Transient cyclophosphamide treatment before intraportal readministration of an adenoviral vector can induce re-expression of the original gene construct in rat liver

Although adenovirus is an attractive vehicle for transferring therapeutic g enes in vivo, animal studies have indicated that the clinical usefulness of adenoviruses maybe limited by their immunogenicity. Although immunosuppres sive strategies around the time of initial exposure of adenoviruses have be en shown to prevent the formation of neutralizing antibodies and permit the successful readministration adenoviruses in animals, the practicality of t he approaches remains questionable. Because the majority of prospective gen e therapy patients have already been infected with wild-type adenoviruses, initial treatment with adenoviruses in humans may correspond to readministr ation of adenoviruses into animals. It is shown here that although intrapor tal infusion of adenoviruses carrying a reporter lacZ resulted in transient high levels of transgene expression in the rat liver, intraportal readmini stration of adenoviruses failed to induce detectable levels of transgene ex pression. Conversely, when animals were treated transiently with cyclophosp hamide before the intraportal readministration of adenoviruses, development of neutralizing antibodies and antigen-specific T cell proliferation in re sponse to adenoviral readministration was significantly suppressed and succ essful re-expression of the transgene was achievable. These results may hav e important implications for efficacy considerations when adenoviral vector s I are employed in clinical settings.