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Gene therapy could make more lungs available for transplants

October 28, 2009 |  4:33 pm

A new gene therapy procedure to restore function in lungs damaged during harvesting from donors could make more lungs available for transplanting, Canadian researchers said today. Currently, only about 15% of potential donor lungs are actually 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, but they are fraught with problems. Because lungs are more likely to be rejected by recipients' bodies, the five-year survival rate isLungs 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 while waiting for a lung transplant last year, according to the Organ Procurement and Transportation 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, which damps inflammation. 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 IL-10 after transplantation increases the likelihood that inflammation will damage the organ and induce rejection.

To circumvent this problem, 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 was sufficient to prevent the lungs from deteriorating and improve the success of transplants in animals. But the team did not stop there. They 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 today in the new journal Science Translational Medicine that they used the technique to Lungs2 remove lungs from pigs -- whose metabolism is similar to that of humans -- perfused them in the domed chamber for 12 hours, then successfully re-implanted them in the animals. They then took human lungs that were considered too damaged for transplantation and subjected them to the same treatment. They found that 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, however.

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 added. The pig transplants involved putting an animal's original lungs back in place. Implanting lungs from a donor might present more problems. The use of adenoviruses has also 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 within a year or so. They will first offer the treatment to patients who have been waiting for a donor organ for a long time and are in immediate danger of dying, and they will carefully explain all the potential risks, he said. He thinks the technique could be widely used for lung transplants within five years, and that it may eventually be applicable to improve survival of other organs as well.

-- Thomas H. Maugh II

Top photo: Dr. Marcelo Cypel, left, and Dr. Shaf Keshavjee deliver the IL-10 gene into human lungs via a bronchoscope. Bottom photo: Human lungs in the domed preservation chamber. Credit: Dr. Marcelo Cypel

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