Viral Vector Gene Therapy for Epilepsy

Theoretically, gene therapy offers an attractive alternative for the treatment of focal epilepsies, and recently, studies have established the basic viability of anti-seizure gene therapy by employing a number of diverse approaches. Using recombinant adeno-associated virus (AAV) vectors, significant seizure suppression has been obtained in vivo by interrupting NMDA receptor function or by altering GABA receptor composition. Similarly, engineering cells to release GABA or adenosine has been shown to exert significant anti-seizure actions. In addition, studies have reported seizure suppression using in vivo, viral vector-mediated expression of GDNF, ICP10PK , or clostridial light chain. At present though, studies with the neuroactive peptides, galanin and neuropeptide Y (NPY), have progressed the furthest. AAV vector-mediated expression and constitutive secretion of galanin essentially prevents electrographic and behavioral seizure activity induced by peripheral kainic acid administration, prevents seizure-induced cell damage, and attenuates the seizure threshold in previously kindled animals. For NPY, AAV vector-mediated expression of prepro-neuropeptide Y delays seizure onset and increases kindling seizure thresholds, while expression and constitutive secretion of NPY (13-36) attenuates kainic acid-induced seizures. These results have proven quite promising, but several key issues remain, including the adequate transduction of chronic seizure-exposed tissue. In light of the present advances, however, gene therapeutic approaches will provide an effective treatment alternative for intractable, focal seizures.