Gene transfer to the airways of patients with cystic fibrosis (CF) could represent a major therapeutic advance for this lethal disease. Although previous work in vitro, in animals and in people with CF has established the feasibility of gene transfer, it has also revealed the limitations of current approaches. The two greatest barriers are limited efficiency of gene transfer from the apical surface of differentiated airway epithelia and limited persistence of expression. The projects in this program utilize novel approaches and models to overcome these barriers. Recent work showed that adeno-associated viruses-5 (AAV5) vectors target the apical surface of differentiated airway epithelia, which makes them an attractive vector. Project by Welsh (subproject 0001) focuses on overcoming the limited packaging capacity of AAV vectors and will test the long-term potential of AAV5 vectors to correct the CF C1- transport defect. In Project by Zabner (subproject 0004), the investigators will study how AAV5 interacts with its apical membrane receptors, sialic acid and PDGF-receptor. They combine this with a structural analysis of the virus and its receptor. Project by McCray (subproject 0005) takes a related approach to achieving apical targeting and long-lasting expression by developing LCMV-pseudotyped lentivirus vectors. They investigate the virus:receptor interactions and will test the ability to achieve persistent expression in airway epithelia. Our ability to answer several crucial questions about gene transfer has been hampered by the lack of an animal model that faithfully reproduces the lung disease found in humans with CF. Project by Welsh (subproject 0006) addresses this problem by developing a porcine model of CF. The PPG benefits from outstanding support by the In Vitro Models and Cell Culture Core, the Gene Transfer Vector Core, and the Administrative Core. These studies will take us closer to our long-term goal of developing new therapies for people who suffer from CF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Banks-Schlegel, Susan P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
Zip Code
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
Montoro, Daniel T; Haber, Adam L; Biton, Moshe et al. (2018) A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560:319-324
Lynch, Thomas J; Anderson, Preston J; Rotti, Pavana G et al. (2018) Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium. Cell Stem Cell 22:653-667.e5
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

Showing the most recent 10 out of 184 publications