Tremendous progress has been made in the development of lung-directed gene therapy for cystic fibrosis (CF) using recombinant adenoviruses. Preclinical experiments and a variety of animal models have been instrumental in developing this technology and evaluating its potential efficacy and safety. Despite tremendous efforts by multiple groups in animal models, several critical issues remain regarding the feasibility of recombinant adenoviral technology for treatment of CF in humans. The improved recombinant adenoviruses developed and tested in Projects I and II will be used in pilot human experiments described in this component of the SCOR. Phase I clinical trials using first generation adenoviruses are underway at the University of Pennsylvania and in collaboration with investigators at the University of North Carolina. The protocol developed at Penn is based on lung-directed gene transfer, while the protocol at UNC has focused on characterizing the feasibility of gene therapy using nasal epithelial as a target. Both trials have been initiated and should be completed before this grant begins. In these initial trials we hope to establish a therapeutic index for first generation viruses as well as to characterize the duration of recombinant gene expression following a single administration of virus. This application is based on the hypothesis that cellular immune responses to genetically modified human airway epithelial cells in vivo will narrow the therapeutic index and limit the stability of genetic correction when using first generation viruses. Second generation recombinant viruses developed in Project I, and evaluated in both Project II and the Animal Models Core, will be used in new human pilot experiments described in this grant. Initial characterization of improved recombinant adenoviruses will utilize a protocol in which virus is targeted to both lung and nose. Safety, biological efficacy, and immunologic responses will be characterized in recipients. The most promising recombinant adenovirus will be characterized in another protocol designed to evaluate the feasibility of repeated administration. We will incorporate into these clinical protocols surrogate endpoints to better predict clinical efficacy based on the knowledge gained in Project II.
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