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Journal of Virology, December 1998, p. 9818-9826, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Influence of Cell Polarity on Retrovirus-Mediated Gene Transfer to Differentiated Human Airway Epithelia

Guoshun Wang,1 Beverly L. Davidson,2 Paul Melchert,1 Vladimir A. Slepushkin,2 Helmuth H. G. van Es,3 Mordechai Bodner,4 Doug J. Jolly,4 and Paul B. McCray Jr.1,*

Departments of Pediatrics1 and Internal Medicine,2 University of Iowa College of Medicine, Iowa City, Iowa 52242; IntroGene, Leiden, The Netherlands3; and Chiron Technologies-Center for Gene Therapy, San Diego, California 921214

Received 6 May 1998/Accepted 17 August 1998

Gene transfer with recombinant murine leukemia viruses (MuLV) provides the potential to permanently correct inherited lung diseases, such as cystic fibrosis (CF). Several problems prevent the application of MuLV-based recombinant retroviruses to lung gene therapy: (i) the lack of cell proliferation in mature pulmonary epithelia, (ii) inefficient gene transfer with a vector applied to the apical surface, and (iii) low titers of many retroviral preparations. We found that keratinocyte growth factor (KGF) stimulated proliferation of differentiated human tracheal and bronchial epithelia. Approximately 50% of epithelia divided in response to KGF as assessed by bromodeoxyuridine histochemistry. In airway epithelia stimulated to divide with KGF, high-titer ampho- and xenotropic enveloped vectors preferentially infected cells from the basal side. However, treatment with hypotonic shock or EGTA transiently increased transepithelial permeability, enhancing gene transfer with the vector applied to the mucosal surfaces of KGF-stimulated epithelia. Up to 35% of cells expressed the transgene after gene transfer. By using this approach, cells throughout the epithelial sheet, including basal cells, were targeted. Moreover, the Cl- transport defect in differentiated CF airway epithelia was corrected. These findings suggest that barriers to apical infection with MuLV can be overcome.

* Corresponding author. Mailing address: Department of Pediatrics, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242. Phone: (319) 356-4866. Fax: (319) 356-7171. E-mail: paul-mccray{at}uiowa.edu.

Journal of Virology, December 1998, p. 9818-9826, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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