ADENOVIRUS MEDIATED GENE TRANSFER FOR CYSTIC FIBROSIS

本研究的主要目的是评价单次递增剂量的AD2/CFTR-2雾化吸入对囊性纤维化患者肺的安全性和生化疗效。为了实现这一目标，同时评估和模拟与向下呼吸道输送AD2/CFR-2相关的潜在风险，单次递增剂量的AD2/CFR-2将(通过支气管镜)输送到囊性纤维化患者的单肺叶，然后将相同剂量的AD2/CFR-2雾化吸入肺内。囊性纤维化是一种致命性常染色体隐性遗传病，影响25,000至30,000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、无法茁壮成长、糖尿病、肝硬变、间歇性低钠脱水、无精子症和鼻窦炎。目前非特异性治疗改善了发病率，但50%的患者生存时间只有30年。这种疾病是由编码囊性纤维化跨膜传导调节蛋白(CFTR)的基因突变引起的，CFTR是一种形成氯通道的蛋白质，受磷酸化和细胞内核苷酸的调节。Cftr基因突变导致cftr氯通道活性丧失，从而导致该病的显著生理学特征：受影响的心音不全导致电解质转运缺陷。我们目前对cftr结构和功能的了解表明，基因转移可能代表着治疗的重要进展。基因缺陷的体外纠正证明了利用合适的载体传递系统进行体内纠正的可行性。在这项研究中，研究人员正在评估单次递增剂量的AD2/CFTR-2下呼吸道给药的安全性和生化疗效。在调查过程中，给药将从直接、叶、支气管镜给药转变为全肺、雾化给药。这是目前北美唯一获得批准的针对CF的气雾剂基因治疗方案。以安全的方式成功地证明效果应该允许在有效性试验中对重复给药进行后续研究。

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.