Liposomal DNA vectors for cystic fibrosis gene therapy. Current applications, limitations, and future directions

The etiology of cystic fibrosis (CF), current therapies, and recent experimental molecular based therapies are briefly described including the use of recombinant human deoxyribonuclease I (rhDNase), nonsteroidal antiinflammatory drugs (ibuprofen), the sodium channel blocking diuretic amiloride, and uridine triphosphate (UTP), a chloride secretagogue. The original approach to CF gene therapy using recombinant replication defective adenovirus and its potential benefits as well as shortcomings are also briefly discussed. More recently, the use of nonviral cationic liposome plasmid complexes to deliver cystic fibrosis transmembrane conductance regulator (CFTR) cDNA has been successfully demonstrated in both transgenic mice and in human patients. The formulations and delivery protocols employed by various investigators are discussed in detail and summarized for comparison in a table. While all investigators show transfection and expression of the transgene to some extent, the experimental conditions vary widely, greatly frustrating attempts to establish common modalities or underlying mechanisms. The numerous safety studies both in experimental animals and in human volunteers are also discussed in detail. Again, the absence of standard protocols as well as a lack of rigorous toxicity study design and analysis precludes generalizations as to the innocuousness of cationic liposomes and cationic liposome plasmid complexes. Suitably designed toxicity, pharmacokinetic and metabolic studies of these new 'drug' modalities, and clearer definitions of the expected outcomes of efficacy and toxicity are desirable.