Scientists from the University of California, Riverside, have developed a molecule that increased survival in mouse models of amyotrophic lateral sclerosis (ALS). The candidate targets a gene previously found to affect the onset and progression of the neurodegenerative disease.
In 2012, a team led by the University Hospitals Leuven in Belgium identified the gene EphA4 as a potential target for ALS treatment. They examined more than 3,000 ALS patients and found that individuals with lower levels of EphA4 tended to have later disease onset and survive longer than those with higher levels.
But until now, no research has turned up an EphA4-targeting agent that was effective in animal models of ALS, Maurizio Pellecchia, a professor of biomedical sciences, said in a statement.
The UC Riverside team, led by Pellecchia, developed a molecule to target the EphA4 receptor. Their work was based on the idea that blocking the gene with an antagonist would prolong survival.
But it turned out that the molecule, one of more than 100,000 candidates, increased the mice’s survival by acting as an agonist rather than an antagonist—promoting a chemical action rather than blocking one.
“We show that 123C4 interacting with EphA4 causes the receptor to be internalized by a process known as endocytosis—a process initiated only by an agonist. We hypothesize that by inducing receptor internalization, 123C4 effectively removes EphA4 from the surface of motor neurons,” Pellecchia said in the statement.
The researchers plan to develop more molecules based on 123C4 for testing in motor neurons and in animal models of ALS, according to the statement. And while the road from mouse models to the clinic will be difficult, Pellecchia’s team is not alone: San Diego-based Iron Horse Therapeutics is working on translating this class of drugs into the clinic, he said. GlaxoSmithKline and Avalon Ventures launched Iron Horse, which was founded based on Pellecchia’s work, in 2015.
While the current research focused on ALS, the expression of EphA4 is also linked to abnormal blood clotting, spinal cord and brain injury, Alzheimer’s disease and gastric and pancreatic cancers. Therefore the researchers believe that 123C4 could have applications in human disorders beyond ALS.