HERPES-SIMPLEX VIRAL VECTORS EXPRESSING BCL-2 ARE NEUROPROTECTIVE WHEN DELIVERED AFTER A STROKE

Considerable interest has focused on the possibility of using viral ve ctors to deliver genes to the central nervous system for the purpose o f decreasing necrotic neuronal injury. To that end, we have previously shown that a herpes simplex virus (HSV) vector expressing Bcl-2 could protect neurons from ischemia. In that study, vector was delivered be fore the ischemia. However, for such gene therapy to be of clinical us e, vectors must be protective even if delivered after the onset of the insult. In the present study, we show that an HSV vector expressing B cl-2 protects stria;al neurons when delivered after focal ischemia. Ra ts were exposed to middle cerebral artery occlusion for 1 hour, follow ed by reperfusion, and damage was assessed 48 hours later. Delivery of the Bcl-2 vector 30 minutes after reperfusion (i.e., 1,5 hours after ischemia onset) prevented any significant loss of virally-targeted neu rons in the striatum. In contrast, in rats microinfused with a vector only expressing a reporter gene, a highly significant loss of neurons occurred. By 4 hours into the rt perfusion period (5 hours after ische mia onset), delivery of the Bcl-2 vector was no longer protective. The se data show the efficacy of postinsult gene therapy strategies fur th e brain, underline the finite length of this temporal therapeutic wind ow, and support the growing evidence attesting to the neuroprotective potential of Bcl-2.