Gene Therapy Heals Injured Lungs for Transplantation

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There is a continual shortage of organs to use for patients on transplantation lists. Help may be on its way in the form of gene therapy used to heal injured lungs which will then be suitable for transplantation.

Scientists at the McEwen Centre for Regenerative Medicine, University Health Network have successfully used gene therapy to repair injured human donor lungs in the lab. It’s a great first step which could potentially increase the number of suitable lungs available for transplantation.

The pioneering work has been done by a team of researchers led by Dr. Shaf Keshavjee, Senior Scientist at the McEwen Centre for Regenerative Medicine, University Health Network and Director of the Lung Transplant Program, University Health Network. The research team developed a simple technique of ex vivo gene delivery to donor lungs is effective in improving lung function. The healed lung is then able to be implanted into a recipient’s body. Their results, "Functional Repair of Human Donor Lungs by IL-10 Gene Therapy," are published in the October 28, 2009 edition of the journal Science Translational Medicine.

The researchers used a novel approach to overcome some of the challenges of gene therapy, first developing a strategy to preserve lungs at normal body temperature with the lungs kept outside the body in a protective dome. This protective dome, the Toronto XVIVO Lung Perfusion System, continuously pumps a bloodless solution of oxygen, proteins and nutrients into injured donor lungs, mimicking normal physiological conditions. This is the key which makes it possible for the injured cells to begin repairing themselves, and also sets the stage for more sophisticated repair techniques to be applied to donor lungs.

The researchers first worked with pig and then human donor lungs which were unsuitable for transplantation. The Toronto XVIVO Lung Perfusion System kept the lungs warmed to normal body temperature. The researchers then injected a specially engineered adenovirus vector with an added IL-10 gene through the windpipe into the human lungs.

The study found that the control lungs maintained on the Toronto Lung Perfusion System alone did not deteriorate and remained stable. More exciting was the finding that the donor lungs that received the gene therapy, in addition to the ex vivo perfusion, significantly improved their function with regards to blood flow throughout the lungs and their ability to take in fresh oxygen and get rid of carbon dioxide. The boosted IL-10 effect lasts for up to 30 days in the lung.

The IL-10 gene, normally found in animal and human cells, plays a role in inhibiting the immune response to infection or foreign materials such as transplanted organs. The researchers found that the lungs begin producing the new IL-10 anti-inflammatory proteins about six hours after insertion.

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More than 80% of potential donor lungs are injured and show inflammation during the process of brain death and intensive care related complications, and cannot be used for transplantation. Moreover, inflammation and organ rejection are the two main complications after transplant surgery.

According to the National Heart, Lung, and Blood Institute lung transplants aren't very common in the United States due to the small number of donor organs available. Slightly more than 1,400 lung transplants were done in 2007. More donor lungs would mean a larger number of suitable lungs available for transplant. 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.

"Everything we can do to prevent lung injury, especially in the first 72 critical hours after surgery, would have a significant impact on survival and quality of life after transplantation," notes Dr. Marcelo Cypel, a transplant surgical fellow at Toronto General Hospital who is the first author of the paper. Dr. Cypel adds that patients who have severe early lung injury are at greater risk of dying after surgery, and have higher rates of organ rejection later on.

Dr. Keshavjee also emphasizes that clinical trials on humans would be the next step in testing this promising approach before it could be used on patients waiting for lung transplants. In these future clinical trials, lungs repaired with the gene therapy will be offered to patients waiting for a life-saving lung transplant. The process of gene therapy used on injured lungs will be carefully explained to the patients and, if they consent, the patients will be potentially transplanted with the repaired lungs should no other suitable donor lungs become available. "This work opens the door for a variety of therapies that could potentially be applied to repair various injuries in other donor organs to improve the safety and outcome of transplants," adds Dr. Keshavjee.

Other members of the team who contributed to this study include: Mingyao Liu, Matt Rubacha, Jonathan Young, Shin Hirayama, Masaki Anraku, Masaaki Sato, Marc de Perrot, Thomas Waddell of the McEwen Centre for Regenerative Medicine and the University of Toronto; Jeffrey Medin, Ontario Cancer Institute, Princess Margaret Hospital; and Arthur Slutsky, St. Michael's Hospital.

Journal Reference
Shaf Keshavjee et al. Functional Repair of Human Donor Lungs by IL-10 Gene Therapy. Science Translational Medicine, October 28, 2009

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Sources for this article:
University Health Network News Release
National Heart, Lung, and Blood Institute

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