Demyelination but no cognitive, motor or behavioral deficits after adenovirus-mediated gene transfer into the brain

Adenovirus-mediated gene transfer of interferon gamma (AdlFN) elicits rejection of intracerebral Lewis lung carcinoma. In this system, gene transfer into brain parenchymal cells is both necessary and sufficient to generate the antitumor response. Despite persistent parenchymal inflammation and demyelination, wild-type mice injected intracerebrally with either AdlFN or β-galactosidase adenovirus (AdBGAL) perform as well as non-injected animals in behavioral, memory, and motor tests. Both AdlFN and AdBGAL elicit demyelination whose incidence rises sharply when the lowest effective dose of AdlFN is exceeded. Therefore, transfer of interferon gamma into brain parenchyma does not seem to elicit detectable cognitive, behavioral or motor deficits. Furthermore, gene transfer into the brain, by adenoviral vectors currently in clinical trials, is associated with a narrow therapeutic window where the incidence of demyelination rises sharply soon after the effective dose is achieved.