Comparison between intratracheal and intravenous administration of liposome-DNA complexes for cystic fibrosis lung gene therapy.
Intratracheal (i.t.) and intravenous (i.v.) delivery of DNA-vector formulations are two strategies to obtain gene transfer to the lung, it is still uncertain, however, which of these two modes of delivery will be more effective in the treatment of cystic fibrosis and other lung diseases. In this study, we attempted to optimize formulations of the cationic liposome DODAC:DOPE (dioleoyldimethylammonium-chloride: dioleoylphosphatidylethanolamine) complexed to plasmids encoding chloramphenicol acetyltransferase for i.t. and i.v. injection into CD-2 mice and compared the two methods. Our results showed that both methods conferred reporter gene expression in the lung that was significantly higher relative to injection of plasmid DNA alone. Expression using either mode of administration was maximal 24 h after injection and declined to around 10% of day 1 levels 2 weeks after injection. For i.v. delivery of DODAC. DOPE-DNA complexes multilamellar vesicles were more effective than large unilamellar vesicles in all organs investigated. Recombinant DNA could be detected in the distal lung region following either route of administration. However, i.t. administration predominantly led to DNA deposition in epithelial cells lining the bronchioles, e.g. in clara cells, whereas i.v. administration resulted in DNA deposition in the alveolar region of the lung including type II alveolar epithelial cells.
Griesenbach
U
U
Research Institute, MRC Group in Lung Development, Hospital of Sick Children, Toronto, ON, Canada.
Chonn
A
A
Cassady
R
R
Hannam
V
V
Ackerley
C
C
Post
M
M
Tanswell
A K
AK
Olek
K
K
O'Brodovich
H
H
Tsui L-C
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001980:Bronchi; D002412:Cations; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics*; D003550:Cystic Fibrosis / Q000628:therapy*; D004847:Epithelial Cells / Q000201:enzymology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D008815:Mice, Inbred Strains; D010714:Phosphatidylethanolamines / Q000008:administration & dosage*; D011650:Pulmonary Alveoli; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage*; D014132:Trachea / Q000201:enzymology
D002412:Cations; D008081:Liposomes; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; C094877:dioleoyl phosphatidylethanolamine; C015831:dimethyldioctadecylammonium; D015500:Chloramphenicol O-Acetyltransferase