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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。囊性纤维化（CF）是一种常染色体隐性遗传疾病，发病率约为1/3300活产婴儿（16）。这是由于CFTR基因的缺陷，该基因位于7号染色体上（4，20）。CFTR可作为cAMP激活的氯离子通道发挥作用，也可调节其他氯离子通道的活性（10、22、23、28）。通过一种尚未完全理解的机制，CFTR缺陷使受影响的个体极易受到铜绿假单胞菌和金黄色葡萄球菌等微生物的慢性支气管内感染（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中的CFTR功能来解决CF中的主要缺陷（8，21）。对于患有CF的患者的肺部疾病的治疗，基因递送系统将最有可能必须作为气雾剂施用。适用于将CFTR基因递送至CF肺的有前景的基因转移系统是腺相关病毒载体（5）。已经完成了几项tgAAVCF的临床研究; 90名患有囊性纤维化的青少年和成人接受了tgAAVCF，没有明显毒性的证据。已经将tgAAVCF滴注到上颌窦、鼻和单个肺叶中，以及作为气雾剂通过口服吸入递送到整个肺。最近，完成了通过口服气雾吸入递送的tgAAVCF的多剂量、双盲、安慰剂对照的II期研究（17），其显示与接受安慰剂的受试者相比，tgAAVCF治疗的受试者在第30天的FEV 1在统计学上显著改善。痰液IL-8水平在随机分配至tgAAVCF的受试者中降低，而在随机分配至安慰剂的受试者中升高。本研究的目的是使用更大的样本量证实肺功能和细胞因子水平的改善，以及在最近完成的研究中观察到的对安全性无不良影响。更大的样本量还将允许我们进一步探索基线AAV中和抗体滴度的影响，以及用tgAAVCF进行基因转移后高AAV中和抗体滴度水平对肺功能的发展。此外，将根据CF基因型和性别对受试者进行分层，以确定其对tgAAVCF基因转移后肺功能的影响。

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.