SCCMPod-558: The Future of Xenotransplantation

Dr. McLaughlin: Hello and welcome to the Society of Critical Care Medicine podcast. I'm your host Diane McLaughlin. Today I'm joined by Muhammad Mansoor Mohiuddin to discuss his Max Harry Weill Honorary Lecture, The Remarkable Potential of Xenotransplantation.

He is a professor of surgery and director of the Cardiac Xenotransplantation Program at the University of Maryland School of Medicine in Baltimore, Maryland. Welcome and before we start, do you have any disclosures to report?

Dr. Mohiuddin: We get research funding from United Therapeutics. We've used drugs from Clinics of Pharmaceuticals and Allergan Pharmaceuticals.

Dr. McLaughlin: All right. Well, none of that will bother us today. So I think we just jump in.

This is probably one of the sessions people are most excited about because a lot of people haven't heard of xenotransplantation. I had to do a little research before talking to you today. So could you just briefly describe what xenotransplantation is?

Dr. Mohiuddin: Yeah, you know, I will give a background of why we need xenotransplantation, which is using a non-human organ or cells to replace human organs or cells. Why we need it? Because, you know, there are millions of people throughout the world waiting for an organ for transplant.

As the transplant field has progressed, it has increased the demand of those organs also. So as we speak, someone is dying, waiting for that organ. So there are other alternatives.

I will speak mostly of heart and there are like mechanical devices, total artificial heart. They are trying to print a heart in a 3D technology. They are trying to grow the heart in a petri dish.

So all these technologies are great and sometime will become valid. But as we are developing these technologies, somebody is dying. Every 80 minutes, someone dies in the world.

And almost like 20 people die per day in the world. So it's a huge problem. And what we are suggesting is to have animal organs to replace human organs.

It's not an easy task. You know, we have to select which animal to use. And there are more ethical issues surrounding animals than human.

When the xenotransplantation field started, you know, they were focusing more on non-human primates, which was an ideal donor because of its close phylogenetically, it's very close to humans. However, found these transmission with those organs and also, you know, each non-human primate takes about 20 years to get to the size of an adult human. And they breed just like us, you know, give one offspring at a time.

More because of viral transmission issues like HIV, the field diverted from non-human primates. So the next best option they found was pigs. And there are many reasons they were pigs.

One of the reasons is that now the genome very well, although phylogenetically, it's very far from human, it's not the reason that we picked it because it's close to human. It's very far and there are numerous antigens in pigs that are immunogenic to humans. So since we now know the genome completely and have the technology like CRISPR-Cas9, you know, we can either delete certain genes or add certain genes because we found that there are certain mechanisms like clotting or complement activation.

That pathway requires human molecules and the pig molecules does not work in those pathways. So the field has evolved because, you know, we learn how to genetically modify these pigs. You know, the pigs grow very well in captivity.

They breed in large numbers. So a litter size is almost like 10 or more. They grow very fast.

So within a year, you know, the size of an organ is compatible to human. There are multiple advantages. The anatomy is very similar of organs.

The heart in particular is very similar, although the physiology is a little different.

Dr. McLaughlin: So this isn't something that is a dream or a hypothesis. This is actively happening that we're breeding pigs for the purpose of xenotransplantation, genetically modifying them, and then successfully transplanting?

Dr. Mohiuddin: Used to be a dream. A lot of people used to call it voodoo. You know, there are several sarcastic remarks like, you know, xenotransplantation is the future and always will be.

So those kind of remarks have been floating around. I've been in this field for 33 years just focusing on this and have gone through very tough time because, you know, it was very difficult to overcome xenograft rejection, which happens so fast that you can see a graft reject right in front of your eye. So with the help of gene modification and modifying immune suppression, which also is very different from what we use in allotransplantation, we were able to, you know, get a first good survival in a non-human primate model using that as a surrogate for humans and then prolonging graft and then going to FDA asking for permission.

However, FDA has very stringent rules about it, but there is an option at FDA where if a patient has exhausted all the options of, you know, getting a human heart or any mechanical device. And so we have offered to patients the option of xenotransplantation and they have accepted and FDA would get granted permission just for single patient transplants. And we have done two of them.

And since we have done it, you know, there are several other transplants done in kidneys, liver, and there are two human beings with kidney transplantation still alive for over three months.

Dr. McLaughlin: Oh, wow.

Dr. Mohiuddin: Yeah.

Dr. McLaughlin: Is that compassionate use? Yes. Okay.

Dr. Mohiuddin: Yeah.

So it's used to call compassionate use. Then they've changed the name to expanded access. Now they call it single patient IND.

Dr. McLaughlin: So you talked a little bit about the differences in immunosuppression. Can you expand on that a little bit?

