Journal article
Transfection of Nasal Mucosa with a Normal alpha1-Antitrypsin Gene in alpha1-Antitrypsin-Deficient Subjects: Comparison with Protein Therapy
Human gene therapy, Vol.11(7), pp.1023-1032
05/2000
DOI: 10.1089/10430340050015338
PMID: 10811231
Abstract
We sought to determine whether a normal alpha 1-antitrypsin (AAT) gene could be expressed in respiratory epithelium and whether local expression would have antiinflammatory effects. In an unblinded study, we delivered a normal AAT gene in a plasmid–cationic liposome complex to one nostril of each of five subjects with AAT deficiency; the other, untreated nostril served as a control. AAT protein concentration in nasal lavage fluid (NALF) increased in the transfected nostril (TN), but not in the control nostril (CN), of every subject, peaking on day 5 at levels about one-third normal (baseline CN, 4.1 ± 1.2 mug/mg of protein; baseline TN, 4.3 ± 1.3; day 5 CN, 4.0 ± 0.5 [p = NS versus baseline]; day 5 TN, 9.0 ± 1.7 [p < 0.5 versus baseline]); isoelectric focusing identified the transgene-generated protein (M) in the only two patients in whom the measurement was possible. The reverse transcriptase-polymerase chain reaction (RT-PCR), performed on NALF from TN and CN of four of the five subjects, was positive for transgene message in TN in all cases and negative in NALF from CN except for one time point in one subject. Interleukin 8 (IL-8) concentrations in NALF were elevated at baseline (normal [N = 10] = 2.5 ± 0.5 ng/mg of protein; baseline TN = 5.5 ± 0.8, p < 0.05 versus normal) and decreased after AAT transfection (TN = 2.9 ± 0.6, p < 0.05 versus baseline) but not in the control nostril (CN = 6.5 ± 2.2, p = NS versus baseline). NALF samples taken from four of the patients while receiving intravenous AAT protein showed normal concentrations of AAT, but IL-8 concentrations (10.5 ± 4.2 ng/mg of protein, p = NS versus baseline) were not decreased from baseline. We conclude that plasmid–cationic liposome delivery of a normal AAT gene to the respiratory epithelium of deficient patients produces potentially therapeutic local AAT concentrations and that AAT gene therapy, unlike AAT protein therapy, is antiinflammatory.
Details
- Title: Subtitle
- Transfection of Nasal Mucosa with a Normal alpha1-Antitrypsin Gene in alpha1-Antitrypsin-Deficient Subjects: Comparison with Protein Therapy
- Creators
- Kenneth L BrighamKirk B LaneBarbara MeyrickArlene A StecenkoStefan StrackDonald R CannonMichelle CaudillAngelo E Canonico
- Resource Type
- Journal article
- Publication Details
- Human gene therapy, Vol.11(7), pp.1023-1032
- DOI
- 10.1089/10430340050015338
- PMID
- 10811231
- NLM abbreviation
- Hum Gene Ther
- ISSN
- 1043-0342
- eISSN
- 1557-7422
- Language
- English
- Date published
- 05/2000
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984040465002771
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