Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs

Abstract

Donor organ allocation is dependent on ABO matching, restricting the opportunity for some patients to receive a life-saving transplant. The enzymes FpGalNAc deacetylase and FpGalactosaminidase, used in combination, have been described to effectively convert group A (ABO-A) red blood cells (RBCs) to group O (ABO-O). Here, we study the safety and preclinical efficacy of using these enzymes to remove A antigen (A-Ag) from human donor lungs using ex vivo lung perfusion (EVLP). First, the ability of these enzymes to remove A-Ag in organ perfusate solutions was examined on five human ABO-A1 RBC samples and three human aortae after static incubation. The enzymes removed greater than 99 and 90% A-Ag from RBCs and aortae, respectively, at concentrations as low as 1 μg/ml. Eight ABO-A1 human lungs were then treated by EVLP. Baseline analyses of A-Ag in lungs revealed expression predominantly in the endothelial and epithelial cells. EVLP of lungs with enzyme-containing perfusate removed over 97% of endothelial A-Ag within 4 hours. No treatment-related acute lung toxicity was observed. An ABO-incompatible transplant was then simulated with an ex vivo model of antibody-mediated rejection using ABO-O plasma as the surrogate for the recipient circulation using three donor lungs. The treatment of donor lungs minimized antibody binding, complement deposition, and antibody-mediated injury as compared with control lungs. 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.

Taking a Deep Breath: an Examination of Current Controversies in Surgical Procedures in Lung Transplantation

“…EVLP has additionally been proposed as a timepoint for therapeutical intervention, and multiple studies have been published on different interventional approaches. Recently, the Toronto group demonstrated a method to convert A antigen donor lungs into universal donor lungs, further increasing the chance of matching a compatible donor and recipient [ 82 ]. Mesenchymal stromal (stem) cells and their extracellular vesicles have also been proposed as a therapeutic for reconditioning ECD lungs and ameliorating ischemia-reperfusion injury [ 83 , 84 ].…”

A transplant compatible with all patients: A salvage underway

“…For this investigation, the scientists employed non-transplantable human donor lungs from type A donors. They used an enzymatic solution to cleanse one of the donor's lungs of A antigens while leaving the other untreated [ 1 ].…”

“…Because no patient has yet had an organ treated according to this approach transplanted, there is still a lot of unknown information concerning the organ's viability and the body's reaction. The researchers, on the other hand, replicated a transplant between persons who are ordinarily incompatible [ 1 ] Moving forward, researchers want to explore antigen re-expression kinetics and long-term post-transplant impacts of the organ donor enzymatic therapy using similar transgenic mice and also working on a clinical trial proposal to put the technology to the test in humans.…”

Transplant Moves One Step Closer to Creating a Purpose-Built Organ

“…"This is ground-breaking research, which is just the beginning of a new era in organ transplantati on," says Marcelo Cypel, MD, professor of thoracic surgery at the University of Toronto in Canada and senior author of a landmark paper that describes the new procedure performed in lungs. 1 He emphasizes the tremendous implicati on of the procedure for O-type pati ents, many of whom spend an excessive amount of ti me on the wait list. For example, an analysis of the 2019-2020 wait ti mes for individuals in Ontario, Canada, seeking a deceased kidney transplant revealed wait ti mes of 2-5 years for individuals with AB type, 3-5 years for individuals with A type, 3-6 years for individuals with B type and 4-6 years for individuals with O type.…”

“…“This is ground‐breaking research, which is just the beginning of a new era in organ transplantation,” says Marcelo Cypel, MD, professor of thoracic surgery at the University of Toronto in Canada and senior author of a landmark paper that describes the new procedure performed in lungs 1 . He emphasizes the tremendous implication of the procedure for O‐type patients, many of whom spend an excessive amount of time on the wait list.…”