Bigger B, Coutelle C
Cystic Fibrosis Gene Therapy Research Group, Division of Cell and Molecular Genetics, Sir Alexander Fleming Building, Imperial College of Science, Technology and Medicine, London, England.
BioDrugs. 2001;15(9):615-34. doi: 10.2165/00063030-200115090-00006.
Since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene nearly 12 years ago, cystic fibrosis (CF) has become one of the most intensively investigated monogenetic disorders considered approachable by gene therapy. This has resulted in over 20 clinical trials currently under way, concluded or awaiting approval. Despite the initial promise of gene therapy for CF, and the demonstration of successful gene transfer to the nose and airways of individuals, it has not so far been as effective as initially projected. Here we discuss the rationale behind CF gene therapy and dissect the vast array of literature representing the work that ultimately brought about the current phase I/II clinical trials. In the context of human trials, we review the limitations of current vector systems for CF gene therapy. We come to the conclusion that at present none of the application methods and vector systems are able to achieve the level and persistence of CFTR gene expression in the affected epithelia of CF patients that is required for therapeutic success. We also outline the challenges that must be overcome and describe some of the novel approaches to be taken in order to attain the curative therapy that was originally envisaged for this disease.
自近12年前发现囊性纤维化跨膜传导调节因子（CFTR）基因以来，囊性纤维化（CF）已成为基因治疗可攻克的研究最为深入的单基因疾病之一。这导致目前有20多项临床试验正在进行、已经结束或等待批准。尽管基因治疗对CF最初抱有希望，并且已证明能成功将基因转移至个体的鼻腔和气道，但到目前为止，其效果尚未达到最初的预期。在此，我们讨论CF基因治疗背后的基本原理，并剖析大量文献，这些文献代表了最终促成当前I/II期临床试验的工作。在人体试验的背景下，我们审视了目前用于CF基因治疗的载体系统的局限性。我们得出的结论是，目前没有任何一种应用方法和载体系统能够在CF患者受影响的上皮细胞中实现治疗成功所需的CFTR基因表达水平和持久性。我们还概述了必须克服的挑战，并描述了为实现最初设想的针对该疾病的治愈性疗法而要采取的一些新方法。
