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Adenosine is a modulator of neuronal activity with anticonvulsant and neuroprotective properties. Conversely, focal deficiency in adenosine contributes to ictogenesis. Thus, focal reconstitution of adenosine within an epileptogenic brain region constitutes a rational therapeutic approach, whereas systemic augmentation of adenosine is precluded by side effects. To meet the therapeutic goal of focal adenosine augmentation, genetic disruption of the adenosine metabolizing enzyme, adenosine kinase (ADK) in rodent cells was used as a molecular strategy to induce adenosine release from cellular brain implants, which demonstrated antiepileptic and neuroprotective properties. Currently, the second generation of adenosine-releasing cells is under development based on the rationale to use human stem cell-derived brain implants to avoid xenotransplantation. To effectively engineer human stem cells to release adenosine, a lentiviral vector was constructed to express inhibitory micro-RNA directed against ADK. Lentiviral knockdown of ADK induced therapeutic adenosine release in human mesenchymal stem cells, which reduced acute injury and seizures, as well as chronic seizures, when grafted into the mouse hippocampus. The therapeutic potential of this approach suggests the feasibility to engineer autologous adenosine-releasing stem cells derived from a patient. Human embryonic stem cells (hESCs) have a high proliferative capacity and can be subjected to specific cellular differentiation pathways. hESCs, differentiated in vitro into neuroepithelial cells and grafted into the mouse brain, displayed intrahippocampal location and neuronal morphology. Using the same lentiviral micro-RNA vector, we demonstrated knockdown of ADK in hESCs. New developments and therapeutic challenges in using human mesenchymal stem cells and hESCs for epilepsy therapy will be critically evaluated.