Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis

• Published in: Gene therapy Vol. 7; no. 13; pp. 1156 - 1165
• Main Authors: HYDE, S. C, SOUTHERN, K. W, EGAN, J. J, SORGI, F. L, HUANG, L, CUTHBERT, A. W, EVANS, M. J, COLLEDGE, W. H, HIGGINS, C. F, WEBB, A. K, GILL, D. R, GILEADI, U, FITZJOHN, E. M, MOFFORD, K. A, WADDELL, B. E, GOOI, H. C, GODDARD, C. A, HANNAVY, K, SMYTH, S. E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-07-2000
• Subjects: Adolescent; Adult; Bacterial Adhesion; Biological and medical sciences; Biotechnology; CFTR protein; Cholesterol - analogs & derivatives; Cystic fibrosis; Cystic Fibrosis - immunology; Cystic Fibrosis - therapy; Cystic fibrosis transmembrane conductance regulator; Cystic Fibrosis Transmembrane Conductance Regulator - analysis; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Deoxyribonucleic acid; DNA; Double-Blind Method; Epithelial cells; Epithelium; Epithelium - chemistry; Expression vectors; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Gene transfer; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Health. Pharmaceutical industry; Humans; Immunohistochemistry; Industrial applications and implications. Economical aspects; Liposomes; Lung diseases; Male; Nasal Mucosa - chemistry; Patients; Phosphatidylethanolamines; Quantitation; Toxicity; Treatment Outcome; Human; Immune response; Respiratory disease; Liposome; Cystic fibrosis; Gene expression; Genetic disease; Genetic transfer; Multiple dose; Gene; DNA; Digestive diseases; Epithelial cell; Clinical trial; Molecular complex; Cystic fibrosis transmembrane conductance regulator; Gene therapy; Vector; Pancreatic disease
• DOI: 10.1038/sj.gt.3301212
• EISSN: 1476-5462
• ISSN: 0969-7128

The major cause of mortality in patients with cystic fibrosis (CF) is lung disease. Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene product in the airways is a potential treatment. Clinical studies in which the CFTR cDNA was delivered to the respiratory epithelia of CF patients have resulted in modest, transient gene expression. It seems likely that repeated administration of the gene transfer vector will be required for long-term gene expression. We have undertaken a double-blinded study in which multiple doses of a DNA/liposome formulation were delivered to the nasal epithelium of CF patients. Ten subjects received plasmid DNA expressing the CFTR cDNA complexed with DC-Chol/DOPE cationic liposomes, whilst two subjects received placebo. Each subject received three doses, administered 4 weeks apart. There was no evidence of inflammation, toxicity or an immune response towards the DNA/liposomes or the expressed CFTR. Nasal epithelial cells were collected 4 days after each dose for a series of efficacy assays including quantitation of vector-specific DNA and mRNA, immunohistochemistry of CFTR protein, bacterial adherence, and detection of halide efflux ex vivo. Airway ion transport was also assessed in vivo by repeated nasal potential difference (PD) measurements. On average, six of the treated subjects were positive for CFTR gene transfer after each dose. All subjects positive for CFTR function were also positive for plasmid DNA, plasmid-derived mRNA and CFTR protein. The efficacy measures suggest that unlike high doses of recombinant adenoviral vectors, DNA/liposomes can be successfully re-administered without apparent loss of efficacy.