Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in social communication and interaction, and by restricted and repetitive behaviors. More than 1,200 genes are known to be associated with ASD. As the term “spectrum” implies, the causes, types of symptoms, and their severity vary greatly from individual to individual.

A Korean research team has come close to identifying the genetic causes of ASD through a long-term study spanning more than 10 years, and has suggested the possibility of “personalized treatment” tailored to subgroups classified by drug response. On 17 September (local time), a research team led by Kim Eunjoon, director of the Synaptic Brain Dysfunctions Research Center at the Institute for Basic Science (IBS), published in the international journal Science the results of an analysis of 1,008 “ribonucleic acid (RNA) sequencing” datasets of gene expression obtained from the prefrontal cortex of 17 different mouse models.

● From synapse research to brain disorder research

Kim studies complex ASD from the perspective of “synapses” in the brain. Synapses, which are the sites where nerve cells exchange signals, are the basic units of brain function.

When Kim began synapse research, synapses were already a core subject for understanding brain function. As genes presumed to be related to ASD were rapidly discovered, it emerged that 15–20% of them were synapse-related genes.

Ahead of the publication of this study, which is expected to be an important milestone, Kim recalled, “I never imagined that the synaptic proteins I was studying would be linked to brain disorders,” adding, “I suddenly developed an ambitious dream of studying brain disorders.”

The reason Kim focused on ASD among various brain disorders is clear. “Because ASD has no medication,” he said. While drugs exist to alleviate comorbid symptoms such as hyperactivity and epilepsy (seizures), there is still no treatment that directly targets core ASD symptoms such as difficulties in social communication or repetitive behaviors.

To empirically demonstrate the association between ASD and synapses, it is necessary to create genetically modified mouse models and observe them over a long period. It takes four to five years just to develop a single mouse model and conduct basic analyses, and seven to eight years to elucidate the molecular mechanisms underlying disease onset and to assess treatment potential.

The long-term, large-scale basic science support provided by IBS since its launch in 2012 created the foundation for turning such concepts into actual research. “In reality, IBS was the only institution that provided an environment where long-term basic research could be conducted stably, so I could not pass up the opportunity to apply for the directorship,” Kim said. “As we pursued research with this dream, it began to seem that the goal of ‘treating ASD’ might actually be achievable.” Over the past decade, the research center has added newly recognized key genes to its research targets and adjusted priorities, building 20–30 types of ASD mouse models to date. In effect, it has established a “test bed” that allows new hypotheses to be verified immediately.

● Will autism also open the way to personalized treatment like diabetes?

Based on its own mouse models, the research center is conducting follow-up studies to identify common pathogenic mechanisms of ASD and explore treatment potential. “We are now in the harvesting phase,” Kim said. One of the成果 is the present study, which is being assessed as having suggested the possibility of personalized treatment for ASD.

When Kim’s team analyzed 1,008 RNA sequencing datasets from the prefrontal cortex of 17 different mouse models, they found that the gene activity states of mice with different gene variants fell largely into two groups. In one group, expression of synapse-related genes responsible for signal transmission between nerve cells decreased, while expression of genes related to gene expression regulation and RNA processing increased. In the other group, the opposite pattern was observed. This suggests that even when the genetic causes that lead to autism differ, molecular states can be similar.

The two groups also responded differently to drugs. When the antidepressant fluoxetine and the mood stabilizer lithium were administered, multiple molecular abnormalities consistently recovered in one group, whereas recovery patterns were inconsistent in the other. “This study has opened the door to ‘subtyping’ research that classifies ASD into multiple groups according to molecular characteristics,” Kim explained.

The ultimate goal is to link diagnosis and treatment to objective biological indicators. The aim is to make ASD treatable in a way similar to diabetes, where blood glucose levels are used to assess drug efficacy and adjust treatment strategies. Kim plans to extend the research to human-derived nerve cells and organoids to determine whether the same classification is possible in humans. Addressing people with autism, Kim said, “For now, we only have animal data, but please wait a little longer,” adding, “We will move closer to personalized treatment.”

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