Toxicity – JoinCells

Toxicity is one of the most common reasons for manufacturers to withdraw drugs and for health organisations to refuse the approval of new drugs. Sometimes as many as one-third of all drugs fail clinical trials because of toxicity. Current toxicity tests are complicated and some even use chemicals that kill the cells, so that researchers have to use a number of different cell cultures during a study, which affects the result. Another challenge is that although traditional animal and cell models stimulate human disease, they never fully mirror all aspects of human immune response. That is why new, more clinically relevant models have to be created to properly assess the safety and risks of potential drugs for humans.

In our pre-clinical toxicity models, human embryonic stem cells (hESCs) are differentiated towards different cell types (neurons, hepatocytes, enterocytes, etc) and aslo in tissue-specific organoids. Such non-diseased cellular models have great advantage over current cell based toxicity tests in cell-type specific relevance. In addition, we are developing hESCs with deletion of genes that are responsible for the majority of drug metabolism, for example, CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2. These cellular pre-clinical models of drug metabolism are of great importance in determining how drugs are metabolised, if there are inhibitors or inducers of some enzymes of drug metabolism. This aspect is very relevant because according to the USA FDA 20% of patients who die in USA hospitals are the product of the adverse effects of drugs in which a drug potentiates or inhibits a drug metabolising enzyme, generating fatal effects.

We are also currently developing co-culture protocols. Co-cultures with hepatic cells and target cells separated by a microfluidic channel can simulate the toxicity effects on selective target cells of different drugs after liver metabolism.