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

M. Suzuki, R. N. Singh, R. G. Crystal

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9 Citations (Scopus)

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 CFTR cDNA controlled by a chimeric, cAMP-regulatable promotor 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 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 promotor for gene therapy for CF, with the promotor and gene product stimulated by the same class of pharmacologic agents.

Original languageEnglish
Pages (from-to)1195-1201
Number of pages7
JournalGene Therapy
Volume4
Issue number11
DOIs
Publication statusPublished - 1 Jan 1997

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Keywords

  • Cystic fibrosis
  • Epithelial
  • cAMP

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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