Neuronal Models Symposium (NeuMoS) 2026

Hideyuki Okano received his M.D. in 1983 and Ph.D. in Medical Science in1988, both from Keio University. Following a postdoctoral fellowship at the Johns Hopkins University School of Medicine, he became a Professor at the Tsukuba University (1994) and the Osaka University (1997). He returned to Keio University in 2001. He served as a Dean of the Keio University School of Medicine and Graduate School of Medicine from 2007 to 2021 and was appointed Visiting Professor at MIT in 2022. He is currently the Director and Distinguished Professor of Keio University Regenerative Medicine Research Center. He has received numerous honors, including the Medal with Purple Ribbon (2009), the Erwin von Bälz Prize (2014), and the Uehara Prize (2022). In July 2025, he became the president of the International Society for Stem Cell Research (ISSCR). His current research focuses on stem cell therapies for spinal cord injuries, as well as iPSCs-based modeling and drug development for neurodegenerative diseases such as ALS and Alzheimer’s disease.

Human iPSC-Based Neuronal Models for ALS Disease Modeling, Drug Discovery, and Reverse Translation

Human induced pluripotent stem cell (iPSC) technology offers a transformative approach to neurological disease modeling and drug discovery by shifting the starting point of therapeutic development from animal models to human patient-derived cells. This is particularly important for amyotrophic lateral sclerosis (ALS), a clinically and genetically heterogeneous disorder in which many compounds effective in rodent models have failed in clinical trials. Patient-derived iPSCs preserve individual genetic backgrounds and disease risk architectures, enabling “disease in a dish” and, more broadly, “humanity in a dish” as a platform for precision medicine.

In this lecture, I will present our iPSC-based strategy for ALS disease modeling and drug discovery. We established robust protocols to generate spinal motor neurons from ALS patient-derived iPSCs and used these cells to recapitulate disease-relevant phenotypes, including neurite degeneration, mitochondrial dysfunction, oxidative stress, and neuronal hyperexcitability. Screening 1,232 compounds using ALS iPSC-derived motor neurons led to the identification of ropinirole hydrochloride, an approved dopamine D2 receptor agonist for Parkinson’s disease, as a candidate anti-ALS drug. Mechanistic studies showed that ropinirole acts through both D2 receptor-dependent and -independent pathways, including suppression of oxidative stress and modulation of mitochondrial function.

Beyond these mechanisms, our reverse translational studies have revealed a disease pathway linking cholesterol biosynthesis, RNA editing, and motor neuron excitability. Transcriptomic analyses of ropinirole-treated ALS motor neurons indicated suppression of SREBF2-dependent cholesterol biosynthesis. In sporadic ALS iPSC-derived lower motor neurons, cholesterol synthesis-related enzymes were elevated, particularly in ropinirole-responsive lines, suggesting that dysregulated lipid metabolism may define a therapeutically relevant ALS endotype. Ongoing studies further suggest that increased cholesterol biosynthesis can reduce ADAR2 expression and impair A-to-I RNA editing of GRIA2/GluA2, a critical mechanism controlling AMPA receptor calcium permeability. Reduced editing may therefore increase calcium influx, promote motor neuron hyperexcitability, and contribute to degeneration. High-density microelectrode array recordings support this model by demonstrating abnormal firing activity in ALS neurons and its modulation by ropinirole.

Finally, I will discuss how iPSCs derived from participants in the ROPALS phase 1/2a clinical trial enabled reverse translational research linking in vitro drug responsiveness with clinical progression. I will also introduce cortical–spinal assembloids and organoid-based neural circuit assays as next-generation models for integrating dying-forward and dying-back mechanisms in ALS.

János Vörös is a Professor in the Institute for Biomedical Engineering of the University and ETH Zurich (Department for Information Technology and Electrical Engineering) heading the Laboratory for Biosensors and Bioelectronics since 2006. János Vörös has studied Physics at the Eötvös Loránd University in Budapest. After receiving a diploma in Physics in 1995, he was a doctoral student at the Department of Biological Physics of the Eötvös University (in collaboration with Microvacuum Ltd.) where he received his PhD in Biophysics in 2000. Since 1998 he was a member of the BioInterface group in the Laboratory for Surface Science and Technology at the Department of Materials of ETH Zurich as visiting scientist, postdoc, and from 2004 as group leader of the Dynamic BioInterfaces group until 2006. Prof. Vörös is interested in research and teaching in the areas of bioelectronics, biosensors, and neuroscience. His group focuses on the development of novel biosensor techniques for diagnostics and single molecule sequencing; on bottom-up neuroscience; as well as on stretchable biohybrid electronic devices.