Transfer of normal human CFTR to human CF epithelial cells, respiratory epithelium of CF mice, or human nasal airways (using adenoviral vectors) may lead to re-establishment of CFTR mediated chloride transport. Gene transfer mediated correction of the CF bioelectric defect in these model systems, and the failure of current therapies to allow CF patients to live beyond young adulthood, indicate the importance of investigating gene transfer-based protocols in the disease and the need for new approaches to CF therapy. Several gene transfer based protocols using recombinant adenovirus to deliver functional CFTR to limited regions of CF respiratory epithelium have been approved previously for use in humans by the FDA. The present protocol is intended to evaluate an alternative, cationic liposome-based mechanism of delivery of normal CFTR to nasal respiratory epithelia of CF patients. We propose to study 9 patients using one-time administration of a single dose of a lipid/DNA formulation containing DMRIE/DOPE (lipid) and plasmid DNA encoding the full length CFTR. The advantages of lipid-based gene transfer are evident, and may include 1) minimal toxicity, 2) less antigenicity than viral DNA delivery vectors, and 3) efficient gene transfer even to non-replicating cells. The nasal airway epithelium is an ideal model for gene transfer of this type, since this epithelium exhibits a CF bioelectric defect and is easily accessible for studies of both safety and biologic effect of DNA/vector administration. In addition, the use of this site in CF patients greatly minimizes the risk of serious complications related to gene transfer to the lower airways. Depending on the results of this initial trial, future development of clinical studies using new lipid reagents and more potent DNA molecules are also intended for development within this proposal.
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