770. Pharmacogenetics of Adenoviruses

Abstract

Pharmacogenetics is the study of genotypic and phenotypic variation between individuals and how it affects drug response. Recombinant viral vectors and naked DNA are employed to deliver therapeutic transgenes in the liver, muscle, tumours and haematopoietic stem cells. However, to rationalise this delivery approach, the factors of variation between patients need to be identified. To study transgene expression variation, following muscle or liver transfection, we transfected various mouse and rat inbred strains with the luciferase transgene under CMV promotor encoded in a recombinant adenovirus serotype 5. It is considered that the differences observed between inbred strains reflect the differences expected between individual patients. We showed that, after liver or muscle transfection, the level of transgene expression depends on the transcription capacity of the animal strain. Indeed, the transcription efficiency varies up to 2 logs between one mouse or rat strains to the other. In order to translate this finding in human we transfected various cell lines of one breast cancer type, namely the ductal adenocarcinoma of the breast. It is believed that the difference observed between these cell lines of similar histological origin reflects the difference that one might encounter between cancer patients suffering from ductal breast cancer. Similarly, to the situation in liver and muscle, the variation of transgene expression was due to a polymorphism of the transcription activity in the cell lines. Further, this polymorphism is not restricted to Ad5 transfection, as we observed it also, in vitro and in vivo, with Ad35 and plasmid vectors. We also studied the influence of the promoter on this variation of transgene expression. The luciferase gene under MPL or modified CMV promoters also showed a polymorphism of expression. Consequently, a polymorphism of transgene expression might be expected in patient population after transfection with Ad5 Ad35, plasmid coding for transgenes under CMV or MLP promoter.