Abstract Epilepsy is a severe neurological disease affecting more than 65 million people worldwide and is characterized by unpredictable abnormal electrical discharges resulting in recurrent seizures. About one third of patients with epilepsy suffer from intractable seizures that do not respond to antiepileptic drugs (AEDs). Neurosurgical interventions and neurostimulator devices are useful options for only a fraction of patients with drug-refractory seizures, underscoring the urgent need to develop new therapies. One strategy with considerable promise is to engraft new neurons to provide enhanced GABAergic inhibition in an activity-dependent manner. However, use of fetal neurons for cell therapy is associated with practical and ethical issues. Therefore, to overcome such hurdles, in our previous studies, we pioneered the transplantation of human pluripotent stem cells (hPSCs)- derived medial ganglionic eminence (MGE)-type human developmental cortical interneurons (cINs) into epileptic mouse brains and demonstrated their integration into dysfunctional circuitry, accompanied by the suppression of seizures and comorbid behavioral abnormalities. Furthermore, we have also determined the optimal stage of human cIN differentiation to ensure maximal integration into host circuitry as well as safety without risk of tumor formation, and developed a method to efficiently generate these safe and highly migratory populations of cINs from hPSCs in large quantities, bringing cell therapy for epilepsy one step closer to reality. However, there are still important issues to address prior to the clinical translation of this promising restorative therapy; 1) what is the synaptic connection specificity of human developmental cINs in adult epileptic circuitry? 2) what are safe and optimal densities of human cIN grafts for inhibition of epileptic host circuitry? 3) do human developmental cIN grafts maintain long-term efficacy and safety in epileptic brains? To tackle these issues, we will test our hypothesis that human iPSC-derived developmental cINs with optimal grafting densities preferentially innervate host excitatory neurons and ameliorate seizure activity with long-term efficacy and safety. We will transplant migratory human cINs into Nod Scid gamma (NSG) mice with intrahippocampal kainic acid-induced temporal lobe epilepsy (KA-TLE), a model of human hippocampal sclerosis, the most common cause of drug-resistant epilepsy, and analyze grafted cINs? synaptic integration specificity and host inhibition in the epileptic brains. The long-term maintenance of anti-epileptic efficacy will be extensively analyzed by 24/7 video-EEG recordings 3 months, 6 months and 9 months after transplantation. We will analyze the grafts immunohistochemically to determine the extent of cell survival, maturation, integration, and most importantly, cell proliferation as a measure of graft safety without risk of uncontrolled growth. Completion of these studies is pivotal for translating this experimental therapy into a viable therapeutic strategy for intractable epilepsy.