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- Title
Widespread and efficient marker gene expression in the airway epithelia of fetal sheep after minimally invasive tracheal application of recombinant adenovirus in utero.
- Authors
Peebles, D.; Gregory, L.G.; David, A.; Themis, M.; Waddington, S.N.; Knapton, H.J.; Miah, M.; Cook, T.; Lawrence, L.; Nivsarkar, M.; Rodeck, C.; Coutelle, C.
- Abstract
Cystic fibrosis is a common lethal genetic disease caused by functional absence of the cystic fibrosis transmembrane conductance regulator (CFTR). Although a candidate disease for in utero gene therapy, demonstration of potentially therapeutic levels of transgene expression in the fetal airways after minimally invasive gene delivery is a mandatory prerequisite before application of this approach in humans can be considered. We report here on the delivery of a ß-galactosidase expressing adenovirus directly to the airways of fetal sheep in utero using ultrasound-guided percutaneous injection of the trachea in the fetal chest. Injection of adenoviral particles to the fetal airways was not associated with mortality and resulted in low-level expression in the peripheral airways. However, complexation of the virus with DEAE dextran, which confers a positive charge to the virus, and pretreatment of the airways with Na-caprate, which opens tight junctions, increased transgene expression, and a combination of these two enhancers resulted in widespread and efficient gene transfer of the fetal trachea and bronchial tree. Using a percutaneous ultrasound-guided injection technique, we have clearly demonstrated proof of principle for substantial transgene delivery to the fetal airways providing levels of gene expression that could be relevant for a therapeutic application of CFTR expressing vectors.Gene Therapy (2004) 11, 70-78. doi:10.1038/sj.gt.3302130
- Subjects
BETA-galactosidase; ADENOVIRUSES; CYSTIC fibrosis; GENE expression; AIRWAY (Anatomy); SHEEP
- Publication
Gene Therapy, 2004, Vol 11, Issue 1, p70
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3302130