Gene therapy for cystic fibrosis using E1-deleted adenovirus: a phase I trial in the nasal cavity. The University of North Carolina at Chapel Hill

Hum Gene Ther. 1994 May;5(5):615-39. doi: 10.1089/hum.1994.5.5-615.


Cystic fibrosis (CF) is an autosomal recessive disease that reflects mutations in the CFTR gene. Multiple mutations in this gene have been detected that lead to a protein (CFTR) that is abnormally metabolized, dysfunction, or both. The full spectrum of the activities of the gene product have not been defined, but it is clear that CFTR can act as a cAMP-regulated Cl- channel. This type of defect is consistent with the physiologic characterization of CF epithelia, which has revealed abnormalities in salt and water transport. In the lung, abnormalities in epithelial salt and water metabolism lead to abnormal mucociliary clearance. This defect in clerance represents a major failure of lung defense and leads ultimately to infection of the lung with Staphylococcus aureus, Pseudomonas aeruginosa, and other bacterial organisms. The chronic inflammatory response to this persistent intraluminal bacterial infection leads to protease-induced destruction of airway walls and finally, lung failure. More than 95% of CF patients die of lung disease. The clinical therapy of CF lung disease is limited to agents designed to promote clearance of secretions from the lung and antibiotics to treat the chronic bacterial infection. Recent laboratory demonstrations that introduction of the normal CFTR cDNA into CF cells corrects the ion transport defects of these cells has led to the hypothesis that gene therapy in the lung can be an effective, novel mode of therapy for this lung disease. The classic gene transfer vectors, e.g., retroviruses, appear to be not well suited for therapy of lung disease because of the low proliferation rate of airway epithelia in vivo. Recently, adenoviruses, which have a natural tropism for airway epithelia, have been genetically modified (E1-deleted) in an attempt to reduce potential toxicity of this virus and provide space for the CFTR cDNA. A series of in vitro studies have shown that this vector is highly efficient for transferring CFTR into airway epithelial cells in culture and correcting the CF defect. Further, studies in whole animals appear to indicate that this mode of gene transfer is associated with a low degree of toxicity. The present study is a dose-effect study designed to test for the safety and efficacy of E1-deleted recombinant adenovirus containing the CFTR cDNA under a CMV-beta-actin promoter in CF nasal epithelia.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Clinical Protocols / standards
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Defective Viruses / genetics*
  • Disease Models, Animal
  • Epithelium / physiopathology
  • Genetic Vectors / genetics*
  • Humans
  • Informed Consent
  • Lac Operon / genetics
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Mice
  • Mice, Nude
  • Quality Control
  • Transplantation, Heterologous


  • CFTR protein, human
  • Membrane Proteins
  • Cystic Fibrosis Transmembrane Conductance Regulator