Alpha-1 Antitrypsin Gene Therapy for Cystic Fibrosis

DESCRIPTION (Applicant's Abstract): The investigators have developed a plasmid vector that expresses the normal human alpha-1 antitrypsin (AAT) gene in human respiratory epithelium when delivered as a plasmid-cationic liposome complex. In subjects with inherited AAT deficiency, they showed that liposome mediated transfer of the normal AAT gene to the nasal respiratory epithelium resulted in expression of the transgene for about a week; local expression of the AAT gene caused a decrease in nasal lavage fluid (NALF) concentrations of the pro-inflammatory cytokine interleukin-8 (IL-8). This was in contrast to intravenous administration of the AAT protein which normalized AM concentrations in NALF, but did not decrease lL-8. The investigators believe that local expression of the gene encoding AAT in respiratory epithelium places the antiprotease activity within cells and in intercellular spaces from which circulating AAT is excluded resulting in anti-inflammatory activity as well as in inactivation of extracellular neutrophil elastase. The investigators hypothesize that expression of the AAT gene in the respiratory epithelium of subjects with cystic fibrosis (CF) will be therapeutic by decreasing inflammation as well as neutralizing extracellular proteases. To test this hypothesis, they will: 1) determine effects of delivering a normal human AAT gene as a plasmid-liposome complex to the nasal mucosal epithelium of subjects with CF on transgene expression and local inflammation and to establish the time course of these responses; 2) determine whether repeated administration of the PAT transgene to the nasal mucosal reproduces the time course of responses to the initial transfection and; 3) collect extensive data related to somatic responses to the transfection procedure. The investigators have all of the approvals from FDA, RAC and the IRB to conduct these studies. In addition geneRx+ holds license to the intellectual property necessary to commercialize this technology. Success of the studies proposed here would provide the necessary basis for conducting studies in which the AAT gene is delivered to the entire lung by aerosolizing liposome-liposome complexes. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE