Genetic heterogeneity in response to adenovirus gene therapy

The number of transduced hepatocytes and the amounts of Ad5 DNA in the livers was similar in both strains, whereas the Brown Norway rats produced 8 to 10 times more of both vector encoded proteins and of transgene mRNA than the Wag/Rij rats.It is concluded that the difference between strains in vector encoded protein expression is due to different transcriptional events. No evidence was obtained to suggest that the differences are related to liver damage influenced by vector toxicity or immune reactions.In the course of studies involving intravenous adenoviral gene transfer, we observed a 10 fold difference in plasma levels of the encoded proteins between two of the rat strains employed: the Wag /Rij and the Brown Norway. These differences were observed for several vector encoded proteins as soon as 2 days after gene delivery and were maintained for one month, after which the levels declined slowly to background. Other investigators described differences of the same order of magnitude between mouse strains in expression of transgenes encoding α1-antitrypsin [1], interleukin-12 [2], and human endostatin [3]. These differences in transgene expression between inbred species may have clinical implications, as differences between inbred strains are considered to reflect differences between individuals of an outbred species.Consequently, the therapeutic efficiency of a transgene could drastically vary from one patient to another. So far, a satisfactory explanation for such strain differences has not been provided. Most authors have attributed the difference of plasma levels of vector encoded protein to immune reactions against the protein or against the vector [4,5]. However, the kinetics of the vector encoded proteins in the plasma do not support regulation by an adaptive immune reaction, as the strain difference is manifest as early as 2 days after administration of the vector. Innate humoral immunity, e.g. the presence of neutralising antibodies against the vector can