Advanced human liver models for the assessment of drug-induced liver injury

Abstract

Drug safety issues continue to occur even with drugs that are approved after the completion of clinical studies. Drug-induced liver injury (DILI) is a major obstacle to drug development, because the liver is the primary site of drug metabolism, and injuries caused during this process are severe. Conventional in vitro human liver models, such as 2-dimensional hepatic cell lines, lack in vivo physiological relevance, and animal studies have limitations in the form of species differences and regulatory restrictions. To resolve this issue, an increasing number of 3-dimensional human liver systems, including organoids, are being developed. In this review, we provide an overview of recent assessments of DILI prediction, approaches for in vitro hepatotoxicity evaluation, and a variety of advanced human liver models. We discuss the advantages, limitations, and future perspectives of current human liver models for accurate drug safety evaluations.

Genome editing for engineering stem cell-derived pancreatic β cells: recent trends and future perspectives

“…In an early study aimed to model type 2 diabetes-associated genetic variants identified through GWASs, Zeng et al [71] used CRISPR/Cas9 to knock out the CDKAL1, KCNQ1, or KCNJ11 genes in ESCs. These specific genes were chosen since they are known to be associated with β-cell function rather than insulin resistance in peripheral tissues, making them suitable candidates for investigation using SC-β cells.…”

“…As T5224 is an inhibitor of the FOS/JUN activator protein-1, they further investigated the role of the FOS/JUN pathway in β-cell dysfunction. Interestingly, the CRISPR-based knock-out of FOS was found to enhance GSIS in vivo [71].…”