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Title: Evaluation of endogenous progenitor cells as vehicles or targets for airway disease therapy
Author: Leoni, Guilia
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Cell-based therapy may provide a novel therapeutic option for treating lung diseases such as cystic fibrosis (CF). Current preclinical studies have had limited success, but have highlighted that cell source and delivery methods may be important variables. The aim of this thesis was to develop a new model for assessment of cell-based treatment strategies for airway disease. I hypothesised (a) that cell engraftment may be enhanced if transplanted cells are directly applied to the airways (topical administration), (b) that prolonged contact time between transplanted cells and the epithelial surface may enhance engraftment and (c) that endogenous lung stem/progenitor cells, and in particular a population of airway basal cells (BCs), may be more likely to engraft than stem/progenitor cells from other tissues, since these cells are already programmed to differentiate into adult respiratory cells. In addition, I assessed if gene transfer into airway BCs is feasible in vivo and ex vivo with the aim of establishing proof-of-concept for the correction of a genetic defect. The results presented in this thesis indicate that the use of the murine nose as a target for cell therapy does not provide any substantial advantage in terms of cell engraftment compared with the more traditional mouse lung models. However, proof-of-principle of cell engraftment was demonstrated, albeit at low efficiency. Attempts to prolong contact time between the transplanted cells and the airways through application of tissue glue did not improve engraftment in mice. I also demonstrated that ex vivo and, importantly, in vivo transduction of BCs with a lentiviral vector is feasible, which may be relevant for the treatment of genetic defects such as CF. I suggest that further assessment of the strategies described in this thesis using larger animal models will be essential to overcome technical limitations encountered in the murine model, before firm conclusions about the potential of cell-therapy approaches for airway disease can be made.
Supervisor: Griesenbach, Uta ; Alton, Eric Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available