Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors

Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is beco ming increasingly clear that some of the genes induced during cerebral isch emia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at levels high enough to be protective. One of the most exciting arenas of such interventions is the us e of viral vectors to deliver potentially neuroprotective genes at high lev els. Neurotrophic herpes simplex viral strains are an obvious choice for ge ne therapy to the brain, and we have utilized bipromoter vectors that are c apable of transferring various genes to neurons. Using this system in exper imental models of stroke, cardiac arrest and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insult s by over-expressing genes that target various facets of injury. These incl ude energy restoration by the glucose transporter (GLUT-1), buffering calci um excess by calbindin, preventing protein malfolding or aggregation by str ess proteins and inhibiting apoptotic death by BCL-2. We show that in some cases, gene therapy is also effective after the onset of injury, and also a ddress whether successful gene therapy necessarily spares function. Althoug h gene therapy is limited to the few hundred cells the vector is capable of transfecting we consider the possibility of such gene therapy becoming rel evant to clinical neurology in the future.