Mitigation of radiation-induced skin injury by AAV2-mediated MnSOD gene therapy.
BACKGROUND
Radiation-induced, long-lived free radicals, reactive oxygen species and pro-inflammatory cytokines have been implicated in the resultant tissue injury after exposure to ionizing radiation.


METHODS
An approach designed to reduce the damaging effects of reactive oxidants employs metalloenzymes of superoxide dismutase (SOD), such as MnSOD. Recombinant adeno-associated virus 2 (AAV2) provides safe and long-term expression in humans. We tested the effectiveness of AAV2-MnSOD-hrGFP, a vector expressing MnSOD and green fluorescent protein (GFP) in preclinical models.


RESULTS
Infection of cultured cells with AAV2-MnSOD-hrGFP showed enhanced expression of MnSOD and GFP. Sustained expression of GFP was achieved for at least 1 month in vivo following administration of AAV2-MnSOD-hrGFP to subcutaneous tissue of C57BL/6J mice. A single subcutaneous injection of AAV2-MnSOD-hrGFP significantly mitigated acute skin injury following single dose of irradiation of either 30 or 35 Gy.


CONCLUSIONS
The proof-of-concept demonstrated in the present study together with the known safety profile in humans indicate that AAV-mediated MnSOD expression has potential countermeasure utility against normal tissue injury following radiation therapy or radiological accident.
Yan
Shiqing
S
Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202, USA.
Brown
Stephen L
SL
Kolozsvary
Andrew
A
Freytag
Svend O
SO
Lu
Mei
M
Kim
Jae Ho
JH
D000818:Animals; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011839:Radiation, Ionizing; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
D049452:Green Fluorescent Proteins; D013482:Superoxide Dismutase