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 cyst ic fibrosis (CF) Cl- transport defect in airway epithelia. These include in efficient transduction with vectors applied to the apical surface, a low ra te 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-ba sed) vector. FIV vector formulated with a calcium chelator transduced fully differentiated, nondividing human airway epithelia when applied to the api cal surface. FIV-based vector encoding the cystic fibrosis transmembrane co nductance regulator cDNA corrected the Cl- transport defect in differentiat ed CI: airway epithelia for the life of the culture (>3 months). When this approach was applied in vivo, FIV vector expressing beta-galactosidase tran sduced 1-14% of adult rabbit airway epithelia. Transduced cells were presen t in the conducting airways, bronchioles, and, alveoli. Importantly, gene e xpression persisted, and cells with progenitor capacity were targeted. FIV- based lentiviral vectors may be useful for the treatment of genetic lung di seases such as CF.