Journal
GENE THERAPY
Volume 10, Issue 2, Pages 163-171Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3301852
Keywords
intrapulmonary gene therapy; MnSOD gene expression
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Funding
- NATIONAL CANCER INSTITUTE [P50CA090440] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL060132] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008444] Funding Source: NIH RePORTER
- NCI NIH HHS [P50 CA 90440] Funding Source: Medline
- NHLBI NIH HHS [R01 HL 60132] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008444] Funding Source: Medline
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Intratracheal (IT) injection of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) complexes prior to whole lung irradiation of C57BL/6J mice provides significant protection from acute and chronic irradiation damage. We determined the duration of increased MnSOD biochemical activity and differential expression of a hemagglutinin (HA) epitope-tagged MnSOD transgene. HA-MnSOD-PL was IT injected at doses of 0-1000 mug, and mice were killed 1,2,3 or 4 days later. Other groups of mice were irradiated to 20 Gy to the pulmonary cavity 24 h after injection and killed at the same time points as non-irradiated mice. Both non-irradiated and irradiated groups of mice showed increased MnSOD biochemical activity with plasmid dose that plateaued at 100 mug of MnSOD plasmid DNA. In control mice, MnSOD biochemical activity decreased at 2, 3 or 4 days after injection. In irradiated mice MnSOD biochemical activity decreased at day 2 but increased on days 3 and 4. HAMnSOD expression decreased in broncheoalveolar macrophages and alveolar type-II cells 3 days after injection in nonirradiated and irradiated mice, but remained elevated in endothelial and epithelial cells past 4 days. The data provide a rationale for every second-day administration of intrapulmonary MnSOD-PL in clinical trials of radioprotective gene therapy. This should be sufficient to provide radioprotection during radiation treatments.
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