Experimental Strategies in Organ Transplantation with Satish Nadig, MD, PhD

Amanda Dee: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm your host, Amanda Dee.

In response to the first successful animal heart transplant into a human patient, internationally renowned transplant surgeon Dr. Satish Nadig reviews some of the scientific developments that have culminated in this moment and stresses the need for other experimental strategies. Dr. Nadig is also the new director of Feinberg's Comprehensive Transplant Center. Thank you for joining us today.

Satish Nadig, MD, PhD: Thanks for having me.

Amanda Dee: As a clinician you specialize in adult and pediatric solid organ transplantation, mainly of the liver, kidney and pancreas. What is the standard of care for treating your patients and what are the primary issues or setbacks with this model, especially for kidney transplant?

Satish Nadig, MD, PhD: Yeah, well, you know, I'm glad you asked that to start with, because I hate saying this, but transplant is just way behind. It is a very young field and many of the anti-rejection medications that we use were developed in the 1970s and 80s and many of the techniques that we use today were just refined in the 1990s. So not that long ago. And for the past decade or so, we really haven't made too much progress scientifically in transplant. So the current standard of care is we wait for people to donate their organs, which in a way is just a fantastic feat in and of itself because my job depends on man's humanity to man. I mean, I don't have a job unless someone gives up a part of themselves, either in life or in passing, to help someone else. And sometimes that's someone else is a stranger.

So we wait for organs to become available. We then take the organs out and preserve them in a preservation solution, often transport them across country or across state lines at least, and transplant them into recipients that are sick and sometimes have very little time to live, or in the case of kidney transplant, have been on dialysis for a long period of time. Those patients have often waited for many years for their transplant. They get transplanted and then they get this anti-rejection medication that goes throughout their entire body to suppress their immune system to keep from rejecting the organ. And there are limitations. The limitations from the outset: the number of organs available are far less than the number of patients in need. So there's a huge disparity amongst organ availability. Then once we take the organs out and put them in a preservation solution, the organs, although preserved, they do undergo some damage that we are just now figuring out how to fix but have not really gotten into clinical practice yet.

Then once they get transplanted, those anti-rejection medications, although necessary, are poisons. They cause the patient to be susceptible to infections and cancers and metabolic diseases, diabetes. And so we have a long way to go. We've done a lot in the last 58 to 60 years to get to where we are right now, but we have a long way to go. What I do think is exciting is that we're on the cusp of the next era of transplant. We're really living history right now, because I think this next decade is going to be the next resurgence or the Renaissance again for transplantation and transplant immunology and science to really push forward the field.

Amanda Dee: And in speaking of new developments in the field, you research nanotherapy and immunoregulation for organ transplantation. Tell me a little bit more about your approach and some of your ongoing preclinical trials.

Satish Nadig, MD, PhD: Yeah, so as I suggested, right now, we take medications that go through our entire bodies to suppress our entire immune system, to keep organs from becoming rejected. So our thought process is slightly different. It's more precise and organ-targeted. Why not treat the organ rather than the patient? And we have a very unique opportunity in transplant because the organ is outside the body for a period of time. Instead of just preserving the organ, as I mentioned to you in the journey of transplantation, why not preserve and pre-treat? So what our lab is looking at is different ways of pre-treatment strategies to condition these organs prior to going into the patient, so we can minimize the anti-rejection medications that the patients are taking it off. And with the goal of completely eradicating these antirejection medications by really just conditioning the organ itself. And so what we did was develop and patent a nanoparticle that has the antirejection medication on the inside of it at one 10th, the dose, because it's targeted to cell subtypes within the organ and the organ itself picks up this antirejection medication prior to transplantation. And what we found in our animal models is that the animals that are being transplanted aren't needing systemic antirejection medication to keep from rejecting the organ, that organs have long-term survival. And so what that allows us to do is move forward in these sort of preclinical trials so that we can refine the dosing and the types of targeting that we could use in order to move forward with clinical trials.

