Nature Medicine
1, 39 - 46 (1995)
doi:10.1038/nm0195-39
Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosisNatasha J. Caplen1, 8, Eric W.F.W. Alton2, 8, Peter G. Mddleton2, Julia R. Dorin3, Barbara J. Stevenson3, Xiang Gao4, Stephen R. Durham5, Peter K. Jeffery6, Margaret E. Hodson7, Charles Coutelle1, Leaf Huang4, David J. Porteous3, Robert Williamson1
& Duncan M. Geddes2
1Department of Biochemistry and Molecular Genetics, St Mary's Hospital Medical School, Norfolk Place, London W2 1PG, UK;
2Ion Transport Unit, National Heart and Lung Institute/Royal Brompton Hospital, Manresa Road, London SW3 6LR, UK;
3MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK;
4Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA;
5Dpartment of Allergy and Clinical Immunology, National Heart and Lung Institute/Royal Brompton Hospital, London, SW3 6LR, UK
6Department of Lung Pathology, National Heart and Lung Institute/Royal Brompton Hospital, London, SW3 6LR, UK
7Department of Cystic Fibrosis, National Heart and Lung Institute/Royal Brompton Hospital, London, SW3 6LR, UK
8Correspondence should be addressed to N.J.C. or E.W.F.W.A. We report the results of a double-blind, placebo-controlled trial in nine cystic fibrosis (CF) subjects receiving cationic liposome complexed with a complementary DNA encoding the CF transmembrane conductance regulator (CFTR), and six CF subjects receiving only liposome to the nasal epithelium. No adverse clinical effects were seen and nasal biopsies showed no histological or immuno-histological changes. A partial restoration of the deficit between CF and non-CF subjects of 20% was seen for the response to low Cl- perfusion following CFTR cDNA administration. This was maximal around day three and had reverted to pretreatment values by day seven. In some cases the response to low Cl- was within the range for non-CF subjects. Plasmid DNA and transgene-derived RNA were detected in the majority of treated subjects. Although these data are encouraging, it is likely that transfection efficiency and the duration of expression will need to be increased for therapeutic benefit.
REFERENCES
- Riordan, J.R. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066−1073 (1989). | PubMed | ISI | ChemPort |
- Welsh, M.J. Abnormal regulation of ion channel) in cystic fibrosis epithelia. FASEB J. 4, 2718−2725 (1990). | PubMed | ISI | ChemPort |
- Knowles, M.R., Gatzy, J.T. & Boucher, R.C. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N. Engl. J. Med. 305, 1489−1495 (1981). | PubMed | ISI | ChemPort |
- Hardcastle, J., Hardcastle, P.T., Taylor, C.J. & Goldhill, J. Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis. Gut 32, 1035−1039 (1991). | PubMed | ISI | ChemPort |
- Drumm, M.L. et al. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell 62, 1227−1233 (1990). | Article | PubMed | ISI | ChemPort |
- Rich, D.P. 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). | Article | PubMed | ISI | ChemPort |
- Alton, E.W.F.W. et al. Non-invasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice. Nature Genet. 5, 135−142 (1993). | PubMed | ISI | ChemPort |
- Hyde, S. et al. Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy. Nature 362, 250−255 (1993). | Article | PubMed | ISI | ChemPort |
- Collins, F.S., Molecular biology and therapeutic implications. Science 256, 774−779 (1992). | PubMed | ISI | ChemPort |
- Rosenfeld, M.A. et al. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68, 143−155 (1992). | Article | PubMed | ISI | ChemPort |
- Crystal, R.C. et al. Protocol for gene therapy of the respiratory manifestations of cystic fibrosis using a replication deficient, recombinant adenovirus to transfer the normal human cystic fibrosis transmembrane conductance regulator cDNA to the airway epithelium. Federal Register 57, 49584. (1992).
- Welsh, M.J. et al. Clinical Protocol. Cystic fibrosis gene therapy using adenovirus vector: In vivo safety and efficacy in nasal epithelium. Hum. gene Ther. 5, 209−219 (1994). | PubMed | ISI | ChemPort |
- Wilson, J.M., Engelhardt, J.F., Grossman, M., Simon, R.H. & Yang, Y., Clinical Protocol: Gene therapy of cystic fibrosis lung disease using El deleted adenovirus: a phase 1 trial. Hum. gene Ther. (In the Press 1994).
- Boucher, R.C. et al. Gene therapy for cystic fibrosis using E1-deleted adenovirus: a Phase I trial in the nasal cavity. Hum. gene Ther. 5, 501−519 (1994). | PubMed | ISI | ChemPort |
- Zabner, J. et al. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75, 1−20 (1993). | Article | PubMed | ISI | ChemPort |
- Crystal, R.G. et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nature Genet. 8, 42−51 (1994). | PubMed | ISI | ChemPort |
- Smith, T.A.G. et al. Adenovirus mediated express levels of human factor IX in mice. Nature Genet. 5, 397−402 (1993). | PubMed | ISI | ChemPort |
- Yei, S., Mittereder, N., Tang, K., O'Sullivan, C. & Trapnell, B.C. Adenovirus-mediated gene transfer for cystic fibrosis. Quantitative evaluation of repeated in vivo vector administration to the lung. Gene Ther. 1, 192−200 (1994). | PubMed | ISI | ChemPort |
- Gao, X. & Haung, L. A novel cationic liposome reagent for efficient transfection of mammalian cells. Biochem. Biophys. Res. Comm. 179, 280−285 (1991). | PubMed | ISI | ChemPort |
- Varney, V.A. et al. Immunohistology of the nasal mucosa following allergen-induced rhinitis. Identification of activated T-lymphocytes, eosinophils and neutrophils. Am. Rev. respir. Dis. 145, 170−176 (1992).
- Alton, E.W.F.W. et al. Nasal potential difference: A clinical diagnostic test for cystic fibrosis. Eur. Resp. J. 3, 922−926 (1990). | ISI | ChemPort |
- Middleton, P.G. et al. Nasal application of the cationic liposome DC-Chol:DOPE does not alter ion transport, lung function or bacterial growth. Eur. Resp. J. 7, 442−445 (1994). | Article | ISI | ChemPort |
- Middleton, P.G., Geddes, D.M. & Alton, E.W.F.W. Protocols for in vivo meaurement for ion transport defects in cystic fibrosis nasal epithelium. Eur. Resp. J.
- Nabel, E.G. et al. Gene transfer in vivo with DNA-Liposome complexes: Lack of autoimmunity and gonadal localization. Hum. gene Ther. 3, 649−656 (1992). | PubMed | ISI | ChemPort |
- Wilson, R. et al. Upper respiratory tract viral infection and mucociliary clearance Eur. J. Resp. Dis., 70,, 272−279 (1987). | ChemPort |
- Fokkens, W.J., Vroom, T.M., Gerritsma, V. & Rijntes, E. A biopsy method to obtain high quality specimens of nasal mucosa. Rhinology 26, 293−295 (1988). | PubMed | ChemPort |
- Mason, D.Y. et al. Detection of T cells in paraffin wax embedded tissue using antibodies against a peptide sequence from CD3 antigen. J. Clin. Pathol. 42, 1194−1120 (1989). | PubMed | ISI | ChemPort |
- Caplen, N.J. et al. Gene therapy for cystic fibrosis in humans by liposome-mediated DNA transfer the production of resources and the regulatory process. Gene Ther. 1, 139−147 (1994). | PubMed | ISI | ChemPort |
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