Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas

Cellular delivery of a replication-conditional herpes simplex virus type 1 (HSV-1) vector provides a means for gene therapy of invasive tumor cells. L acZ-bearing neural precursor cells, which can migrate and differentiate in the brain, were infected with a ribonucleotide reductase-deficient HSV-1 mu tant virus (rRp450) that replicates only in dividing cells. Replication of rRp450 in neural precursor cells was blocked prior to implantation into the tumor by growth arrest in late G(1) phase through treatment with mimosine. Viral titers in the medium of mimosine-treated, rRp450-infected neural pre cursor cells were below detection levels 3 days after infection. In culture , after removal of mimosine and passaging, cells resumed growth and replica tion of rRp450 so that, 7 days later, virus was present in the medium and c ell death was evident. Mimosine-treated neural precursor cells injected int o established intracerebral CNS-1 gliomas in nude mice migrated extensively throughout the tumor and into the surrounding parenchyma beyond the tumor over 3 days. Mimosine-treated neural precursor cells, infected with rRp450 and injected into intracerebral CNS-1 tumors, also migrated within the tumo r with the appearance of foci of HSV-thymidine kinase-positive (TK+) cells, presumably including tumor cells, distributed throughout the tumor and in the surrounding parenchyma over a similar period. This migratory cell deliv ery method has the potential to expand the range of delivery of HSV-1 vecto rs to tumor cells in the brain.