Fig. 2.Transformants releasing E␤C suffered less damage than control lines when EPNs were present. (A) Root damage measured on plants that had received neither WCR eggs nor nematodes was minimal, and there was no difference between transformed and nontransformed plants (n ϭ 5, P ϭ 0.87). (B) Root damage on plants that received only WCR eggs, but no nematodes, was substantial. Again, no significant difference was found between the transformed and nontransformed plants (n ϭ 5, P ϭ 0.18). (C) In plots that received WCR eggs and H. megidis, roots from transformed plants (pooled) had significantly less damage than roots from control lines (n ϭ 30, P ϭ 0.007). Approximately one-quarter of the transformed plants were found not to emit E␤C. Removing these plants from the statistical analysis did not significantly affect the results. The letters above the bars indicate significant differences within a graph. Error bars indicate standard errors.

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Previous studies have demonstrated that delivery of a recombinant adeno-associated virus (AAV) vector encoding the complete human cystic fibrosis transmembrane regulator (CFTR) cDNA (tgAAVCF) to the nose, sinus, and lungs of subjects with cystic fibrosis (CF) was safe and well tolerated. In a small randomized, double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals, encouraging but non-significant trends in pulmonary function and induced sputum interleukin 8 (IL-8) levels were seen at early time points. This larger study was conducted to verify these trends. One hundred and two subjects aged 12 years and older with mild-to-moderate cystic fibrosis (forced expiratory flow in 1 sec [FEV1]:60% predicted) were randomized to two aerosolized doses of 1x10(13)DNase-resistant particles of tgAAVCF (n=51) or matching placebo (n=51) administered 30 days apart. Although tgAAVCF was well tolerated, the study did not meet its primary efficacy end point of statistically significant improvement in FEV1 30 days after initial administration of tgAAVCF compared with placebo. There were no significant differences in spirometric lung function over time, induced sputum biologic markers, or days of antibiotic use in either treatment group. Thus repeated doses of aerosolized tgAAVCF were safe and well tolerated, but did not result in significant improvement in lung function over time. Because gene transfer is the simplest, most basic way to correct the underlying genetic defect that leads to disease in CF, further research is warranted to develop an effective gene transfer agent for the treatment of CF.

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