Induced pluripotent stem cells (iPSCs) can be derived from mature differentiated cells by expression of particular pluripotency genes. The application of iPSC-derived cells in toxicity testing and drug development represents the most advanced and practical use of pluripotent stem cells.
The development of new drugs is very complex, expensive, and time-consuming process where more than 90% of drug candidates fail in clinical trials due to issues of safety and efficacy. Conventional drug discovery and development rely on traditional, expensive, animal (in vivo) models. However, such models rarely mirror the human disease pathological mechanism. Moreover, certain chemicals predicted to be safe from animal studies induce birth defects or serious toxicity in humans. Thus, animal models alone are unreliable for understanding human disease and for screening drug candidates. New test methods should not only be more predictive, but also faster, cheaper, and minimize the use of animals. Disease-specific iPSCs can provide a renewable source of patient-specific cells with genetic background sensitive to disease pathology. Research on iPSCs promises to enhance drug discovery and development by providing tools for drug toxicity screening under development.
iPSCs do not only play a role in bringing hope for a generation of replacement cells for transplantation therapies but also in preclinical toxicity testing for the benefit of patients with neurodegenerative, cardiovascular, and liver diseases. In the context of existing iPSC-derived in vitro model, such as animal iPSCs, and ESCs, human iPSCs provide advantages that can enhance the current approaches to drug discovery.
Fig.1 iPSCs and their potential for toxicity testing and drug screening. (Csobonyeiova, 2016)
Cardiovascular toxicity is a major cause of drug withdrawal during clinical development, accounting for up to 33% of drug failure. It can lead to the formation of reactive oxygen species (ROS), apoptosis, altered contractibility, change in cardiac rhythm, and changed cardiac gene expression. More feasible implementation of iPSCs in drug toxicity testing at this time is on large grids and assayed for toxicity in a manner analogous to high-throughput screens for drug discovery. Using this approach, iPSC technology can be integrated into the current paradigm for drug development as part of safety testing in the early phases of clinical trials. Human iPSC-CMs recapitulate many of the in vivo cardiomyocytes functions and maybe an ideal system for assessing multiple facets of toxicity.
Drug-induced liver injury (DILI) is a severe pathological condition belonging to the most frequent reasons for withdrawal from the market of approved drugs. DILI represents the major cause of acute liver failure and liver transplantation in Western countries. Thus, several new drugs need to be efficiently screened every year to estimate their potential for toxicity. Human iPSC-derived hepatocytes show great promise because of their ability to have a primary tissue-like phenotype, consistent and unlimited availability, and potential to establish genotype-specific cells from different individuals. These reasons make iPSCs an exciting alternative in vitro model system to explore the role of genetic diversity in DILI. Several assays have been developed for measuring general and mechanism-specific hepatotoxicity up to now.
Fig.2 Prediction of the intrinsic drug-induced liver using human ES/iPS-HLCs. (Takayama, 2017)
It is widely believed that for most neurodegenerative diseases, there are no effective therapies, partly because of the limited understanding of the mechanism of these disorders. The iPSC technology is useful not only for understanding the mechanism of reprogramming but also for identifying and suggesting therapies targeting disease course well before cell death and clinical symptoms emerge, which could result in greater success in clinical trials. In the last decade, there are increasing concerns about neurotoxicity induced in humans by exposure to chemicals. Perhaps one of the most powerful applications of iPSCs in the field of neurotoxicology is the ability to assess the response of neurons and neural progenitors to various toxicants. In vitro neuronal differentiation of human iPSCs enables assessment of the interaction between early exposure and subsequent risk of neurodegenerative phenotypes in response to acute, chronic, latent toxicant exposure paradigms.
At this point, the use of iPSCs in drug screening is in its beginning, and progress toward the development of a standardized screening system is still being developed. Devoted to stem cell research for years, Creative Biolabs provides high-quality iPSC services including but not limited to ipsc genome editing, reprogramming, and culture to global customers. Please feel free to contact us for more information.
References
For Research Use Only. Not For Clinical Use.
