GENE THERAPY OF BRAIN TUMORS

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This subcontract investigates the administration and neuropathogenesis of novel virus vectors (retrovirus, herpes simplex type 1 and herpes-amplicon) in nonhuman primates. Initially, we used rhesus monkeys to examine the infiltration of a herpesvirus vector after intracerebral injection (using a novel stereotactic micro-injection apparatus) and the host response to this vector. To date we have examined two animals both animals were given general anesthesia, placed in a sterotactic apparatus, and craniotomies performed under sterile conditions. Using a micro-injection apparatus four 26 gauge needles placed 5 mm apart from one another were inserted 10 mm into the right frontal cortex. Herpesvirus (a total of 1 X 109 pfu in 100 ul/ injection) were injected over 120 minutes. After injection, needles and stereotactic apparatus were removed and the craniotomy sites were closed by routine surgical procedures. One animal was euthanized and examined 48 hours post-injection and one 14 days post-injection. Both animals had complete post-mortem examinations. Both animals had focally extensive malacia at the site of injection. Viral protein was detected in inflammatory cells and occasional neurons in the animal euthanized 48 hours after exposure to the HSV-1 mutant, but not in the animal euthanized and examined at 14 days post injection. Our preliminary studies have shown that naive rhesus monkeys (rhesus herpesvirus B negative) can be infected with HSV-1 and mount an antibody response to HSV-1, but do not develop generalized. Although the rhesus monkey is a suitable model for certain HSV-1 studies, to adequately assess the safety of HSV-1 mutants in man, we are currently using owl monkeys (Aotus sp.), which are susceptible to generalized HSV-1 infection. Presently, two owl monkeys have been infected with HSV-1 mutants (108 pfu) intracerebrally (as described above) and euthanized and examined at four and twelve weeks post infection. Neither viral protein nor significant histopathologic changes were detected in CNS and other tissues examined. Additional animals will be investigated in year three of this proposal.