NEUROTOXICITY OF INTRACEREBRAL INJECTION OF A REPLICATION-DEFECTIVE ADENOVIRAL VECTOR IN A SEMIPERMISSIVE SPECIES (COTTON RAT)

The neurotoxicity of an adenoviral vector (Adv.RSVtk) carrying the gen e for herpes simplex virus thymidine kinase (HSVtk) was tested in the cotton rat a semipermissive host. Adv.RSVtk was injected intracerebral ly in cotton rats at a dose of 5.0 x 10(6) or 7.5 x 10(7) p.f.u. No si gns of illness were observed. Histological inspection at 12 and 28 day s after injection showed inflammation of the ependyma and plexus and a t the injection site. No demyelination, viral inclusions, cerebral ede ma, necrosis, cavities or vascular necrosis were seen in the brains. T here was no significant between animals injected with 5.0 x 10(6) or 7 .5 x 10(7) p.f.u., nor was there a difference between animals analyzed at 12 or 28 days after vector injection. This inflammation was simila r in animals that had been preimmunized with wild-type virus and in an imals that had been treated with ganciclovir. No histopathology was ob served in the lungs of the animals and no replication-competent virus was detected These experiments indicate that Adv.RSVtk has limited neu rotoxicity which would not prohibit ifs use in a limited phase I clini cal trial in humans that have malignant tumors of the central nervous system.