Gene therapy may boost success of lung transplants
New procedure could sharply increase the supply of functional lungs by preventing and possibly repairing organs damaged during harvesting. The process also may decrease rejection by the recipient.
Toronto researchers put harvested lungs in a domed chamber that maintained body temperature and pumped them with oxygen and nutrients, then inserted a gene that induced the lungs to produce the immune molecule IL-10, which has helped reduce inflammation. (Associated Press / October 28, 2009)
Currently, only about 15% of potential donor lungs are used because the rest are too damaged to implant. The new technique, which has not yet been tested in humans, could prevent that damage or even reverse it, potentially expanding the supply of lungs sharply.
Lung transplants are the definitive therapy for many end-stage lung diseases such as emphysema and cystic fibrosis, but they are fraught with problems. Because lungs are more likely to be rejected by recipients' bodies than other organs, the five-year survival rate is only about 50%, lower than that for heart, liver or kidney transplantation.
And because of the shortage of donor lungs, an estimated 234 people in the United States died last year while waiting for a lung transplant, according to the Organ Procurement and Transplantation Network. About 1,800 people in this country are now on the waiting list for a lung, the agency said.
The problem in both cases is inflammation caused by insufficient amounts of an immune molecule called lL-10. Donated lungs are immediately chilled on ice, which destroys any IL-10 that may remain in the lungs, allowing substantial damage to occur before the organ can be implanted. And a lack of the molecule after transplantation increases the likelihood that inflammation will damage the organ and induce rejection.
"Anything that can decrease inflammatory processes would make them more suitable for transplantation and also impact the recipient's ability to reject the organ," said Dr. James McPherson, a thoracic surgeon at Marina Del Rey Hospital who was not involved in the research. "This looks very promising."
To circumvent inflammation, Dr. Shaf Keshavjee and Dr. Marcelo Cypel of the University Health Network in Toronto and their colleagues developed a two-pronged approach.
First, they devised a domed chamber that keeps the lungs at body temperature, preserving IL-10, and that pumps a solution containing oxygen and nutrients through the lungs to keep them alive. That alone prevented the lungs from deteriorating and improved the success of transplants in animals.
The researchers then performed gene therapy on the lungs, using a defanged adenovirus to deliver a gene that is the blueprint for IL-10 into the lung tissue. The gene was quickly taken up by the cells and began producing the molecule, which reduced inflammation.
"We're transducing the cells in the lung to become little IL-10 factories," Keshavjee said in a statement.
The team reported Wednesday in the new journal Science Translational Medicine that they used the technique to remove lungs from pigs -- whose metabolism is similar to that of humans -- perfused them in the domed chamber for 12 hours, then successfully reimplanted them.
They then took human lungs that were considered too damaged for transplantation and subjected them to the same procedure. The treatment significantly improved blood flow through the lungs and improved their ability to take in fresh oxygen and remove carbon dioxide. The higher levels of IL-10 persisted in the lungs for 30 days, suggesting that the procedure could also reduce rejection of the organs. The lungs were not implanted in humans.
The procedure "not only may result in improved preservation of lungs [before transplantation] but also may repair lungs otherwise not suitable for transplantation," Dr. David S. Wilkes of the Indiana University School of Medicine wrote in an editorial accompanying the report.
But several questions remain, he said. Implanting lungs from a human donor might present more problems. And the use of adenoviruses has caused complications in some gene-therapy experiments when the virus inserted the added gene at an inappropriate location.
Keshavjee said the team hopes to begin human trials in a year or so.