LIVER-IN-A-DISH SCREENING SERVICE: ASSESSING DRUG SAFETY IN AFRICAN POPULATIONS

Drug regimens have not been optimised for individuals of African descent. This is due to several converging factors, including Africa’s diverse genetics, disproportionate disease burdens (and consequently a high dependency on specific drug regimens), as well as under-representation of local population groups in clinical trials. Consequently, adverse drug reactions are responsible for one in 12 people being admitted to hospital in South Africa, where hospital services account for approximately  R125 billion in healthcare spending annually. The South African Health Products Regulatory Authority (SAHPRA) is responsible for assessing and approving all potentially marketed drugs based on, among other key features, efficacy and safety data from clinical trials. However, understanding the magnitude of impact, which observed adverse drug reactions may have within a specific population, and evaluating previously unreported adverse drug reactions during postmarketing surveillance, is a challenge because clinical trials predominantly enrol Caucasian populations (from Europe and North America). South Africa encompasses vast genetic diversity (including within the liver drug metabolising genes, thus impacting best treatment outcomes), consequently, there is limited preclinical or clinical data to support data-driven decision-making for drug approval and marketing. Therefore, innovative tools that contribute to evidence-based decision-making, in the context of optimised drug regimens, are needed on the continent. Such a tool must be inexpensive, reproducible, physiologically functional (i.e., act like our liver cells) and contain African-relevant genetic variants of interest.

Combining synthetic biology tools, including induced pluripotent stem cell technology and CRISPR genome engineering – a technique in which a specific sequence of DNA can be precisely modified inside a cell – the CSIR has created a nano-scale cellular tool that mimics liver metabolism of drugs, inclusive of African genetic diversity. CSIR researchers demonstrated functionality of this bioengineered liver-in-a-dish using liquid chromatography tandem mass spectrometry, the gold standard for assessing drug metabolism. Using this method, the CSIR team was able to confirm the metabolism of the sedative drug, midazolam, in the liver-in-a-dish model as occurs within cells in the human liver. This indicates that a key phase I metabolising gene, CYP3A4, is functional in the CSIR-developed African liver-in-a-dish. The gene is responsible for the metabolism of 50% of the drugs on the market, including drug classes such as antidepressants, antipsychotics, antihypertensives and painkillers. The technology therefore, provides a significant degree of confidence to pursue the development of the technology to a minimum viable product within the next two years. The innovation makes it possible to understand how individuals of African descent might metabolise new drugs and to understand adverse drug reactions in diverse populations.