The most effective and economical clinical treatment for end-stage organ failure continues to be organ donation and transplantation. But there’s a central rate-limiting element—the supply of suitable organs. The lack of organs for transplants has serious ramifications, from letting thousands of people die annually while waiting for a donor to horrific worldwide issues like organ trafficking and transplant tourism. The increase in organ failure patients worldwide necessitates novel approaches to reducing transplant wait times while assuring an honest and secure supply of organs.
Making an on-demand organ supply from animals with anatomically and physiologically appropriate organs, like pigs, is one way to solve the issue of organ scarcity. The most prominent recent achievement was the successful transplantation of two genetically modified pig hearts into recently deceased humans—declared brain-dead prior to the transplants and were kept on ventilators and dialysis both before, during, and after the procedures—in June and July by researchers at NYU Langone Health. This comes on the heels of the death of David Bennett, who was the first person to receive a pig heart and lived for nearly two months, in March at the University of Maryland, and the first clinical-grade transplants of gene-edited pig kidneys into brain-dead humans in January at the University of Alabama at Birmingham. Although still in the early stages, pig-to-human xenotransplantation procedures are becoming a reality.
Although xenotransplantation has the potential to revolutionize the way organ failure is treated, it hasn’t been widely used due to two major obstacles: 1) the possibility of virus transmission between species and 2) immune-mediated incompatibilities between species that might cause organ rejection. Essentially, it is necessary to alter pig organs for xenotransplantation to deactivate porcine genes that could negatively interact with the human immune system while also adding human genes to lessen the likelihood of rejection. Now that cutting-edge gene editing technologies have been developed, these old problems can be solved.
eGenesis, a biotechnology company developing human-compatible organs and cells for the treatment of organ failure, is developing several programs across solid organ and cell therapy to address the urgent needs of patients with organ failure and other debilitating diseases. Co-founded by George Church and his former postdoctoral fellow Luhan Yang, eGenesis is committed to ending the global transplant shortage and transforming the treatment of organ failure with lead programs in kidney and islet cell transplantation.
The company, based in Cambridge, Massachusetts, harnesses gene editing technology, including CRISPR, to address the two key issues that have impeded xenotransplantation. First, eGenesis inactivates all endogenous retrovirus sequences within the porcine genome, which prevents the virus from being passed from pig to human and uses biosecure, pathogen-free animal production processes to address the risk of transmission of other viruses. This seminal research was published in August of 2017 in Science, where eGenesis researchers demonstrated the inactivation of Porcine Endogenous Retrovirus (PERV) to prevent cross-species viral transmission and a breakthrough in producing the first PERV-free pigs, an important milestone for xenotransplantation. Second, the company deploys multiplex gene editing to comprehensively address the multiple mechanisms of immune-mediated rejection of the transplanted organ.
GEN Edge spoke with newly promoted CEO Michael Curtis, PhD, previously the President of Research & Development at eGenesis, about how the company is advancing its mission to transform the field of transplantation by offering safe and effective organs and cells to patients in need.
GEN Edge: What was the impetus for starting eGenesis?
Curtis: The primary driver for the foundation of eGenesis was the discovery of CRISPR-Cas and its utility in inactivating endogenous retroviruses in the porcine genome. This work came out of George Church’s lab. The discovery of retroviruses in porcine donors put a chill on xenotransplantation through most of the ‘90s, when no one knew what to do with potential zoonotic transmission risk. In any particular porcine genome, there’ll be 50-80 copies of the retrovirus, and it’s endogenous. There’s no way you can breed it out—it’s just there. When CRISPR came along, George Church showed that you could inactivate the reverse transcriptase in the retroviruses. This allowed us to reduce the risk of zoonotic transmission from porcine donors to recipients.
We also have used modern engineering for the rest of the xenotransplant story. We can knock out antigens responsible for hyper-acute rejection and insert genes that promote long-term graft survival. Together, we have created the most advanced genome engineering platform in the world for creating porcine donors that can provide organs that need to launch from graft survival. We were the first company to have this fully integrated platform that could address all the issues. So, when we started, we wanted to know if we could make all these edits. Now, we have a clinical-stage donor with about 70 edits if you include retrovirus plus knockouts on stock ends. We’ve shown that that donor produces kidneys that can survive in a monkey for over 600 days post-transplant. By putting all these pieces together, we’ve been able to make the product that can realize this vision of using porcine donors as organ donors for human transplants.
