Gene transfer to the airways of patients with cystic fibrosis (CF) could represent a treatment breakthrough. However, nineteen years after the identification of the CFTR gene, we still lack new therapies based on advancements in our understanding of the genetic basis of CF. While the principles of gene transfer are sound and have been demonstrated in cell culture and animal models, the promise of the approach has not yet been translated into """"""""gene therapy"""""""" for CF. One reason for this delay has been the absence of an animal model that mimics the disease in which to test novel therapies. To overcome this bottleneck, the investigators of this PPG recently developed a new model of the disease by disrupting CFTR gene function in pigs, whose lungs resemble those of humans. This remarkable model exhibits features of CF in humans, including meconium ileus, pancreatic insufficiency, liver and gall bladder disease, and absence of CFTR anion transport in nasal and tracheal epithelia. Early signs in the longestlived animal suggest the spontaneous development of pulmonary inflammation and infection. In this Program, four senior and highly accomplished investigators will seize this unique opportunity and use CFTR-/- and CFTR AF508/AF508 pigs to study gene based therapies for lung disease. Project 1 focuses on the use of lentiviral vectors with envelopes that target the apical surface of epithelia to attain persistent expression of CFTR. They will develop an optimal lentiviral envelope for gene transfer to pig epithelia and test this in the CFTR AF508/AF508 model. Project 2 will use directed evolution of AAV vectors to develop more efficient AAV capsids for targeting the epithelial cells of the airways. They will then use these novel tools to transduce ain/vay epithelia and express CFTR with a goal of preventing or delaying the onset of pulmonary manifestations of CF in a pig model. Project 3 will continue to develop the CF pig model to address key issues including: correction of meconium ileus, the identification of modifier genes of the CF phenotype, and investigating the timing of CFTR expression needed to have a therapeutic effect. Project 4 will develop targeted RNA interference (RNAi) as a therapeutic tool for CF. Proof of principle studies will target the chemokine IL-8 using both viral and non-viral delivery approaches. The Project Leaders have an outstanding track record of collaboration in CF, and here they are focused on a common goal. Their research is highly creative and is supported by four cores that provide innovative services and key infrastructure. The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease.
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