A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction.
Gene Ther
; 3(9): 797-801, 1996 Sep.
Article
in En
| MEDLINE
| ID: mdl-8875228
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Therapy
/
Gene Expression
/
Cystic Fibrosis Transmembrane Conductance Regulator
/
Cystic Fibrosis
/
Genes, Recessive
Type of study:
Guideline
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Gene Ther
Year:
1996
Document type:
Article