Gene transfer to airway epithelia could provide an important new treatment for cystic fibrosis (CF) lung disease. A common problem with current vector systems is that the efficiency of gene transfer to differentiated human airway epithelia is limited. In work supported by this Program, we have investigated the advantages and limitations of adenoviral and non-viral vectors. By combining the two systems, we have utilized their unique advantages and avoided many of the limitations. In so doing, we have developed novel vector systems, including Ad:CaPi co- precipitates. This vector shows markedly enhanced gene transfer to differentiated airway epithelia. Moreover, preliminary data suggest that the Ad:CaPi co-precipitates do not produce additional toxicity. In this Project we focus on six questions. 1) How do Ad:CaP co-precipitates infect cells? 2) What properties of Ad:CaPi co-precipitates are important for gene transfer? 3) What cells are targeted by Ad:CaPi co- precipitates and other complexes? 4) Can complexes shield adenovirus from neutralizing antibodies? 5) Can other vectors, including AAV, be incorporated into CaPi co-precipitates? The results of these studies will improve our understanding of the mechanisms and barriers and gene transfer, will have application of several different vector systems, and should ultimately lead to improved gene transfer for CF airway disease.
| Meyerholz, David K; Sieren, Jessica C; Beck, Amanda P et al. (2018) Approaches to Evaluate Lung Inflammation in Translational Research. Vet Pathol 55:42-52 |
| Rosen, Bradley H; Evans, T Idil Apak; Moll, Shashanna R et al. (2018) Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets. Am J Respir Crit Care Med 197:1308-1318 |
| Mao, Suifang; Shah, Alok S; Moninger, Thomas O et al. (2018) Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling. Proc Natl Acad Sci U S A 115:1370-1375 |
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| Meyerholz, David K; Stoltz, David A; Gansemer, Nick D et al. (2018) Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs. Lab Invest 98:825-838 |
| Gray, Robert D; Hardisty, Gareth; Regan, Kate H et al. (2018) Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis. Thorax 73:134-144 |
| Thornell, Ian M; Li, Xiaopeng; Tang, Xiao Xiao et al. (2018) Nominal carbonic anhydrase activity minimizes airway-surface liquid pH changes during breathing. Physiol Rep 6: |
| Reznikov, Leah R; Meyerholz, David K; Abou Alaiwa, Mahmoud et al. (2018) The vagal ganglia transcriptome identifies candidate therapeutics for airway hyperreactivity. Am J Physiol Lung Cell Mol Physiol 315:L133-L148 |
| Meyerholz, David K; Beck, Amanda P; Goeken, J Adam et al. (2018) Glycogen depletion can increase the specificity of mucin detection in airway tissues. BMC Res Notes 11:763 |
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