Amanda Dee: And a myriad of developments, like some of the ones that you're talking about now, made possible the extraordinary pig heart transplant that a lot of people are talking about right now at the University of Maryland. let's talk a little bit more about this case. What was required for a pig heart to become a viable organ for transplant, and what are you and other physician scientists watching for next?

Satish Nadig, MD, PhD: You know, this is what's so exciting about transplantation and what I alluded to in the beginning: we are living history. There's not many fields out there right now where every day is a breakthrough. And you know this feat that happened at the University of Maryland was no small step. It was a large step for medicine and a large step for transplantation. It really moves the field forward. Is it the panacea? Maybe not, but it does move our knowledge of what can be done forward. Xenotransplantation, the idea of taking an organ from one species and putting it into a human or transplanting across species has been around for, frankly, centuries. If you look at mythology from Greek mythology or any sort of cultural mythology, people have always been fascinated with taking a tissue type from one animal and putting it into another animal.

So this has been attempted before. In the early 80s, there was attempt of a baboon heart and a young child that didn't work out very well. Within a month, the child had passed away and the baboon heart didn't work. Everybody really was pushing forward for xeno, but then it lost its luster, really in the 80s and 90s, as there was just no way to try to get the organs from not undergoing what we call hyperacute rejection or rejection right away. And there's a very famous saying in transplantation around that time by some pioneers in transplant who said, "Xenotransplantation is around the corner, and always will be." Knowing that we were working towards it, but will we ever reach it? And I think we're kind of at the point where we may have hit the corner and we may be really pushing forward with this resurgence for xenotransplantation by groups in New York and Alabama, and now in Maryland, the first in Maryland was a pig heart into a living human.

What allowed us to do that -- us meaning the scientists in the world of transplant immunology -- was being able to figure out that there were proteins on the pig heart that was intrinsic to the pig that needed to be knocked out in order for the organ to be accepted. And so there's this technology called gene editing, which came about recently, and we were able to use that gene editing technology to really knock down the proteins on that pig heart. And those researchers at Maryland really push forward with this, the immunology behind this, so that they can knock out all of the immunologic proteins, but also proteins that allow the heart to grow, so growth factors so the heart doesn't outgrow the chest of the human. And it was a 10-gene knockout pig sponsored by a company called Revivicor. And University of Maryland was able to use that pig and transplant the patient.

In the short term, this is a huge, huge success story. What we'll be looking at, as a community of scientists and clinicians, is will this organ last in the long run? So the main problem with organ transplant now is organs don't last forever. And the disease process that occurs is chronic transplant dysfunction or the vascular disease. This is the disease that affects the blood vessels supplying within each of these organs. So we'll look to see if that is accelerated or if there's any problems with the organ in the medium- to long-term and what regimen of anti-rejection medication the patients will need. And if that will cause untoward side effects as well.

Amanda Dee: And what ethical questions does this case and xenotransplantation more broadly bring into focus?

Satish Nadig, MD, PhD: So a few things. From the animal rights side, you can see that there's a lot of ethical questions of whether animals should be used in this way. From the human perspective, I think that right now the allocation of organs to patients is something that we take very seriously when we put a patient on the list. One of the things we have to make sure is will that patient be a good steward of the organ because someone has given up this organ. So if a patient shows non-compliance with medications or an inability to take their medications or inability for the interest of taking care of the organ, then they're really not a good candidate for this organ. So after we have what would be an unlimited supply of organs, we have to decide what are the parameters that are gonna be in place to pick and choose who we transplant from a medical perspective. So the quality around that is going to be something that we're all going to have to come together as a community to come up with parameters to know the best patients to put these organs in.

Amanda Dee: You recently started serving as director of Feinberg's Comprehensive Transplant Center. And as you've mentioned, this is a field that's living history. What is your vision for the center?

