October 29, 2009
Gene Therapy Repairs Damaged Lungs For Transplants
Canadian researchers have successfully used gene therapy to repair injured human donor lungs, making them potentially suitable for transplantation into patients, The Associated Press reported.
The study has lung specialists hopeful they can boost the number of lungs available for people desperately in need.Dr. Michael Bousamra of the University of Louisville, who wasn't involved in the new project, said the approach has the potential to change the way they do things.
Experts say typically only about 15 percent of the lungs now provided from otherwise good organ donors are usable for transplant.
Oftentimes, airways are damaged as doctors try to keep the donor alive, or brain death causes massive inflammation that triggers further damage. Transplanted lungs are often vulnerable to a cascade of inflammation in the first three days post-surgery.
Lung transplant recipients barely have a 50 percent survival rate for the first 5 years, which is worse than for heart, liver or kidney recipients.
The researchers from Toronto's University Health Network hope to be the first to save donated lungs that otherwise would be discarded.
They discovered that a gene which produces a substance called interleukin-10 is the key to saving damaged lungs. IL-10 tamps 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 IL-10 remains from functioning.
A team of scientists, led by Dr. Shaf Keshavjee, the University Health Network's lung transplant chief, created a body-temperature chamber that will keep the lungs alive outside the body.
They were able to create 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.
After that they insert a gene into those lungs that will quickly produce high levels of IL-10 and reverse the inflammation.
Keshavjee's team stuck the IL-10 gene into an adenovirus, from the family of cold viruses, so it would be taken up by lung cells; they were then were able to snake the virus inside the airways of the dome-preserved lung.
The researchers discovered that lungs receiving the gene therapy significantly improved their ability to take in fresh oxygen and get rid of carbon dioxide. When lungs are injured, fluid breaks barriers to leak where only air is supposed to be, and that damage was fixed, they reported.
Keshavjee said they're transducing the cells in the lung to become little IL-10 factories.
"It's personalized medicine for the organ, if you will," he explained.
So far, they have 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. Sometime in the next year Keshavjee hopes to try the experiment on human patients.
Should the IL-10 last long enough, it could potentially help protect against post-transplant inflammation.
But tests should track how long repaired lungs last in animals before they're tried in people, specialists said.
Indiana University lung specialist Dr. David Wilkes cautioned in an editorial published with the research that some gene therapy experiments have documented side effects from adenovirus.
The adenovirus disappears relatively soon after delivering the gene, lessening risk of body-wide side effects, Keshavjee said.
"If effective, these approaches will truly be a breath of fresh air for prospective lung transplant recipients," Wilkes concluded.
It is estimated that the number of donor organs available for lung transplants could easily be doubled with this technique to treat and improve donor lungs.
The full study was published in Wednesday's journal Science Translational Medicine.
Image 1: Dr. Marcelo Cypel, Toronto General Hospital Surgical Lung Transplant Fellow, and Dr. Shaf Keshavjee, Senior Scientist in the McEwen Centre for Regenerative Medicine, University Health Network and Director of the Lung Transplant Program, UHN are delivering the IL-10 gene into human donor lungs via a bronchoscope. Both are observing the catheter used to deliver the gene as it progresses inside the trachea towards the lungs. Credit: Dr. Marcelo Cypel
Image 2: Dr. Marcelo Cypel, Toronto General Hospital Surgical Lung Transplant Fellow, and Dr. Shaf Keshavjee, Senior Scientist in the McEwen Centre for Regenerative Medicine, University Health Network and Director of the Lung Transplant Program, UHN assess the quality of human donor lungs treated with gene therapy via X-ray. This is one of several indicators used to assess whether human donor lungs have improved after gene therapy treatment. Credit: Dr. Marcelo Cypel
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