We have had three non-human primate recipients survive post-transplantation for over a year, two recipients for over 500 days, and one for over 600 days. We’ve completed 15 total transplants, with several that are still ongoing. We were initially targeting one year, and now we’re getting more recipients past one year. We think six months would probably be enough to get the transplants into the clinic. Our goal is to produce a kidney that survives in a patient for at least three years.
GEN Edge: How does the economics of porcine-to-human xenotransplantation compare to the current strategy using human donors?
Curtis: Kidney transplant kidneys are essentially “free” because they’re donated. But they’re also unreliable and tough to get. If you can solve the shortage and supply problem, you can completely transform how you think about transplants. For example, you can rethink how long an organ needs to survive. Right now, an organ needs to survive for 15 years because that’s probably the only one you’ll get. But if you knew you could get a second or a third one, maybe a five-year organ is plenty. You could get three transplants over 15 years. The longer, the better. I think the transplant surgeons and community fully support short-duration transplants out of the gate. We know dialysis is not an excellent treatment. People decline on dialysis. Wouldn’t it be better if we could transplant patients preemptively before they ever had dialysis? It would be, but there’s no way we could do that now with the current supply, setting the stage for how transformative fixing the supply challenge will be in organ transplants.
Suppose you talk to a patient and give them the value proposition to provide them with a year off from dialysis in our first trial. While there’s a risk it will fail, patients say that they’ll take it because if they’re on dialysis, they may have already gone through one kidney. The kidney they got may have failed. They’re on dialysis and know they’ll never get another kidney. If you’re over 50 years old, forget it—you’re not going to get a kidney on the current allocation system. Your only choice is dialysis or something new. So, our technology is incredibly compelling.
When I first joined the company, I thought xenotransplantation was maybe science fiction. How real is that?! It always amazes me that we have a primate with a porcine kidney in them supporting their life for the past 600 days. The way that model works is we take out the native kidneys of the monkey, put in the single porcine kidney, and put the animal on immuno-suppression we use clinically. Twenty years ago, those experiments never went past 30 days. Ten years ago, you’d start to break the hundred-day barrier. Right now, we are consistently getting to hundred-plus days. Now we have one that’s at 600 days. The proof is the data; the editing directly leads to long-term graph survival.
GEN Edge: How is the pipeline at eGenesis structured?
Curtis: What separates us from any other player in this space is that we have a world-class engineering team in Cambridge, Massachusetts, founded by several members from George Church’s lab and a Wisconsin group producing our transgenic donors. One of the technologies that goes unspoken here is the somatic cell nuclear transfer process—turning an edited cell into a porcine donor. We used the same technology to clone Dolly in the ‘90s. We are experts in porcine cloning. Last year, we made over 500 donors at our facility in Wisconsin. So, we can turn single-cell editing into fully mature adult donating animals.
We make many donors. We have one set of genetics with retroviral inactivation—triple knockout—plus seven human regulatory genes. We do a series of somatic cell nuclear transfers every week to make additional donors. Any given week, we will produce 10-15 piglets. Then we just turn the crank. One of the challenges is that it takes four months for a piglet to be born and then 2-3 months of maturation prior to transplant. By the time we’re doing a transplant, we’ve been producing the donor for about 6-7 months. So, there’s a steady state that we get to where we’re producing 15-20 donors every week.
We also can do non-human primate transplants. That’s not trivial. All our transplants have been done by human transplant surgeons. Now we can do transplants through our academic collaborators at a scale I don’t think anyone else can. We did over 40 transplants last year across our programs, and no one else is doing that many.
From a company-build perspective, we’ve put all the pieces you need to enable this technology under one roof. It allows us to move at a speed that I don’t think anyone else can, and it’s also a significant barrier to entry. You can’t get these capabilities off the shelf. You can probably count the number of experts on porcine cloning on two hands. Then the ability to raise enough capital to fund all this and get us to where we are. We have been successful in raising capital. All of that is required to make this a reality.
GEN Edge: What are the major milestones for eGenesis in the near future?