Dr. Mohiuddin: LO rejection is mostly T cell mediated and, you know, all the CNI inhibitors and other drugs like MMF have been very successful with the steroids in overcoming transplantation. You know, we've evolved from not having any of those and the cyclosporine era came as a type of treatment and all the other drugs. And then finally, when CNI inhibitors came in, you know, it changed the field of transplantation.

However, the rejection in xenograft is very different. It's primarily and every one of us have a large amount of antibody against pigs, not because we eat them, but millions of years ago, we have deleted certain antigens because of, you know, some catastrophe in the world. When we are infected by certain bacteria and viruses, they express those antigens.

Then we see those antigens and produce antibodies. So we have a basal level of high antibodies in our body that recognizes big antigens and immediately attacks the endothelial cells and causes that to swell and rupture and cause rejection. In fact, when you do a unmodified pig heart into a baboon, which is a surrogate for human, you know, you can see that heart getting black and, you know, rejecting right in front of you.

Dr. McLaughlin: Like literally while you're transplanting, you're seeing it fail.

Dr. Mohiuddin: As you reperfuse, you'll see the heart immediately rejecting within minutes. So just imagine, you know, we have come this far from getting rejection within minutes to now having people live with that organ. For months.

For months.

Dr. McLaughlin: That's incredible. So how are you making the antibody changes in order to prevent this instant rejection?

Dr. Mohiuddin: We are working with our sponsors, United Therapeutics, who have the technology to modify the genes. We identify what are the genes of interest and they use the Cas9 technique. They take the eggs out of the ovary, you know, take the genetic material out and then put a new construct of genes in that egg, put the egg back into the uterus, and the new pig is born after 114 days that has all these desired genes.

You know, the sky's the limit. With this technique, you can change almost all the genes, but whether or not that will make the pig viable or not, that remains to be seen. But at this point, there are two companies who are making those pigs.

So we have used in our two patients, the heart transplant patient, they had 10 genes modified. So four genes were knocked out and six human genes were knocked into those pigs. The other company has done 69 gene modifications, but out of those 69 genes, 59 are knocking out various, a particular virus and all the genes of that virus, a retrovirus, which has not shown to be infective for humans, but you know, just to make sure that it's not there and they have knocked it out.

Dr. McLaughlin: They found that one of those companies is more successful than the other or no?

Dr. Mohiuddin: United Therapeutic is a bigger company. They focus on multiple things. They have pulmonary hypertension drug.

They are working on 3D printing. They are working on getting the lungs, which have not been used to, you know, make them usable. They have, you know, multiple areas where they are working, whereas the other major company, Genesis, is focusing on only xenotransplantation.

It's a much smaller company. There are other companies. There are people in Germany who are making it, but the funding is the major barrier, which I will also discuss because each transplant that we did, our first patient lived for 60 days.

In 60 days, we burned about 1.5 million. Wow. That's the reason, you know, there are several other investigators who may have better ideas or would like to try their ideas in this field, but doing these transplants is extremely expensive.

Dr. McLaughlin: And we're in an interesting time for funding. Of course.

Dr. Mohiuddin: I mean, yeah. I just don't want to get into that.

Dr. McLaughlin: Yeah.

Dr. Mohiuddin: You know, we are all, we don't know whether when we go back, we'll have any fundings. Maybe we'll have that funding released to us or not, you know, so that the institutions are getting a big hit with that 15% indirect. So, you know, you're all feeling it.

Dr. McLaughlin: What do these patients eventually pass from? You said 60 days.

Dr. Mohiuddin: So in our first patient, there was a latent virus, percocine CME virus that was detected. And we first thought that played a role, but after doing investigation for almost two years now, we now know that that was a latent virus that was hiding very deep in the endothelial cells and other cells. DNA may have just been released into the circulation after those cells die.

And we didn't find any infections related to that virus in our patients. So we think that, you know, that virus was just a distraction in our first case.

Dr. McLaughlin: Red herring.

Dr. Mohiuddin: Yeah. And definitely in both cases, we've seen the evidence of AMR, antibody-mediated rejection. And we believe that the immunosuppression that we successfully tried and that got us to this point could not be used to that effectiveness in the human.

The reason being that, you know, the patient, the two patients that we picked were at the brink of dying, right? So the first patient was in the hospital for 60 days on ECMO. And the second patient, although walked in, but is not arrested twice before the surgery.

So then those patients, if we had not intervened, would have died within, you know, next few days. So it was a tough battle. And we had to, you know, scale back our immunosuppression multiple times or even stop it at certain time to make sure that we are saving the patient.

But that made the heart vulnerable to rejection. So, you know, that was a delicate balance. So, you know, going forward, you know, we would like to go, we've been screening for our third patient, but we want to have a patient in better shape who could at least, you know, withstand our immunosuppression.

