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

Research output: Contribution to journalArticle

  • J R Dorin
  • R Farley
  • S Webb
  • S N Smith
  • E Farini
  • S J Delaney
  • B J Wainwright
  • E W Alton
  • D J Porteous

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Original languageEnglish
Pages (from-to)797-801
Number of pages5
JournalGene Therapy
Issue number9
Publication statusPublished - 1996


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.

    Research areas

  • Animals, Chlorides, Crosses, Genetic, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Electric Conductivity, Forskolin, Gene Expression, Gene Therapy, Genes, Recessive, Genotype, Intestines, Mice, Mice, Mutant Strains, Phenotype, RNA, Messenger

ID: 1427701