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Journal of Virology, November 1999, p. 9446-9455, Vol. 73, No. 11
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.
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
*
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.
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