Xenotransplantation comes of age

eGenesis publishes key long-term survival data on kidney xenotransplantation, readies for human trials as early as next year.

A recent publication in Nature has increased hopes that xenotransplantation – transplanting organs from an animal source into a human recipient – may soon enter human trials. US biotech eGenesis disclosed long-term survival data from a proof-of-concept study, demonstrating the viability of genetically engineered donor kidneys from pigs transplanted into monkeys.

The study’s findings constitute the largest and most comprehensive preclinical dataset published in a domain where recipient survival has typically been limited to weeks or months. Notably, one recipient survived for more than two years (758 days), adding further weight to calls for human clinical trials of the technology.

Longevity.Technology: In the United States alone, more than 100,000 people are on organ transplantation waitlists, with fewer than 40% ultimately receiving a potentially life-saving organ. Furthermore, the existing organ transplantation paradigm faces challenges due to organ incompatibility and variable donor organ quality. Xenotransplantation offers hope to thousands of people worldwide, but the field must overcome significant challenges before it can deliver on its promise. With this latest development in terms of long-term survival, eGenesis appears to be closing in on the clinic. We caught up with the company’s CEO, Dr Michael Curtis, to find out more.

The major focus of eGenesis’s work is to address the primary risks associated with cross-species transplantation, namely: acute rejection, recipient compatibility, and transmission of viral infection from donor to host.

The genetically engineered porcine donor kidneys used by eGenesis in the Nature study underwent several key modifications, including knocking out three genes responsible for the production of antigens associated with hyperacute rejection. The company also inserted seven human transgenes responsible for regulating various pathways known to modulate rejection, and deactivated retroviruses present in the porcine genome.

Xenotransplantation comes of age
Mike Curtis is CEO of eGenesis

“Until the discovery of CRISPR-Cas9, there was no way to edit all the 50 to 70 copies of this retrovirus that are in the pig genome,” says Curtis. “The donor in the Nature paper has triple knockout, seven transgenes added, and then inactivation of 59 copies of the retrovirus, for a total of 69 edits. That makes it the most highly edited porcine donor ever.”

Long-term survival improvements

But, of course, all the edits in the world mean nothing without beneficial results to the host, and Curtis is quick to point out the huge strides that have been made in terms of long-term survival rates.

“If you look at pig kidney transplants into primates over the past several decades, rarely do you see something break 100 days’ survival,” he says. “Now we’re talking about a donor that addresses all the challenges of xenotransplantation cross species and produces long term outcomes. From a clinical translation perspective, the FDA wants to see your donors performing out to at least a year in the monkey post-transplant. We now have seven recipients that have made it out to that 12-month endpoint, which is unique in the field.”

While a survival rate of one to two years may not sound like a lot, when it comes to kidney failure, it’s potentially game changing.

“In the case of renal failure, we’re competing with patients on chronic dialysis,” says Curtis. “If you find yourself on dialysis, there’s a 50% chance that you’ll pass away in the next five years. By contrast, if you get a human kidney transplant, you’re looking at many years of post-transplant survival. What we want to do is get people off dialysis and into transplant.”

Curtis goes on to explain that eGenesis’s initial clinical goal is a post-transplant survival rate of three years, because “three years on transplant is better than three years on dialysis.”

“Of course, long term we want to see decades or more of post-transplant survival, but we need to start somewhere,” he adds. “Also, all the genes we’re adding to the porcine genome are human genes, and the immunosuppression that we’re using in the monkeys is optimized for people. So we also believe that the outcomes in the clinic will be even better than what we’ve seen in primates.”

Xenotransplantation’s road to the clinic

One of the supervisors of the Nature study, Dr Tatsuo Kawai, a professor of surgery at Harvard Medical School, echoes Curtis’s optimism when it comes to translating results into humans.

“This is a major step forward for the field of transplantation,” says Kawai. “One of the biggest hurdles has been long-term survival of the genetically engineered organ in the NHP [non-human primate] recipient, and this dataset demonstrates remarkable progress in editing the porcine genome to minimize hyperacute rejection, improve recipient compatibility and address the risk of viral transmission from donor to host. We anticipate that transplant outcomes in humans will be even more favorable, as these gene edited organs are a better match for humans, as compared with NHPs.”

