MOLECULAR STRATEGIES FOR THERAPY OF CYSTIC-FIBROSIS

Cystic fibrosis (CF), a lethal disease common to Caucasians, is charac terized by a defect in the CF transmembrane conductance regulator and the resulting defective cAMP-regulated Cl- secretion by epithelial cel ls. Clinical manifestations include both pancreatic and pulmonary insu fficiency. Traditional therapeutic modalities address these problems w ith pancreatic enzyme replacement, vitamins and nutritional supplement ation, antibiotics, and respiratory therapy. However, newer therapies directed at the specific underlying defects have emerged. In this revi ew, we discuss agents that increase Cl- secretion via preserved Cl- se cretory pathways, such as uridine triphosphate, or that enhance Na+ re sorption, such as amiloride, thereby correcting altered airway secreti ons. We also discuss agents, including deoxyribonuclease (DNase), that directly reduce sputum viscosity. CF is an early target for in vivo g ene therapy, since it is a monogenic autosomal recessive disease in wh ich restoration of normal cAMP-regulated Cl- conductance can be achiev ed by complementation with a normal gene. The early clinical gene ther apy work, with gene introduction by both viral and nonviral vectors, i s discussed.