A MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE II STUDY OF AEROSOLIZED

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。囊性纤维化（CF）是一种常染色体隐性遗传病，发病率约为1 / 3300活产（16）。这是由于位于7号染色体上的CFTR基因存在缺陷（4,20）。CFTR可以作为camp激活的氯离子通道，也可以调节其他氯离子通道的活性（10,22,23,28）。CFTR缺陷通过一种尚未完全了解的机制，强烈地使受影响的个体易患慢性支气管内感染，如铜绿假单胞菌和金黄色葡萄球菌（19）。CFTR缺陷也可能加剧肺部微生物定植的炎症反应(9)。基因治疗有望通过重建肺部CFTR功能来解决CF的原发性缺陷（8,21）。对于CF患者肺部疾病的治疗，基因传递系统很可能必须以气雾剂的形式给药。适用于将CFTR基因传递到CF肺的一种很有前景的基因转移系统是腺相关病毒载体(5)。tgAAVCF已完成多项临床研究；90名患有囊性纤维化的青少年和成人接受了tgAAVCF治疗，没有明显毒性的证据。tgAAVCF已被灌注到上颌窦、鼻子和单肺叶中，并以气雾剂的形式通过口服吸入到整个肺中。最近，一项多剂量、双盲、安慰剂对照的口服气雾剂吸入tgAAVCF的II期研究完成（17），结果显示，与接受安慰剂治疗的受试者相比，tgAAVCF治疗第30天的FEV1有统计学显著改善。随机分配到tgAAVCF组的受试者的痰IL-8水平下降，随机分配到安慰剂组的受试者的痰IL-8水平升高。本研究的目的是通过更大的样本量来证实最近完成的研究中观察到的肺功能和细胞因子水平的改善，以及对安全性的不良影响。更大的样本量也将允许我们进一步探索基线AAV中和抗体滴度的影响，以及发展高AAV中和抗体滴度对tgAAVCF基因转移后肺功能的影响。此外，将根据CF基因型和性别对受试者进行分层，以确定tgAAVCF基因转移后对肺功能的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cystic fibrosis (CF) is an autosomal recessive disorder with an incidence of approximately 1 in 3300 live births (16). It is due to defects in the CFTR gene, which is located on chromosome 7 (4,20). The CFTR can function as a cAMP-activated chloride channel and can also regulate the activity of other chloride channels (10,22,23,28). Through a mechanism that is not fully understood, CFTR defects strongly predispose affected individuals to chronic endobronchial infections with organisms such as Pseudomonas aeruginosa and Staphylococcus aureus (19). The CFTR defect may also exacerbate the inflammatory response to microbiological colonization of the lung (9). Gene therapy holds the promise of addressing the primary defect in CF by reconstituting CFTR function in the lung (8,21). For treatment of lung disease in patients with CF, a gene delivery system will most likely have to be administered as an aerosol. A promising gene transfer system that is applicable to delivering the CFTR gene to the CF lung is the adeno-associated viral vector (5). Several clinical studies of tgAAVCF have been completed; 90 adolescents and adults with cystic fibrosis have received tgAAVCF without evidence of significant toxicity. tgAAVCF has been instilled into the maxillary sinus, nose, and single lung lobe, as well as delivered as an aerosol by oral inhalation to the entire lung. Recently, a multi-dose, double-blind, placebo-controlled phase II study of tgAAVCF delivered by oral aerosol inhalation was completed (17) showing statistically significant improvement in FEV1 at Day 30 of the tgAAVCF treated subjects compared to those who received placebo. Sputum IL-8 levels decreased in subjects randomized to tgAAVCF, and increased in subjects randomized to placebo. The purpose of this study is to confirm with a larger sample size, the improvement in pulmonary function and cytokine levels, and no adverse effects on safety, observed in the recently completed study. The larger sample size will also allow us to further explore the effect of baseline AAV neutralizing antibody titer, and the development of high AAV neutralizing antibody titer levels on pulmonary function after gene transfer with tgAAVCF. In addition, subjects will be stratified by CF genotype and gender, to determine their impact on pulmonary function after gene transfer with tgAAVCF.