Theoretically, viral vector gene therapy holds great promise for the treatment of epilepsy, where in vivo expression of foreign genes could potentially suppress focal seizure sensitivity. Neurotransmitter receptors and ion channels offer obvious gene therapy targets, but a successful outcome is dependent upon the pattern of viral Vector transduction which to date cannot be predicted a priori. One means to circumvent this potential impediment would be to express an endogenous inhibitory neuropeptide that is subsequently secreted from the transduced cell. Two endogenous peptides, galanin (GAL) and neuropeptide Y (NPY), both can potently suppress limbic seizure activity. Recent preliminary findings with adeno-associated virus vectors (AAV) show that the secretion signal sequence for the laminar protein, fibronectin, can secrete vector-derived gene product in vitro and when placed in front of the GAL coding sequence, suppresses in vivo focal seizure sensitivity in a regulatable fashion and attenuates kainic acid-induced cell death in the hippocampus. Therefore, the present proposal will test the hypothesis that in vivo secretion of vector derived GAL or NPY will suppress acute seizure activity, reduce kainic acid seizure associated cell death and retard the spontaneous seizure activity that develops after pilocarpine administration. First, recombinant AAV vectors containing fibronectin secretory sequence in front of GAL or NPY coding sequences will be infused into the inferior colliculus, and both the persistence of seizure suppression and the ability to regulate gene expression will be evaluated. Then, these same recombinant AAV vectors will be tested in the kainic acid seizure model, evaluating if transduction of hippocampal hilar neurons can alter acute seizure sensitivity and seizure-induced cell damage. Subsequently, it will be determined if these AAV vectors can prevent the development of spontaneous seizures following pilocarpine-induced seizures. The findings from these studies could lead to a novel gene therapeutic approach to the treatment of epilepsy.
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