Dr. McLaughlin: My first job was as a nurse in the heart failure ICU at Cleveland Clinic. So these were our patients, the ones waiting for heart transplants. And there are a lot that never get it.

And to have some type of option sounds way better to me than nothing. But I imagine a lot of people have ethical concerns about crossing from human to animal. How do you address these comments?

Dr. Mohiuddin: So that was a major concern. First concern is that, you know, are we coursing this patient into something that even we don't know that, you know, whether it will work or not. So we had to first make sure that, you know, the patient is in his right mind giving the consent.

So in the first patient, we had four psychiatric opinions, two internal and two external, just to make sure. And when they cleared that patient that if he's giving the consent, you know, he understands what he's giving consent to. And we are indebted to those patients who, you know, knowingly that, you know, because everything was explained to them very clearly that, you know, this is an experimental procedure.

We don't know whether you're going to even survive through the surgery or not, because we don't know. We have prevented that hyper acute rejection, the baboons, but nobody has tested them, you know, humans. So we could see that, you know, some other factors influencing the rejection.

So these two patients were gracious enough to say that, you know, even if you learn something from it, our work will be done. You know, they understood that, you know, we will not give them extended life, but they opted for the benefit of others. Wow.

Dr. McLaughlin: And then the general public and their opinion about xenotransplantation, what have you found?

Dr. Mohiuddin: So, you know, that was a pleasant surprise because we thought that we will hear a lot of backlash from the general public that, you know, what we are doing, how can we offer this kind of things and from animal rights people. But fortunately, you know, to my surprise, we got overwhelmingly positive response. People have come to us and said that, where were you 10 years ago when our loved one died?

You know, we have our own transplant surgeon at our institution who almost died getting her second kidney transplant because she couldn't find it. And luckily she was able to find it. She said that I would have taken this in a heartbeat at that stage.

It's different asking a young athlete, 20-year athlete, that would you take a big heart? But when you ask these people who have been waiting and have no other options, they would take in a heartbeat. And most of them have.

Whoever we have offered, they are seriously considering. Definitely there are people who would say, I would rather die than take a big heart. And there are a lot of religious restrictions.

Being a Muslim myself, you know, it was a task for me to convince. I'm also president of International Xenotransplant Association. So we have made a concentrated effort to get different religious beliefs also.

So we held multiple conventions where we invited leaders of different religious beliefs. And they all have, you know, unanimously have given us this permission saying that saving life take precedence over everything else, right? So if you are saving life, even if it's coming from a pig, which is prohibited for eating in certain religions, but still, you know, for saving life, you can use the organ or cells from that pig.

Dr. McLaughlin: What's the future now for xenotransplantation? I know some of it's up in the air, pending funding, but where do you see the field in 10 years?

Dr. Mohiuddin: So that's a great question because the success will come in increments, not, you know, suddenly you will find someone, you know, living for years. So that we are encouraged by these two patients with kidney transplants walking around in New York and Boston, you know, doing their daily activities without any problem and not having to go through dialysis three or five times a week. You know, that's a big achievement.

But we still feel that certain more genetic modifications are required in the pig. We need to, you know, modify our immunosuppression further. The ideal goal is to have a pig that will not even, pig organ that will not even require immunosuppression because we have this technique, but that's a very idealistic approach and that will not happen for years because the companies who make these pigs, you know, want to have product pig, settle on certain genes, then show the efficacy and safety of those organs and then try to further modify it and change it. So as you have also heard, he has given permission of first clinical trial for kidneys and that they have given permission for limited six-patient trial, which will be done one after the other, given a gap of at least 12 weeks in between. And once they see, you know, safety and efficacy in that, in those patients, they will expand the trial.

So I think we are going in the right directions. Heart is a difficult, you know, since I work with hearts, hearts is a difficult organ because it doesn't have a backup. You know, if kidney fails, you can go back on dialysis, but in heart, a person, you know, dies.

So that's why, and the mechanisms are, some of them are similar, but there are different mechanisms that are governing the, you know, rejection in both organs. Liver is a very promising option because you can do partial liver transplant. And as you know, the liver grows.

So one has been done in China where they transplanted a piece of pig liver and left a major portion of human liver. That was not enough to sustain life, but that pig liver, although it rejected, but it gave time and performed function for enough time that the remaining liver grew to a size that was able to sustain life. So then they took out that pig liver, but this patient is still alive.

Dr. McLaughlin: Oh, that's interesting. Are we doing that in the United States?

Dr. Mohiuddin: Yes. So as a single patient, compassionate use, we, you know, University of Pennsylvania has done three, I think, transplants in a decedent model though. So decedent is another model that people are utilizing because at NYU, they use a decedent model and studied rejection for 61 days.

