Abstract
In pharmaceutical development, developmental toxicity tests using animals to assess impacts on embryos and fetuses are essential, as clinical trials present significant challenges. These tests require substantial investments of time, effort, and resources due to species differences. Some drugs, like thalidomide, do not affect rodents but cause severe malformations in humans. Moreover, the specificity of new modalities, such as nucleic acid therapeutics, toward human complicates safety assessment through traditional animal testing. Addressing this urgent issue necessitates the development of high-throughput, accurate in vitro methods capable of precisely predicting developmental impacts. Our research has developed a developmental toxicity evaluation method using human iPSCs, focusing on the disruption of signal transduction by chemical substances (DynaLux/c). This method has demonstrated high accuracy and comprehensive coverage in detecting developmental toxicants, particularly through analyzing dynamic changes in FGF-SRF signal disruption by a 24-hour live-cell luciferase assay.
Currently, we have enabled continuous detection of dynamic signal disruptions by incorporating a real-time luminescence measurement device with cell culturing capabilities into DynaLux/c. This integration significantly reduces testing time to one week and allows for detailed analysis. Additionally, we've also established the Wnt-TCF/LEF signal disruption reporter system, like the FGF signal. Now, we're attempting to elucidate the molecular mechanisms of DynaLux/c detecting developmental toxicity.
