This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0189OCv1 34/1/56    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, X. Articles by Engelhardt, J. F. Search for Related Content PubMed PubMed Citation Articles by Liu, X. Articles by Engelhardt, J. F.

Species-Specific Differences in Mouse and Human Airway Epithelial Biology of Recombinant Adeno-Associated Virus Transduction

Department of Anatomy and Cell Biology, Department of Internal Medicine, and Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, College of Medicine, University of Iowa, Iowa City, Iowa

Correspondence and requests for reprints should be addressed to John F. Engelhardt, Ph.D., Roy J. Carver Chair of Molecular Medicine, Department of Anatomy and Cell Biology, University of Iowa School of Medicine, 51 Newton Road, Room 1–111 BSB, Iowa City, IA 52242. E-mail: john-engelhardt{at}uiowa.edu

Differences in airway epithelial biology between mice and humans have presented challenges to evaluating gene therapies for cystic fibrosis (CF) using murine models. In this context, recombinant adeno-associated virus (rAAV) type 2 and rAAV5 vectors have very different transduction efficiencies in human air–liquid interface (ALI) airway epithelia (rAAV2 rAAV5) as compared with mouse lung (rAAV5 >> rAAV2). It is unclear if these differences are due to species-specific airway biology or limitations of ALI cultures to reproduce in vivo airway biology. To this end, we compared rAAV2 and rAAV5 transduction biology in mouse and human ALI cultures, and investigated the utility of murine F508 cystic fibrosis transmembrane conductance regulator (CFTR) ALI epithelia to study CFTR complementation. Our results demonstrate that mouse ALI epithelia retain in vivo preferences for rAAV serotype transduction from the apical membrane (rAAV5 >> rAAV2) not seen in human epithelia (rAAV2 rAAV5). Viral binding of rAAV2 and rAAV5 to the apical surface of mouse ALI airway epithelia was not significantly different, and proteasome-modulating agents significantly enhanced rAAV2 transduction to a level equivalent to that of rAAV5 in the presence of these agents, suggesting that the ubiquitin/proteasome pathway represents a more significant intracellular block for rAAV2 transduction of mouse airway epithelia. Interestingly, cAMP-inducible chloride currents were enhanced in F508CFTR mouse ALI cultures, making this model incompatible with CFTR complementation studies. These studies emphasize species-specific differences in airway biology between mice and humans that significantly influence the use of mice as surrogate models for rAAV transduction and gene therapy for CF.

Key Words: recombinant adeno-associated virus • airway model • serotype • tropism

This article has been cited by other articles:

				X. Liu, M. Luo, L. Zhang, W. Ding, Z. Yan, and J. F. Engelhardt Bioelectric Properties of Chloride Channels in Human, Pig, Ferret, and Mouse Airway Epithelia Am. J. Respir. Cell Mol. Biol., March 1, 2007; 36(3): 313 - 323. [Abstract] [Full Text] [PDF]

				Z. Yan, D. C. M. Lei-Butters, X. Liu, Y. Zhang, L. Zhang, M. Luo, R. Zak, and J. F. Engelhardt Unique Biologic Properties of Recombinant AAV1 Transduction in Polarized Human Airway Epithelia J. Biol. Chem., October 6, 2006; 281(40): 29684 - 29692. [Abstract] [Full Text] [PDF]