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Lungs Deemed Too Damaged for Transplanting Repaired With Outside-the-Body Gene Therapy

Call it a genetic patch job for worn lungs: Canadian researchers took donated lungs deemed too damaged to transplant and repaired them with outside-the-body gene therapy.

It will take lots more research to see if the fix lasts, to find out if the lungs work as well back inside a body as they do inside a see-through life-support dome in the laboratory. But the study published Wednesday has lung specialists hopeful they can boost the number of lungs available for people desperately in need.

"We've been banging our heads against the wall with respect to lung transplant survival for quite some time," said Dr. Michael Bousamra of the University of Louisville, who wasn't involved in the new project.

"It's a long way from prime-time," cautioned Bousamra, lung transplant chief at Jewish Hospital in Louisville, Ky. But, he added, "This approach has the potential to change the way we do things."

Only about 15 percent of the lungs now provided from otherwise good organ donors are usable for transplant.

The problem often isn't that the lungs were diseased. Rather, the delicate airways were damaged as doctors tried to keep the donor alive, or brain death caused massive inflammation that triggered further damage. And lungs that are transplanted are vulnerable to a cascade of inflammation in the first three days post-surgery.

In fact, the five-year survival of lung transplant recipients is barely 50 percent, worse than for heart, liver or kidney recipients.

The new research, from Toronto's University Health Network, aims first to save donated lungs that otherwise would be discarded — and if that works, it might help fend off post-transplant damage, too.

The key: A gene that produces a substance called interleukin-10. Among IL-10's many jobs is tamping down inflammation from the very molecules most prone to damage lungs. But when lungs are donated, they're quickly put on ice to stop tissue deterioration, and that keeps whatever IL-10 remains from working.

So Dr. Shaf Keshavjee, University Health Network's lung transplant chief, devised a two-part fix: First, create a body-temperature chamber that will keep the lungs alive outside the body. His team created a protective dome to house the lungs, where a solution of oxygen and nutrients is pumped into them, mimicking the body but minus the blood.

Second, insert a gene into those lungs that will quickly produce high levels of IL-10 and reverse the inflammation.

His team reports success in Wednesday's journal Science Translational Medicine. They stuck the IL-10 gene into an adenovirus, from the family of cold viruses, so it would be taken up by lung cells, and snaked the virus inside the airways of the dome-preserved lung.

Using lungs first from a handful of pigs and then from humans — 10 donor lungs that had been rejected for transplant — the team found that lungs receiving the gene therapy significantly improved their ability to take in fresh oxygen and get rid of carbon dioxide, they reported. When lungs are injured, fluid breaks barriers to leak where only air is supposed to be, and that damage was fixed.

"The beauty of what we're doing here, is we're transducing the cells in the lung to become little IL-10 factories," Keshavjee said. "It's personalized medicine for the organ, if you will."

The human lungs weren't transplanted into sick patients. That's a much bigger step that Keshavjee hopes to try in an experiment sometime in the next year. But he transplanted a few pigs with repaired pig lungs, and found they were functioning significantly better four hours after transplant than lungs that didn't get gene therapy.

Moreover, if the IL-10 lasts long enough, it potentially could help protect against post-transplant inflammation, too, a question for future experiments. Specialists said those tests should track how long repaired lungs last in animals before they're tried in people.

Some gene therapy experiments have documented side effects from adenovirus, cautioned Indiana University lung specialist Dr. David Wilkes in an editorial published with the research.

Keshavjee said the adenovirus disappears relatively soon after delivering the gene, lessening risk of body-wide side effects.

"If effective, these approaches will truly be a breath of fresh air for prospective lung transplant recipients," Wilkes concluded.