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Ability of a chimeric cAMP-responsive promoter to confer pharmacologic control of CFTR cDNA expression and cAMP-mediated Cl- secretion.
| Publication Type | Academic Article |
| Authors | Suzuki M, Singh R, Crystal R |
| Journal | Gene Ther |
| Volume | 4 |
| Issue | 11 |
| Pagination | 1195-201 |
| Date Published | 11/01/1997 |
| ISSN | 0969-7128 |
| Keywords | Colforsin, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Gene Expression Regulation, Gene Transfer Techniques, Genetic Therapy |
| Abstract | 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. |
| DOI | 10.1038/sj.gt.3300512 |
| PubMed ID | 9425443 |