als is a perplexing finding. While studies of murine models have led to tremendous advances in our understanding of CF, they have been poor models of respiratory gene transfer in man, because they do not develop the severe inflammatory response and thickened mucus associated with CF lung disease [14]. Anatomical and physiological features underpin these species differences. Mice lack bronchial submucosal glands, leading to the production of fewer secretions in their lungs compared to humans [15]. In addition, Clsecretion in the murine lung is performed predominantly by an alternative Clchannel, not the CFTR channel, and CFTR mRNA levels are lower throughout the murine pulmonary epithelium than in the lungs of man [16]. Therefore, model systems that are more representative of the barriers to gene transfer in the human airway are needed to develop protocols and vectors for gene therapy of CF. The report in this issue by Emerson et al., from the UK CF Gene Therapy Consortium (www.cfgenetherapy.org.uk), investigates gene transfer in the sheep lung as an alternative large animal model for respiratory gene transfer. The size, anatomy, and physiology of sheep and human lungs are similar, and human and sheep CFTR share similarities of sequence and developmental expression. Naked DNA, or a formulation of DNA and the cationic liposome GL-67/DOPE, was deposited in specific lung segments by bronchoscopy. Levels of the reporter gene, chloramphenicol transacetylase (CAT), were assessed quantitatively at the levels of both protein and mRNA, and the inflammatory response was assessed at increasing DNA dosage levels. The authors compared their findings in the sheep with previous murine studies using similar vectors and with a similar study in the pig lung performed with a different, nonviral vector system [17]. One of the more striking differences between the studies in sheep and mice was that transfections with GL67 along with 1mM or 2 mM DNA, produced 500 or 4,400-fold less CAT protein, respectively, than was achieved in mice. Further, CAT protein levels in mouse lung after GL67 transfection were ten-fold higher than naked DNA transfection, while in sheep the difference was only three fold. By contrast, naked DNA performed equally as well as GL67 in clinical studies [18]. While further data is required for a comparison of sheep and pig lung transfections, both studies highlight how sheep and/or pig models may help bridge the gap between results in murine models of CF and results in the clinic. The use of large animal models potentially heralds a new direction and new opportunities in preclinical studies of CF gene therapy, particularly in the key area of vector developPERSPECTIVE