ADENOVIRUS MEDIATED GENE TRANSFER FOR CYSTIC FIBROSIS

本研究的主要目的是评估单次递增剂量的Ad 2/CFTR-2雾化吸入囊性纤维化患者肺部的安全性和生化疗效。 为了实现这一目标，同时评估和最小化与向下呼吸道递送Ad 2/CFTR-2相关的潜在风险，在将相同剂量雾化至肺之前，将单次递增剂量的Ad 2/CFR-2（通过支气管镜）递送至囊性纤维化患者的单个肺叶。囊性纤维化（CF）是一种致命的常染色体隐性遗传疾病，影响25，000至30，000名美国人。 这种疾病的一些症状包括慢性支气管炎和肺炎、阻塞性肺病、胰腺功能不全、发育不良、糖尿病、肝硬化、间歇性低钠性脱水、无精子症和鼻窦炎。 目前非特异性治疗已改善了发病率，但50%的患者生存期仅为30年。这种疾病是由编码囊性纤维化跨膜传导调节因子（CFTR）蛋白的基因突变引起的，CFTR蛋白形成由磷酸化和细胞内核苷酸调节的氯离子通道。 CFTR基因突变导致CFTR氯离子通道活性丧失，从而导致该疾病的标志性生理学：受影响的无上皮细胞的电解质转运缺陷。 我们目前对CFTR结构和功能的了解表明，基因转移可能代表治疗的重要进展。体外基因缺陷校正的证明确立了用合适的载体递送系统进行体内校正的可行性。 在这项研究中，研究人员正在评估单次递增剂量的Ad 2/CFTR-2输送到下气道的安全性和生化功效。 在研究过程中，给药方式将从直接、肺叶、支气管镜给药改为全肺、气雾剂给药。 这是目前北美唯一获批的CF气溶胶基因治疗方案。 以安全的方式成功证明疗效应允许在疗效试验中对重复给药进行随访研究。

The primary objective of this study is to evaluate the safety and biochemical efficacy of single escalating doses of Ad2/CFTR-2 aerosolized to thelungs of cystic fibrosis patients. To achieve this objective while assessing and mimizing potential risks associated with delivery of Ad2/CFTR-2 to the lower airways, single escalating doses of Ad2/CFR-2 will be delivered (through a bronchoscope) to a single lobe of the lung of cystic fibrosis patients prior to aerosolizing the same dose to the lung. Cystic Fibrosis (CF), is a lethal autosomal recessive disease which affects between 25,000 and 30,000 Americans. Some symptoms of the disease include chronic bronchitis and pneumonia, obstructive lung diseae, pancreatic insufficiency, failure to thrive, diabetes, cirrhosis, intermittent hyponatremic dehydration, azospermia, and sinusitis. Currently nonspecific therapy has improved morbidity, but 50% patietn survival is only 30 years. The disease results from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a protein which forms a chloride channel that is regulated by phosphorylation and by intra-cellular nucleotides. Mutations in the CFTR gene cause a loss of CFTR chloride channel activity and thus contribute to the hallmark physiology of the disease: defective electrolyte transport by affected apithelia. Our current understanding of the structure and function of CFTR suggests that gene transfer could represent an important advance in treatment. The demonstration of in vitro correction of the gene defect established thefeasibility of in vivo correction with the appropriate vector-delivery system. In this study, the investigators are assessing the safety and biochemical efficacy of single escalating doses of Ad2/CFTR-2 delivered to the lower airway. Delivery will move from direct, lobar, bronchoscopic administration to a whole lung, aerosol method during the course of the investigation. This is currently the only approved aerosol gene therapy protocol for CF in North America. Successful demonstration of effect in a safe manner should allow follow up studies on repetitive dosing in an efficacy trial.