Advantages
- Avoiding the risk of teratoma formation in cell transplantation therapy using pluripotent stem cells (PSC) as a cell source.
- Some DHODH inhibitors are used clinically as immunosuppressants, etc.
Background and Technology
For establishing PSC-based regenerative medicine, it is necessary to develop methods that eliminate any contaminating undifferentiated PSCs in the differentiated cell fraction.
We have previously identified new inhibitor for DHODH, an essential enzyme in the de novo pyrimidine synthesis pathway, which specifically killed glioblastoma-initiating cells, using a drug screening and also demonstrated that several DHODH inhibitors, including Brequinar (BRQ), selectively killed mouse PSCs, embryonic stem cells and iPSCs. We further showed that BRQ and another DHODH inhibitor ASLAN could eliminate human iPSCs at low concentration. Notably, the inhibitors showed little cytotoxicity to either tissue-specific stem cells, mouse neural stem cells and human iPSC-derived mesenchymal stem cells (iMSCs), or their differentiated cells. Given that DHODH inhibitors have been approved and are under clinical development as immunosuppressants, infectious disease treatments, and anticancer agents, our data suggest that DHODH inhibitors are critical and immediately available chemicals for promoting PSC-based regenerative therapies.
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Patents and References
- Patent pending: WO2020/130077 (Applicant: Hokkaido University)
- Echizenya et al., Neuro Oncol 2020
- Kondo, Stem Cells 2021
- Alakashi et al., Front Cell Dev Biol 2023
Principal Investigator
Toru KONDO, Prof. (Institute for Genetic Medicine, Hokkaido University)
Current Stage using Human iPS cells and Next Step
- It has been confirmed that BRQ selectively kills undifferentiated human iPS cells without affecting the differentiation process of iMSCs into adipocytes, osteoblasts, and chondrocytes.
- We are looking for companies that further develop and commercialize this technology by themselves for regenerative medicine and drug development using iPS cells.
- This research is being carried out with the cooperation of Makoto Ikeya, Assoc. Prof. Center for iPS Cell Research and Application (CiRA), Kyoto University.
Project No. BK-04736