Experimental drug BIA 10-2474 deactivates proteins in human nerve cells
hDMT researchers publish article in Science on safer drug testing using human cellular models
hDMT researchers co-authored an article in Science on the effects of the chemical BIA1 10-2474 on human nerve cells. In 2016 in a clinical trial with this drug in Rennes, France, serious adverse events occurred affecting five participants, including the death of one man. The article shows that the effects and side effects in humans of a new drug like this cannot always be predicted by animal testing. The researchers stress the importance of using and developing new human cellular models before testing drugs in humans. Models like these are developed in the Netherlands in the Organ-on-Chip Consortium hDMT.
At high doses, drug candidate BIA 10-2474 binds not only to the protein that it targets, but to other proteins as well. It thus deactivates proteins that are involved in the metabolism of nerve cells. This is what an international group of researchers from Leiden University and Erasmus MC, among others, write in Science (9 June).
The researchers, led by Mario van der Stelt (Leiden Institute of Chemistry) and Steven Kushner (Department of Psychiatry, Erasmus MC), defined the action profile of BIA 10-2474, an experimental drug that is intended to treat chronic pain.
Unexpected side effects
Before new drugs are approved, they undergo extensive animal and human testing to prove their safety and efficacy. In January 2016, during a clinical study of BIA 10-2474, a test subject died as a result of brain damage and four others were hospitalized with mild to severe neurological symptoms.
Although the exact cause of these serious side effects is not yet known, the French authorities did have a suspicion. BIA 10-2474 inhibits the activity of FAAH, a protein that plays a role in the sensation of pain in the body. The French authorities suspected that high doses of BIA 10-2474 inhibited not only FAAH but also one or more other proteins that are related to FAAH. However, it was not known which proteins these were.
Advanced biochemical methods
The international research group used advanced biochemical methods, including activity-based protein profiling, to determine the proteins to which the candidate drug reacts. In addition to FAAH, they identified other proteins that were permanently deactivated following the administration of a high dose of BIA 10-2474. These proteins are involved in the metabolism of fats in nerve cells. This was confirmed by further tests on human nerve cells. Genetic defects in one of the proteins that was found, PNPLA6, had already previously been linked to human neurodegenerative disorders.
Mario van der Stelt concludes: 'Our results show that BIA 10-2474 is not selective at high doses and deactivates multiple proteins. This disrupts the metabolism of human nerve cells. From our data, we cannot yet conclude that this was the reason for the fatal outcome of the clinical study. Further research is needed, but our results do give us important new clues for where to look.'
Recommendation for future drugs research
Kushner: 'The safety testing in animals of BIA 10-2474 were not successful in predicting the side effects in humans. This underscores the importance of expanding drug testing to include new human cellular models that are better able to determine the safety profile of experimental drugs.' Van der Stelt adds: 'When developing new drugs that permanently deactivate proteins, their detailed action profile needs to be determined at an early stage. This allows you to make a better assessment of the maximum dose of a candidate drug.'
Annelot van Esbroeck and Anthe Janssen, PhD candidates in Van der Stelt's research group, researched the action profile of BIA 10-2474 together with researchers from Erasmus MC and three international groups of researchers. These included the group headed by Ben Cravat at the Scripps Research Institute in the United States. It was Cravat who discovered the enzyme FAAH.
The research was funded in part by an ECHO grant from NWO Chemical Sciences.
- - Abstract of the Science article Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474
- - New clues to why a French drug trial went horribly wrong (Science)
- - Wikipedia on BIA 10-2474
- - press release Leiden University
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