Cystic fibrosis (CF) is characterized by a reduced chloride secretion mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and a Na+ hyperabsorption the via amiloride-sensitive epithelial sodium channel (ENaC). Since activation of Cl- conductance failed and amiloride therapy gives only temporary relief, we proposed to inhibit Na+ hyperabsorption with antisense oligonucleotides (AON). These AON are short synthetic DNA molecules (15 - 18 bases) complementary to mRNA sequences encoding for the a-ENaC subunit. Previously, it could be demonstrated in Xenopus laevis oocytes that AON against highly conserved regions of the a- ENaC subunit inhibit Na+ absorption with high long term efficiency. Ussing chamber studies with primary cultures of human nasal epithelia cells (HNE) grown on permeable membranes also revealed a markedly reduction of Na+ hyperabsorption. The control measurements showed a large inhibition of the Na+ current through ENaC by application of amiloride. The same monolayers were then subsequently transfected with AON for 48 h and measured again. The amiloride-sensitive Na+ absorption was reduced by about 60 % after AON treatment. From these orientating studies we expect a long lasting suppression of the excessive Na+ absorption in CF by an AON therapy, thereby improving life quality of the patients.