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Sounds of Science is a monthly podcast about beginnings: how a molecule becomes a drug, how a rodent elucidates a disease pathway, how a horseshoe crab morphs into an infection fighter. The podcast is produced by Eureka, the scientific blog of Charles River, a contract research organization for drug discovery and development. Tune in and begin the journey.
Mary Parker:
I'm Mary Parker, and welcome to this episode of Eureka's Sounds of Science.
For anyone who needs a new organ, the wait can be terrifying. It is more than likely that you will never get a match, and even if you do, there's a high risk of organ rejection. Much research has been done on alternatives, but the most promising avenue seems to be genetically modified donor animals.
Today I am joined by Mike Curtis, president and CEO of eGenesis, a biotech company focused on advancing xenotransplantation from research into the clinic. And Dr. Leonardo Riella, medical director of kidney transplantation for Massachusetts General Hospital. They bring perspectives from industry and patient care, and their teams worked together to successfully transplant a genetically engineered pig kidney into a human patient. The transplant was authorized by the U.S Food and Drug Administration under the Expanded Access Pathway. Welcome, Mike and Leo.
Mike Curtis:
Thank you. Great to be here.
Leo Riella:
Thank you, Mary. Pleasure to be here.
Mary Parker:
I'm glad to have you both. This is a fascinating topic, and obviously one of crucial importance to a lot of patients. So let's go ahead and begin. Can we start with a bit of background on you both? Mike, how did you end up in this field?
Mike Curtis:
Yeah, again, thanks for the opportunity to participate. So I've been in the biotech pharma space for over 30 years, mostly in traditional drugs, small molecules, biologics. And I was approached with this idea of xenotransplantation about five years ago. And for me it was a really compelling opportunity from a science perspective, really cutting-edge science, but also then from a patient perspective. And the opportunity, the unmet need here is tremendous. And there's so few treatments for patients that to me, add those two together. And it was very compelling, but I felt like the technology was demonstrating that it had what was required to move into the clinic. And so that's what we've been focused on for the past four or five years.
Mary Parker:
And what was some of your educational background coming into this?
Mike Curtis:
So I have a PhD in cell and molecular biology, but most of the experience that's been important in what we're doing here at eGenesis is translating drugs that are ideas at the bench into clinical trials. So I've been fortunate to be involved in the approval of several novel drugs and really bringing that experience to bear on xenotransplantation, a field where there really hasn't been any, until recently, a clinical translation. And I think now we're at the beginning of seeing a number of clinical trials beginning in the next 12 to 24 months.
Mary Parker:
That's a really valuable perspective to be bringing to this since it's like such a brand new mode of treating patients. So that's excellent.
How about you, Dr. Riella? What is your background?
Leo Riella:
Mary, so I'm a physician scientist. So I did my training in internal medicine, nephrology, and then transplantation, and a PhD in transplant immunology. So I wear the two hats. One, taking care of patients. And I think there's no better field in medicine than transplantation. We interact with patients that have end-organ disease, and we are able to provide a treatment that gets them back the quality of life that they deserve, that they wish for. And so it is for that reason one of the most gratifying clinical areas in medicine.
But then on the side of innovation and research, there's so many exciting things going on in our lab and in partnerships, such as the one that we're discussing today with eGenesis, where we're trying to solve some of the challenges that we see in the clinics such as organ shortage. But that goes beyond that, even using new anti-rejection medications or developing protocols that would induce tolerance, patients that would not require anti-rejection medications. So it is a quite exciting field and multidisciplinary, and I think that's what attracted me to it in the first place.
Mary Parker:
Was there any particular moment in your educational or practice background that made you decide to specialize in transplantation?
Leo Riella:
I think my first exposure to transplant was involving bone marrow transplantation, where patients would completely get a new immune system. And it's such a complex nature in the sense that you have the medicine part, you have the infectious disease part, you have all the potential complications of drugs, and how can you create such a therapy that ended up treating cancers and at the same time giving them an immune system that is competent enough to protect them against infection? So that multidisciplinary nature of transplant I think was one of the first things that got me attracted.
But then kidney transplantation in particular, it's such an incredible experience. Once you see a patient coming from dialysis, struggling with those three times a week sessions, low energy, getting a kidney transplant, and within two to four weeks they're walking, they have good energy, they can eat whatever they want without those restrictions. So it's life changing in many ways.
