Journal article
Correction of cAMP-Stimulated Fluid Secretion in Cystic Fibrosis Airway Epithelia: Efficiency of Adenovirus-Mediated Gene Transfer In Vitro
Human gene therapy, Vol.5(5), pp.585-593
05/01/1994
DOI: 10.1089/hum.1994.5.5-585
PMID: 7519884
Abstract
Adenovirus vectors are a promising vehicle to deliver cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to airway epithelia. However, the value of adenovirus vectors will depend on the efficiency with which the vector can correct the defective fluid transport that is thought to underlie the pathogenesis of the disease. To address the efficiency of gene transfer, we applied adenovirus vectors expressing CFTR (Ad2/ CFTR-1) or ββ-galactosidase to the mucosal surface of primary cultures of airway epithelial cells grown as polarized epithelial monolayers on permeable filter supports. These conditions provide a model that reproduces the physiology of the airways
in vivo
. We found that after adding 1 moi Ad2/CFTR-1 to the mucosal surface, cAMP agonists stimulated fluid secretion that was within the range observed in epithelia from normal subjects. When we measured electrolyte transport, we found that as little as 0.1 moi partially restored cAMP-stimulated Cl
-–
secretion, and at 10 moi Cl
-–
secretion was in the normal range. A related vector encoding ββ-galactosidase generated activity in approximately 20% of cells at an moi of 1 and 90% of cells at an moi of 10. These data suggest that Ad2/CFTR-1 is very efficient at restoring normal fluid and electrolyte transport to CF airway epithelia. Thus, they suggest that relatively low input doses could be used for gene transfer to CF airway epithelia.
The value of adenoviral vectors for gene transfer to the airways of patients with CF will depend on the efficiency with which the vector corrects defective fluid transport, balanced against any possible adverse effects. Here we report that reasonable mois of Ad2/CFTR-1 restore cAMP-mediated fluid secretion to CF airway epithelia modeled
in vitro
. The efficiency of Ad2/CFTR-1 at correcting the physiologic defect that characterizes CF suggests that adenoviral vectors offer a feasible approach for treatment of CF airway epithelia.
Details
- Title: Subtitle
- Correction of cAMP-Stimulated Fluid Secretion in Cystic Fibrosis Airway Epithelia: Efficiency of Adenovirus-Mediated Gene Transfer In Vitro
- Creators
- Joseph ZabnerLarry A CoutureAlan E SmithMichael J Welsh
- Resource Type
- Journal article
- Publication Details
- Human gene therapy, Vol.5(5), pp.585-593
- Publisher
- Mary Ann Liebert, Inc
- DOI
- 10.1089/hum.1994.5.5-585
- PMID
- 7519884
- ISSN
- 1043-0342
- eISSN
- 1557-7422
- Language
- English
- Date published
- 05/01/1994
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Neurosurgery; Internal Medicine
- Record Identifier
- 9984020655502771
Metrics
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