Interactions of adenovirus vectors with blood: implications for intravascular gene therapy applications

Despite various obstacles the promise of gene therapy has begun to be realized, as demonstrated by the successful phenotypic correction of X-linked SCID in infants. Although ex vivo gene therapy is advantageous, many diseases, for example, disseminated cancers, require intravascular administration of the gene therapy vector in vivo. In this scenario, the development of sophisticated vectors suitable for targeted intravascular gene delivery is required to both improve efficacy and minimize toxicity. Vectors based on adenovirus (Ad) show immense promise because they are highly efficient in transducing non-dividing cells, can tolerate substantial genetic manipulation (eg, the incorporation of targeting agents), can be produced to high titer, do not integrate into the genome, and have undergone significant investigation in the clinic. However, the use of Ad-based vectors is limited by the inherent hepatic tropism of intravascularly administered Ad, which precludes targeted delivery to alternative organs or disease sites, and by the associated host inflammatory responses to the vector. An improved knowledge of the complex series of interactions is of fundamental importance to the field. This review discusses the current understanding of Ad vector and host interactions, as well as suitable technologies for optimizing delivery to target cells in vivo.