A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction

Gene Ther. 1996 Sep;3(9):797-801.


Quantifying the level of transgene expression necessary for phenotypic effect is an important consideration in designing somatic gene therapy protocols. A nonlinear relationship between phenotype and gene activity is predicted by control analysis for any autosomal recessive condition. The unaffected phenotype of heterozygotes for autosomal recessive disorders demonstrates that 50% of the normal level of gene expression is sufficient to prevent disease. By extension, an exaggerated and positive effect on the mutant phenotype is predicted to arise from only a small addition of normal transgene expression delivered by gene therapy. We tested this expectation directly by intercrossing mice carrying different Cftr alleles which modulate Cftr gene expression from 0 to 100%. We demonstrate that 5% of the normal level of Cftr gene expression results in a disproportionately large correction of the chloride ion transport defect (50% of normal) and essentially complete rescue of the intestinal disease (100% survival). It follows that even modest levels of transgene expression and only partial correction of CFTR channel activity may have a significant clinical impact.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorides / metabolism
  • Colforsin / pharmacology
  • Crosses, Genetic
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / physiopathology
  • Cystic Fibrosis / therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Electric Conductivity
  • Gene Expression*
  • Genes, Recessive / genetics*
  • Genetic Therapy / methods*
  • Genotype
  • Intestines / chemistry
  • Intestines / physiopathology
  • Mice
  • Mice, Mutant Strains
  • Phenotype
  • RNA, Messenger / analysis


  • Chlorides
  • RNA, Messenger
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Colforsin