A framework has been established to objectively select animal models that most accurately reflect different types of patients with drug-resistant epilepsy. The findings are expected to improve the accuracy and success rate of preclinical research for new drug development.
A research team involving Kim Jun-ho, a clinical fellow in the Department of Neurology, and Lee Sang-bo, a researcher in the Department of Biomedical Systems Informatics at Yonsei University College of Medicine, has identified suitable animal models for different types of drug-resistant epilepsy by comparing genetic information from humans and animals, Yonsei University College of Medicine said on Aug. 6.
Kim and Lee were co-first authors of the study. Professor Kim Sang-woo of the Department of Biomedical Systems Informatics and Professor Kim Won-joo of the Department of Neurology served as co-corresponding authors.
Drug-resistant epilepsy is a condition in which seizures cannot be adequately controlled despite medication. Developing new treatments requires preclinical research using animals to assess efficacy and safety before they are administered to humans. Preclinical research is the stage of evaluating the effectiveness and safety of a new treatment using cells or animals before it is administered to humans.
However, there has been no objective standard for determining which animal models most accurately reflect the characteristics of patients’ diseases. As a result, researchers have often selected animal models based on their own experience.
The research team conducted a large-scale transcriptomic analysis by integrating 694 human brain tissue samples with 362 brain tissue samples from rodent models, including mice and rats.
The transcriptome is the complete set of genes expressed within a cell. It is used to identify changes in gene expression at the molecular level as diseases develop or progress.
The researchers developed a system called SIALAP to classify animal models based on six criteria: animal species, epilepsy induction method, administration route of the inducing drug, lesion lateralization, age and disease phase. SIALAP is an acronym formed from the first letters of Species, Induction method, Administration route, Lateralization, Age and Phase.
The analysis found that a mouse model in which kainate, an epilepsy-inducing substance, was injected into the hippocampus most closely reproduced the condition of patients with drug-resistant epilepsy accompanied by hippocampal sclerosis.
Hippocampal sclerosis is a condition in which nerve cells in the hippocampus, a brain region responsible for memory, are damaged and the tissue becomes hardened. It is considered one of the major causes of drug-resistant epilepsy.
In contrast, a rat model in which epilepsy was induced through repeated electrical stimulation of the hippocampus most closely reflected the condition of patients with epilepsy without hippocampal sclerosis.
This is the first study to confirm at the molecular level that different animal models can each represent different types of epilepsy. The researchers expect that selecting appropriate animal models based on patients’ disease types will enable more accurate evaluation of the efficacy of drug candidates.
The study was led by early-career physician-scientists trained through Yonsei University College of Medicine’s Convergence Training Program for Physician-Scientists. The program supports physicians who have completed medical school and clinical training in entering biomedical research.
Kim said, “There has always been a need for objective criteria to select animal models that best reflect each patient’s type of epilepsy. I hope this study will contribute to more accurate preclinical research and the development of new treatments.”
Professor Kim Sang-woo said, “This is the first study to objectively evaluate the accuracy of animal models by comparing genetic information from humans and animals. The findings are expected to be applicable to drug development for various intractable diseases beyond epilepsy.”
Professor Kim Won-joo said, “This is the first study worldwide to systematically validate how well animal models reflect human diseases at the transcriptomic level. We hope this achievement will serve as a new milestone for preclinical epilepsy research worldwide.”
The study was published in the latest issue of the international journal Nature Communications.