LIPOSOMAL DNA VECTORS FOR CYSTIC-FIBROSIS GENE-THERAPY - CURRENT APPLICATIONS, LIMITATIONS, AND FUTURE-DIRECTIONS

The etiology of cystic fibrosis (CF), current therapies, and recent ex perimental molecular based therapies are briefly described including t he use of recombinant human deoxyribonuclease I (rhDNase), nonsteroida l antiinflammatory drugs (ibuprofen), the sodium channel blocking diur etic amiloride, and uridine triphosphate (UTP), a chloride secretagogu e. The original approach to CF gene therapy using recombinant replicat ion defective adenovirus and its potential benefits as well as shortco mings are also briefly discussed. More recently, the use of nonviral c ationic liposome plasmid complexes to deliver cystic fibrosis transmem brane conductance regulator (CFTR) cDNA has been successfully demonstr ated in both transgenic mice and in human patients. The formulations a nd delivery protocols employed by various investigators are discussed in detail and summarized for comparison in a table. While all investig ators show transfection and expression of the transgene to some extent , the experimental conditions vary widely, greatly frustrating attempt s to establish common modalities or underlying mechanisms. The numerou s 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 prec ludes generalizations as to the innocuousness of cationic liposomes an d cationic liposome plasmid complexes. Suitably designed toxicity, pha rmacokinetic and metabolic studies of these new 'drug' modalities, and clearer definitions of the expected outcomes of efficacy and toxicity are desirable.