Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect

被引:137
作者
Wang, GS
Slepushkin, V
Zabner, J
Keshavjee, S
Johnston, JC
Sauter, SL
Jolly, DJ
Dubensky, TW
Davidson, BL
McCray, PB
机构
[1] Univ Iowa, Coll Med, Dept Pediat, Program Gene Therapy, Iowa City, IA 52242 USA
[2] Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA
[3] Univ Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada
[4] Chiron Technol, Ctr Gene Therapy, San Diego, CA 92121 USA
关键词
D O I
10.1172/JCI8390
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 CI: 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.
引用
收藏
页码:R55 / R62
页数:8
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