Measure and Interpretation of CF Gene Therapy Trial Results
Authors: Eric Alton, Duncan Geddes, Deborah Gill, Andy Greening, Chris Higgins, Steve Hyde, J.Alastair Innes, David Porteous, Myra Stern
Journal: Molecular Therapy (2000)

To the Editor: We read with interest the trial reported by Noone et al. regarding the use of a cationic liposome (EDMPC) to transfer the CFTR gene into the nasal epithelium of CF subjects (1Noone P.G. et al.Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis.Mol. Ther. 2000; 1: 105-114Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). The study reported no significant improvement in the key parameter of chloride conductance when assessed in vivo in the nasal epithelium of these patients. Much of the discussion of the paper related to a comparison to previous similar studies, using cationic liposome in the nose and lungs of CF patients. We wish to express our concern regarding some of the authors’ comments, in that they could potentially be misunderstood. 1The authors exhort the field to be as rigorous and critical as they were about study design. Specifically, they commented on the apparent novelty of their study in using three sequential baseline measurements with which to compare the postdosing assessments. The authors undertook nine nasal PD measurements within a 10-day period and found significant changes in the third day pretreatment compared to the first 2 days. Each of our reported nasal trials also used three sequential measurements of baseline. We did not undertake the predosing nor postdosing PD measurements on a daily basis because of concerns that too many measurements over a short time period could potentially produce the types of effects Noone et al. reported. Importantly, we carefully and rigorously analyzed our posttreatment data against all three, only two, or only one baseline measurement in exactly the same fashion as reported by Noone et al. We did not see a similar effect and indeed, if anything, found the PD measurement closest to the time point of administration to be the lowest, i.e., most cystic value. Thus, in summary, we are sure the Noone et al. comments on this type of protocol are of great relevance to any future studies using their daily measurement protocol. They should not, however, be related to the differing protocols used by others.2Noone et al. described the changes noted in our studies as “small” or “very small,” being around 2 to 4 mV. As with all scientific studies, it is key to indicate the denominator for such measurements and, second, to record whether they were significantly different compared to a placebo group. The “small” changes to which Noone et al. referred represent approximately 20% restoration of the basic CF defect toward normal values and were significantly different from the placebo group.3Noone et al. questioned several points of detail within the studies. In particular, they commented on their use of low chloride and isoproterenol, which they suggested was in contrast to variable protocols being used by other groups. However, the majority of the studies that they referred to also used the same low chloride and isoproterenol, since we and others have clearly reported this to be the optimal discriminator between CF and non-CF.4They referred to the lung trial recently reported (2Alton E.W. et al.Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: A double-blind placebo-controlled trial.Lancet. 1999; 353: 947-954Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar), which showed a significant degree of correction in the lower airways of CF subjects, following administration of CFTR lipid 67 complex. They suggested that the low chloride response reported may have been the result of inflammation, as evidenced by flu-like symptoms. We rigorously looked for inflammation, including repeated lower airway biopsies and induced sputum, and saw no evidence for this.5We have also tested EDMPC, the cationic liposome used in the Noone et al. study, and directly compared this with other liposomes such as DC Cholesterol and lipid 67 in a wide range of in vitro and in vivo studies. Entirely consistent with the reported findings in the Noone et al. paper, we find little evidence of gene transfer efficiency using EDMPC. We suggest that this may be a key determining factor in the outcome of the reported study.