Radiation oncologist Joel Greenberger of the University of Pittsburgh and his colleagues have been experimenting with a transgene--manganese superoxide dismutase plasmid liposome (MnSOD-PL)--that has shown the ability to protect cells from radiation in vitro. Tested in mice in specific organs, such as the lungs and bladder, the transgene conferred significant protection and is currently being tested in human lung cancer patients undergoing radiation therapy. The new work shows that mice intravenously infused with the transgene enjoy protection throughout their bodies when exposed to radiation at levels known to kill 50 percent of their normal peers.
"These are experiments in which mice are given total body radiation, simulating what would happen in the event of exposure to a fission bomb or a dirty bomb with significant inhalation or ingestion of radiation," Greenberger explains. "That's what's known as the LD 50/30: lethal to 50 percent of the mice in 30 days. With this gene therapy, instead of 50 percent dying, we have about 80 percent surviving."
The transgene seems to work by inserting itself into the mitochondria. Once there, it convinces the cell to overproduce MnSOD, which apparently repels the damaging effects of radiation-produced free radicals. "The material is getting into the cells and it's just buffering or preventing the depletion of the antioxidant pool," Greenberger says. "It gives cells, tissues and organs time to repair themselves."
The effect is transient; the body flushes the transgene within 72 hours unless more is administered. And it is that very transience that seems to confer the protection; mice bred to overproduce MnSOD have no greater ability to survive radiation for reasons that remain unclear. The effect has withstood repeated tests and seems to shield the body, tissue, organ or cell for the duration of its persistence in the mitochondria. "The protection is from the inside out," Greenberger notes. "This is something that would be given to first responders." His team is now searching for a smaller molecule with similar effects that could be delivered in a pill or via a skin patch. Greenberger presented the finding on June 3 at a meeting of the American Society of Gene Therapy.