Satish Nadig, MD, PhD: So the mission of the center that we instituted upon my arrival was patient-centric impact through quality, innovation and education. So the quality that Northwestern strives for is always excellence. That has to be the first and foremost thing we think about. We all always have our patients in the center and are providing the best quality that we can. In addition to that, it's important that we innovate, that we push the envelope. And so one of the things that Northwestern has always done is be on the leading edge of innovation in transplantation. We have the largest number of patients off of anti-rejection medications because of the studies that Dr. Joseph Leventhal, one of my partners, has been leading called the FREEDOM Trials, which are tolerance-induction strategies where we are using cell therapies to keep patients off of antirejection medications. So over 30 patients are off anti-rejection medications with these protocols.

Satish Nadig, MD, PhD: We're also pushing forward with nanotherapy. As I suggested, we have the Simpson Querrey BioNanotechnology, Institute led by world leaders, and nanotherapies, and being able to apply those therapies and technologies to transplantation. We also, on the clinical side, I have very strong interests in improving our access to care and reducing racial and ethnic disparities amongst healthcare individuals in transplantation with our program, such as the African American Transplant Access Program, the AATAP program, led by Dinee Simpson and the Hispanic access program led by Dr. Caicedo. So there are many things that we're doing on the spectrum of science and clinical research to just change the paradigm of transplant. So my vision for Northwestern Feinberg School of Medicine and, and Northwestern University's Comprehensive Transplant Center is to not just do more transplants, which is also great by saving more lives, but doing them differently and looking back and saying Northwestern changed the paradigm of how we practice transplant medicine.

Amanda Dee: And can you elaborate a little bit more on some of the disparities that certain marginalized groups like African Americans and Hispanic individuals face when seeking an organ transplant?

Satish Nadig, MD, PhD: Well, I think we're seeing it with COVID. I think that COVID brought out all of the things that happen with the healthcare system in America, by ripping off the Band-Aid of what's beneath, in healthcare disparities. It's not a secret that certain communities find it more difficult to navigate the system of American healthcare and being able to get access to organ transplantation. The same population is the one that's suffering most from high blood pressure and diabetes and on dialysis. So you can see communities, in particular on the South and the West Side of Chicago, where dialysis centers outnumber grocery stores. And we need to get out into communities and allow for transplant to be an option, because transplant is a cure and it is an option to get people off of dialysis, for example.

Amanda Dee: More than six thousand patients die each year waiting for an organ transplant, according to the U.S. Department of Health & Human Services. For listeners who aren't considering organ donation or hesitant about donating, what would you say to them? What myths might you dispel?

Satish Nadig, MD, PhD: You know, I think that the most important thing to know is it's important for us not to be spectators, but participants. And how we participate in the development of these paradigm shifts and transplantation is to register to be an organ donor, is to consider living organ donation. The safety of living organ donation has been something that we've all looked at for decades. And we have a robust living donor liver and a living donor kidney transplant program here at Northwestern. And the patients do fantastic. And not only that, the emotional satisfaction of saving a patient, another person's life, often a loved one, but sometimes a stranger is something they keep with them forever. They're true heroes. And of course, all of the patients who have decided to give organs in passing are the heroes that save the majority of our patient's lives on a daily basis. And these families are allowed to have the spirit of their loved one live on.

Amanda Dee: And is there anything else that you want to add about your new role as the director of the Comprehensive Transplant Center or for students or trainees who are considering organ transplant?

Satish Nadig, MD, PhD: Yeah, I, you know, honestly, the thing that I'm excited the most, the reason I came to Northwestern is because I wanted to be part of the change. And I, I think that it's so exciting that right now, there are very few fields that you'll see on the news every day, almost about how things are happening differently. And 50 years from now, people will look back and say that this was the time and era in transplant where that next leap was made. And it's important for me that Northwestern has a seat at that table and is in the center of that conversation.

Amanda Dee: Well, thank you so much, Dr. Nadig, for sharing your time and expertise with us.

Satish Nadig, MD, PhD: Thank you for having me. And please consider organ donation and watch out for the next advancements in transplantation.

Amanda Dee: If you are a regular listener of Breakthroughs, be sure to rate, review and subscribe on Apple Podcasts. Thanks for listening.