title: A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction.
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.
authors.affiliation: MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Dorin
authors.forename: R
authors.initials: R
authors.lastname: Farley
authors.forename: S
authors.initials: S
authors.lastname: Webb
authors.forename: S N
authors.initials: SN
authors.lastname: Smith
authors.forename: E
authors.initials: E
authors.lastname: Farini
authors.forename: S J
authors.initials: SJ
authors.lastname: Delaney
authors.forename: B J
authors.initials: BJ
authors.lastname: Wainwright
authors.forename: E W
authors.initials: EW
authors.lastname: Alton
authors.forename: D J
authors.initials: DJ
authors.lastname: Porteous
mesh_terms: D000818:Animals; D002712:Chlorides / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003433:Crosses, Genetic; D003550:Cystic Fibrosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004553:Electric Conductivity; D015870:Gene Expression; D005808:Genes, Recessive / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005838:Genotype; D007422:Intestines / Q000737:chemistry / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D002712:Chlorides; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin