A variety of vector strategies have been proposed to accomplish gene therapy for cystic fibrosis (CF). In this regard, a great deal of interest has focused on the utility of replication-defective adenoviral vectors to achieve direct in situ CFTR gene delivery to affected airway epithelium. Towards this goal, this vector has demonstrated the capacity to achieve efficient gene transfer in vitro to human airway epithelial cells and in vivo to intact airway epithelium in animal models. This latter capacity to accomplish relatively efficient in vivo gene delivery to pulmonary epithelia has distinguished this vector, and thus recommended its employ for human clinical gene therapy trials for CF. Despite these considerations, a number of factors have now been appreciated which have limited the utility of this vector agent for CF gene therapy, at least in its present form. In this context, vector administration has been associated with significant inflammatory and immunologic consequences. In addition, the actual efficacy of transduction of mature airway epithelium is not as efficient as initially reported. Thus, to render these vehicles useful for CF gene therapy, strategies must be developed to address the issues of vector immunogenicity as well as efficacy of target cell transduction. In this latter regard. The basis of vector transductional inefficiency for airway epithelium is understood to derive from a relative paucity of receptors for adenoviral binding and internalization. Thus, methods to redirect the virus into receptor pathways relevant to pulmonary cellular targets would be predicted to augment overall gene transfer efficacy. This approach, however, is undermined by the relative paucity of characterized pulmonary epithelial-specific receptors. Thus, the definition of such cellular markers for airway epithelium would be adjunctive to re-targeting strategies to augment adenoviral vector efficacy. It is thus our hypothesis that we can modify adenoviral tropism as a means to augment transductional efficiency of mature airway epithelium. Further, we propose that the definition of airway cell-specific markers will facilitate this approach by providing selective cellular pathways for vector targeting.
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