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- Title
Restoring ciliary function to differentiated primary ciliary dyskinesia cells with a lentiviral vector.
- Authors
Ostrowski, L E; Yin, W; Patel, M; Sechelski, J; Rogers, T; Burns, K; Grubb, B R; Olsen, J C
- Abstract
Primary ciliary dyskinesia (PCD) is a genetically heterogenous autosomal recessive disease in which mutations disrupt ciliary function, leading to impaired mucociliary clearance and life-long lung disease. Mouse tracheal cells with a targeted deletion in the axonemal dynein intermediate chain 1 (Dnaic1) gene differentiate normally in culture but lack ciliary activity. Gene transfer to undifferentiated cultures of mouse Dnaic1−/− cells with a lentiviral vector pseudotyped with avian influenza hemagglutinin restored Dnaic1 expression and ciliary activity. Importantly, apical treatment of well-differentiated cultures of mouse Dnaic1−/− cells with lentiviral vector also restored ciliary activity, demonstrating successful gene transfer from the apical surface. Treatment of Dnaic1flox/flox mice expressing an estrogen-responsive Cre recombinase with different doses of tamoxifen indicated that restoration of ∼20% of ciliary activity may be sufficient to prevent the development of rhinosinusitis. However, although administration of a β-galactosidase-expressing vector into control mice demonstrated efficient gene transfer to the nasal epithelium, treatment of Dnaic1−/− mice resulted in a low level of gene transfer, demonstrating that the severe rhinitis present in these animals impedes gene transfer. The results demonstrate that gene replacement therapy may be a viable treatment option for PCD, but further improvements in the efficiency of gene transfer are necessary.
- Subjects
LENTIVIRUS diseases; CILIARY body; CILIARY motility disorders; HEMAGGLUTININ; GENETIC transformation; LUNG disease treatment
- Publication
Gene Therapy, 2014, Vol 21, Issue 3, p253
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2013.79