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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)797-801
Number of pages5
JournalGene Therapy
Volume3
Issue number9
Publication statusPublished - 1996

Keywords

  • 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

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