A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis.
A third-generation adenoviral vector containing recombinant human cystic fibrosis transmembrane conductance regulator (CFTR) gene was delivered by bronchoscope in escalating doses to the conducting airway of 11 volunteers with cystic fibrosis. Assessments of dose-limiting toxicity (DLT), efficiency of gene transfer, and cell-mediated and humoral immune responses to vector administration were performed. DLT, manifest by flulike symptoms and transient radiographic infiltrates, was seen at 2.1 x 10(11) total viral particles. A highly specific assay for gene transfer was developed using in situ hybridization with an oligoprobe against unique vector sequence. Detectable gene transfer was observed in harvested bronchial epithelial cells (<1%) 4 days after vector instillation, which diminished to undetectable levels by day 43. Adenovirus-specific cell-mediated T cells were induced in most subjects, although only mild increases in systemic humoral immune response were observed. These results demonstrate that gene transfer to epithelium of the lower respiratory tract can be achieved in humans with adenoviral vectors but that efficiency is low and of short duration in the native CF airway.
Zuckerman
J B
JB
Department of Medicine, University of Pennsylvania, and the Wistar Institute, Philadelphia 19104, USA. zuckej@mail.mmc.org
Robinson
C B
CB
McCoy
K S
KS
Shell
R
R
Sferra
T J
TJ
Chirmule
N
N
Magosin
S A
SA
Propert
K J
KJ
Brown-Parr
E C
EC
Hughes
J V
JV
Tazelaar
J
J
Baker
C
C
Goldman
M J
MJ
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics*; D001483:Base Sequence; D003550:Cystic Fibrosis / Q000276:immunology / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D015342:DNA Probes; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D008168:Lung / Q000378:metabolism*; D009500:Neutralization Tests
C505032:CFTR protein, human; D015342:DNA Probes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator