Ability of a chimeric cAMP-responsive promoter to confer pharmacologic control of CFTR cDNA expression and cAMP-mediated Cl- secretion. Academic Article uri icon

Overview

MeSH

  • Adenoviridae
  • Anions
  • Cell Line
  • Chlorides
  • Combined Modality Therapy
  • Cyclic AMP
  • DNA, Complementary
  • Genetic Vectors
  • Humans
  • Promoter Regions, Genetic

MeSH Major

  • 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.

publication date

  • November 1997

has subject area

  • Adenoviridae
  • Anions
  • Cell Line
  • Chlorides
  • Colforsin
  • Combined Modality Therapy
  • Cyclic AMP
  • Cystic Fibrosis
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • DNA, Complementary
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Promoter Regions, Genetic

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/sj.gt.3300512

PubMed ID

  • 9425443

Additional Document Info

start page

  • 1195

end page

  • 1201

volume

  • 4

number

  • 11