Severance Hospital researchers identify animal models best suited to each epilepsy type

Researchers have established objective criteria for selecting the animal model that best reflects the disease characteristics of individual patients with drug-resistant epilepsy.

A research team at Yonsei University College of Medicine compared brain tissue transcriptomes from humans and rodents to identify the most suitable animal model for each type of drug-resistant epilepsy, Severance Hospital said Thursday.

The study was led by early-career physician-scientists from Yonsei University College of Medicine's convergence physician-scientist training program. Kim Jun-ho, a clinical instructor in the Department of Neuroscience, and Lee Sang-bo, a researcher in the Department of Biomedical Systems Informatics, served as co-first authors. Kim Sang-woo, a professor in the Department of Biomedical Systems Informatics, and Kim Won-ju, a professor in the Department of Neuroscience, served as co-corresponding authors.

Drug-resistant epilepsy is a condition in which seizures cannot be controlled even with medication. Developing new treatments requires preclinical animal studies before therapies can be applied to humans.

However, objective criteria for determining which animal model best reflects the disease characteristics of actual patients have been lacking. Animal models have often been chosen based on a researcher's experience, leaving open the possibility that a model mismatched to a patient's specific epilepsy type could be used.

The team integrated 694 human brain tissue samples with 362 rodent brain tissue samples — from mice and rats — and conducted large-scale transcriptome analysis. The transcriptome is the complete set of genes expressed within a cell and is used to analyze disease characteristics at the molecular level.

The team then developed a systematic classification framework called SIALAP, which categorizes animal models across six criteria: species, method of epilepsy induction, route of drug administration, laterality, age and disease stage.

The study demonstrates that no single animal model can represent all patients with drug-resistant epilepsy — the appropriate model must vary according to each patient's disease characteristics. By matching animal models to patient subtypes, the research suggests preclinical findings are more likely to translate into effective treatments.

The analysis found that a mouse model in which kainic acid, an epilepsy-inducing agent, was injected into the hippocampus — the brain region responsible for memory — most accurately reproduced the condition of patients with drug-resistant epilepsy accompanied by hippocampal sclerosis, a form of the disease involving damage to hippocampal neurons.

By contrast, a rat model in which epilepsy was induced through repeated electrical stimulation of the hippocampus best reflected the condition of epilepsy patients without hippocampal sclerosis.

The research team said this is the first time different animal models have been confirmed at the molecular level to each represent a distinct type of epilepsy.

The study grew out of Yonsei University College of Medicine's convergence physician-scientist training program, which supports physicians who have completed clinical training after medical school as they enter biomedical research. Kim and Lee are both conducting drug development research as physician-scientists.

The findings were published in the latest issue of Nature Communications.