Functional evidence of CFTR gene transfer in nasal epithelium of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpin-enzyme complex receptor

被引:52
作者
Ziady, AG
Kelley, TJ
Milliken, E
Ferkol, T
Davis, PB [1 ]
机构
[1] Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA
[3] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA
关键词
receptor-mediated gene transfer; poly-L-lysine; airway epithelia; apical gene delivery; CF mutant mice;
D O I
10.1006/mthe.2002.0556
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Molecular conjugates that target the serpin-enzyme complex receptor transfer the cDNA encoding human cystic fibrosis transmembrane conductance regulator (CFTR) to the nasal epithelium of cystic fibrosis mutant mice. These complexes effect partial correction of the chloride transport defect as assessed by in vivo nasal potential difference measurements, produce immunohistochemical staining for CFTR, and restore expression of nitric oxide synthase-2 (NOS-2), which is downregulated in the epithelium of mice and humans with cystic fibrosis. Complexes that lack the receptor ligands were ineffective, so receptor access was essential. Mice treated with receptor-targeted lacZ showed beta-galactosidase expression in epithelial cells and submucosal glands, but no electrophysiologic correction or NOS-2 expression, so simply accessing the serpin-enzyme complex receptor was not sufficient to produce the observed electrophysiologic or immunohistochemical changes. Correction of the cAMP-stimulated chloride transport was dose related at days 7 and 12 after complex administration, but, for most animals, nasal potential difference had returned to baseline by day 18. Molecular conjugates targeting the serpin-enzyme complex receptor, used to compact plasmid DNA, hold promise for gene therapy of cystic fibrosis.
引用
收藏
页码:413 / 419
页数:7
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