NEW YORK (Reuters Health) - Researchers converted human lungs from type A to type O in a proof-of-concept study that could lead to an expanded pool of universal donor organs for transplant.
"We were pleasantly surprised with how efficient the treatment was in removing the A antigens from the lung cells in a very short period of time," Dr. Marcelo Cypel of Toronto General Hospital Research Network, University Health Network in Ontario told Reuters Health by email. "The removal of >97% of A antigens is very promising."
"We are planning to start some initial clinical trials in the next 12-18 months," he said. "To make sure we do a safe stepwise approach we are going to start using A2 donors, which are A-type donors that have a much lower A antigen expression compared to A1 donors. As we obtain more pre-clinical data, we will expand to all A types in the future."
As reported in Science Translational Medicine, to convert type A red blood cells (RBCs) to type O, Dr. Cypel and colleagues combined the enzymes FpGalNAc deacetylase and FpGalactosaminidase, a combination previously shown to effectively achieve the conversion.
They tested the ability of the enzymes to remove A antigen (A-Ag) in organ perfusate solutions using five human ABO-A1 RBC samples and three human aortae after static incubation. The enzymes removed greater than 99% and 90% A-Ag from the RBCs and aortae, respectively, at concentrations as low as 1 mcg/ml.
The team then studied eight ABO-A1 human lungs using an ex vivo lung perfusion (EVLP) system. Baseline analyses of A-Ag in lungs showed that the antigens were expressed mainly in the endothelial and epithelial cells. EVLP of lungs using the enzyme-containing perfusate removed over 97% of endothelial A-Ag within 4 hours, with no treatment-related acute lung toxicity.
They then simulated an ABO-incompatible transplant using human donor lungs unsuitable for transplant from type A donors, treating one donor lung with the enzymes while the other lung from the same donor served as an untreated control.
After adding type O blood with high concentrations of anti-A antibodies to the EVP circuit, they found that enzyme treatment minimized antibody binding, complement deposition, and antibody-mediated injury, compared to the control lungs, which showed signs of rejection.
The authors conclude, "These results show that depletion of donor lung A-Ag can be achieved with EVLP treatment. This strategy has the potential to expand ABO-incompatible lung transplantation and lead to improvements in fairness of organ allocation."
Dr. Cypel said, "This approach, if proven to be successful in clinical trials, will transform the way organs are allocated. It will create a much more equal organ distribution, and transplant teams will be able to use the next organ on the sickest patient independently of their blood type."
The team is starting a similar study with kidneys "soon," he noted.
Dr. Konrad Hoetzenecker, Surgical Director of the Vienna Lung Transplant Program at the Medical University of Vienna, commented in an email to Reuters Health, "Despite numerous efforts to increase the donor pool, there is still an unmet demand for lung allografts. As a consequence, centers are confronted with a high wait list mortality - especially of blood group ABO-O patients with small, retracted chests. The idea of blood group incompatible lung transplantation is intriguing and could be a solution for this problem."
"This work once more underlines the importance of EVLP as a platform in research," he added. "It offers the unique chance to assess new therapeutics and their effect on human tissue without the risk of harming a patient."
SOURCE: https://bit.ly/3hezX6l Science Translational Medicine, online February 16, 2022.
Reuters Health Information © 2022