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Journal of Virology, November 1999, p. 9446-9455, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Repeated Delivery of Adeno-Associated Virus Vectors to the Rabbit Airway

Suzanne E. Beck,1,2,* Lori A. Jones,3 Kye Chesnut,4 Scott M. Walsh,5 Thomas C. Reynolds,3 Barrie J. Carter,3 Frederic B. Askin,6 Terence R. Flotte,4 and William B. Guggino1,2,7,*

Eudowood Division of Pediatric Respiratory Sciences1 and Departments of Pediatrics,2 Physiology,7 Biomedical Engineering,5 and Pathology,6 The Johns Hopkins University School of Medicine, Baltimore, Maryland; Gene Therapy Center of the University of Florida, Gainesville, Florida4; and Targeted Genetics Corporation, Seattle, Washington3

Received 18 March 1999/Accepted 16 July 1999

Efficient local expression from recombinant adeno-associated virus (rAAV)-cystic fibrosis (CF) transmembrane conductance regulator (CFTR) vectors has been observed in the airways of rabbits and monkeys for up to 6 months following a single bronchoscopic delivery. However, it is likely that repeated administrations of rAAV vectors will be necessary for sustained correction of the CF defect in the airways. The current study was designed to test the feasibility of repeated airway delivery of rAAV vectors in the rabbit lung. After two doses of rAAV-CFTR to the airways, rabbits generated high titers of serum anti-AAV neutralizing antibodies. Rabbits then received a third dose of a rAAV vector containing the green fluorescent protein (GFP) reporter gene packaged in either AAV serotype 2 (AAV2) or serotype 3 (AAV3) capsids. Each dose consisted of 1 ml containing 5 × 109 DNase-resistant particles of rAAV vector, having no detectable replication-competent AAV or adenovirus. Three weeks later, GFP expression was observed in airway epithelial cells despite high anti-AAV neutralizing titers at the time of delivery. There was no significant difference in the efficiency of DNA transfer or expression between the rAAV3 and rAAV2 groups. No significant inflammatory responses to either repeated airway exposure to rAAV2-CFTR vectors or to GFP expression were observed. These experiments demonstrate that serum anti-AAV neutralizing antibody titers do not predict airway neutralization in vivo and that repeated airway delivery rAAV allows for safe and effective gene transfer.

* Corresponding author. Mailing address: The Johns Hopkins University School of Medicine, WBSB 210, 725 Rutland Ave., Baltimore, MD 21205. Phone: (410) 955-7166. Fax: (410) 955-0461. E-mail for Suzanne E. Beck: sbeck{at}jhmi.edu. E-mail for William B. Guggino: wguggino{at}jhmi.edu.

Journal of Virology, November 1999, p. 9446-9455, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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