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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。囊性纤维化是一种常染色体隐性遗传病，发病率约为3300例活产儿中的1例(16例)。这是由于位于染色体7(4，20)上的CFTR基因的缺陷所致。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(10，22，23，28)的活性。通过一种尚未完全了解的机制，CFTR缺陷极易使受影响的个体容易受到诸如铜绿假单胞菌和金黄色葡萄球菌等生物的慢性支气管内感染(19)。CFTR缺陷也可能加重肺部微生物定植引起的炎症反应(9)。基因治疗有望通过重建肺中CFTR的功能来解决CF的主要缺陷(8，21)。对于CF患者的肺部疾病的治疗，基因递送系统很可能必须以气雾剂的形式给予。腺相关病毒载体(5)是一种很有前途的基因转移系统，可用于将CFTR基因转移到肺组织中。TgAAVCF的几项临床研究已经完成；90名患有囊性纤维化的青少年和成年人接受了tgAAVCF治疗，但没有明显毒性的证据。TgAAVCF已被注入上颌窦、鼻腔和单个肺叶，并以气雾剂的形式通过口服吸入到整个肺。最近，一项多剂量、双盲、安慰剂对照的口服雾化吸入tgAAVCF第二阶段研究已经完成(17)，结果显示，与服用安慰剂的受试者相比，服用tgAAVCF的受试者在第30天的FEV1有显著改善。在随机服用tgAAVCF的受试者中，痰IL-8水平降低，而在随机服用安慰剂的受试者中，IL-8水平升高。这项研究的目的是用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。更大的样本量也将使我们能够进一步探讨基线AAV中和抗体滴度的影响，以及tgAAVCF基因转移后高AAV中和抗体水平对肺功能的影响。此外，受试者将根据CF型和性别进行分层，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.