title: A novel system for mitigation of ectopic transgene expression induced by adenoviral vectors.
abstract: Adenoviral (Ad) vectors are good candidates for gene therapy in view of their high in vivo gene delivery efficiency. However, greater control over the tissue distribution of transgene expression is required to avoid potentially deleterious effects in non-target organs. In this regard, the liver is particularly at risk due to the high natural tropism of Ad for this organ, where dose limiting toxicity has been seen due to toxic transgene expression. We hypothesized that the cre/loxP system could be utilized to reduce unintended transgene expression at this site. This concept was tested using an Ad vector (AdLCLLL) carrying a reporter gene cassette in which the promoter and luciferase gene were flanked by LoxP sequences. Co-administration of this vector with a second vector carrying the cre recombinase gene in vitro and in vivo resulted in specific down-regulation of transgene expression. This novel approach thus has the potential to improve the safety of gene therapy strategies that rely upon the delivery of genes which may be hepatotoxic.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: P N
authors.initials: PN
authors.lastname: Reynolds
authors.forename: M D
authors.initials: MD
authors.lastname: Holmes
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: L
authors.initials: L
authors.lastname: Kaliberova
authors.forename: D T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects*; D019426:Integrases / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D019076:Transgenes; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics
chemical_list: D014764:Viral Proteins; D008156:Luciferases; C045073:Cre recombinase; D019426:Integrases