Cystic fibrosis (CF) lung disease is caused by a single gene defect which leads sequentially over years to abnormal epithelial electrolyte transport, viscous mucus secretions, obstruction of the small airways, infection, inflammation, pulmonary fibrosis, respiratory failure and death. Current approaches to gene therapy utilize a transient non- integrating virus, adenovirus, administered to adult CF patients, after irreversible lung injury has occurred. We have developed an alternative vector system, based on adeno-associated virus (AAV), a nonpathogenic human isolate which integrates stably with high efficiency into the genome of respiratory epithelial cells, both in vivo and in vitro. This type of vector might be used for stable correction of the gene defect early in life, prior to onset of irreversible lung disease. We propose to test AAV vector safety and efficacy in nonhuman primates. Clinical studies will then test the hypotheses that l) AAV-CF gene vector administration will result in recombinant CFTR protein expression and correction of airway epithelial electrolyte transport in adult CF patients, at a vector dose which results in minimal or no toxicity, and 2) that the duration of AAV- CFTR vector expression will be longer than that observed with adeno-CFTR vectors. It is hoped that these trials will lay the groundwork for long- term stable correction of the CF defect in the lungs of younger CF patients, and thereby extend and improve the quality of their lives.
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