Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus

We sought to evaluate the ability of an E1(-), E3(-) adenovirus (Ad) vector (Ad(GV)CFTR10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals w ith cystic fibrosis (CF). We administered Ad(GV)CFTR10 at doses of 3 x 10(6 ) to 2 x 10(9) plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-der ived versus endogenous CFTR mRNA in airway epithelial cells prior to therap y, as well as 3 and 30 days after therapy. The data demonstrate that (a) th is strategy appears to be safe; (b) after the first administration, vector- derived CFTR cDNA expression in the CF airway epithelium is dose-dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector dose s; (c) expression is transient, lasting less than 30 days; (d) expression c an be achieved with a second administration, but only at intermediate doses , and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not clos ely correlate with induction of systemic anti-Ad neutralizing antibodies. T he major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is li mited in time. Although this can be initially overcome by repetitive admini stration, unknown mechanisms eventually limit this strategy, and further re petitive administration does not lead to repetitive expression.