Abstract
Human cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in transgenic mice under the control of transcriptional elements derived from the human surfactant protein C (SP–C) gene. The hCFTR mRNA was expressed in lungs and testes: in the lung, we found hCFTR mRNA in bronchiolar and alveolar epithelial cells, and CFTR protein in respiratory epithelial cells. While the level of expression of hCFTR mRNA varied, hCFTR mRNA and protein were detected in pulmonary epithelial cells of several lines. Lung weight, morphology, somatic growth and reproductive capacity were not altered by expression hCFTR in lung and testes of the transgenics. Our findings suggest that hCFTR can be safely transferred to lung epithelial cells for CF therapy.
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References
Boat, T., Welsh, M. & Beaudet, A. In The Metabolic Basis of Inherited Disease 2649–2680 (McGraw-Hill, New York 1989).
Li, M. et al. Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium. Nature 331, 358–360 (1988).
Frizzell, R., Rechkemmer, G. & Shoemaker, R. Altered regulation of airway epithelial cell chloride channels in cystic fibrosis. Science 233, 558–560 (1986).
Welsh, M. An apical-membrane chloride channel in human tracheal epithelium. Science 232, 1648–1650 (1986).
Rommens, J. et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059–1065 (1989).
Riordan, J. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066–1073 (1989).
Drumm, M. et al. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell 62, 1227–1233 (1990).
Rich, D. et al. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 347, 358–363 (1990).
Rosenfeld, M. et al.In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68, 143–155 (1992).
Korfhagen, T. et al. Cis-acting sequences from a human surfactant protein gene confer pulmonary-specific gene expression in transgenic mice. Proc. natn. Acad. Sci. U.S.A. 87, 6122–6126 (1990).
Glasser, S., Korfhagen, T., Bruno, M., Dey, C. & Whitsett, J. Structure and expression of the pulmonary surfactant protein SP-C gene in the mouse. J. biol. Chem. 265, 21986–21991 (1990).
Glasser, S. et al. Genetic element from human surfactant protein SP-C gene confers branchiolar-alveolar cell specificity in transgenic mice. Am. J.Physiol. L349–L356 (1991).
Tresize, A. & Buchwald, M. In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator. Nature 353, 434–437 (1991).
Trapnell, B. et at. Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. Proc. natn. Acad. Sci. U.S.A. 88, 6565–6569 (1991).
Marino, C., Matovcik, L., Gorelick, F. & Cohn, J. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. J. Clin. Invest. 88, 712–716 (1991).
Marino, C. et al. Localization of the Cystic fibrosis transmembrane conductance regulator in pancreas. Gastroenterology 100, A287 (1991).
Tata, F. et al. Cloning the mouse homologous of the human cystic fibrosis transmembrane conductance regulator gene. Genomics 10, 301–307 (1991).
Fiedler, M., Nemecz, Z. & Shull, G. Cloning and sequence analysis of the rat cystic fibrosis transmembrane conductance regulator. Am. J. Physiol. (in the press).
Gregory, R. et al. Expression and characterization of the cystic fibrosis transmembrane conductance regulator. Nature 347, 382–386 (1990).
Cheng, S. et al. Defective intracellular transport and processing is the molecular basis of most cystic fibrosis. Cell 63, 827–834 (1990).
Anderson, M., Rich, D., Gregory, R., Smith, A. & Welsh, M. Generation of cAMP-activated chloride currents by expression of CFTR. Science 251, 679–682 (1991).
Ditullio, P. et al. Production of cystic fibrosis transmembrane regulator in the milk of transgenic mice. Biotechnology 10, 74–77 (1992).
Chirgwin, J., Przybyla, A., MacDonald, R. & Rutter, W. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18, 5294–5299 (1979).
Maniatis, T., Fritsch, E. & Sambrook, J. 77–78, 80–83, 371–372 (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1982).
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Whitsett, J., Dey, C., Stripp, B. et al. Human cystic fibrosis transmembrane conductance regulator directed to respiratory epithelial cells of transgenic mice. Nat Genet 2, 13–20 (1992). https://doi.org/10.1038/ng0992-13
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DOI: https://doi.org/10.1038/ng0992-13
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