Curtis: In the following year, I want to see continued progress in non-human primate renal transplants. If we have a non-human primary that’s 600 days post-transplant, there’s a reasonable expectation that we can see long-term transplant function in the clinical study. We aim to build the dataset to support that first human study with the kidney.
In our ex vivo liver perfusion program, the intention is to take a patient who’s an end-stage liver failure and then perfuse their blood through a porcine liver. This was done in the ‘90s with unmodified livers with some success. The concern was the retroviral risk in the nineties, but we also didn’t have the editing we have now. Now, we would expect longer-duration perfusions. We’re going to do a study on a decedent recipient, riffing off work done at New York University and the University of Alabama, Birmingham, using decedent recipients for kidney transplants. We intend to use this model for a liver perfusion study.
The third piece is heart transplants, motivated by the work done at the University of Maryland. We plan to generate pediatric and adult heart transplant data in the baboon model as the foundation for moving either into compassionate use, similar to what the team at Maryland did or, more importantly, to a full clinical trial within the next 18 months. Looking at the next 12 months, we want to get the value inflection points across our kidney, liver profusion, and heart programs.
GEN Edge: What major challenges lie ahead for eGenesis?
We have a very clear scientific plan, and now it’s a matter of operating that plan. With three programs coming up, we have adequate numbers of donors to support these trials. It’s just about executing at this point. We’ve completed the engineering on the donors. The modifications are stable, and we’re not going to be changing them for the next year for these particular programs. It’s about execution over the next 12-18 months.
The other big piece is getting regulatory buy-in for several of these things. For instance, in our kidney program, we expect to meet with the agency later this month to gain agreement on our clinical plans. Similarly, based on the success in the recipient studies for our ex vivo liver perfusion program, we’d be going to the agency looking to move into a phase one study next. Then, we’re also looking to get the agency’s buy-in on our non-clinical plans for the heart.
What’s compelling is the endpoints in the transplants are very robust. In relatively small studies, we can see how well the products perform. We don’t need extensive transplant studies to understand whether the transplants are successful. If you save someone’s life, they’re alive. If you don’t, they’re not. It’s very black and white when technology works and when it doesn’t.
GEN Edge: As the new CEO, how are you moving the vision of eGenesis?
Curtis: My 30-year career has been in moving products into the clinic. The company had reached a point where we had got the platform up and running. We have developed our first fully edited donors, and the next two to three years are all about clinical translation and moving these products from nonclinical development into the clinic. So it was like the perfect timing. This leadership role will help drive the platform into those first clinical trials. With my experience and where the company needed to go, I think it was the right timing.
GEN Edge: What are some of the critical milestones for eGenesis in the upcoming decade?
For the first generation of products, the goal is to solve the supply problem for there to be enough organs to go around. When we go into the clinic for the first time, it’ll be using immunosuppression. It’ll look a lot like allogenic transplantation from an execution perspective. But the ultimate goal of the engineering project is to eliminate the need for immunosuppression. Can we engineer the porcine donor to prevent or reduce the immunosuppression burden on patients? One of the reasons we built the platform is that we know there’s an iterative component to this. The first products won’t be the last. It will be a multi-generation. We see this in about every area of the pharma business and product development, where you have the next generation of products that leverage the findings from this generation to make a better product.
Our ultimate goal is to solve this organ shortage problem and eliminate the need for immunosuppression. So that’s the vision. Science repeatedly shows that you give enough time, give enough effort, and solve the problems. We view this long vision for organ transplant as potentially porcine donors with that next generation of engineering. I think we are the only group in the world that’s addressing all of the barriers to xenotransplantation. We’re in this for however long it takes to realize the vision of organs that don’t require suppression. Our current focus is to get into those first clinical trials to see where we are. Our products have the legs to help patients and solve solid organ shortages.
We used to say xenotransplantation was science fiction. Now, it’s science fact. The Maryland team with Mr. Bennett’s transplant and taking that first step. The first heart transplant recipient survived for 18 days, and Mr. Bennett’s heart functioned for 49 days right out of the gate. So, you couldn’t ask for anything better as a starting point. Of course, that’s not the outcome we want for Mr. Bennett. But these little steps will be required to realize that big vision. It’s a great starting point. I think you will see a consistent flow of clinical studies. But the problem is, you’ve got to be able to make donors.