Cell Therapy for Treatment of Epilepsy

Abstract Cell transplantation could offer a strategy to overcome pharmacoresistance in epilepsy if transplanted cells can survive long term within the host brain, migrate into appropriate brain regions, differentiate into interneurons (INs) that increase inhibitory tone within the epileptic network, and integrate into the circuitry by forming synapses with host neurons. Several studies have demonstrated all of the above-mentioned prerequisites of a successful IN transplantation using rodent INs derived from the medial ganglionic eminence (MGE). They showed that INs are effective in decreasing seizure frequency consistently and in the long term across a variety of animal models. Behavioral comorbidities of epilepsy could be alleviated, and even hippocampal neuropathology of the disease was reduced. While use of rodent INs is feasible for preclinical research, a human cell product is needed for clinical translation. Protocols for IN in vitro differentiation from human pluripotent stem cells (PSCs) have been developed. First, data from transplantation studies in models of epilepsy confirm the promising disease-modifying activity that was observed with rodent MGE-derived INs: human IN transplantation was effective in reducing seizure burden, while no obvious adverse effects were associated with it. Further research on characterization of cells prior to transplant, process improvements, and good manufacturing practice production will be needed to ensure safety of an IN cell product; however, the recent advances in our ability to generate MGE-like cells from PSCs, in-depth characterization of cells with modern techniques and the combinatorial use of electrophysiology, optogenetics, and translational immunodeficient animal models to evaluate disease-modifying activity have brought human IN transplantation significantly closer to clinical application.