And that learning was very important because they were able to see rejection and then were able to intervene and reverse that rejection, which is very important. And identifying it at an earlier stage and being able to reverse it, you know, is an important aspect of prolonging the graft. And they have certainly done that.

And using that knowledge, they applied to a living patient. Their first patient did not do well, you know, because there was an LVAD also transplanted along with kidney. But in the second patient, you know, she's doing very well.

She had an episode of rejection, but they overcame it, same as their decedent patient. And now this patient is doing well.

Dr. McLaughlin: And again, like you mentioned earlier, these are very, very sick patients, probably more so than most of the patients on the transplant list.

Dr. Mohiuddin: Exactly. And kidney patients may not be that sick. But, and also, you know, if you're tired of, you know, getting dialysis five times a week, which is, you know, you know, takes the life out of you also.

People opt into this method. And then with dialysis, in this case, a patient they have picked, and the reason they were allowed to use this patient because they lost access to all the vessels, right? So, you know, you need to have access for the dialysis, and these patients had lost all these accesses.

And some of them have peripheral vascular disease and all that. So, those patients are eligible for xenotransplantation. And as you know, if you have another kidney transplant, or some patients are very sensitized, meaning that they have a lot of antibodies already against alloantigens, but we have seen that, you with xenoantigens.

Also, having a sensitized patient is difficult. For allotransplantation, that certainly falls in the non-eligibility criteria. Some, you know, in xenotransplantation, the promise is that, you know, you can also give it to the children.

Children are congenital malformations. They, in heart, they have no option because, you know, even if you give the heart or any other mechanical device, first, there's no mechanical device of that size. And even if that is, you know, the child is growing, and the heart is growing.

So, it cannot cope with that. And it's very difficult to find child donor for the children. And as you know, the immune system is continuously evolving in children.

So, it's better to do these in children where you can overcome the immune rejection, and they may get, you know, tolerized, and you may not even have to give immune suppression.

Dr. McLaughlin: Oh, that would be incredible. Yeah. If there was one thing you wanted somebody that was listening to this podcast to take away about xenotransplantation, what would it be?

Dr. Mohiuddin: Well, I mean, my convincing pitch has always been that, you know, I've spent 33 years and never, never for a day believed that it will not work. I'm certain that this will work. You know, just looking at patients, number of patients who benefit from it, we are calculating only the patients who are on the waiting list.

But just imagine, you know, a heart failure patient who knows that, you know, in 10 years, I'm going to get a heart, get into heart failure. And, you know, my other organs are going to shut down. What if he's offered that at an earlier stage before his other organs are affected?

So, that a pig's lifespan is about 20 years. A healthy pig heart that has no chance of rejection would be a very valid option for everyone who, once it's practiced, that will be a choice. Of course, the patient will have to make her choice, but it will be something that they will seriously consider.

Dr. McLaughlin: Would you take a pig heart?

Dr. Mohiuddin: Dr. Montgomery, who did this kidney transplant at NYU, is a heart transplant patient himself. We understand that I will have a better knowledge of, you know, how this field is progressing. And there is a option.

And if I get to that stage, you know, and I feel that we can add a significant amount of life, not for me only, but for my family, that would be great. Because, you know, the 60 or 40 days that we gave the patients, their families appreciated it a lot. The first patient family was not very close.

Those 60 days brought them very close together. The second patient, you know, although he wanted to live more, both of them, but they were able to do a few things that they thought that they won't have time to do. But again, even a single day of survival after this process is a success.

But, you know, we are now setting our bar higher because we've got up to 60 days of survival. A kidney patient is surviving for almost three months. It will be a slow progress, but we are getting there.

Dr. McLaughlin: Well, like I said at the very beginning, it's very exciting and I think should give people hope about the future and what's coming down the pipeline.

Dr. Mohiuddin: Another thing, you know, finances, right? I mean, you know, I have had NIH funding. I've worked for NIH for 13 years, but that funding is not enough.

So we need help from private industry like United Therapeutics and eGenesis. I mean, without their help, we couldn't have progress to this stage.

Dr. McLaughlin: This concludes another episode of the Society of Critical Care Medicine podcast. If you're listening on your favorite podcast app and you liked what you heard, consider rating and leaving a review. Thank you so much for joining us for the Society of Critical Care Medicine podcast.

I'm Diane McLaughlin.

Announcer: Diane C. McLaughlin, DNP, AGA, CNP, BC, CCRN, FCCM, is a neurocritical care nurse practitioner at University of Florida Health Jacksonville. She is active within SCCM, serving on both the APP Resource and Ultrasound committees and is a social media ambassador for SCCM.

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