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Mitigation of radiation-induced skin injury by AAV2-mediated MnSOD gene therapy
Shiqing Yan1, Stephen L Brown, Andrew Kolozsvary
1Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202, USA.
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.
