the role of recently cloned various glycogenes in multiple fibrosis disease models using a comprehensive RNAi. We have succeeded in discovering a regulatory glycogene family, which we have designated as the “G family”, encompassing novel therapeutic targets for the treatment of fibrosis. Identified targets are also validated in mouse and rat disease models by Stelic scientists and external collaborators using several series of RNAi.
Since the extent of glycogene expression is relatively weak compared to other molecules, high dose injection is not required to achieve effective blocking. In addition, distinct glycogenes are up-regulated by distinct tissues according to local disease conditions. Therefore, selective blockade of a site-specific glycogene does not inhibit the actions of distinct glycogenes of other intact tissues, indicating that glycogene-based therapy is effective with low incidence of side effects.
