AdCFTR for Cystic Fibrosis
Samuel C. Wadsworth
Cystic fibrosis (CF) is a recessive, monogenic, lethal disorder caused by defects in a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR) . Approximately 60,000 individuals are affected worldwide. CFTR is an ion channel that functions to allow the secretion of chloride from within cells. While epithelia throughout the body are affected by mutations in CFTR , the predominant cause of morbidity and mortality in CF patients is lung disease. As there is no known way to restore airway cells to the lung following ex vivo manipulation, treatment of airway disease in vivo is required. Thus the rationale for CF gene therapy is clear: Introduce a copy of the normal CFTR cDNA (because the gene is very large1) into airway cells within the lung to restore CFTR activity. The number of CFTR molecules per airway cell is low, suggesting that even a modest level of vector-directed gene expression would suffice. Moreover, it has been estimated that restoration of CFTR activity to 3 to 6% of airway cells would be sufficient to restore the chloride and fluid secretion properties of the airway epithelium. The rationale for attempting CF gene therapy with Ad vectors also seems clear: well defined molecular biology, ability to infect nondividing cells, potential for large-scale growth at high titer, and ability to infect cells within the lung. However, since the target cells within the lung are not permanent, repeated administration will be required for Ad-based CF gene therapy, increasing the likelihood of the generation of neutralizing antibodies and the attendant potential to limit greatly the efficacy of long term treatment.