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

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Publication Year:
2023
Authors:
Marina Bershteyn, Sonja Broer, Mansi Parekh, Yves Maury, Steven Havlicek, Sonja Kriks, Luis Fuentealba, Seonok Lee, Robin Zhou, Geetha Subramanyam, Meliz Sezan, Eric Steven Sevilla, Whitney Blankenberger, Julien Spatazza, Li Zhou, Hubert Nethercott, David Traver, Philip Hampel, Hannah Kim, Michael Watson, Naomi Salter, Anastasia Nesterova, Wai Au, Arnold Kriegstein, Arturo Alvarez-Buylla, John Rubenstein, Gautam Banik, Alessandro Bulfone, Catherine Priest, Cory R Nicholas
PubMed ID:
37802038
Funding Grants:
Public Summary:
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.
Scientific Abstract:
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.