Xenotransplantation comes of age
CRISPR-edited porcine kidney survived and supported life for 758 days in non-human primates. CD31 positive endothelial cells are stained in green, human CD46 (one of the seven knock in genes) is shown in fuchsia, C4d (a molecule that plays a role in the hosts’ immune response) is represented in red, and nuclei are stained in blue.

The data published in Nature is, according to Curtis, a critical step towards translation into human clinical trials.

“We hear stories all the time of patients who are dying of kidney failure, so is there a population of patients that we could, from a safety, efficacy, and risk-benefit standpoint, support a first trial?” says Curtis. “We’ve now had four meetings with the FDA about our platform, two specifically on our kidney program, so we have good clarity on what the agency is looking for, as far as the first trials go.”

Asia trial by next year?

But eGenesis is not only focusing on the FDA when it comes to potential clinical trials. Curtis says the company is also looking at opportunities in Asia and has already formed a partnership with a Japanese company to open the possibility of doing trials in the region.

“The unmet need in Asia is even more dire than it is in the US,” he says. “The typical wait time for a cadaveric kidney in the US is five to seven years on dialysis. In Asia, it’s over 15 years. This is because the donor pool of cadaveric kidneys for kidney transplant is far less than it is in the US. So, the Japanese regulators are very interested in cross-species transplantation as a solution to the organ shortage that they’re facing.”

Of course, the big question now is how quickly can we expect to see kidney xenotransplantation enter clinical trials?

“Here in the United States, I think we could expect the first trial for kidney sometime towards the end of 2025,” says Curtis. “The main driver of that is a 12-month, IND-enabling transplant study that the agency is looking for. However, in Asia there’s an alternative regulatory path, a ‘research clinical trial’ that has been used in regenerative medicine. This may enable us to start a small trial, where we can study transplant in two or three patients, as early as the end of next year.”

Liver perfusion program

In addition to its progress in kidney transplantation, eGenesis is concurrently progressing its other programs focused on extracorporeal liver perfusion and cardiac transplant. When it comes to liver failure, Curtis says that the current options for patients are limited.

“As terrible as dialysis is as far as outcomes go, you can spend years on dialysis and still live your life,” he says. “In case of liver failure, there’s nothing except transplant.”

The liver perfusion technology that eGenesis is working on is based on research conducted in the 1990s, which showed that porcine liver could be used to perfuse a patient with liver failure as a “bridge”, allowing more time to find a suitable human donor.

“We’ve been studying this for the past year with our transgenic porcine donors,” says Curtis. “In the past, you might get five or six hours of perfusion before the liver would swell and occlude and you would lose all blood flow. We’ve now run experiments for over three days of continuous perfusion, where our modified liver allows human blood compatibility and gives you very long perfusion times.”

eGenesis has already held talks with the FDA about its liver program, and Curtis is optimistic about moving into clinical trials relatively soon.

“If you look at compassionate use heart transplants, I think there’s a really strong rationale for doing compassionate use liver perfusion in patients that are imminently facing death as their liver fails,” he says. “We’ve discussed two or three days of perfusion decedents with the agency, which would support initiation of a clinical trial for liver perfusion, and which we expect to start next year.”

The heart of the matter

Last year, the first pig to human heart transplant was successfully conducted by doctors at the University of Maryland, which Curtis says was “incredibly exciting” for eGenesis.

“The initial intention of those transplants is really to bridge patients to human heart transplantation,” he says. “And where that’s even more of a dire situation is in children who need a heart transplant – about 50% of those kids die waiting for a donor, because there isn’t the technology to bridge them like adults.”

Curtis reveals that eGenesis is working with two pediatric heart transplant surgeons to use porcine hearts as a bridge to human transplantation.

“We are looking to bridge heart function for 100 to 120 days to create a three-to-four-month window to find a human heart for these kids,” he says. “In our preclinical work in primates, we’re getting close to the 100-day post-transplant mark, and we intend to continue working on those transplants into next year. We think the heart data so far has been so promising that we could be looking at doing bridging pediatric heart transplants with our porcine heart as early as next year, in compassionate use cases.

While some might argue that the kidney and heart, essentially a filter and a pump, are relatively straightforward organs from a xenotransplantation perspective, Curtis believes more complex organs will also be possible in due course.

“There’s no question that things that we’re learning from kidney and heart are informing how we go about editing the more immunoreactive organs,” he says. “More editing is going to be required, but I can envision a future where we can make transplantable lungs, transplantable livers and more. Ultimately, the vision here is to produce a transgenic donor that removes the need for immunosuppression.”