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J. Virol. doi:10.1128/JVI.00227-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

SUCCESSFUL RE-ADMINISTRATION OF LENTIVIRAL VECTOR TO NASAL EPITHELIA WITHOUT BLOCKING IMMUNE RESPONSES

Program in Gene Therapy, Carver College of Medicine Department of Pediatrics, and Dows Institute for Dental Research Department of Periodontics, The University of Iowa, Iowa City, IA 52242

^* To whom correspondence should be addressed. Email: patrick-sinn{at}uiowa.edu.

	Abstract

For many envisioned applications of lentiviral vectors as tools in respiratory biology and therapeutic gene delivery, the efficiency of gene transfer must be improved. We previously demonstrated stable, persistent (>11 months) in vivo expression following a single application of a feline immunodeficiency virus (FIV)-based lentiviral vector (GP64-FIV) to murine nasal epithelia. Here we investigate the efficacy of repeatedly administering lentiviral vectors to the airways. Using quantitative bioluminescent imaging, we found that consecutive daily dosing achieved a linear increase in gene expression and greatly increased the number of epithelial cells targeted. Surprisingly, reporter gene expression also increased additively following each of 7 doses of FIV delivered over consecutive weeks (1 dose/week), without the development of systemic or local neutralizing antibodies. This approach enhanced expression of both reporter and therapeutic transgenes. Transduction efficiency achieved following a single dose of FIV expressing mouse erythropoietin was insufficient to increase hematocrit, whereas 7 consecutive daily doses significantly increased hematocrit. These unexpected results contrast strikingly with findings reported for adenoviral vectors. Prolonged gene expression has been observed in vivo following a single dose of viral vector, however, depending on the application, repeated vector administration may be necessary to achieve stable, therapeutic gene expression.