The relevancy of mouse models to human disease can be a harbinger of success for clinical trials.
However, the inherent differences in the types and levels of genes expressed in mice and humans is one of the main reasons clinical trials fail, note researchers in a report recently published in Stem Cell Reports.
To further examine the translational difficulties of research in mice to humans, specifically for Multiple Sclerosis (MS) research, the University at Buffalo researchers performed gene-expression analysis on differentiating human oligodendrocyte progenitor cells (OPCs) – a subtype of glial cells in the central nervous system.
“Currently, there is a large effort directed at the induction of oligodendrocytes by promoting differentiation Fraser Sim, PhD, associate professor, Neuroscience, Pharmacology and Toxicology, GGB, at the University at Buffalo told us. “[The research’s] results provide a resource to compare the pharmacological targets across species in an unbiased manner.”
The research was initiated to define similarities and differences between oligodendrocyte progenitor cell (OPC) differentiation in the human brain and in rodents, Sim noted.
“The rationale being that we need to model pathways and therapeutic targets that have the potential to work in humans and without this knowledge promising results in mouse studies may fail in the clinical setting due to these species differences,” he added.
Results from the research form a database that Sim and others will use to determine whether genes of interest are shared between species, “and are expressed in a manner consistent with a role in both human and rodent OPC differentiation,” Sim explained.
Target identification and the BIA 10-2474 tragedy
The challenge of comparing pharmacological targets across species was also recently highlighted in the research following the Biotrial-run clinical trial of Bial Laboratory’s molecule, BIA 10-2474
The molecule was developed to inhibit the activity of fatty acid amide hydrolase (FAAH), an enzyme that when inhibited results in the accumulation of fatty acid amides.
However, an international group of researchers was able to determine that high doses of the molecule inhibited other related proteins. Steven Kushner from the Department of Psychiatry, Erasmus MC, and research lead, told us previously that the Bial compound had many other targets, in addition to FAAH and FAAH II.
“Our brain is dramatically different from that of animals,” he said, explaining there is reasons to believe that the cause of toxicity may be specific to humans, or at least distinct from the animals used in preclinical testing.
Ultimately, the researchers weren’t able to conclusively determine if the off-target proteins were the cause of the adverse events in the BIA 10-2474 clinical trial, but Kushner stressed the simple fact that human biology is inherently different from animals.