Transfection of nasal mucosa with a normal alpha(1)-antitrypsin gene in alpha(1)-antitrypsin-deficient subjects: Comparison with protein therapy

We sought to determine whether a normal alpha(1)-antitrypsin (AAT) gene cou ld be expressed in respiratory epithelium and whether local expression woul d have antiinflammatory effects. In an unblinded study, we delivered a norm al AAT gene in a plasmid-cationic liposome complex to one nostril of each o f five subjects with AAT deficiency; the other, untreated nostril served as a control. AAT protein concentration in nasal lavage fluid (NALF) increase d in the transfected nostril (TN), but not in the control nostril (CN), of every subject, peaking on day 5 at levels about one-third normal (baseline CN, 4.1 +/- 1.2 mu g/mg of protein; baseline TN, 4.3 +/- 1.3; day 5 CN, 4.0 +/-: 0.5 [p = NS versus baseline]; day 5 TN, 9.0 +/- 1.7 [p < 0.5 versus b aseline]); isoelectric focusing identified the transgene-generated protein (M) in the only two patients in whom the measurement was possible. The reve rse transcriptase-polymerase chain reaction (RT-PCR), performed on NALF fro m TN and CN of four of the five subjects, was positive for transgene messag e in TN in all cases and negative in NALF from CN except for one time point in one subject. Interleukin 8 (IL-8) concentrations in NALF were elevated at baseline (normal [N = 10] = 2.5 +/- 0.5 ng/mg of protein; baseline TN = 5.5 +/- 0.8, p < 0.05 versus normal) and decreased after AAT transfection ( TN = 2.9 +/- 0.6, p < 0.05 versus baseline) but not in the control nostril (CN = 6.5 +/- 2.2, p = NS versus baseline). NALF samples taken from four of the patients while receiving intravenous AAT protein showed normal concent rations of AAT, but IL-8 concentrations (10.5 +/- 4.2 ng/mg of protein, p = NS versus baseline) were not decreased from baseline. We conclude that pla smid-cationic liposome delivery of a normal AAT gene to the respiratory epi thelium of deficient patients produces potentially therapeutic local AAT co ncentrations and that AAT gene therapy, unlike AAT protein therapy, is anti inflammatory.