Journal
MOLECULAR THERAPY
Volume 5, Issue 4, Pages 413-419Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/mthe.2002.0556
Keywords
receptor-mediated gene transfer; poly-L-lysine; airway epithelia; apical gene delivery; CF mutant mice
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Funding
- NHLBI NIH HHS [T32 HL07415] Funding Source: Medline
- NIDDK NIH HHS [R01 DK52981, P30 DK27651] Funding Source: Medline
- PHS HHS [R01 58318] Funding Source: Medline
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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.
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