Project III, """"""""Gene Transfer In Vivo in CF Patients"""""""", proposes to identify safe and effective vectors towards the goal of gene therapy of CF lung disease. Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the CF transmembrane regulator (CFTR) gene; early death reflects progressive pulmonary disease associated with thick airway secretions and abnormal airway epithelial function. Gene transfer of the normal cftr gene to airway epithelia in vivo offers promise of improved and longer lifespan. This project will test the safety and efficacy of currently promising gene transfer vectors, and newly developed vectors, in vivo in CF patients. Initial studies will focus on an E1-deleted (replication-defective) recombinant adenovirus containing the CFTR-cDNA under a CMV-beta-actin promoter (Ad5-CB-CFTR), and cationic liposomes complexed to a CFTR plasmid with a CMV promoter (lipo-CMV-CFTR). The Ad5- CB-CFTR vector has received approval from the RAC for use in human studies.
The Specific Aims for the study of different gene transfer vectors will follow the same general paradigm, i.e., initial studies will focus on testing the safety and efficacy of these vectors for gene transfer in the nasal epithelium of CF patients. Safety studies will assess both local and systemic inflammatory and immunologic responses, including local production of inflammatory cells, cytokines, and the duration of viral shedding. Studies of biologic efficacy of gene transfer will assess the time course of any correction of ion transport defects by sequential measures of nasal PD and expression of CFTR mRNA and CFTR protein in airway epithelia. If gene transfer in the nasal epithelium is sufficiently safe and efficacious, studies will extend to acute local administration into the lung of CF patients. Subsequent studies will explore repetitive administration to the nose and lung as appropriate. This project allows for parallel study of several gene transfer vectors, and the overall PPG allows for rapid iteration between projects regarding vector development, studies in pertinent animal models, and clinical studies in humans to best develop safe and effective gene transfer vectors. Information regarding the efficacy of gene transfer, as well as the magnitude and mechanism of any inflammatory response, will allow rapid iteration with pilot projects, Project I and Project II and will allow rapid development of improved capability for gene transfer. We have extensive experience in clinical trials, and as effective gene transfer vectors become available, we are prepared to extend this study of gene transfer into a trial of clinical efficacy.
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