Mary Parker:
It's funny you should mention bone transplantation. This month's, the July podcast episode is with a mother whose daughter is getting the sickle cell treatment. And one thing she mentioned about getting the gene therapy for sickle cell that I'd never realized was that afterwards, her daughter has to start at the very beginning in terms of her vaccinations from infancy onward, which is something that I'd never considered before. That's really fascinating.
Leo Riella:
It's a complete reset of the immune system.
Mary Parker:
Yeah. So before we get into further details, can we take a moment to appreciate your volunteer patient Rick Slayman? Unfortunately, he passed a few months after his procedure, though from what I understand, he had a few medical issues simultaneously. Can you tell me a bit about them and how important these patients are to these clinical trials?
Leo Riella:
Yeah. Patients like Rick Slayman are crucial for us to be able to advance certain therapies that are on the research umbrella to bring to the clinic. And I think the field of xenotransplantation is in particular one where it takes a lot of courage. And I think truly among everything that we've done so far, Mr. Slayman is really the big hero in taking risk. Because there are a lot of things that we were able to predict, and many others that were just unknown since transplant from a genetic edited pig into a human was never done in a living human being. So there were so many things that we could not predict. And so him willing to take that risk and having the idea that it may not benefit him necessarily alone, but to be a step forward for the entire field, was really something that I think moved all of us. And we hope that we can keep pushing this field so other patients will benefit from it.
Mary Parker:
Yeah. Mike, anything to add to that? I mean, I know clinical trials are something that you're very familiar with, obviously.
Mike Curtis:
Absolutely. The progression in this field is completely related to the patient's willingness to participate. I think if you go back to the early days of human-to-human transplantation, it was the same story. Some patients have to decide to go first. And when we've spoken to patients who've had a kidney transplant for 15 or 20 years, they realize that someone in the early days made that sacrifice for them. And so many of those patients are looking to pay that forward for this next generation of patients in these new technologies. So it's a really incredible field to be involved with, with this kind of altruistic view from these patients that are willing to give back because someone gave it back for them long ago.
Mary Parker:
Yeah, it makes perfect sense. So Leo, can you tell us from your boots on the ground perspective what the prospects are for patients who are on the organ wait list now? Set up the problem that you're trying to solve here.
Leo Riella:
So we have close to a hundred thousand kidney transplant patients in the US waiting for a kidney transplant. So these are patients that if we had a kidney today, we would transplant them. And what ended up happening with these patients is that, because of the organ shortage, they have to wait years to get a kidney transplant. Depending on the blood group and other characteristics, it may be up to seven or eight years.
Unfortunately, the treatment that they have to receive until they go through the transplant, it's called dialysis that filters the blood. But even though it keeps patients alive, it is a treatment that carries significant complications. And what's unfortunate is that if you add these complications over time, many of these patients who are candidates today that would transplant and place a kidney, if we had it, three, four years down the line, they will be too sick or they may die even before getting a transplant. So it's such a frustrating aspect of the care that we do in transplantation, where we know the best treatment for many of these patients, and unfortunately we just don't have the organs in order to transplant them in a timely manner.
Mary Parker:
Yeah. So going on to the sort of hopefully solving this problem angle, Mike, can you give us sort of a thumbnail sketch of how eGenesis got started, and what xenotransplantation is?
Mike Curtis:
The idea of xenotransplantation, which is broadly defined as cross-species transplant, so taking organs from one animal and putting it into another, really originated when people first started about thinking about replacing organs. Some of the first transplants were actually organs from one animal into humans that didn't go very well. eGenesis entered the field about seven years ago, and we're able to leverage 40 or 50 years of research of physicians like Leo in the field of cross-species transplantation, as well as modern advances in molecular biology. And one of the big ones that we leverage is the discovery of CRISPR-Cas9. CRISPR-Cas9 is a tool that allows us to engineer genomes in a way we could only dream about 15 years ago. So eGenesis incorporates these advances in cross-species transplant understanding that have been evolving for decades with this modern molecular biology to produce the most advanced engineered porcine donor in history.
So the donor that was used in Mr. Slayman's transplant carried a total of 69 edits to the porcine genome. And those edits are to address several different aspects of transplant. One is, one of the fears of cross-species transplantation is what we call zoonotic transmission. So a disease from one animal impacting humans. We inactivate what are called endogenous porcine retroviruses. So these are viruses that harbor themselves in the porcine genome, and there is no way to get rid of them. Once they're in there, you can't breed them out. But using CRISPR-Cas9, we can actually go into the genome and selectively edit them out or inactivate them. So Mr. Slayman's donor carried a total of 59 edits to inactivate retroviruses.
