Epilepsy is a chronic neurological disorder characterized by recurrent seizures. Despite the availability of many antiepileptic drugs (AEDs), 30% of the patients are resistant to standard therapies. GABAA receptor (GABAAR) expression and function are altered in the epileptic tissue, resulting in impaired inhibition and reduced sensitivity to GABAergic AEDs. Therefore, we are developing a gene therapy strategy for focal drug-resistant epilepsy based on the overexpression of specific GABAAR subunits in hippocampal excitatory neurons, aiming at increasing network inhibition and enhancing the effectiveness of GABAergic AEDs. We developed lentiviral vectors (LVs) encoding GABAAR subunits, under the control of a neuron-specific promoter. In vitro experiments demonstrated co-expression and correct subunit processing in primary neurons transduced with LVs. Further, patch clamp analysis indicated increased chloride conductance in transduced neurons, suggesting formation of functional GABAARs. Preliminary in vivo experiments showed that vectors induce overexpression of both receptor subunits when injected in the hippocampal parenchyma. Further experiments are ongoing to assess the synaptic localization of the overexpressed subunits and the modified GABAARs composition. Nonetheless, the already available findings demonstrate the feasibility of obtaining neuron-specific functional GABAAR overexpression by using our gene therapy approach, a first step to develop a therapeutic strategy for the treatment of drug-resistant epilepsy.