A DEMONSTRATION USING MOUSE MODELS THAT SUCCESSFUL GENE-THERAPY FOR CYSTIC-FIBROSIS REQUIRES ONLY PARTIAL GENE CORRECTION

Quantifying the level of transgene expression necessary for phenotypic effect is an important consideration in designing somatic gene therap y protocols. A nonlinear relationship between phenotype and gene activ ity is predicted by control analysis for any autosomal recessive condi tion. The unaffected phenotype of heterozygotes for autosomal recessiv e disorders demonstrates that 50% of the normal level of gene expressi on is sufficient to prevent disease. By extension, an exaggerated and positive effect on the mutant phenotype is predicted to arise from onl y a small addition of normal transgene expression delivered by gene th erapy. We tested this expectation directly by intercrossing mice carry ing different Cftr alleles which modulate Cftr gene expression from 0 to 100%. We demonstrate that 5% of the normal level of Cftr gene expre ssion 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). If follows that even modest levels of transgene expression and only partial correction of CFTR ch annel activity may have a significant clinical impact.