EVIDENCE FOR SAFETY AND EFFICACY OF DOTAP CATIONIC LIPOSOME-MEDIATED CFTR GENE-TRANSFER TO THE NASAL EPITHELIUM OF PATIENTS WITH CYSTIC-FIBROSIS

In cystic fibrosis (CF), mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in defective transepithelia l ion transport, leading to life shortening inflammatory lung disease. Before lung studies, we tested the safety and efficacy of gene delive ry to the nasal epithelium of CF patients using pCMV-CFTR-DOTAP cation ic liposome complex. A single dose of 400 mu g pCMV-CFTR:2.4 mg DOTAP was administered in a randomised, double-blinded fashion to the nasal epithelium of eight CF patients, with a further eight receiving buffer only. Patients were monitored for signs and symptoms for 2 weeks befo re treatment and 4 weeks after treatment. Inflammatory cells were quan tified in a nasal biopsy taken 3 days after treatment. There was no ev idence for excess nasal inflammation, circulating inflammatory markers or other adverse events ascribable to active treatment. Gene transfer and expression were assayed by the polymerase chain reaction. Transge ne DNA was detected in seven of the eight treated patients up to 28 da ys after treatment and vector derived CFTR mRNA in two of the seven pa tients at +3 and +7 days. Transepithelial ion transport was assayed be fore and after treatment by nasal potential difference during drug per fusion and by SPQ fluorescence halide ion conductance. Partial, sustai ned correction of CFTR-related functional changes towards normal value s were detected in two treated patients. The level of gene transfer an d functional correction were comparable to those reported previously u sing adenoviral vectors or another DNA-liposome complex, but here were sustained and uncompromised by false positives. These results justify further studies with pCMV-CFTR-DOTAP aimed at treating CF lung diseas e.