And then we do another 10 edits to eliminate what we call hyperacute rejection. So if we take a wild-type porcine kidney with no edits and just transplant that into a monkey, it'll be rejected in a matter of minutes to hours, and no longer be functional. By making these edits, we eliminate that hyper-rejection response. And then we add seven regulatory human trans genes to promote long-term graft survival and compatibility. So you add all those together, and we think we've produced an organ in the pig that has the best chance to help patients like Mr. Slayman.
Mary Parker:
Is there any element of personalized medicine? Did you take any of Mr. Slayman's genes in order to make the organ in theory more compatible?
Mike Curtis:
Yeah. No, we didn't in this case. It's conceptually a really interesting idea, you know, customized organs for each subject. Unfortunately, our technology is not quite there. I mean, there's definitely ideas of how to do it. And one thing I have absolutely learned about being in this transplant field is never say never. I do think someday that'll be a reality, but right now we make what we consider a universal donor. So this animal could be used for any patient suffering from, we think, any patient suffering from kidney failure.
Mary Parker:
That's great, actually, because it makes it seem like it might be a little bit more accessible. Because obviously you don't want to invent something that only the 0.5% of the population is going to be able to afford to use. So if it's something that's a little more universal, not exactly off the shelf, but as close as you can get, that seems like a good thing.
And just out of curiosity, a friend actually asked me this when I mentioned I was interviewing you guys: are you able to increase the size of the kidney? Because I'm assuming pig kidneys are smaller than human kidneys.
Mike Curtis:
I mean, that's a really good question. The selection of the pig breed that we use is one of the first things that we discussed when we got into the field. We pick a pig breed that fully grown is between 150 kilos and 200 kilos. So that animal produces an organ that is correctly sized for human recipients. That's the intention. Because a large, what we call a large, what we typically think of as a farm pig, produces organs that are too large. And so other approaches that have been to do genetic modifications to the genome to control organ size. But organ size is absolutely a consideration that we have to take into account when we pick the breed of pigs to use.
What's interesting when we think about xenotransplantation, typically allotransplantation patients receive one kidney. Because donors have two, but we try to split them up to give two people a chance to get a kidney. In the case of xeno where you have no limit on supply, you could in theory transplant two kidneys. And that's something we're thinking about now as we're starting to move into the clinic. Is there a scenario where we would actually want to give a patient two kidneys?
Mary Parker:
So Mike, what have been some of the regulatory concerns regarding xenotransplantation? You mentioned the zoonotic diseases. Is there anything else that regulators are worried about with this technology?
Mike Curtis:
I think it starts there. And if you look at the progression of the field for the past 20 years, when the retrovirus risk was discovered, no one really knew what to do about it. And it really slowed the progression of advancement in xenotransplantation. So when we talk to the FDA, a lot of their questions are around ensuring that we're not going to have a zoonotic transmission from pigs to people.
The second piece of it is: how do we know that these organs actually have a reasonable chance of helping patients like Mr. Slayman? And then when we move into the clinic, we need to move into patients that have the right risk benefit. And I think this is where, as Leo was describing Mr. Slayman, he had reached close to the end of his treatment options that were available to him, and suddenly this experimental therapy made sense. So early on, it's not going to be for everyone. We need to match what we don't know, which is still quite a bit, against what we do know, which maybe this could help patients in the one to two year timeframe and build that data.
Mary Parker:
That makes perfect sense. And it leads back into the value of these patients agreeing to go through with these procedures. I've mentioned her before. I had a friend who came on the podcast who had very late stage cancer, I think she had a few cancers. And she was involved in a couple of clinical trials knowing full well that they would do nothing for her, but hoping that the research that was gained from her participation would then be used in people in earlier stages of their cancer and possibly lead to something being helped for someone in the future.
So I think that it seems like, especially with people out there helping the patients and patient advocates, they're fully aware of this being experimental, this being kind of risky. But at the same time, balancing that, like you said, with the risk and the fact that they're running out of options.
Mike Curtis:
And I think as the team's developing these products, the first question we always ask ourselves is: do we think this is a good idea? Do we know enough? Are we confident enough that we're giving patients a reasonable chance of success? If we can't answer that question, then we never approach patients like Mr. Slayman, right? But we have reached the point with these products where we feel for the right patients that there's a reasonable chance of success and it's something that's worth trying. And I think what's really changed in the field over the past four or five years. We've made advances that, again, weren't possible 10 years ago. And now I think we're starting to get to the point where we have that confidence. We still don't know how it's going to work, but we feel very confident that we have a reasonable chance of success.
