Immune parameters affecting adenoviral vector gene therapy in the brain.

Abstract

Gene therapy utilizing replication deficient adenoviral vectors represents a potentially promising approach to the treatment of brain tumors. Limited duration of systemic transgene expression and inefficient transduction following repeat systemic vector administration secondary to an effective anti-vector immune response limits the potential application of first generation adenoviral vectors. Whether host immune responses will significantly limit the use of these vectors within the immunopriviledged environment of the central nervous system remains to be elucidated. Following a single intravenous injection of a beta-galactosidase expressing adenoviral vector (Ad.CMV-betagal), we found maximal betagal transgene expression in systemic sites (i.e. liver) at day 4, with almost complete disappearance by day 7. In contrast, significant beta-galactosidase activity was seen for greater than 28 days following a single intracerebral inoculum of virus. Rechallenge experiments demonstrated complete protection against repeat systemic vector administration, whereas intracerebral transgene expression was not affected by prior systemic or intracerebral exposure to adenoviruses. These data suggest that systemic anti-adenoviral vector immune responses are attenuated within the central nervous system and may not pose as significant a problem for the treatment of brain tumors as for other systemic indications.