08 Sep Polygenic Diagnostic Testing Helps Determine Risk of Drug Induced Liver Disease
MedicalResearch.com Interview with:
Takanori Takebe MD
Director for Commercial Innovation, Center for Stem Cell and Organoid Research and Medicine (CuSTOM)
Assistant Professor, University Cincinnati
Department of Pediatrics, Cincinnati Children’s
Professor, Institute of Research
Tokyo Medical and Dental University, Japan
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Drug induced liver injury (DILI) is rare yet highly unpredictable disorder that oftentimes causes drug failure withdrawn from the market during clinical trial even at a very rare incidence of DILI (1/10,000). Indeed, one particular drug TAK875 (Fasigliam) was the case despite promising efficacy. This not only disappoints patient but impact significant financial risk to pharmaceuticals.
In collaboration with DILI genomics consortium at US, EU and UK, we’ve found +20,000 genetic make up (variants) defines potential risk of developing Drug induced liver injury thru amplifying cellular stress signal cascades that were investigated by human cell, organoid and patient datasets.
MedicalResearch.com: What should readers take away from your report?
- Pharmaceutical preclinical screen byin vitro high risk human organoid testing may increase success probability of clinical trial by minimizing DILI risk.
- Polygenic genetic diagnostic testing might inform individual’s risk of Drug induced liver injury caused by medications.
- Drug induced cell stress signal cascades might be a potential druggable target against drug induced liver injury.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
1. For drug development purpose, the established cell or organoid based experimental screen system would be most informative yet need a third-party validation.
2. For genetic testing, we need more people (different ethnicity for example) to be engaged and analyze efficacy of prediction prospectively.
3. For DILI drug, we’ve highlighted some clinically active compound such as Bardoxolone methyl is effective in mitigating DILI phenotype in a dish. If this is proven in human, this drug can be repurposed for the DILI prevention.
Koido, M., Kawakami, E., Fukumura, J. et al. Polygenic architecture informs potential vulnerability to drug-induced liver injury. Nat Med (2020). https://doi.org/10.1038/s41591-020-1023-0
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