The Changing Paradigm in Preclinical Toxicology: in vitro and in silico Methods in Liver Toxicity Evaluations

Authors

Fozia Noor, Université du Luxembourg

Document Type

Book Chapter

Publication Date

2019

Abstract

In vitro methods, based on human primary cells, cell lines, and genetically modified reporter cell lines, have greatly expanded the scope of in vitro toxicology. Other significant progress in the area of human-induced pluripotent stem cells (hiPSCs) (Asgari et al., 2010; Schwartz et al., 2014; Shinde et al., 2016; Shtrichman, Germanguz and Itskovitz-Eldor, 2013) is allowing the application of patient and disease-specific hiPSCs (Ghodsizadeh et al., 2010; McCracken et al., 2014; Siller et al., 2013). Moreover, the tools of precise genome editing with engineered nucleases, such as the zinc finger nucleases (zfns), the transcription activator-like effecter nucleases (talens) and, more recently, the Clustered Regularly Interspaced Short Palindromic Repeats (crispr) associated Cas9 technology (Gaj, Gersbach and Barbas, 2013; Kim, 2016; Komor, Badran and Liu, 2017) have opened up tremendous opportunities for the development of cell lines, especially those of human origin (Tobita, Guzman-Lepe and de L’Hortet, 2015). crispr/Cas9 technology was reported for genome editing in hiPSCs (Flaherty and Brennand, 2015; Li et al., 2014; Seah et al., 2015; Suzuki et al., 2014). Another study reported on the simultaneous reprogramming and gene correction of patient fibroblasts (Howden et al., 2015). Since 2015, more than 3,000 articles were published on studies using crispr/Cas9 genome editing, including more than 900 articles using the technology in mammalian cells (PubMed, accessed June 11, 2017). With further technological developments, these human in vitro cellular models shall be highly useful in the screening of compounds for personalized medicine, allowing optimum therapy with minimum or no adverse effects, and in the study of adverse outcomes in different strata of population. In addition to high-content screening, where several parameters are measured as simultaneous readouts in single cells (Gasparri, 2009), high-content imaging will play an important complimentary role in systems biology approaches (van Vliet et al., 2014). High-content platforms have been already used for the screening of compounds (Bale et al., 2014; Sirenko et al., 2014; Tolosa et al., 2014).

Comments

open access book chapter

Recommended Citation

Noor, F. (2019). The changing paradigm in preclinical toxicology: in vitro and in silico methods in liver toxicity evaluations. In Animal Experimentation: Working Towards a Paradigm Change (pp. 610-638). Brill.