Our lab group demonstrated the first successful CFTR gene transfer by AAV2CFTRto pulmonary epithelium of rodents, non-human primates, and human CF volunteers. We showed that AAV vectors have great potential as gene therapeutic agents. Studies originating from a prior budget period lead to the first use of rAAV in humans. Many pre-clinical and clinical trials showed that AAV vectors can be used safely. However, unlike our results in primates, CFTR mRNA expression has not been demonstrated in human studies. In both non-human primates and humans, transduction requires the instillation of large titers of recombinant AAV2. Thus the goal of current budget period was to evaluate new AAV-CFTRserotypes containing more powerful promoters of CFTR expression. This effort was successful and lead to the choice of AAV1-26-264CFTR driven by a powerful chicken beta actin (CBA) promoter. The overall goal the renewal is to provide the critical next steps in developing AAV1 -CFTR as a therapeutic agent. The hypothesis to be tested is that development of a new AAV1-26-264 vector serotype with CBA promoter delivered to the airways will be safe and result in increased levels of recombinant gene expression. Three overall questions will be addressed. Will dosing with a pseudotyped AAV 1 vector leads to increased expression from the recombinant vector? Will dosing with a pseudotyped AAV 1 vector leads to increased immune response? Does aerosol delivery of new higher titer AAV1-CFTRvectors administered to CF patients with Mild Lung Disease lead to widespread gene transfer and CFTR expression?

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National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Johns Hopkins University
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