When the human genome was sequenced in 2000, it was hoped it would simplify the search for medicines – just compare the genome of someone with a disease to the healthy standard, identify the mutated gene, and develop a drug targeting that gene product.  It turned out disease states were much more complicated, usually involving a multitude of altered genes, or even in cases of one key mutation a multitude of altered gene up-regulation and down-regulation compensation responses. By now, however, increases in computer speed and efforts in AI-type approaches are starting to be capable of handling the complexity. In this paper, the authors applied sophisticated mathematical analysis to the genomic alterations found in epilepsy patients, specifically those genes involved in metabolism. They found that one of the most significant alterations points to an enzyme called dihydroorotate dehydrogenase (“DHODH” for short). There is a known inhibitor of DHODH – teriflunomide, a drug already approved for multiple sclerosis. The authors employed teriflunomide and found that it had an effect on a variety of firing and transmission behaviors of brain cells in culture. They further tried intracerebroventricular injections of teriflunomide into mice, and found that it reduced susceptibility to seizures (seizures induced by treatment with pentylenetetrazole, the “PTZ mouse model”, one of the most widely used animal seizure models). As for Dravet, the functional results with Dravet mice were a bit narrow – the threshold for seizures induced by temperature was raised to 38.6 degrees C in the teriflunomide-treated group from 37.0 degrees in the control group. While this may not light up DHODH as a major target for Dravet therapy, it is encouraging to see proposed targets from genomic analyses starting to be verified experimentally.

Styr et al. Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility. Neuron 2019 102, 1–16 doi.org/10.1016/j.neuron.2019.03.045