Attenuated multi–mutated herpes simplex virus–1 for the treatment of malignant gliomas

We have created a double mutant of the herpes simplex virus (HSV) type 1 (termed G207) with favourable properties for treating human malignant brain tumours: replication–competence in glioblastoma cells (and other dividing cells), attenuated neurovirulence, temperature sensitivity, ganciclovir hypersensitivity, and the presence of an easily detectable histochemical marker. G207 has deletions at both γ34.5 (RL1) loci and a lacZ gene insertion inactivating the ICP6 gene (UL39). G207 kills human glioma cells in monolayer cultures. In nude mice harbouring subcutaneous or intracerebral U–87MG gliomas, intraneoplastic inoculation with G207 causes decreased tumour growth and/or prolonged survival. G207 is avirulent upon intracerebral inoculation of mice and HSV–sensitive non–human primates. These results suggest that G207 should be considered for clinical evaluation in the treatment of glioblastomas.