Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis

Gene transfer is an attractive option to treat the basic defect in cystic f ibrosis. In a double-blind, placebo-controlled, rising-dose tolerance study in the nasal epithelium, we tested the safety and efficacy of a cationic l iposome [p-ethyl-dimyristoylphosphadityl choline (EDMPC) cholesterol] compl exed with an expression plasmid containing hCFTR cDNA. Eleven adult CF pati ents were studied in a protocol that allowed comparisons within individual subjects: vector and placebo were sprayed into alternate nostrils at interv als over 7 h. After dosing, vector-specific DNA was present in nasal ravage of all subjects for up to 10 days. There were no adverse events. The vecto r-treated epithelium did not exhibit a significant increase in CFTR-mediate d Cl- conductance from baseline and was not different from the placebo-trea ted nostril: mean Delta CFTR Cl- conductance, mV +/- SEM, -1.6 +/- 0.4 vs - 0.6 +/- 0.4 respectively. CFTR-mediated Cl- conductance increased toward no rmal during repetitive nasal potential difference measurements over the 3 d ays before dosing which influenced the postdosing calculations. No vector-s pecific mRNA was detected in the nasal epithelial scrape biopsies, although endogenous CFTR mRNA was detected in all subjects. We conclude that the li pid-DNA complex is safe, but did not produce consistent evidence of gene tr ansfer to the nasal epithelium by physiologic or molecular measures.