Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect.
Several problems limit the application of gene transfer to correct the cystic fibrosis (CF) Cl(-) transport defect in airway epithelia. These include inefficient transduction with vectors applied to the apical surface, a low rate of division by airway epithelial cells, failure of transgene expression to persist, and immune responses to vectors or vector-encoded proteins. To address these issues, we used a feline immunodeficiency virus-based (FIV-based) vector. FIV vector formulated with a calcium chelator transduced fully differentiated, nondividing human airway epithelia when applied to the apical surface. FIV-based vector encoding the cystic fibrosis transmembrane conductance regulator cDNA corrected the Cl(-) transport defect in differentiated CF airway epithelia for the life of the culture (>3 months). When this approach was applied in vivo, FIV vector expressing beta-galactosidase transduced 1-14% of adult rabbit airway epithelia. Transduced cells were present in the conducting airways, bronchioles, and alveoli. Importantly, gene expression persisted, and cells with progenitor capacity were targeted. FIV-based lentiviral vectors may be useful for the treatment of genetic lung diseases such as CF. This article may have been published online in advance of the print edition.
Wang
G
G
Program in Gene Therapy, Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Slepushkin
V
V
Zabner
J
J
Keshavjee
S
S
Johnston
J C
JC
Sauter
S L
SL
Jolly
D J
DJ
Dubensky
T W
TW
Davidson
B L
BL
McCray
P B
PB
D000818:Animals; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000235:genetics*; D008168:Lung / Q000473:pathology*; D013997:Time Factors; D014132:Trachea / Q000378:metabolism; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000235:genetics
C505032:CFTR protein, human; D002712:Chlorides; D018076:DNA, Complementary; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D001616:beta-Galactosidase