Promoters influence the kinetics of transgene expression following adenovector gene delivery.

BACKGROUND: The kinetics of gene expression from adenovirus-based delivery vectors will be an important variable influencing the efficacy and toxicity of these vectors. As different promoters have variable strengths and kinetic profiles, the optimal dose of a therapeutic transgene product over time may be achieved by varying the promoter.
METHODS: We analyzed several viral and cellular promoters in the context of adenovector gene delivery in the mouse. The kinetics of transgene expression was evaluated following intramuscular and intravenous delivery.
RESULTS: Transgene expression from the cytomegalovirus (CMV) promoter was rapidly down-regulated in the tissues following intravenous administration of adenovectors. In contrast, transgene expression from the Rous sarcoma virus (RSV) promoter increased over time such that, at 3 weeks, expression was 10-fold higher than that from the CMV promoter-containing vector in all tissues. The kinetics of transgene expression from these vectors was similar when they were delivered via the intramuscular route in BALB/c, C57BL/6 and immunodeficient mice. Efficient repeat administration of an adenovirus vector, in the presence of neutralizing antibodies, was achieved in the skeletal muscle and transgene expression persisted with the same kinetics as in naïve animals.
CONCLUSIONS: These results demonstrate that the in vivo kinetics of transgene expression by adenovectors is greatly influenced by the promoter. Adenovectors can be designed to deliver a transient bolus or a sustained level of protein expression in the target tissue depending on the requirements for particular indications. These results have implications for both therapeutic and vaccine indications.