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.
Wonseok Chang, Amy Seomin Kwak, Seung-Ho Han et al.· Pharmaceutics· 0 citations
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.
A. A. Martins, A. Muotri· Stem Cells and Development· 0 citations
Human pluripotent stem cell-derived brain organoids have emerged as a transformative platform for modeling Alzheimer’s disease (AD), thus addressing long-standing translational obstacles posed by the disease’s complex etiology and interspecies differences. This review systematically examines methodological advances in brain organoid technology, from basic fabrication and brain-region-specific organoids to multicellular assembloids that incorporate microglia and vascular components, with an emphasis on strategies for overcoming fetal-like phenotypes. We surveyed literature published between 2018 and April 2026 that focused on human iPSC-derived organoid models that recapitulate core AD pathologies, including Aβ plaques, tau tangles, neuroinflammation, and blood–brain barrier dysfunction. Key findings demonstrate that organoids effectively capture genotype–phenotype relationships for major AD genes (APP, PSEN1, PSEN2, and APOEε4), enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms. Organoids have also been successfully applied to patient-specific “avatar” models and high-throughput drug screening, thus advancing precision medicine approaches. However, current technological bottlenecks—including a lack of functional vascularization, batch-to-batch variability, and insufficient standardization—limit the full recapitulation of chronic, age-dependent AD pathology. This review critically evaluates these limitations, addresses ethical considerations surrounding neural organoids, and looks forward to future integration with artificial intelligence, spatial omics, and multi-organ systems to accelerate the translation of organoid-based discoveries into clinical applications.
Qing Zhao, Songtao Li, Yanxiu Ju et al.· Frontiers in Cell and Develo...· 0 citations
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.
Alica M. Goldman, Nora Wong, A. Vezzani et al.· Epilepsy Currents· 0 citations
Perinatal brain injury (PBI) is a leading cause of childhood morbidity and mortality, often resulting in long-term neurological deficits. Despite its relatively high prevalence, PBI lacks reliable biomarkers for early detection and effective therapeutic approaches. The etiology of PBI is multifactorial and includes not only preterm birth but also hypoxia-ischemia, infection, and inflammation. While animal models and two-dimensional cell cultures have contributed to our understanding of PBI pathophysiology as well as to the development of novel treatment strategies, they fail to fully capture the complexity of injury in the developing human brain. Human brain organoids have recently emerged as transformative platforms recapitulating key features of fetal-neonatal brain development, including relevant cell types, gene expression patterns, cytoarchitecture, and functional electrophysiological properties. This model therefore provides opportunities to investigate the mechanisms underlying perinatal insults and serves as a promising tool for novel treatments such as stem cell-based therapy, drug discovery and screening, helping to bridge the translational gap between preclinical studies in animal models and clinical applications. Recent innovations, including the development of vascularization strategies, the incorporation of glial cells, brain organoid-on-chip technologies, and assembloids, have further increased the physiological relevance of these methods. This review highlights recent advances in organoid-based models of PBI and highlights their potential and challenges as next-generation tools for mechanistic studies and therapeutic innovations.
Zahra Dehghani, D. Surbek, M. Joerger-Messerli et al.· Stem Cell Research & The...· 0 citations
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.
Sudha R. Guttikonda, Christopher D. Makinson· Biological Psychiatry· 0 citations