Recent advances and ongoing challenges of human cortical organoid models of genetic and acquired epilepsies hold promise for advancing mechanistic understanding of epilepsy and enabling the development of more precise therapeutic strategies.
Abstract
Epilepsy is a common and heterogeneous group of neurologic disorders characterized by recurrent unprovoked seizures. With a diverse array of genetic and acquired etiologies, the mechanisms linking insults to epileptogenesis and network hyperexcitability remain poorly understood. Although animal models have provided critical insights into seizure generation and disease mechanisms, differences in human cortical development and limitations in recapitulating spontaneous seizure phenotypes observed in patients highlight the need to develop complementary human-based models. Human pluripotent stem cell-derived brain organoids, including patient-derived and CRISPR-engineered models, offer an increasingly powerful human-specific platform to investigate epilepsy-associated disruptions in neuronal production and differentiation, interneuron migration, and network activity. In this review, we discuss recent advances and ongoing challenges of human cortical organoid models of genetic and acquired epilepsies. Together with established animal models, organoid-based approaches hold promise for advancing mechanistic understanding of epilepsy and enabling the development of more precise therapeutic strategies.
Epilepsy is increasingly recognized as a multiscale network disorder rather than solely a condition of neuronal hyperexcitability, and the coordinated use of complementary human-relevant platforms may help incorporate multiscale mechanistic insights into therapeutic development and evaluation, narrow persistent translational gaps, and support more predictive and mechanism-informed treatment strategies.
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Human brain organoids have evolved from early neurodevelopmental models into platforms for therapeutic discovery. Here, we highlight two cases in which organoid-derived findings enabled FDA-approved clinical trials. Patient-derived organoids modeling Pitt-Hopkins syndrome revealed human-specific, TCF4-dependent abnormalities and supported the development of a regulated AAV gene therapy. In parallel, Rett syndrome organoids cultured aboard the International Space Station uncovered space-induced neural senescence, characterized by retroelement-associated neuroinflammation, prompting evaluation of antiretroviral therapy. These examples illustrate how organoids can reveal disease mechanisms that are inaccessible or incompletely reproduced in animal models, while animal studies remain essential for validation and safety assessment. As the field advances, matching model complexity to experimental purpose-and ensuring reproducibility, scalability, and accessibility-will be critical. Human brain organoids are crossing a translational threshold, emerging as engines of therapeutic discovery and gateways to clinical intervention.
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This review synthesizes advances in neuroimmunology, clinical phenotyping, diagnostics, immunomodulatory and antiseizure therapies, neuromodulation, and patient and family centered outcomes, and outlines future directions focused on biomarker-driven precision medicine, disease-modifying strategies, and interdisciplinary care models.
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How human cellular models have advanced basic and translational research in ASD is examined and key cellular and molecular convergent phenotypes that have emerged are identified.
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