Cystic Fibrosis has emerged as an important early model in the development of somatic gene therapies. Recombinant adenoviruses are potentially useful vehicles for gene delivery in the CF lung because of high efficiencies of gene transfer demonstrated with animal models. In most experiments, however, expression of the recombinant gene has been transient and associated with inflammation in areas of the lung into which the recombinant virus was targeted. An important premise of this grant is that recombinant adenoviruses will lead to an effective cure for cystic fibrosis, however, the current technologies fall far short of achieving this goal. An additional limitation is our relative lack of knowledge about primary pathogenesis leading to a paucity of useful surrogate endpoints to predict clinical efficacy. This SCOR application represents an organized effort in the context of the Institute for Human Gene Therapy at the University of Pennsylvania to develop recombinant adenoviral technology for CF gene therapy. Important hypotheses that provide the foundation for this application is cellular and humoral immune response to first generation recombinant adenoviruses underlie important limitations that have been encountered with early preclinical and clinical models. The first project directed by Dr. Jim Wilson attempts to characterize the specific nature of the immune responses that limit first generation technology and to develop improved recombinant adenoviruses to circumvent these problems. The second project by Dr. John Engelhardt utilizes useful animal models to better define the primary pathogenic mechanisms responsible for CF lung disease. Promising new adenoviral technologies will be evaluated in these animal models in an attempt to predict clinical efficacy. The final project by Dr. Cynthia Robinson utilizes improved technologies that emerge from Projects I and II in human clinical trials. The goal of the human pilot experiments is to identify specific configurations of the recombinant virus and conditions of its administration that lead to safe and prolonged genetic correction. Principles of primary pathogenesis learned in Projects II will be used in the human trials to evaluate surrogate endpoints of clinical efficacy. Existing cores in the Institute for Human Gene Therapy will be used to support these activities. These include the following: 1) Vector Core - evaluation of biological samples for the presence of recombinant nucleic acid sequences; 2) Morphology Core - evaluation of tissues using techniques of light and electron microscopy for the presence and consequences of recombinant gene expression; 3) Animal Models Core - responsible for performing preclinical toxicology experiments in rodents and primates in preparation for human trials; 4) Human Applications Laboratory - a manufacturing facility for the production of clinical grade viral production lots and the evaluation of biological samples for transgene sequences, and 5) Administrative Core - will provide administrative support to the program.
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