Alpha-1 Antitrypsin Gene Therapy for Cystic Fibrosis

描述(申请人摘要)：研究人员研制出一种质粒型 在人中表达正常人α-1抗胰蛋白酶(AAT)基因的载体 呼吸道上皮以阳离子脂质体质粒复合体的形式输送。 在遗传性AAT缺乏的受试者中，他们表明脂质体介导了 将正常的AAT基因转移到鼻呼吸道上皮导致 转基因表达约一周；AAT基因的局部表达 导致鼻腔灌洗液(NALF)浓度下降 促炎细胞因子白介素8(IL-8)。与此形成鲜明对比的是 静脉注射使AM正常化的AAT蛋白 在NALF中的浓度，但不降低LL-8。调查人员认为 AAT编码基因在呼吸道上皮处的局部表达 细胞内和细胞间隙中的抗蛋白酶活性 循环中的AAT被排除在外，导致抗炎活性以及 使细胞外中性粒细胞弹性蛋白酶失活。调查人员 推测AAT基因在猪呼吸道上皮细胞中的表达 囊性纤维化的受试者将通过减少 炎症以及中和细胞外的蛋白酶。为了测试这一点 假设，他们将：1)确定提供正常人类AAT的效果 基因对受试者鼻粘膜上皮的质粒-脂质体复合体 卡介苗对转基因表达和局部炎症的影响 这些反应的时间进程；2)确定重复给药是否 将PAT转基因到鼻黏膜再现了反应的时间进程 3)收集与体细胞相关的大量数据 对转染法的反应。调查人员掌握了所有 FDA、RAC和IRB批准进行这些研究。此外 Generx+拥有商业化所需的知识产权许可证 这项技术。在这里提出的研究的成功将提供 进行将AAT基因传递到 通过雾化脂质体-脂质体复合体进入整个肺。 建议的商业应用：不可用

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