CNS tumors are the second most common pediatric neoplasms after leukemia. Many tumors are still uncurable by current treatment including surgery, irradiation and chemotherapy. We want to introduce a specific adenoviral gene therapy model against glioblastoma by using the nestin regulatory regions to drive the expression of the herpes simplex thymidine kinase (HSV tk) gene in these tumour cells.

The nestin gene encodes for an intermediate filament protein which is predominantly expressed in the progenitor cells of the developing CNS. When the progenitor cells differentiate to neurons or to glial cells they downregulate expression of nestin and express other members of the intermediate filament family. However many CNS tumours re-express the nestin gene, a property which enables us to develop our specific treatment against these cells.

The HSV tk protein phosphorylates the drug ganciclovir which leads to DNA breaks and inhibition of transcription, causing cell-death. We generated adenoviral vectors carrying the lacZ gene or the thymidine kinase gene under the regulation of the nestin enhancer, called ad.nes .lacZ showed that 60 - 70% of the cells expressed lacZ. In ongoing studies the ad.nes.tk vector is evaluated in a glioblastoma rat model, which enables us to quantity the tumor eradication in vivo.

In conclusion we have shown that the nestin enhancer is functional in glioblastoma cells. The possibility of specifically expressing the HSV tk gene in CNS tumour cells but not in surrounding CNS tissue in vivo will be discussed.