The PPO """"""""Gene Therapy for Cystic Fibrosis"""""""" proposes to develop gene transfer vectors for the therapy of CF lung disease, optimize them for efficacy and safety, and test them in an in vivo model system (mouse) and in human subjects. The PPG will combine three key elements to achieve this goal: 1) novel vector design; 2) gene targeted murine models; and 3) - efficient clinical testing of vectors in man. To accomplish this goal, a PPG consisting of three Projects, four Cores, and 12 Pilot and Feasibility Projects is proposed. Project I will focus on vector design. Adeno- associated virus (AAV), molecular conjugates, and hybrid vectors will be constructed and tested. Project II will capitalize on the availability of a spectrum of mouse models, including """"""""CF mice"""""""" and mice expressing immunologic deficiencies created by gene targeting, to maximize the efficacy and safety of gene transfer vectors. The project will place a major emphasis on the inflammation/immunologic safety aspects of gene therapy, initially focussing on adenoviral based vectors. Project III will conduct clinical studies of gene transfer using both adenoviral and liposome vectors in CF patients. For rapid and safe vector assessments, the nasal cavity will be emphasized for testing. The PPG Projects will be supported by a Cell Culture Core, a Vector Core and a Morphology/Morphometry Core . In addition, two Pilot and Feasibility Cores are proposed: the non-CF related Pilot and Feasibility Core (Core E) includes gene therapy projects directed at animal models of atherosclerosis and hemophilia; the CF-related Pilot and Feasibility Core (F), includes 10 projects, focussed on airway epithelial biology, vector design, promoter development, and animal model development/application. In summary, the PPG consists of a series of highly interactive projects designed to facilitate the design, testing, and successful use of gene transfer vectors in patients with cystic fibrosis.
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