Researchers at the University of Alabama at Birmingham (UAB) have discovered that immunosuppressant’s that are US Food and Drug Administration (FDA) approved—and that are currently in use for human-to-human transplants—are the optimal choices for an immunosuppression regime for pig-to-human kidney transplants.
The findings of this research, published in the Journal of Clinical Investigation by Jayme Locke (Marnix E. Heersink School of Medicine, Birmingham, USA), establish “the ideal immunosuppression regimen for pig-to-human kidney xenotransplantation, and it is a regimen that is already FDA-approved and that we routinely use for human-to-human allotransplantation,” according to Locke.
In a video posted on the UAB website, Locke expanded on the new research. “One of the things that has been really important to our group here at UAB,” she stated, “is how to facilitate this kind of transplant using standard medications that we use across the USA—and across the world—in the setting of human-to-human. In other words, we want to use the same medications so that the only thing that is different is the organ source; in this case, being from a genetically edited pig, as opposed to a human donor.” According to Locke, this new study has shown that this is, in fact, possible.
The key factor in this study, which is the third peer-reviewed article that has been published by UAB research teams since 2022 on the topic, is the use of complement inhibitors. “After the first study, […] we observed a unique pathologic finding,” said Locke. “Our colleague,” she continued, “Dr Huma Fatima, in the Department of Pathology here at UAB, observed something called thrombotic microangiopathy [TMA]. In the setting of human-to-human transplantation, when you see TMA that early after a transplant, it makes you concerned that there’s some sort of immunologic response, meaning the immune system is reacting negatively to that new transplant and that that patient is perhaps at risk for an early and very aggressive rejection.”
Locke went on to state that if there was an intervention ahead of time, before the transplant takes place, by giving this complement inhibitor that prevents the formation of the membrane attack complex—which is how complement comes together and creates what Locke referred to as “essentially the drill on a surface of a cell that pokes little holes in the cell wall”—but if this can be prevented pre-emptively, they can avoid these “early deleterious consequences”. In fact, when a complement inhibitor was given, not only were negative consequences removed, but Locke stated that they even “saw outstanding renal function, in fact life-sustaining renal function”.
This study was conducted using the Parsons model, in which three male decedents, aged 57, 65, and 53 years, respectively, underwent bilateral native nephrectomies followed by crossmatch-compatible xenotransplantation with 10 gene-edited pig kidneys, that expressed two human transgenes responsible for classical complement cascade inhibition (CD46, DAF; [2]), with standard immunosuppression. Locke, however, stated that she had hopes for further research that moved past the use of the Parsons model. “My hope for 2024,” she stated, “is that the US FDA will issue an IND [Investigational New Drug Application] and that we—or others—will be able to move into a phase 1 clinical trial in living persons. I think we’re ready for that in kidney [transplantation], I think that’s the next natural step, and I think we need to do it. We have a lot of people, every day, who lose their lives to end-stage kidney disease, because we simply don’t have enough organs available for transplant. We have this, [which] I think is a very viable option available, and I think it’s time to move into the living.”
Sharing her final thoughts, Locke stated that “the importance of the Journal of Clinical Investigation paper is that it really demonstrates for the first time that we can use US FDA-approved, common immunosuppressant medications for pig-to-human kidney xenotransplantation and in that context, we can see life-sustaining renal function”.
