Gene therapy to aid lung transplants

“Donated lungs that have to be discarded because they are not good enough for transplant can now be repaired and made suitable for patients,” The Times has reported.

The study behind the news looks at an experimental gene therapy technique that has been tested on pig and human lungs. Under this technique, a gene known as IL-10 is introduced into the lung tissue cells to alter their behaviour. The research showed that in experimental conditions the gene combatted the damaging inflammation that sometimes causes problems in lung transplants.

The importance of the research is emphasised in a journal editorial, which points out that only 15% of donor lungs are currently suitable for transplantation, therefore this process may become important if it proves successful in future studies.

The study is of interest because the five-year survival rate of patients have lung transplants is approximately 50%, significantly worse than the survival rates for heart, liver, or kidney transplantats. More research is necessary before the technique can be applied to clinical transplants of the lungs or other organs.

Where did the story come from?

This research was carried out by Dr Marcelo Cypel and colleagues from the McEwen Centre for Regenerative Medicine in Toronto, and elsewhere in Canada and the US. The study was funded by grants from the Canadian Institute of Health Research and by National Institutes of Health in the US. It was published in the peer-reviewed medical journal Science Translational Medicine.

What kind of scientific study was this?

In this laboratory study the researchers tested a new gene therapy on lungs from pigs and damaged human donor lungs.

The researchers explain that more than 80% of potential donor lungs are injured during the donor's brain death and from complications experienced in intensive care, and therefore they cannot be used for transplantation. The researchers wanted to test whether it was possible to repair some of this damage using a technique caled 'gene delivery', in which a new gene is introduced to cells by combining it with a virus. Once introduced, the gene would alter the behaviour of the cells. In this case, it was hoped that the new gene would increase the viability of transplants using lung tissue.

Transplantation itself can damage the lung because as blood returns to the lung, it alters the level of some chemicals known as pro-inflammatory mediators. The substances TNF alpha and IL-6 increase, while the protein IL-10 reduces in response to the injury. This is thought to raise the risk of rejection.

The researchers first took the organs and preserved them at normal body temperature. A solution of oxygen, proteins and nutrients was pumped over the damaged tissues, allowing cells to begin repairing themselves. This process of perfusion, called EVLP, lasted 12 hours.

Next, a common cold virus that had been genetically engineered to carry the foreign IL-10 gene carried this foreign DNA into the host cells. This technique, known as AdhIL-10 gene delivery, has been studied before, but in this case it was used to transfer the gene into cells so that they would manufacture more of the IL-10 protein. This protein is reduced when lung tissue is damaged, therefore the researchers hoped that stimulating the cells to produce more IL-10 would boost the production of the proteins, thus helping to protect the lungs.

The researchers measured this ‘IL-10 effect’ by comparing the amount of the protein in the pig and human lungs before and after 12 hours of the EVLP.

What were the results of the study?

The gene therapy significantly improved blood flow and the ability of the lungs to take in oxygen and expel carbon dioxide.

The 'IL-10 effect' was found to last 30 days in human lungs. Consequently, researchers say, the organ should function better at the time of transplant, and that this “should lead to more predictable, safer outcomes”.

What interpretations did the researchers draw from these results?

The researchers say that by demonstrating that the AdhIL-10 gene therapy approach works in pig and human models, they have shown that the inflammation in injured human donor lungs can be reduced.

They hope to study the technique further, and say that if future tests are successful then the treatment could lead to more lung transplants using organs, which currently have to be discarded. They add that the technique may also find a use in other organ transplants, such as kidney, heart and liver.

What does the NHS Knowledge Service make of this study?

The preliminary study suggests a way of addressing some current problems in lung transplantation. Commentators say it could potentially repair donor lungs before transplant, but also might prevent lung injury after transplantation. Some points of caution are mentioned by the researchers and in the accompanying editorial:

• The leading cause of death in lung transplant recipients is a condition called bronchiolitis obliterans syndrome, in which scar-type tissue forms in the small airways in the lung and blocks them. It remains unclear if this gene therapy will reduce the rates of this.
• Human lungs rejected for transplantation have often been subjected to multiple injuries and damage due to the length of time the donor was in hospital. This damage may not be the same as that present in the lungs used in this study. This could mean that the results may differ in more damaged lungs.

Overall, this is an interesting study, which used a new type of therapy. The early signs are that the technique should be studied in larger animal transplantation research before it could be applied in human trials.