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

Abstract

Although adenovirus is an attractive vehicle for transferring although intraportal infusion of adenoviruses carrying a therapeutic genes in vivo, animal studies have indicated reporter lacZ gene resulted in transient high levels of transthat the clinical usefulness of adenoviruses may be limited gene expression in the rat liver, intraportal readministration by their immunogenicity. Although immunosuppressive of adenoviruses failed to induce detectable levels of transstrategies around the time of initial exposure of adenogene expression. Conversely, when animals were treated viruses have been shown to prevent the formation of neutransiently with cyclophosphamide before the intraportal tralizing antibodies and permit the successful readminisreadministration of adenoviruses, development of neutration of adenoviruses in animals, the practicality of the tralizing antibodies and antigen-specific T cell proliferation approaches remains questionable. Because the majority of in response to adenoviral readministration was significantly prospective gene therapy patients have already been suppressed and successful re-expression of the transgene infected with wild-type adenoviruses, initial treatment with was achievable. These results may have important impliadenoviruses in humans may correspond to readminiscations for efficacy considerations when adenoviral vectors tration of adenoviruses into animals. It is shown here that are employed in clinical settings.

Increased revascularization efficacy after administration of an adenovirus encoding VEGF121

“…[13][14][15][16] Alternatively, investigators have attempted to prevent activation of immune cells by administering immunosuppressant agents along with adenovirus vector. 8,[17][18][19][20][21][22] Although results from these studies are encouraging, there are significant risks associated with systemic immune suppression.…”

A Glucocorticoid Reduces Adverse Effects of Adenovirus Vectors in the Cochlea

“…The decrease in efficiency may be explained by the presence of neutralizing antibodies. Such antibodies have been detected in the sera of animals after a single administration [Kuriyama et al, 1999]. It is presently unclear whether the reduction in transgene expression following the second inoculation is due to the lower efficiency of transfection or impaired/reduced gene expression in transduced cells.…”

“…Agents such as FK506, cyclosporin A and deoxyspergualin reduce inflammation and permit prolonged transgene expression. The mechanism of action of these agents is thought to involve prevention of neutralizing antibody formation [Vilquin et al, 1995;Smith et al, 1996;Yang et al, 1996a, b;Kaplan and Smith, 1997;Bouvet et al, 1998;Cichon and Strauss, 1998;Kuriyama et al, 1999]. Administration of monoclonal antibodies such as anti-CD40 ligand antibody and CTLA4Ig around the time of the first vector administration has also been shown to prevent the formation of neutralizing antibody against the adenovirus and permit successful readministration of the virus [Lei et al, 1996;Yang et al, 1996a, b;Scaria et al, 1997;Jooss et al, 1998].…”

“…Mild immune response has been documented following a single inoculation of adenovirus vector into the inner ear [Raphael et al, 1996]. Moreover, in many cases the inner ear host is preimmunized to the adenovirus type 5 as a result of previous infections [Kuriyama et al, 1999], thereby complicating even a first inoculation of the replicationdeficient vector.…”

Particle-mediated gene transfer into murine livers using a newly developed gene gun

“…Although viral vectors or the vector-producing cells are being tested for in vivo gene transfer, [1][2][3][4][5][6] the use of nonviral in vivo gene transfer technologies has been much more limited. However, steady progress has been made in several areas of nonviral gene transfer methods.…”