The McCown laboratory focuses upon the development of safe, effective gene therapies for the treatment of neurological disorders, especially epilepsy. We have developed a novel gene therapy platform where therapeutic genes can be expressed and constitutively secreted from AAV transduced cells. Using this novel platform, we have demonstrated that AAV-mediated expression and constitutive secretion of the inhibitory neuroactive peptides, galanin or neuropeptide Y, can attenuate focal seizure sensitivity, prevent seizure-induced cell death and block both electrographic and behavioral limbic seizures. In addition to these therapeutic approaches, we also utilize AAV vectors as a means to delineate basic mechanisms that contribute to neurological disorders, such as the contribution of TNF-alpha to seizure activity. Finally, a critical element to CNS gene therapy involves the need for selective delivery of therapeutic genes to areas of neuropathology or selective transduction of specific cell types involved in the neurological disorder. To this end, we have employed AAV DNA capsid shuffling and directed evolution to create novel chimeric AAV vectors that subserve specific therapeutic applications. Innovative outcomes include the rescue of chimeric AAV vectors that upon peripheral administration, selectively cross the seizure compromised blood brain barrier and transduce cells, as well as the creation of an oligodendrocyte selective, chimeric AAV. Thus, overall the McCown laboratory seeks to discover, characterize and utilize novel AAV vectors in order to advance the understanding and treatment of neurological disorders.