Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia.
We developed a helper-dependent adenoviral vector for cystic fibrosis lung gene therapy. The vector expresses cystic fibrosis transmembrane conductance regulator (Cftr) using control elements from cytokeratin 18. The vector expressed properly localized CFTR in cultured cells and in the airway epithelia of mice. Cftr RNA and protein were present in whole lung and bronchioles, respectively, for 28 days after a vector dose. Acute inflammation was minimal to moderate. To test the therapeutic potential of the vector, we challenged mice with a clinical strain of Burkholderia cepacia complex (Bcc). Cftr knockout mice (but not Cftr+/+ littermates) challenged with Bcc developed severe lung histopathology and had high lung bacteria counts. Cftr knockout mice receiving gene therapy 7 days before Bcc challenge had less severe histopathology, and the number of lung bacteria was reduced to the level seen in Cftr+/+ littermates. These data suggest that gene therapy could benefit cystic fibrosis patients by reducing susceptibility to opportunistic pathogens.
Koehler
David R
DR
Programme in Lung Biology Research and Canadian Institutes of Health Research Group in Lung Development, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
Sajjan
Umadevi
U
Chow
Yu-Hua
YH
Martin
Bernard
B
Kent
Geraldine
G
Tanswell
A Keith
AK
McKerlie
Colin
C
Forstner
Janet F
JF
Hu
Jim
J
D000704:Analysis of Variance; D000818:Animals; D019121:Burkholderia Infections / Q000235:genetics / Q000517:prevention & control*; D019556:COS Cells; D002522:Chlorocebus aethiops; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000502:physiology*; D012141:Respiratory Tract Infections / Q000235:genetics / Q000517:prevention & control*; D014162:Transfection
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator