Drapkin P T, O'Riordan C R, Yi S M, Chiorini J A, Cardella J, Zabner J, Welsh M J
Program in Gene Therapy, Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
J Clin Invest. 2000 Mar;105(5):589-96. doi: 10.1172/JCI8858.
Developing gene therapy for cystic fibrosis has been hindered by limited binding and endocytosis of vectors by human airway epithelia. Here we show that the apical membrane of airway epithelia express the urokinase plasminogen activator receptor (uPAR). Urokinase plasminogen activator (uPA), or a 7-residue peptide derived from this protein (u7-peptide), bound the receptor and stimulated apical endocytosis. Both ligands enhanced gene transfer by nonspecifically bound adenovirus and adeno-associated virus vectors and by a modified adenovirus vector that had been coupled to the u7-peptide. These data provide the first evidence that targeting an apical receptor can circumvent the two most important barriers to gene transfer in airway epithelia. Thus, the uPA/uPAR system may offer significant advantages for delivering genes and other pharmaceuticals to airway epithelia.
人类气道上皮细胞对载体的结合和内吞作用有限，这阻碍了囊性纤维化基因治疗的发展。在此我们表明，气道上皮细胞的顶端膜表达尿激酶型纤溶酶原激活物受体（uPAR）。尿激酶型纤溶酶原激活物（uPA）或源自该蛋白的七肽（u7肽）与该受体结合并刺激顶端内吞作用。这两种配体均通过非特异性结合的腺病毒和腺相关病毒载体以及与u7肽偶联的修饰腺病毒载体增强了基因转移。这些数据首次证明，靶向顶端受体可规避气道上皮细胞基因转移的两个最重要障碍。因此，uPA/uPAR系统在向气道上皮细胞递送基因和其他药物方面可能具有显著优势。
