Korst R J, McElvaney N G, Chu C S, Rosenfeld M A, Mastrangeli A, Hay J, Brody S L, Eissa N T, Danel C, Jaffe H A
Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 2):S75-87. doi: 10.1164/ajrccm/151.3_Pt_2.S75.
Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The major manifestations are on the airway epithelial surface, with purulent mucus, recurrent infections, chronic inflammation, and loss of lung function. Consequent to mutations in both parental genes, airway epithelial cells have insufficient CFTR function. Because this can be corrected in vitro by transfer of the normal CFTR gene into airway epithelial cells, it is reasonable to hypothesize that the respiratory manifestations of CF could be prevented by transfer of the normal human CFTR cDNA to the airway epithelium in vivo. Over the past 6 years, our laboratory has developed a strategy to accomplish this goal using a replication deficient E1-E3- recombinant adenovirus (Ad) serotype 5 vector containing the normal human CFTR cDNA (AdCFTR). Studies with experimental animals demonstrate that with administration of such a vector to the airways, the human CFTR cDNA could be transferred to the airway epithelium, with expression of the human CFTR cDNA for at least 6 weeks. Extensive preclinical studies in vitro and in vivo demonstrated that the risks to humans were sufficiently low to initiate a Phase I trial using the AdCFTR vector to treat the respiratory manifestations of CF in humans. Following approval by the National Heart, Lung, and Blood Institute Institutional Review Board, the National Institutes of Health Biosafety Committee, the National Institutes of Health Recombinant DNA Advisory Committee, and the Food and Drug Administration, we initiated the first human trial of gene therapy for CF on April 17, 1993. The clinical study is still ongoing, with safety and efficacy data being evaluated, but there is clear evidence that it is feasible to transfer and express the normal CFTR cDNA to the airway epithelium in vivo in individuals with CF.
囊性纤维化（CF）由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起。主要表现在气道上皮表面，有脓性黏液、反复感染、慢性炎症以及肺功能丧失。由于父母双方基因均发生突变，气道上皮细胞的CFTR功能不足。因为通过将正常CFTR基因导入气道上皮细胞可在体外纠正这一情况，所以合理推测，将正常人CFTR cDNA体内导入气道上皮可预防CF的呼吸道表现。在过去6年里，我们实验室已开发出一种策略来实现这一目标，即使用携带正常人CFTR cDNA（AdCFTR）的复制缺陷型E1-E3重组腺病毒（Ad）血清型5载体。对实验动物的研究表明，向气道给予这种载体后，人CFTR cDNA可被导入气道上皮，且人CFTR cDNA可表达至少6周。广泛的体外和体内临床前研究表明，对人类的风险足够低，可启动使用AdCFTR载体治疗人类CF呼吸道表现的I期试验。经国家心肺血液研究所机构审查委员会、美国国立卫生研究院生物安全委员会、美国国立卫生研究院重组DNA咨询委员会以及食品药品管理局批准后，我们于1993年4月17日启动了首例CF基因治疗人体试验。该临床研究仍在进行中，安全性和有效性数据正在评估，但有明确证据表明，在CF患者体内将正常CFTR cDNA导入并表达于气道上皮是可行的。
