Based on the theoretical concern that chronic over-expression of the exogenous CFTR protein could be associated with adverse effects following gene transfer, we have constructed a replication-deficient adenovirus (Ad) vector containing the normal human CFTR cDNA controlled by a chimeric, cAMP-regulatable promoter responsive to agents that elevate intracellular cAMP levels. Studies with the IB3 human CF-derived respiratory epithelial line as a model target for CF gene therapy and forskolin to elevate cAMP levels demonstrated that following infection with the AdCF126(CRE8) CFTR vector, there was a marked increase in CFTR mRNA levels after forskolin addition. There was an associated correction of cAMP-mediated Cl- secretion that could be further increased with additional forskolin. cAMP-mediated Cl- secretion was corrected with vector doses as low as 0.2 MOI, a dose that can be achieved in vivo in humans. These observations suggest the feasibility of using a regulatable promoter for gene therapy for CF, with the promoter and gene product stimulated by the same class of pharmacologic agents.