Ability of a chimeric cAMP-responsive promoter to confer pharmacologic control of CFTR cDNA expression and cAMP-mediated Cl- secretion

Gene Therapy
M SuzukiR G Crystal

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.

Citations

May 26, 2005·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Uta GriesenbachUNKNOWN UK Cystic Fibrosis Gene Therapy Consortium
Oct 8, 2003·Molecular Therapy : the Journal of the American Society of Gene Therapy·Lawrence E OstrowskiWanda K O'Neal
Nov 9, 2018·Genes·Ashley L CooneyPatrick L Sinn

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