title: Factors influencing adenovirus-mediated airway transduction in fetal mice.
abstract: Intra-amniotic injection of adenovirus allows transduction of the fetal airways following natural fetal breathing movements. This administration method is promising for use in gene therapy for cystic fibrosis and other diseases for which the main target for exogenous gene expression is the lung. Here we have investigated factors that may affect the efficacy of gene transfer to the murine fetal lung. We examined marker compound distribution and transgene expression (from a first-generation adenoviral vector) at different stages of development. This demonstrated that fetal breathing movements at 15-16 days of gestation are of sufficient intensity to carry marker/vector into the fetal lungs. These movements can be significantly stimulated by the combination of intra-amniotic theophylline administration and postoperative exposure of the dam to elevated CO(2) levels. However, the most important factor for efficient and consistent pulmonary transgene delivery is the dose of adenoviral vector used, as both the degree of transduction and the percentage of lungs transduced increases with escalating viral dose.
authors.affiliation: Gene Therapy Research Group, Department of Cell and Molecular Biology, SAF Building, Imperial College, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: S M K
authors.initials: SM
authors.lastname: Buckley
authors.forename: S N
authors.initials: SN
authors.lastname: Waddington
authors.forename: S
authors.initials: S
authors.lastname: Jezzard
authors.forename: L
authors.initials: L
authors.lastname: Lawrence
authors.forename: H
authors.initials: H
authors.lastname: Schneider
authors.forename: M V
authors.initials: MV
authors.lastname: Holder
authors.forename: M
authors.initials: M
authors.lastname: Themis
authors.forename: C
authors.initials: C
authors.lastname: Coutelle
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002244:Carbon / Q000737:chemistry; D002245:Carbon Dioxide / Q000378:metabolism; D003102:Colloids / Q000737:chemistry; D003550:Cystic Fibrosis / Q000628:therapy; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D008168:Lung / Q000196:embryology*; D051379:Mice; D013806:Theophylline / Q000008:administration & dosage; D013997:Time Factors; D014132:Trachea / Q000196:embryology*; D019076:Transgenes
chemical_list: D003102:Colloids; D002245:Carbon Dioxide; D002244:Carbon; D013806:Theophylline; D000241:Adenosine