Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy

作者：Marina Bershteyn, Sonja Bröer, Mansi Bharat Parekh, Yves Maury, Steven Havlicek, Sonja Kriks, Luis C. Fuentealba, Seonok Lee, Robin Zhou, Geetha Subramanyam, Meliz Sezan, Eric Steven Sevilla, Whitney B. Blankenberger, Julien Spatazza, Li Zhou, Hubert E. Nethercott, David J. Traver, Philip Hampel, Hannah Hayoung Kim, Michael J. Watson, Naomi Salter, Anastasia P. Nesterova, Wai Au, Arnold R. Kriegstein, Arturo Álvarez-Buylla, John L.R. Rubenstein, Gautam Banik, Alessandro Bulfone, Catherine A. Priest, Cory R. Nicholas · 发表于：Cell stem cell · 年份：2023 · DOI：10.1016/j.stem.2023.08.013 · 被引用次数：76 · 研究领域：Neurogenesis and neuroplasticity mechanisms、Pluripotent Stem Cells Research、Neuroscience and Neuropharmacology Research

Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.