Mary Parker:
Leo, I see you nodding. You're even closer to the patient perspective, I guess. You agree?
Leo Riella:
Yes. The safety, as Mike was commenting, it's such a priority. Independent of which research we're doing, we want to make sure that we are not causing more harm than good. And I think in the safety category of xeno infections, those zoonoses, was really kind of a big category. And I think that the work that eGenesis has done with the donor, gene-edited porcines, have been incredible. So following guidelines from the FDA, all the testing that's done in a recurrent basis to ensure that these donors prior to transplant do not have any infections that could be negatively impact patients.
And then once they get transplanted into patients like Mr. Slayman, then there's also a very aggressive monitoring that happens independent of symptoms. So what we call passive monitoring. So you collect blood every two weeks, and we run a panel of potential pathogens, both humans, but also ones that could come from the donor. And that level of investigation is so important, because we want to make sure that we don't carry greater risk than what we predicted for.
Mary Parker:
Dr. Riella, what are some of the risks associated with organ rejection?
Leo Riella:
So organ rejection is a constant threat in human transplantation in general. So whenever you're doing a transplant in which the organ comes from an individual that's different genetically than you, there will be that immune system that may recognize specific proteins, specific molecules on that donor organ that may trigger an immune response. So in addition to some of the things that Mike commented on in terms of genetic modifications that we can do in the donor pig in order to increase that compatibility, it is still required us to control the immune system on the recipient. So we use a combination of medications. And I think one of the biggest advancements that happened in xenotransplantation was really learning what types of drugs were necessary in order for us to prevent the rejection and get that longevity that was so important for us to feel confident that was time to move to the clinic.
And in particular, one of these medications that was used in the preclinical studies with the eGenesis donor pigs that made a huge difference in preventing rejection from happening and prolonging the survival of those kidney transplants. So using just traditional immune suppression, unfortunately we could not reproduce the good results that we have seen in humans. And it was the combination of some of the drugs that we are currently using in the clinic with some other drugs that are yet not approved by the FDA to be using transplantation, but with great potential that we were able to control the immune system and allow these kidneys to survive one, two years in the preclinical models.
Mary Parker:
Finally, for Leo. Do you have confidence and hope that this will help your patients in the future within your career?
Leo Riella:
Absolutely. And one of the reasons is that the treatment option, dialysis, it's not truly a long-term treatment that our patients can go through. So it was never meant to be a long-term treatment. It was initially probably thought as a temporary treatment until the kidneys kind of recover for whatever threat or event kind of happened. So now we have over 600,000 patients in the US on dialysis on a weekly basis. And so this is a number that for me is unbearable. We have a better treatment, and a majority of these patients may qualify if we do it in a timely manner.
So this is the first step. So I think, as Mike commented on, there will be, I think, more challenges and barriers that we'll face. But we're moving in the right direction, and we hope that we will be able to offer this to our patients in the future as an alternative to human transplantation.
Mary Parker:
And finally, for you, Mike, what does this research look like globally? Are there other countries working on this? Or are you planning to scale up?
Mike Curtis:
Oh yeah, absolutely. I mean, the amount of inbound interest following Mr. Slayman's transplant was really profound. We've been working with our collaborators in Japan for the past year or so. There have been other groups around the country around the world that have been trying to do something similar to what we've done at eGenesis, modifying the porcine genome to produce organs that are compatible with people. But now that we have this kind of donor that we're taking into the clinic, there's lots of interest from around the world to bring this into other geographies. Because as dire is the unmet need here as the United States, it's equal or even worse in some other countries. So the appetite or interest in xenotransplantation is very, very high.
Well, we produced our first animals in Japan this past spring to set up the possibility of doing studies in Japan. And then if you look more broadly, there's been tremendous interest from India, Taiwan, Korea. Again, countries all that suffer from the same challenge of just inadequate treatments for patients suffering from end-stage renal disease. So it is absolutely a worldwide problem trying to position ourselves to help patients cross the globe.
Mary Parker:
That sounds amazing. That sounds really promising. Well, thank you both so much for joining me and sharing your expertise on this topic. It's been extremely fascinating.
Leo Riella:
Thank you, Mary.
Mike Curtis:
Thank you.