Abstract
Based on the theoretical concern that chronic overexpression 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 infec- tion with the AdCF126(CRE8) CFTR vector, there was amarked 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.
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Suzuki, M., Singh, R. & Crystal, R. Ability of a chimeric cAMP-responsive promoter to confer pharmacologic control of CFTR cDNA expression and cAMP-mediated Cl− secretion. Gene Ther 4, 1195–1201 (1997). https://doi.org/10.1038/sj.gt.3300512
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DOI: https://doi.org/10.1038/sj.gt.3300512